CN107074816B - Heterocyclic derivative, preparation method and medical application thereof - Google Patents

Heterocyclic derivative, preparation method and medical application thereof Download PDF

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CN107074816B
CN107074816B CN201680003424.0A CN201680003424A CN107074816B CN 107074816 B CN107074816 B CN 107074816B CN 201680003424 A CN201680003424 A CN 201680003424A CN 107074816 B CN107074816 B CN 107074816B
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alkyl
ethyl
cyano
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methoxy
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CN107074816A (en
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魏用刚
邱关鹏
郑苏欣
雷柏林
王松
叶飞
刘建余
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Sichuan Haisco 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
    • A61K31/33—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Abstract

A compound shown in general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof, a preparation method and application in preparing a medicament for treating airway obstructive diseases, wherein the compound shown in general formula (I) is

Description

Heterocyclic derivative, preparation method and medical application thereof
Technical Field
The invention relates to a heterocyclic derivative, a preparation method and application thereof in medicine, in particular to a compound with muscarinic receptor antagonism and/or β2-new heterocyclic derivatives with adrenergic receptor agonistic activity or stereoisomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, pharmaceutical compositions thereof and their use in medicine.
Background
Bronchodilators, which are widely used in clinics, include muscarinic receptor antagonists and β2-adrenergic agonists.
Muscarinic receptor antagonists exert their effect on bronchodilation by lowering vagal cholinergic levels of airway smooth muscle. Currently used inhaled muscarinic receptor antagonists include ipratropium bromide, oxitropium bromide, glycopyrronium bromide, tiotropium bromide, aclidinium bromide and umeclidinium bromide. Among them, ipratropium bromide and oxitropium bromide are short-acting drugs, and require multiple administrations per day, which brings inconvenience to patients and may cause poor compliance due to frequent administrations, thereby risking inadequate treatment. Addisomidine administered twice daily may cause severe adverse effects including paradoxical bronchospasm, new narrow angle glaucoma or exacerbation, new urinary retention or exacerbation, and is not suitable for patients under 18 years of age. Even when administered by inhalation, some muscarinic receptor antagonists enter the circulatory system, resulting in systemic side effects such as dry mouth, gastrointestinal symptoms, urinary retention, urinary tract infection, and the like. Such as glycopyrrolate and tiotropium bromide.
Therefore, there is a need to develop novel muscarinic receptor antagonistic active drugs, particularly novel muscarinic receptor antagonistic active drugs which are administered by inhalation and have high potency, long action time and reduced systemic side effects. Provides more clinical medication options for patients.
β2Adrenergic agonists reverse bronchoconstrictor responses to various mediators, such as acetylcholine, by stimulating adrenergic receptors on airway smooth muscle β is currently used2Adrenergic agonists including salbutamol, salmeterol, arformoterol, formoterol, vilanterol and indacaterol these drugs, in addition to improving lung function, also improve patient quality of life and reduce exacerbation2Adrenergic agonists are more effective than either therapeutic agent alone, and muscarinic receptor antagonists and β are now clinically used2Adrenergic agonists are prepared into compound preparations for treating asthma and severe COPD, and the compound preparations mainly comprise Anoro Ellipta (umeclidinium bromide/vilanterol), Ultibro Breezhaler (glycopyrronium bromide/indacaterol), ipratropium bromide/salbutamol and the like. The compound preparation has better treatment effect than the single preparation, but has higher requirements on preparation.
Therefore, it is also desired to develop a compound having muscarinic receptor antagonism and β2-adrenergic stimulationDual action drugs, such as dual action drugs, which have the pharmaceutical advantages of a combination of two components, while possessing a single molecular pharmacokinetics, are administered as a single therapeutic agent, providing bronchodilatory action from two distinct and potentially synergistic modes of action, and, in addition, muscarinic receptor antagonism and β2Adrenergic agonist dual action (MABA) compounds may also be combined with corticosteroid (ICS) anti-inflammatory agents drugs to form two therapeutic agents (MABA/ICS) to provide triple action therapeutic effects (Expert opin investig. drugs (2014)23 (4): 453-.
Therefore, there is a need to develop novel compounds with muscarinic receptor antagonism and/or β2-an adrenergic agonist active agent to provide a more effective monotherapeutic dose or combination formulation, providing more clinical medication options for the patient.
Disclosure of Invention
The invention provides a compound shown in a general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof,
Figure GPA0000231962000000031
wherein:
a is selected from 0, 1, 2, 3, 4 or 5;
b is selected from 0, 1, 2, 3 or 4;
R1each independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano, -OR1a、-C(O)OR1b、-SR1c、-S(O)R1d、-S(O)2R1eor-NR1fR1g；
R2Each independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano, -OR1a、-C(O)OR1b、-SR1c、-S(O)R1d、-S(O)2R1eor-NR1fR1g；
R1a、R1b、R1c、R1d、R1e、R1fAnd R1gEach independently selected from H or C1-4An alkyl group;
alternatively, R1f、R1gA 3-, 4-, 5-or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S;
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group;
c is selected from 0, 1, 2, 3 or 4;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, C1-4Alkyl or C1-4An alkoxy group;
R4is selected from C1-6Alkylene radical, C2-6Alkenylene or C2-6Alkynylene, said alkylene, alkenylene or alkynylene being optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4Substituted by a substituent of alkylene;
x is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3;
R5selected from F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl, -C (O) O-C1-4Alkyl, -OC (O) -C1-4Alkyl or-C (O) NH2The alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, NH2and-C (O) NH2Optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-；
Ya、YbEach independently selected from H or C1-4An alkyl group; or Ya、YbTogether with the carbon atom to which they are attached form a 3-, 4-, 5-or 6-membered carbocyclic ring;
n is 0, 1 or 2;
e is selected from 0, 1, 2, 3 or 4;
R6each independently selected from F, Cl, Br, I, C ═ O, cyano, C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 groups selected from F, Cl, Br, I, CH2F、CHF2、CF3Or a cyano group;
alternatively, two R6May form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring, optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R7is selected from C1-6Alkylene optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4An alkylene group;
alternatively, two R7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R8、R9each independently selected from H or C1-4An alkyl group;
Figure GPA0000231962000000041
represents β -adrenoceptor binding group.
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
Figure GPA0000231962000000051
represents β -adrenoceptor binding group;
b is preferably
Figure GPA0000231962000000052
R10、R11、R12、R13、R14、R15、R16、R17Or R18Each independently selected from H, F, Cl, Br, I, CF3、OH、-CH2OH, cyano, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, -C (O) C1-4Alkyl, -C (O) OC1-4Alkyl, -NHC (O) H, -NHS (O)2-C1-4Alkyl, -NHS (O)2-NH2or-NHS (O)2-NHC1-4Alkyl, Q is selected from-CRq1＝CRq2-、-CRq1Rq2CRq3Rq4-, -O-, -S-or-CRq1Rq2O-, said Rq1、Rq2、Rq3Or Rq4Each independently selected from H, F, Cl, Br, I or C1-4An alkyl group;
b is more preferably
Figure GPA0000231962000000053
Figure GPA0000231962000000054
Wherein Q is selected from-CH ═ CH-, -CH2CH2-, -O-, -S-or-CH2O-；
B is further preferably
Figure GPA0000231962000000055
Figure GPA0000231962000000056
B is further preferably
Figure GPA0000231962000000057
Q is selected from-CH ═ CH-, -CH2CH2-, -O-, -S-or-CH2O-；
a is selected from 0, 1, 2, 3, 4 or 5;
b is selected from 0, 1, 2, 3 or 4;
R1each independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano, -OR1a、-C(O)OR1b、-SR1c、-S(O)R1d、-S(O)2R1eor-NR1fR1g；
R2Each independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano, -OR1a、-C(O)OR1b、-SR1c、-S(O)R1b、-S(O)2R1eor-NR1fR1g；
R1a、R1b、R1c、R1d、R1e、R1fAnd R1gEach independently selected from H or C1-4An alkyl group;
alternatively, R1f、R1gA 3-, 4-, 5-or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S;
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group;
c is selected from 0, 1, 2, 3 or 4;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, C1-4Alkyl or C1-4An alkoxy group;
R4is selected from C1-6Alkylene radical, C2-6Alkenylene or C2-6Alkynylene, said alkylene, alkenylene or alkynylene being optionally further substituted by 0, 1,2.3, 4 or 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4Substituted by a substituent of alkylene;
x is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3;
R5selected from F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl, -C (O) O-C1-4Alkyl, -OC (O) -C1-4Alkyl or-C (O) NH2The alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, NH2and-C (O) NH2Optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-；
Ya、YbEach independently selected from H or C1-4An alkyl group; or Ya、YbTogether with the carbon atom to which they are attached form a 3-, 4-, 5-or 6-membered carbocyclic ring;
n is 0, 1 or 2;
e is selected from 0, 1, 2, 3 or 4;
R6selected from F, Cl, Br, I, C ═ O, cyano and C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 groups selected from F, Cl, Br, I, CH2F、CHF2、CF3Or a cyano group;
alternatively, two R6May form, together with the atoms to which they are attached, a 3-, 4-, 5-or 6-membered carbocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I,Cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R7is selected from C1-6Alkylene optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4An alkylene group;
alternatively, two R7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R8、R9each independently selected from H or C1-4An alkyl group.
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
b is selected from
Figure GPA0000231962000000071
R10、R11、R12、R13、R14、R15、R16、R17Or R18Each independently selected from H, F, Cl, Br, I, CF3、OH、-CH2OH, cyano, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, -C (O) C1-4Alkyl, -C (O) OC1-4Alkyl, -NHC (O) H, -NHS (O)2-C1-4Alkyl, -NHS (O)2-NH2or-NHS (O)2-NHC1-4Alkyl, Q is selected from-CRq1＝CRq2-、-CRq1Rq2CRq3Rq4-, -O-, -S-or-CRq1Rq2O-, said Rq1、Rq2、Rq3Or Rq4Each independently selected from H, F, Cl, Br, I or C1-4Alkyl radical；
B is preferably
Figure GPA0000231962000000072
Figure GPA0000231962000000073
Q is selected from-CH ═ CH-, -CH2CH2-, -O-, -S-or-CH2O-；
B is further preferably
Figure GPA0000231962000000074
Figure GPA0000231962000000075
a is selected from 0, 1, 2, 3, 4 or 5; preferably 0, 1 or 2;
b is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;
R1each independently selected from F, Cl, Br, I, CF3Cyano, hydroxy, C1-4Alkyl radical, C1-4Alkoxy or C1-4An alkylthio group; preferably F, Cl, Br, I, CF3Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio; more preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;
R2each independently selected from F, Cl, Br, I, CF3Cyano, hydroxy, C1-4Alkyl radical, C1-4Alkoxy or C1-4An alkylthio group; preferably F, Cl, Br, I, CF3Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio; more preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group; preferably H, methyl, ethyl or isopropyl;
c is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, C1-4Alkyl or C1-4An alkoxy group; preferably F, Cl, Br, I, CF3OH, cyano, methyl, ethyl, methoxy or ethoxy; more preferably F, methyl or ethyl;
R4is selected from C1-6Alkylene radical, C2-6Alkenylene or C2-6An alkynylene group; preferably C1-6An alkylene group; more preferably methylene, ethylene, propylene or butylene, optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4Substituted by a substituent of alkylene;
x is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3;
R5each independently selected from F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C2-4Alkynyl, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl or-C (O) O-C1-4Alkyl, said alkyl, alkoxy, cycloalkyl and NH2Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl, alkoxy, cycloalkyl, alkynyl and NH2Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent; r5Preferably F, Cl, Br, CH2F、CHF2、NH2Cyano, nitro, OCH2F、OCHF2、OCF3Methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyloxy, ethynyl, propynyl, -S (O)2CH3、-C(O)CH3、-C(O)OCH3or-C (O) OCH2CH3；R5More preferably F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF2、CF3Methoxy, ethoxy, -OCHF2、-OCF3Cyclopropyloxy, ethynyl or propynyl;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-; preference is given to-CYaYb-, -N-, -O-or-S-;
Ya、Ybeach independently selected from H or C1-4An alkyl group; preferably H, methyl or ethyl; or Ya、YbTogether with the carbon atom to which they are attached form a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably a 3-or 4-membered carbocyclic ring;
n is 0, 1 or 2;
e is selected from 0, 1, 2, 3 or 4;
R6each independently selected from F, Cl, Br, I, C ═ O, cyano, C1-4Alkyl or C1-4An alkoxy group; preferably F, Cl, Br, I, C ═ O, cyano, methyl, ethyl, methoxy or ethoxy, said alkyl, alkoxy, methyl, ethyl, methoxy or ethoxy optionally being further substituted by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, CH2F、CHF2、CF3Or a cyano group;
alternatively, two R6May form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring, optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R7is selected from C1-6An alkylene group; preferably C1-4An alkylene group; more preferably methylene, ethylene, propylene or butylene, said alkylene, methylene, ethylene, propylene or butylene being optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4An alkylene group; preferably F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy or phenyl; more preferably F, Cl, Br, cyano, OH, methyl, ethyl, methoxy, ethoxy or phenyl;
alternatively, two R7aMay form, together with the atoms to which they are attached, a 3, 4, 5 or 6 membered carbocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R8、R9each independently selected from H or C1-4An alkyl group; h, methyl or ethyl is preferred.
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
b is selected from
Figure GPA0000231962000000091
Figure GPA0000231962000000092
Q is selected from-CH ═ CH-, -CH2CH2-, -O-, -S-or-CH2O-；
B is preferably
Figure GPA0000231962000000093
Figure GPA0000231962000000094
a is selected from 0, 1, 2, 3, 4 or 5; preferably 0, 1 or 2;
b is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;
R1each independently selected from F, Cl, Br, I, CF3Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio;preferably F, Cl, Br, hydroxyl, methyl, ethyl, methoxy or ethoxy;
R2each independently selected from F, Cl, Br, I, CF3Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio; preferably F, Cl, Br, hydroxyl, methyl, ethyl, methoxy or ethoxy;
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group; preferably H, methyl, ethyl or isopropyl;
c is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, methyl, ethyl, methoxy or ethoxy; preferably F, methyl or ethyl;
R4is selected from C1-6An alkylene group; preferably methylene, ethylene, propylene or butylene, optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4Substituted by a substituent of alkylene; r4Preferably methylene, ethylene, propylene, -C (CH)3)2CH2-、-CH2C(CH3)2-、-CH(CH3)CH2-or-CH2CH(CH3)-；
X is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3;
R5each independently selected from F, Cl, Br, CH2F、CHF2、NH2Cyano, nitro, OCH2F、OCHF2、OCF3Methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyloxy, ethynyl, propynyl, -S (O)2CH3、-C(O)CH3、-C(O)OCH3or-C (O) OCH2CH3(ii) a Preferably F, Cl, Br,Cyano, methyl, ethyl, propyl, isopropyl, CHF2、CF3Methoxy, ethoxy, -OCHF2、-OCF3Cyclopropyloxy, ethynyl or propynyl;
y is selected from-CYaYb-, -N-, -O-, -S-, -S (O) -or-S (O)2-; preference is given to-CYaYb-, -N-, -O-or-S-;
Ya、Ybeach independently selected from H or C1-4An alkyl group; preferably H, methyl or ethyl; or Ya、YbTogether with the carbon atom to which they are attached form a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably a 3-or 4-membered carbocyclic ring;
n is 0, 1 or 2;
e is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;
R6each independently selected from F, Cl, Br, I, C ═ O, cyano, methyl, ethyl, methoxy, or ethoxy;
alternatively, two R6May form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring, optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R7is selected from C1-4An alkylene group; preferably methylene, ethylene, propylene, butylene or
Figure GPA0000231962000000101
The methylene, ethylene, propylene, butylene or
Figure GPA0000231962000000102
Optionally further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4An alkylene group; preferably F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy or phenyl; more preferably F, Cl, Br, cyano, OH, methyl, ethyl, methoxy, ethoxy or phenyl;
R7preferably methylene, ethylene, propylene, -C (CH)3)2CH2-、-CH2C(CH3)2-、-CH(CH3)CH2-、-CH2CH(CH3) -or
Figure GPA0000231962000000111
R8、R9Each independently selected from H or C1-4An alkyl group; h, methyl or ethyl is preferred.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, wherein the compound is a compound selected from the group consisting of compounds represented by the general formula (II):
Figure GPA0000231962000000112
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group; preferably H, methyl, ethyl, propyl or isopropyl;
c is selected from 0, 1, 2, 3 or 4; preferably 0 or 1;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, C1-4Alkyl or C1-4An alkoxy group; preferably F, methyl, ethyl, propyl, methoxy or ethoxy;
R4is selected from C1-6An alkylene group; preferably C1-4Alkylene optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
x is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3; preferably 0 or 1;
R5selected from F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl, -C (O) O-C1-4Alkyl, -OC (O) -C1-4Alkyl or-C (O) NH2(ii) a Preferred are F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl or-C (O) O-C1-4Alkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, NH2and-C (O) NH2Optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-; preference is given to-CYaYb-, -N-, -O-or-S-;
Ya、Ybeach independently selected from H or C1-4An alkyl group; preferably H, methyl, ethyl or propyl; or Ya、YbMay form a 3-, 4-, 5-or 6-membered carbocyclic ring together with the carbon atoms to which they are attached;
e is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2; more preferably 0;
R6selected from F, Cl, Br, C ═ O, cyano and C1-4Alkyl or C1-4An alkoxy group; preferably F, Cl, C ═ O, cyano, methyl, ethyl, methoxy or ethoxy;
alternatively, two R6May form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably 3 or 4, said carbocyclic ring being optionally further substituted by 0 to 5From F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy; preferably F, Cl, OH, cyano, methyl, ethyl, methoxy or ethoxy;
n is 0, 1 or 2;
R7is selected from C1-6An alkylene group; preferably C1-4Alkylene optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy or phenyl; preferably F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4An alkoxy group; more preferably F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
alternatively, two R7aMay form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably 3-or 4-membered carbocycle, optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R8、R9each independently selected from H or C1-4An alkyl group; preferably H, methyl or ethyl;
b is selected from
Figure GPA0000231962000000121
Q is selected from-CH ═ CH-, -CH2CH2-, -O-, -S-or-CH2O-。
In a preferable embodiment of the invention, the compound shown in the general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof is selected from compounds shown in the general formula (II),
w is-O-or-N (W)a)-；
WaSelected from H, methyl or ethyl;
c is 0;
R4selected from methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
x is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3;
R5selected from F, Cl, Br, CH2F、CHF2、NH2Cyano, nitro, OCH2F、OCHF2、OCF3Methyl, ethyl, methoxy, ethoxy, methylthio, -S (O)2CH3、-C(O)CH3、-C(O)OCH3or-C (O) OCH2CH3(ii) a Preferably F, Cl, Br, CH2F、CHF2Cyano, nitro, OCH2F、OCHF2、OCF3Methyl, ethyl, methoxy or ethoxy; more preferably F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-; preference is given to-CYaYb-、-NYa-, -O-or-S-;
Ya、Ybeach independently selected from H, methyl or ethyl; or Ya、YbMay form a 3-, 4-, 5-or 6-membered carbocyclic ring together with the carbon atoms to which they are attached; preferably a 3-or 4-membered carbocyclic ring;
e is 0, 1 or 2;
R6selected from F, Cl, Br, C ═ O, cyano, methyl, ethyl, methoxy or ethoxy;
n is 0, 1 or 2;
R7selected from methylene, ethylene, propylene or
Figure GPA0000231962000000131
The methylene, ethylene, propylene or
Figure GPA0000231962000000132
Optionally intoOne step is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R8、R9each independently selected from H, methyl or ethyl; preferably H or methyl;
b is selected from
Figure GPA0000231962000000133
Figure GPA0000231962000000134
In a preferred embodiment of the present invention, the compound represented by formula (I) or formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the compound is selected from one of the following structures:
Figure GPA0000231962000000135
Figure GPA0000231962000000141
Figure GPA0000231962000000151
the present invention relates to the provision of a compound according to formula (I) or (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, maleate, hydroxymaleate, glutarate, fumarate, tartrate, succinate, benzenesulfonate, p-toluenesulfonate, benzoate, salicylate, phenylacetate, cinnamate, lactate, malonate, pivalate, malate, mandelate, oxalate, gallate, gluconate, laurate, palmitate, pectate, picrate, citrate, methanesulphonic acid, hexanesulphonate, saccharin (phthalimide) or a combination thereof; preferably hydrochloride, sulfate, trifluoroacetate, fumarate, tartrate, succinate, oxalate, methanesulphonic acid, saccharine or combinations thereof.
The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the general formulae (I) or (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient, wherein the composition may further comprise one or more additional therapeutic agents, preferably wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid and a β -adrenergic receptor agonist.
The invention also relates to application of the compound shown in the general formula (I) or (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof in preparing medicaments for treating the airway obstruction diseases; preferably, for use in the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
The present invention also relates to a method for treating an obstructive airways disease which comprises administering a compound according to any one of the present invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutical composition according to the present invention.
The present invention also relates to a method of treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound according to any one of the present invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutical composition according to the invention.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include isotopes thereof, and carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include isotopes of carbon12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also known as deuterium), tritium (T, also known as deuterium), and isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"alkyl" means a straight and branched chain monovalent saturated hydrocarbon group, the backbone comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, straight and branched chain groups, most preferably 1 to 2 carbon atoms, examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like; said alkyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH2F、-CHF2、-CF3Hydroxy, -SR18Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C2-8Alkenyl radical, C2-8Alkynyl, - (CH)2)q-C(＝O)-R19、-(CH2)q-C(＝O)-O-R19、-(CH2)q-C(＝O)-NR19R19a、-(CH2)q-S(＝O)m-R18、-O-C(＝O)-O-R18or-NR18R18aWherein R is substituted by a substituent of (1)19And R19aEach independently selected from HHydroxy, amino, carboxy, C1-8Alkyl radical, C1-8Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; r19And R19aEach independently selected from H, unsubstituted C1-6Alkyl group of (1). Alkyl, R, as appearing herein18And R18aAs defined above.
"alkylene" refers to a straight and branched chain divalent saturated hydrocarbon radical, including- (CH)2)v- (v is an integer of 1 to 10), examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like; said alkylene group may optionally be further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, -CH2F、-CHF2、-CF3Hydroxy, -SR18Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C2-8Alkenyl radical, C2-8Alkynyl, - (CH)2)q-C(＝O)-R19、-(CH2)q-C(＝O)-O-R19、-(CH2)q-C(＝O)-NR19R19a、-(CH2)q-S(＝O)m-R18、-O-C(＝O)-O-R18or-NR18R18aWherein R is substituted by a substituent of (1)19And R19aEach independently selected from H, hydroxy, amino, carboxyl and C1-8Alkyl radical, C1-8Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; r19And R19aEach independently selected from H, unsubstituted C1-6Alkyl group of (1). Alkylene, as used herein, is defined as above.
"alkoxy" refers to a monovalent radical of an O-alkyl group, where alkyl is as defined herein, and alkylene examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-1-butoxy, and 2-methyl-1-butoxy, and the like.
"alkenyl" means a straight and branched chain monovalent unsaturated hydrocarbon group having at least 1, and usually 1, 2 or 3 carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the main chain, examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, and the like, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; said alkylene group may optionally be further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, -CH2F、-CHF2、-CF3Hydroxy, -SR18Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C2-8Alkenyl radical, C2-8Alkynyl, - (CH)2)q-C(＝O)-R19、-(CH2)q-C(＝O)-O-R19、-(CH2)q-C(＝O)-NR19R19a、-(CH2)q-S(＝O)m-R18、-O-C(＝O)-O-R18or-NR18R18aWherein R is substituted by a substituent of (1)19And R19aEach independently selected from H, hydroxy, amino, carboxyl and C1-8Alkyl radical, C1-8Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; r19And R19aEach independently selected from H, unsubstituted C1-6Alkyl group of (1). Alkenyl as used herein, is defined as above.
"alkynyl" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1, 2 or 3 carbon-carbon triple bonds, and the backbone includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, with examples of alkynyl including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl, and the like; said alkylene group may optionally be further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, -CH2F、-CHF2、-CF3Hydroxy, -SR18Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C2-8Alkenyl radical, C2-8Alkynyl, - (CH)2)q-C(＝O)-R19、-(CH2)q-C(＝O)-O-R19、-(CH2)q-C(＝O)-NR19R19a、-(CH2)q-S(＝O)m-R18、-O-C(＝O)-O-R18or-NR18R18aWherein R is substituted by a substituent of (1)19And R19aEach independently selected from H, hydroxy, amino, carboxyl and C1-8Alkyl radical, C1-8Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; r19And R19aEach independently selected from H, unsubstituted C1-6Alkyl group of (1). Alkynyl, as found herein, is defined as above.
"carbocycle" refers to a 3 to 10 membered monocyclic or 4 to 12 membered bicyclic ring system, saturated or unsaturated, to which a bridged or spiro ring may be attached, non-limiting examples include cyclopropyl, cyclobutylAlkyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and
Figure GPA0000231962000000171
the carbocyclyl may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH2F、-CHF2、-CF3Hydroxy, -SR18Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C2-8Alkenyl radical, C2-8Alkynyl, - (CH)2)q-C(＝O)-R19、-(CH2)q-C(＝O)-O-R19、-(CH2)q-C(＝O)-NR19R19a、-(CH2)q-S(＝O)m-R18、-O-C(＝O)-O-R18or-NR18R18aWherein R is substituted by a substituent of (1)19And R19aEach independently selected from H, hydroxy, amino, carboxyl and C1-8Alkyl radical, C1-8Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; r19And R19aEach independently selected from H, unsubstituted C1-6Alkyl group of (1). Carbocycle as used herein is defined as above.
"heterocyclic" means a saturated or unsaturated non-aromatic ring which may be a 3-to 10-membered monocyclic ring or a 4-to 12-membered bicyclic ring and which contains from 1 to 4 heteroatoms selected from N, O or S, preferably a 4-to 8-membered heterocyclic group, the optionally substituted N, S ring of which may be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or carbon atom, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1,3-dioxane, azepin, oxepanyl, thiepin, oxazepin, thiepin, piperidyl, homopiperidinyl, furyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, piperazinyl, homopiperazinyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, thiaoxazolidyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiaentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyranyl, pyrrolopyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolyl, oxazepin, thiazepin, piperidyl, thiomorpholinyl, thianyl, thia-thienyl, thiapyranyl, thia-yl, thia-thienyl, thia-yl, thia-, Pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, pyrazolylimidazolinyl and imidazolidinyl groups. Said heterocyclyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH2F、-CHF2、-CF3Hydroxy, -SR18Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C2-8Alkenyl radical, C2-8Alkynyl, - (CH)2)q-C(＝O)-R19、-(CH2)q-C(＝O)-O-R19、-(CH2)q-C(＝O)-NR19R19a、-(CH2)q-S(＝O)m-R18、-O-C(＝O)-O-R18or-NR18R18aWherein R is substituted by a substituent of (1)19And R19aEach independently selected from H, hydroxy, amino, carboxyl and C1-8Alkyl radical, C1-8Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; r19And R19aEach independently selected from H, unsubstituted C1-6Alkyl group of (1). Heterocyclyl, as used herein, is defined as above.
"β -adrenoceptor binding group" refers to a moiety capable of binding to β -adrenoceptorSee, for example, review article "β -acquired receptors in Comprehensive Medicinal Chemistry, 1990, B.E.Main, p187(Pergamon Press)". the above groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627 non-limiting examples include
Figure GPA0000231962000000191
B is selected from
Figure GPA0000231962000000192
R10、R11、R12、R13、R14、R15、R16、R17Or R18Each independently selected from H, F, Cl, Br, I, CF3、OH、-CH2OH, cyano, carboxyl, C1-4Alkyl radical, C1-4Alkoxy, -C (O) C1-4Alkyl, -C (O) OC1-4Alkyl, -NHC (O) H, NHS (O)2-C1-4Alkyl, NHS (O)2-NH2Or NHS (O)2-NHC1-4Alkyl, Q is selected from-CRq1＝CRq2-、-CRq1Rq2CRq3Rq4-, O, S or-CRq1Rq2O-, said Rq1、Rq2、Rq3Or Rq4Each independently selected from H, F, Cl, Br, I or C1-4An alkyl group.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.
"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the biological effectiveness and properties of the free acid or free base are maintained and the free acid is obtained by reaction with a non-toxic inorganic or organic base or a salt of the free acid obtained by reaction with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as iron salts, copper salts, cobalt salts, etc.; organic base salts such as ammonium salts, triethylamine salts, pyridine salts, picoline salts, 2, 6-lutidine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, cyclohexylamine salts, ethylenediamine salts, guanidine salts, isopropylamine salts, trimethylamine salts, tripropylamine salts, triethanolamine salts, diethanolamine salts, ethanolamine salts, dimethylethanolamine salts, dicyclohexylamine salts, caffeine salts, procaine salts, choline salts, betaine salts, benzamidine penicillin salts, glucamine salts, N-methylglucamine salts, theobromine salts, tromethamine salts, purine salts, piperazine salts, morpholine salts, piperidine salts, N-ethylpiperidine salts, tetramethylamine salts, dibenzylamine salts, phenylglycine alkyl ester salts and the like; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide and the like; inorganic acid salts such as hydrochloride, nitrate, sulfate, perchlorate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; arylsulfonates such as benzenesulfonate, p-toluenesulfonate and the like; organic acid salts such as acetate, benzoate, fumarate, formate, trifluoroacetate, furoate, gluconate, saccharin (saccharate), glutamate, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfamate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronate, galacturonate, citrate, lysine, arginine, aspartate, cinnamate, and the like.
"pharmaceutical composition" means a mixture of one or more compounds of the present invention or physiologically/pharmaceutically acceptable salts thereof with other ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and excipients.
"carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
"prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a compound of the invention that is biologically active. Prodrugs of the invention are prepared by modifying functional groups in compounds of the invention, which modifications may be removed by routine manipulation or in vivo, to yield the parent compound.
"cocrystals" or "cocrystals" refers to a crystal of Active Pharmaceutical Ingredient (API) and cocrystal former (CCF) bound by hydrogen bond or other non-covalent bond, wherein pure states of API and CCF are both solid at room temperature and a fixed stoichiometric ratio exists between the components, cocrystals are multicomponent crystals comprising a binary cocrystal formed between two neutral solids and a polybasic cocrystal formed from neutral solids and a salt or solvate, and the "cocrystal former" includes, but is not limited to, various pharmaceutically acceptable acids, bases, nonionic compounds, water, amino acids, alcohols or other solvents, non-limiting examples of which include alanine (Ala), valine (Val), leucine (L eu), proline (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), tyrosine (ne), proline (Pro), phenylalanine (Phe), tryptophan (Trp), glutamic acid (Glu), glutamic acid, aspartic acid, glutamic acid, aspartic acid, glutamic acid, aspartic acid, glutamic acid, arginine-2-arginine, glutamic acid, arginine, glutamic acid, arginine, glutamic acid, glutamic.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
An "effective dose" refers to an amount of a compound that elicits a physiological or medical response in a tissue, system, or subject that is sought, including an amount of the compound that, when administered to a subject, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated.
"solvates" refers to compounds of the invention or salts thereof, which also include stoichiometric or non-stoichiometric amounts of solvents bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
Detailed Description
The technical solutions of the present invention are described in detail below with reference to the drawings and the embodiments, but the scope of the present invention includes but is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift () at 10-6The units in (ppm) are given. NMR was measured by using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument to measure the solventIs deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HP L C was determined using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100 × 4.6.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by the thin layer chromatography (T L C) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1L volume.
The hydrogen atmosphere refers to a reaction flask with a hydrogen balloon attached to it of about 1L volume.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
In the examples, M is mole per liter, unless otherwise specified.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
CHO: refers to a formyl group.
TBS: refers to tert-butyl dimethyl silicon base.
Boc: refers to tert-butyloxycarbonyl.
TFA: trifluoroacetic acid.
Intermediate 1: 6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde
6-methoxy-1-prop-2-enoyl-indoline-5-carbaldehyde
Figure GPA0000231962000000221
The first step is as follows: 6-methoxyindoline (1b)
6-methoxyindoline
Figure GPA0000231962000000222
6-methoxyindole (1a) (5.0g, 33.97mmol) was dissolved in acetic acid (50m L), nitrogen was used as a blanket, sodium cyanoborohydride (5.34g, 84.94mmol) was added to the reaction mixture, the reaction was carried out at 25 ℃ for 2 hours, water (80m L) was added to the reaction mixture, the reaction mixture was cooled to 0 ℃, sodium hydroxide was carefully added to adjust the pH to 12-13, ethyl acetate (80m L) was added, the layers were extracted, the aqueous phase was extracted with ethyl acetate (30m L× 2), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue after concentration of the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v): 0: 1-1: 4) to give the title compound 6-methoxyindoline (1b) as a yellow oil (4.4g, 87% yield).
1H NMR(400MHz，CDCl3)7.00(dd，1H)，6.28-6.24(m，2H)，3.76(s，4H)，3.56(t，2H)，2.97(t，2H)。
LCMS m/z＝150.1[M+1]。
The second step is that: 5-bromo-6-methoxyindoline (1c)
5-bromo-6-methoxyindoline
Figure GPA0000231962000000223
6-Methoxyindoline (1b) (22g, 147.46mmol) was dissolved in ethyl acetate (200m L), 1, 3-dibromo-5, 5-dimethylhydantoin (CAS: 77-48-5) (21.08g, 73.73mmol) was added at 0 ℃ to react at 0 ℃ for 2 hours, 15% potassium carbonate solution (250m L) was added to the reaction mixture, the mixture was fully stirred and then extracted for separation, the organic phase was dried over anhydrous sodium sulfate, the filtrate was filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 0: 1 to 1: 9) to obtain the title compound 5-bromo-6-methoxyindoline (1c) as a purple liquid (16g, 47.57% yield).
1H NMR(400MHz，CDCl3)7.19(t，1H)，6.26(s，1H)，3.80(s，3H)，3.56(t，2H)，2.95(t，2H)。
LCMS m/z＝228.1[M+1]。
The third step: 5-bromo-6-methoxyindoline-1-carbamic acid tert-butyl ester (1d)
tert-butyl 5-bromo-6-methoxyindoline-1-carboxylate
Figure GPA0000231962000000231
5-bromo-6-methoxyindoline (1c) (16g, 70.15mmol) was dissolved in tetrahydrofuran (70m L), di-tert-butyl dicarbonate (22.97g, 105.22mmol) and 4-dimethylaminopyridine (1.71g, 14.03mol) were added, and the mixture was reacted at room temperature for 2 hours, water (50m L) and ethyl acetate (50m L) were added to the reaction solution to extract the separated layers, the aqueous phase was extracted with ethyl acetate (30m L), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether (v/v): 0: 1 to 1: 19) to obtain the title compound, tert-butyl 5-bromo-6-methoxyindoline-1-aminocarboxylate (1d), a purple white solid (17g, 74% yield).
1H NMR(400MHz，CDCl3)7.70-7.50(m，1H)，7.25(s，1H)，3.97(t，2H)，3.89(s，3H)，3.01(t，2H)，1.56(s，9H)。
LCMS m/z＝350.0[M+23]。
The fourth step: 5-formyl-6-methoxyindoline-1-carbamic acid tert-butyl ester (1e)
tert-butyl 5-formyl-6-methoxyindoline-1-carboxylate
Figure GPA0000231962000000232
5-bromo-6-methoxyindolin-1-aminocarboxylic acid tert-butyl ester (1d) (17g, 51.80mmol) was dissolved in tetrahydrofuran (300M L) and reacted at-78 ℃ for 30 minutes under nitrogen protection with the addition of a 2.5M N-butyllithium N-hexane solution (22.8M L, 56.98mmol), N-dimethylformamide (18.93g, 259mmol) was added at-78 ℃ and the reaction was allowed to gradually reach room temperature for 1 hour, water (200M L) and ethyl acetate (100M L) were added to the reaction mixture, the aqueous phase was extracted once with ethyl acetate (100M L), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v): 0: 1 to 1: 4) to give the title compound tert-butyl 5-formyl-6-methoxyindolin-1-aminocarboxylate (1e), a yellow solid (8.6g, 60% yield).
1H NMR(400MHz，CDCl3)10.29(s，1H)，7.56(d，2H)，4.02(t，2H)，3.93(s，3H)，3.03(t，2H)，1.58(s，9H)。
LCMS m/z＝278.1[M+Na]。
The fifth step: 6-methoxyindoline-5-carbaldehyde (1f)
6-methoxvindoline-5-carbaldehyde
Figure GPA0000231962000000233
5-formyl-6-methoxyindoline-1-carbamic acid tert-butyl ester (1e) (8.6g, 31mmol) was dissolved in dichloromethane (50m L), trifluoroacetic acid (18g, 160mmol) was added, the reaction was carried out at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, aqueous ammonia was added to adjust the pH to 9, water (100m L) and dichloromethane (100m L) were added, extraction was carried out, the aqueous phase was extracted once with dichloromethane (50m L), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 9 to 4: 1) to give the title compound 6-methoxyindoline-5-carbaldehyde (1f), a yellow solid (2.7g, 49% yield).
1H NMR(400MHz，CDCl3)10.13(s，1H)，7.55(s，1H)，6.08(s，1H)，4.44(s，1H)，3.83(s，3H)，3.68(t，2H)，2.99(t，2H)。
LCMS m/z＝178.1[M+1]。
And a sixth step: 6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (intermediate 1)
6-methoxy-1-prop-2-enoyl-indoline-5-carbaldehyde
Figure GPA0000231962000000241
6-Methoxyindoline-5-carbaldehyde (1f) (0.100g, 0.564mmol) was dissolved in ethyl acetate (10M L), triethylamine (0.428g, 4.23mmol) was added, nitrogen was added, acrylic acid (0.102g, 1.41mmol) was added dropwise, the mixture was raised to 40 ℃ and 1-propylphosphoric anhydride (0.449g, 1.41mmol) was added dropwise to react at 40 ℃ for 4 hours, the reaction mixture was added to ethyl acetate (20M L), washed with 2M hydrochloric acid solution (20M L) and 3% sodium hydroxide solution (20M L) in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (intermediate 1), a yellow solid (0.08g, 61% yield).
1H NMR(400MHz，CDCl3)10.33(s，1H)，8.06(s，1H)，7.65(s，1H)，6.58(t，2H)，5.88(dd，1H)，4.23(t，2H)，3.95(s，3H)，3.17(t，2H)。
LCMS m/z＝232.1[M+1]。
Intermediate 2: 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2)
7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1，3-benzothiazol-2-one
Figure GPA0000231962000000242
Figure GPA0000231962000000251
The first step is as follows: 7- [ (1R) -2-azido-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (2b)
7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1，3-benzothiazol-2-one
Figure GPA0000231962000000252
7- [ (1R) -2-azido-1-hydroxy-ethyl ] -4-hydroxy-3H-1, 3-benzothiazol-2-one (2a) (prepared by reference to WO2009098448A 1) (0.56g.2.2mmol) was dissolved in N, N-dimethylformamide (20m L), imidazole (0.6g, 8.9mmol) was added, tert-butyldimethylchlorosilane (1.3g, 8.9mmol) was added in portions, a catalytic amount of 4-dimethylaminopyridine was added, the temperature was raised to 40 ℃ and stirred for 7 hours, the reaction solution was poured into water (100m L), extracted with ethyl acetate (100m L× 1), the organic phase was washed with a saturated aqueous sodium chloride solution (100m L× 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was chromatographed on a silica gel column (ethyl acetate/petroleum ether (v/v) ═ 0/1 to 5/95), and the title compound 7- [ (1R) -2-azido-1- [ tert-butyl-ethyl ] benzothiazol-2-one (3H ] -4-silyloxy-2-one (yield 80%).
1H NMR(400MHz，CDCl3)8.25(s，1H)，6.92(d，1H)，6.71(d，1H)，4.78(dd，1H)，3.41(dd，1H)，3.25(dd，1H)，1.05-0.98(m，9H)，0.92-0.88(m，9H)，0.28(t，6H)，0.12(d，3H)，-0.04(d，3H)。
The second step is that: 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2)
7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1，3-benzothiazol-2-one
Figure GPA0000231962000000253
7- [ (1R) -2-azido-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (2b) (0.85g, 1.8mmol) was dissolved in ethyl acetate (20m L), 10% (w/w) palladium on carbon (0.085g) was added and stirred under a hydrogen balloon at normal pressure overnight the reaction was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2) as a pale black solid (0.7g, 90% yield).
1H NMR(400MHz，CDCl3)6.89(d，1H)，6.68(t，1H)，4.64(dd，1H)，2.88(ddd，2H)，1.04-0.96(m，9H)，0.95-0.87(m，9H)，0.33-0.23(m，6H)，0.12-0.06(m，3H)，-0.04--0.11(m，3H)。
Example 1: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (Compound 1)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000261
The first step is as follows: [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B)
[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000262
6-methoxy-1-propyl-2-enoyl-indole-5-carbaldehyde (intermediate 1) (0.608g, 2.63mmol) was dissolved in 2-methyltetrahydrofuran (10m L), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (0.600g, 2.02mmol) was added, acetic acid (0.243g, 4.05mmol) was added, microwave reaction was performed at 100 ℃ for 1 hour, the reaction solution was concentrated, dichloromethane (20m L) and a saturated sodium bicarbonate solution (20m L) were added, the aqueous phase was extracted with dichloromethane (20m L× 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the residue after concentration of the filtrate under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 1 to 1: 0, methanol: dichloromethane (v/v) ═ 3: 97) to obtain the title compound [1- [3- (5-formyl-6-methoxy-indoline-1-oxophenyl) -indole-5-carbaldehyde (1-piperidinyl) in yield (72.67%).
1H NMR(400MHz，CDCl3)10.32(s，1H)，8.08(d，1H)，7.97(s，1H)，7.64(s，1H)，7.50(t，2H)，7.45-7.39(m，1H)，7.39-7.33(m，3H)，7.23(dd，1H)，7.14(td，1H)，6.61(s，1H)，4.82(s，1H)，4.13(t，2H)，3.92(s，3H)，3.15(t，2H)，2.97(s，2H)，2.80(s，4H)，2.54(s，2H)，2.13-1.98(m，2H)，1.82(s，2H)。
LCMS m/z＝528.1[M+1]。
The second step is that: [1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (1C)
[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000271
[1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.670g, 1.27mmol) was dissolved in a mixed solution of dichloromethane (10m L) and methanol (10m L), 5- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -8-hydroxy-1H-quinolin-2-one (1D) (0.425g, 1.27mmol) was added, reaction was carried out at room temperature for 1 hour, sodium triacetoxyborohydride (0.811g, 3.81mmol) was then added to the reaction solution, reaction was carried out at room temperature for 3 hours, dichloromethane (20m L) and a saturated sodium bicarbonate solution (20m L) were added to the reaction solution, the separated layers were extracted with dichloromethane (20m L× 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: 1 v-1 g, 2-phenyl-1H-phenyl-quinoline-2-ethyl ] -4-piperidinyl ] N- (2-phenyl) carbamate (1R-phenyl) as a yellow solid, yield [ (1R) -1 g, 2-phenyl) was 99H-phenyl) as title compound, 2-phenyl-2-oxo-2-phenyl ] ethyl-8-hydroxy-2-quinolinone.
1H NMR(400MHz，DMSO-d6)10.27(s，1H)，8.61(s，1H)，8.18(d，1H)，7.79(s，1H)，7.45-7.24(m，10H)，6.99(d，2H)，6.90(d，1H)，6.47(d，1H)，5.12(dd，1H)，4.52-4.38(m，1H)，4.08(dd，2H)，3.72-3.54(m，5H)，2.99(t，2H)，2.69-2.53(m，8H)，2.18(t，2H)，1.71(s，2H)，1.46(dd，2H)，0.84(d，9H)，0.03(d，3H)，-0.12--0.25(m，3H)。
LCMS m/z＝423.8[M/2+1]。
The third step: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (Compound 1)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000281
[1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (1C) (0.620g, 0.733mmol) was dissolved in dichloromethane (8m L), triethylamine trihydrofluoride salt (1.18g, 7.33mmol) was added, reaction was carried out at room temperature for 24 hours, the reaction mixture was added with water (20m L) and dichloromethane (20m L), 3% sodium hydroxide solution was added to adjust pH to about 12, extraction was carried out for separation layers, the aqueous phase was extracted with dichloromethane (20m L× 2), the organic phases were combined, washed with saturated brine (20m L× 1) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: 1 v/v) [ (1) for 1g, 3-phenyl-quinoline-1-ethyl ] -2-phenyl-1-phenyl-8-hydroxy-2-phenyl-propyl ] -4-piperidine compound (0.8g, 3-phenyl-8H-phenyl-8-phenyl) ethyl-8-phenyl-8-7 mmol).
1H NMR(400MHz，CD3OD)8.18(d，1H)，7.80(s，1H)，7.55(d，1H)，7.47-7.19(m，8H)，7.12(d，1H)，7.04-6.89(m，2H)，6.53(d，1H)，5.22-5.10(m，1H)，4.70-4.57(m，1H)，4.13(t，2H)，3.79(d，2H)，3.73(d，3H)，3.08(t，2H)，2.95-2.84(m，2H)，2.84-2.64(m，6H)，2.42(d，2H)，1.88(d，2H)，1.65(d，2H)。
LCMS m/z＝366.7[M/2+1]。
Example 2: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (Compound 2)
[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000282
The first step is as follows: [1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (2A)
[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Dissolving [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.500g, 0.948mmol) in dichloromethane (10m L) and methanol (10m L), adding N- [5- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -2-hydroxy-phenyl ] methanesulfonamide (2B) (0.342g, 0.948mmol), reacting at room temperature for 1 hour, adding sodium triacetoxyborohydride (0.605g, 2.84mmol), reacting at room temperature for 3 hours, adding dichloromethane (20m L) and saturated sodium bicarbonate solution (20m L), extracting the aqueous phase with dichloromethane (20m L× 1), combining the organic phases, drying without water, filtering, concentrating under reduced pressure, purifying the filtrate by silica gel chromatography (ethyl acetate: 1 v) ═ 1g, 2 v ═ phenyl-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.1 g, 0.948mmol), and purifying the residue by silica gel column chromatography (ethyl acetate: 1 v) [ (1g, 2-phenyl) to obtain a yellow sodium hydroxide (3-phenyl) amide [ (1-phenyl ] piperidine) as a yellow solid.
1H NMR(400MHz，DMSO-d6)8.77(s，1H)，7.98(s，1H)，7.64-7.40(m，9H)，7.33(d，1H)，7.20(s，1H)，7.11(dd，1H)，6.97(d，1H)，4.83(dd，1H)，4.68-4.54(m，1H)，4.26(t，2H)，3.86(s，3H)，3.77(dd，2H)，3.46(s，1H)，3.18(t，2H)，3.08-3.02(m，3H)，2.76(dd，7H)，2.33(dd，2H)，1.87(s，2H)，1.60(d，2H)，0.99(s，9H)，0.16(d，3H)，0.01(d，3H)。
LCMS m/z＝436.7[M/2+1]。
The second step is that: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (Compound 2)
[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000291
Dissolving [1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (2A) (0.530g, 0.608mmol) in dichloromethane (8m L), adding triethylamine trihydrofluoride (0.980g, 6.08mmol), reacting at room temperature for 24 hours, adding water (20m L) and dichloromethane (20m L) to the reaction solution, adjusting pH to about 12 by adding 3% sodium hydroxide solution, extracting the aqueous phase with dichloromethane (20m L× 2), combining the organic phases, washing the organic phase with a saturated brine (20m L), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 1 ═ v [ (3-phenyl ] amino ] methyl ] -4-hydroxy-3- (methanesulfonamido) phenyl ] methyl ] -4-piperidine [ (3-phenyl ] carbamate (0.3-3-2-phenyl) yield ═ 3-3 m L%).
1H NMR(400MHz，CD3OD)7.90(s，1H)，7.55(d，1H)，7.45-7.21(m，9H)，7.08(s，1H)，7.02(dd，1H)，6.85(d，1H)，4.69(dd，1H)，4.65-4.56(m，1H)，4.14(t，2H)，3.82(d，2H)，3.78(s，3H)，3.12(t，2H)，2.94-2.87(m，3H)，2.86-2.62(m，8H)，2.37(t，2H)，1.92-1.79(m，2H)，1.70-1.56(m，2H)。
LCMS m/z＝379.6[M/2+1]。
Example 3: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indoline-1-carboxylate (Compound 3)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000301
The first step is as follows: 2-bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3B)
2-bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000302
Bromoethanol (1.4g, 11.29mmol) was dissolved in dichloromethane (20m L), triethylamine (1.8g, 14.11mmol) was added, nitrogen was substituted three times, a solution of triphosgene (1.34g, 4.51mmol) in dichloromethane (10m L) was added dropwise at 0 ℃ and the reaction was gradually raised to room temperature for 1 hour to obtain reaction solution 1. 6-methoxyindoline-5-carbaldehyde (3A) (1.00g, 5.64mmol) was dissolved in tetrahydrofuran (20m L), triethylamine (1.8g, 14.11mmol) was added dropwise at 0 ℃ and the reaction solution 1 was gradually raised to room temperature for 1 hour, the reaction solution was concentrated, water (30m L) and dichloromethane (30m L) were added, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether (v/v) ═ 1: 9: 3: 7) to obtain 2-bromoethyl-6-indoline-carboxylate (title yield 1.81 g, 5g, 5.81% indole-carboxylate).
1H NMR(400MHz，CDCl3)10.31(s，1H)，7.62(d，2H)，4.55(s，2H)，4.15-4.08(m，2H)，3.94(s，3H)，3.62(s，2H)，3.09(t，2H)。
LCMS m/z＝328.0[M+1]。
The second step is that: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3C)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-formyl-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000311
2-bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3B) (1.5g, 4.6mmol) was dissolved in acetonitrile (20m L) and tetrahydrofuran (10m L), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (1.4g, 4.6mmol) and triethylamine (1.8g, 18mmol) were added, reaction was carried out at 80 ℃ for 8 hours, ethyl acetate (30m L) and water (30m L) were added to the reaction liquid, extraction was carried out, the aqueous phase was extracted with ethyl acetate (20m L× 1), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 3: 7: 3), to obtain the title compound 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5-formyl-6-methoxy-indoline-1-carboxylate (yield: 56% of yellow solid (C4).
1H NMR(400MHz，CDCl3)10.30(s，1H)，8.09(d，1H)，7.62(s，2H)，7.52-7.44(m，2H)，7.44-7.32(m，4H)，7.22(dd，1H)，7.16-7.09(m，1H)，6.58(s，1H)，4.78-4.69(m，1H)，4.35(s，2H)，4.06(t，2H)，3.92(s，3H)，3.07(t，2H)，2.83-2.66(m，4H)，2.36(s，2H)，1.93(s，2H)，1.69(d，2H)。
LCMS m/z＝544.1[M+1]。
The third step: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indoline-1-carboxylate (3D)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000312
Dissolving 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5-formyl-6-methoxy-indole-1-carboxylate (3C) (0.700g, 1.29mmol) in dichloromethane (10m L) and methanol (10m L), adding (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.431g, 1.29mmol), reacting at room temperature for 1 hour, adding sodium triacetoxyborohydride (0.823g, 3.86mmol), reacting at room temperature for 3 hours, adding dichloromethane (20m L) to the reaction solution, adding saturated aqueous sodium bicarbonate solution (20m L), extracting the aqueous phase with dichloromethane (20m L× 1), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue with silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 0, 0: 1 v) [ (2-piperidinyl ] ethyl 5-methoxy-indole-1-carboxylate (3C) (0.700g, 1H) -8-hydroxyquinoline-2 (1H) -ethyl-2- (1H) -carbonyl-2- (3-oxo-2H) -2-phenyl-2- [ (9) ethyl-2, yield [ [ (9) ethyl ] indole-2-oxo ] ethyl ] -2-hydroxy-2-oxo-2-ethyl-phenyl-2-ethyl-2-oxo-ethyl-2-one [ (0 ] ethyl-2, 3-ethyl-8-.
1H NMR(400MHz，CD3OD)8.20(d，1H)，7.55(s，1H)，7.42-7.20(m，9H)，7.14(d，1H)，7.02-6.89(m，2H)，6.55(d，1H)，5.31(s，1H)，4.64(s，1H)，4.37(s，2H)，4.01(t，2H)，3.89(s，2H)，3.73(s，3H)，3.12-3.03(m，2H)，2.98(t，2H)，2.90-2.71(m，4H)，2.52(s，2H)，1.88(s，2H)，1.68(s，2H)，0.86(d，9H)，0.16-0.01(m，3H)，-0.16(d，3H)。
LCMS m/z＝431.7[M/2+1]。
The fourth step: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indoline-1-carboxylate (Compound 3)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000321
Dissolving 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indoline-1-carboxylate (3D) (0.740g, 0.858mmol) in dichloromethane (8m L), adding triethylamine trihydrofluoride (1.38g, 8.58mmol), reacting at room temperature for 24 hours, adding water (20m L) and dichloromethane (20m L) to the reaction solution, adjusting pH to 12 by adding 3% sodium hydroxide solution, extracting the aqueous phase with dichloromethane (20m L× 2), combining the organic phases, washing with saturated sodium chloride aqueous solution (20m L× 1) in this order, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 1 ═ v [ (0 g) phenyl-piperidinyl ] amino ] -6-methoxy-indoline-1-carboxylate (0.97%) to obtain the title compound (8m L [ (. 3H) as yellow solid.
1H NMR(400MHz，CD3OD)8.22(d，1H)，7.57(d，1H)，7.52-7.30(m，7H)，7.30-7.23(m，2H)，7.16(d，1H)，7.03-6.92(m，2H)，6.57(d，1H)，5.19(dd，1H)，4.67-4.55(m，1H)，4.36(s，2H)，4.04(t，2H)，3.80(d，2H)，3.76(s，3H)，3.04(t，2H)，2.92(t，2H)，2.77(s，4H)，2.44(s，2H)，1.87(s，2H)，1.66(s，2H)。
LCMS m/z＝374.6[M/2+1]。
Example 4: [1- [3- [6- [ [ [ (2R) -2-hydroxy- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate (Compound 4)
[1-[3-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000331
The first step is as follows: 7-methoxy-1, 2, 3, 4-tetrahydroquinoline (4B)
7-methoxy-1，2，3，4-tetrahydroquinoline
Figure GPA0000231962000000332
7-methoxy-3, 4-dihydro-1H-quinolin-2-one (4A) (1.0g, 5.64mmol) was dissolved in tetrahydrofuran (15m L), nitrogen blanketed, lithium aluminum hydride (0.428g, 11.3mmol) was added at 0 deg.C, reacted at room temperature for 3 hours, cooled to 0 deg.C, and quenched by careful addition of water (2m L), ethyl acetate (20m L) was added, the mixture was filtered through celite, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 7-methoxy-1, 2, 3, 4-tetrahydroquinoline (4B), a yellow liquid (0.58g, 63% yield).
1H NMR(400MHz，CDCl3)6.83(d，1H)，6.19(dd，1H)，6.02(d，1H)，3.71(s，4H)，3.29-3.19(m，2H)，2.68(t，2H)，1.97-1.81(m，2H)。
LCMS m/z＝164.1[M+1]。
The second step is that: 6-bromo-7-methoxy-1, 2, 3, 4-tetrahydroquinoline (4C)
6-bromo-7-methoxy-1，2，3，4-tetrahydroquinoline
Figure GPA0000231962000000333
7-methoxy-1, 2, 3, 4-tetrahydroquinoline (4B) (0.100g, 0.613mmol) was dissolved in ethyl acetate (10m L), 1, 3-dibromo-5, 5-dimethylhydantoin (0.088g, 0.306mmol) was added at 0 ℃ and reacted at 0 ℃ for 2 hours, 15% potassium carbonate solution (20m L) was added to the reaction solution, followed by stirring well, ethyl acetate (20m L) was added, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 0: 1 to 1: 9) to give the title compound 6-bromo-7-methoxy-1, 2, 3, 4-tetrahydroquinoline (4C), a purple liquid (0.105g, 70.8% yield).
1H NMR(400MHz，CDCl3)7.06(s，1H)，6.05(s，1H)，3.79(s，3H)，3.30-3.22(m，2H)，2.66(t，2H)，1.89(dd，2H)。
LCMS m/z＝242.9[M+1]。
The third step: 7-methoxy-1, 2, 3, 4-tetrahydroquinoline-6-carbaldehyde (4D)
7-methoxy-1，2，3，4-tetrahydroquinoline-6-carbaldehyde
Figure GPA0000231962000000341
6-bromo-7-methoxy-1, 2, 3, 4-tetrahydroquinoline (4C) (0.500g, 2.07mmol) was dissolved in tetrahydrofuran (15M L), under nitrogen protection, 2M solution of isopropyl magnesium chloride in tetrahydrofuran (1.15M L, 2.27mmol) was added at-10 deg.C, the reaction was warmed to 0 deg.C for 1 hour-25 deg.C, 2.5M solution of N-butyl lithium in N-hexane (4M L, 10.3mmol) was added at-10 deg.C, N-dimethylformamide (0.755g, 10.3mmol) was added at-10 deg.C, the reaction was gradually warmed to room temperature for 0.5 hour, the reaction solution was poured into water (20M L) solution of citric acid (1g), ethyl acetate (20M L) was added, the aqueous phase was extracted with ethyl acetate (10M L× 1), the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was filtered, the filtrate was concentrated by silica gel column chromatography (ethyl acetate 1 v) to obtain a yellow compound (4: 1-4 g, 4-8 g) of quinoline, the title compound was purified by silica gel chromatography (4: 4-4 g).
1H NMR(400MHz，CDCl3)10.10(s，1H)，7.45(s，1H)，5.88(s，1H)，4.64(s，1H)，3.80(s，3H)，3.39-3.30(m，2H)，2.69(t，2H)，1.96-1.85(m，2H)。
LCMS m/z＝192.1[M+1]。
The fourth step: 7-methoxy-1-propyl-2-enoyl-3, 4-dihydro-2H-quinoline-6-carbaldehyde (4E)
7-methoxy-1-prop-2-enoyl-3，4-dihydro-2H-quinoline-6-carbaldehyde
Figure GPA0000231962000000342
7-methoxy-1, 2, 3, 4-tetrahydroquinoline-6-carbaldehyde (4D) (1.5g, 7.84mmol) was dissolved in ethyl acetate (30m L), triethylamine (5.95g, 58.8mmol) was added, acrylic acid (1.41g, 19.6mmol) was added dropwise, the mixture was raised to 40 ℃ and 1-propylphosphoric anhydride (6.24g, 19.6mmol) was added dropwise to react at 80 ℃ for 4 hours, the reaction mixture was added with ethyl acetate (20m L) and water (20m L), extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v): 0: 1 to 3: 7) to give the title compound 7-methoxy-1-propyl-2-enoyl-3, 4-dihydro-2H-quinoline-6-carbaldehyde (4E) as a yellow solid (1.1g, 57% yield).
1H NMR(400MHz，CDCl3)10.37(s，1H)，7.63(s，1H)，6.84(s，1H)，6.61(dd，1H)，6.47(dd，1H)，5.76(dd，1H)，3.89-3.81(m，5H)，2.72(q，2H)，2.02-1.93(m，2H)。
LCMS m/z＝246.2[M+1]。
The fifth step: [1- [3- (6-formyl-7-methoxy-3, 4-dihydro-2H-quinolin-1-yl) -3-oxo-propyl ] 4-piperidinyl ] N- (2-phenylphenyl) carbamate (4F)
[1-[3-(6-formyl-7-methoxy-3，4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000351
7-methoxy-1-propyl-2-enoyl-3, 4-dihydro-2H-quinoline-6-carbaldehyde (4E) (1.1g, 4.48mmol) was dissolved in 2-methyltetrahydrofuran (10m L), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (1.33g, 4.48mmol) was added, triethylamine (0.908g, 8.97mmol) was added, microwave reaction was performed at 100 ℃ for 1 hour, the reaction solution was concentrated, methylene chloride (20m L) and a saturated aqueous sodium bicarbonate solution (20m L) were added, extraction was performed, the aqueous phase was extracted with methylene chloride (20m L× 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated, the residue was chromatographed on a silica gel column under reduced pressure (ethyl acetate: petroleum ether (v/v) ═ 1: 1 to 1: 0, methanol: methylene chloride (v/v) ═ 3: 97) to give the title compound [1- [3- (6-formyl-7-methoxy-2-quinolinecarboxylate-6H-oxo-phenyl-6-carbaldehyde (1g, 4g) as a yellow solid, yield).
1H NMR(400MHz，CDCl3)10.36(s，1H)，8.08(d，1H)，7.60(s，1H)，7.52-7.44(m，2H)，7.44-7.39(m，1H)，7.39-7.31(m，3H)，7.26-7.19(m，2H)，7.16-7.08(m，1H)，6.59(s，1H)，4.80-4.65(m，1H)，3.89(d，3H)，3.80-3.70(m，2H)，2.83-2.62(m，8H)，2.29(s，2H)，2.00-1.88(m，4H)，1.75-1.56(m，2H)。
LCMS m/z＝542.1[M+1]。
And a sixth step: [1- [3- [6- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (4G)
[1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000352
Dissolving [1- [3- (6-formyl-7-methoxy-3, 4-dihydro-2H-quinolin-1-yl) -3-oxo-propyl ] 4-piperidinyl ] N- (2-phenylphenyl) carbamate (4F) (0.700G, 1.29mmol) in dichloromethane (10m L) and methanol (10m L), adding (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.432G, 1.29mmol), reacting at room temperature for 1 hour, adding sodium triacetoxyborohydride (0.826G, 3.88mmol), reacting at room temperature for 3 hours, adding dichloromethane (20m L) and saturated aqueous sodium bicarbonate solution (20m L), extracting the aqueous phase with dichloromethane (20m L× 1), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, isolating the residue by silica gel chromatography (ethyl acetate-1 v) [ (1H-piperidinyl) and purifying the title compound with ethyl-2-phenyl-quinolinyl ] N- (1H-piperidinyl) to obtain a yellow oil (R) -5- (2-1G, 2-phenyl) ethyl-8-hydroxyquinoline-2-1H-1G-piperidinyl) compound (0.7-1H).
LCMS m/z＝430.8[M/2+1]。
The seventh step: [1- [3- [6- [ [ [ (2R) -2-hydroxy- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate (Compound 4)
[1-[3-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000361
[1- [3- [6- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (4G) (1.1G, 1.3mmol) was dissolved in dichloromethane (8m L), triethylamine trihydrofluoride (2.1G, 13mmol) was added, reaction was carried out at room temperature for 24 hours, the reaction mixture was added with water (20m L) and dichloromethane (20m L), pH was adjusted to around 12 by adding 3% sodium hydroxide solution, the aqueous phase was extracted with dichloromethane (20m L× 2), the organic phases were combined, washed with saturated chlorinated aqueous solution (20m L× 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the compound [1- [6- [2- (2H) -6-t-butyl (4H-piperidinyl ] N- (2-phenyl) carbamate as a white solid (0.1H-phenyl) quinoline-4-dihydro-2H-quinolin-1-yl ] -4-piperidinyl ] carbamate (1-phenyl) acetate, yield).
1H NMR(400MHz，CD3OD)8.03(s，1H)，7.47(s，1H)，7.40-7.12(m，10H)，7.03(s，1H)，6.95(d，1H)，6.50(d，1H)，5.33(dd，1H)，4.82(s，1H)，4.17(s，2H)，3.74(d，3H)，3.69(t，2H)，3.64-3.43(m，2H)，3.39(s，2H)，3.19-2.96(m，6H)，2.63(t，2H)，2.14-1.65(m，6H)。
LCMS m/z＝373.7[M/2+1]。
Example 5: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (Compound 5)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate
Figure GPA0000231962000000371
The first step is as follows: 2- (4-benzyloxy-3-chloro-phenyl) aniline (5C)
2-(4-benzyloxy-3-chloro-phenyl)aniline
Figure GPA0000231962000000372
O-iodoaniline (5B) (4.0g, 18mmol) was dissolved in ethylene glycol dimethyl ether (5m L) and water (5m L), and (4-benzyloxy-3-chloro-phenyl) boronic acid (5A) (4.8g, 18mmol) and potassium carbonate (10g, 73mmol) were added, tetratriphenylphosphine palladium (1.1g, 0.91mmol) was added under nitrogen protection, microwave reaction was performed at 120 ℃ for 1 hour, ethyl acetate (50m L) and water (50m L) were added to the reaction solution, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 0: 1 to 1: 9) to give the title compound 2- (4-benzyloxy-3-chloro-phenyl) aniline (5C) as a yellow solid (4.5g, 80% yield).
1H NMR(400MHz，CDCl3)7.51-7.45(m，3H)，7.43-7.36(m，2H)，7.36-7.29(m，1H)，7.26(dd，1H)，7.16-7.10(m，1H)，7.07(dd，1H)，7.02(d，1H)，6.80(m，1H)，6.74(dd，1H)，5.19(s，2H)，3.76(s，2H)。
LCMS m/z＝310.1[M+1]。
The second step is that: 4- [ [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamoyloxy ] piperidine-1-carboxylic acid tert-butyl ester (5E)
tert-butyl 4-[[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamoyloxy]piperidine-1-carboxylate
Figure GPA0000231962000000381
2- (4-benzyloxy-3-chloro-phenyl) aniline (5C) (2.3g, 7.4mmol) was dissolved in toluene (50m L), triphosgene (0.88g, 3.0mmol) was added, reaction was carried out at 125 ℃ for 4 hours, tetrahydrofuran (100m L) was added after concentration, tert-butyl 4-hydroxy-piperidine-1-carboxylate (5D) (1.5g, 7.4mmol) was added, triethylamine (2.3g, 22mmol) was added, reaction was carried out at 70 ℃ for 2 hours, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 0: 1 to 1: 9) to give the title compound, tert-butyl 4- [ [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamoyloxy ] piperidine-1-carboxylate (5E), as a yellow oil (3.5g, 88% yield).
LCMS m/z＝559.2[M+23]。
The third step: 4-piperidinyl N- [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamate (5F)
4-piperidyl N-[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamate
Figure GPA0000231962000000382
Tert-butyl 4- [ [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamoyloxy ] piperidine-1-carboxylate (5E) (3.5g, 6.5mmol) was dissolved in dichloromethane (10m L), trifluoroacetic acid (10m L) was added, reaction was carried out at room temperature for 2 hours, the reaction solution was concentrated, pH was adjusted to 8 to 9 with aqueous ammonia, dichloromethane (50m L) was added, extraction was carried out, the aqueous phase was extracted with dichloromethane (20m L× 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (methanol/dichloromethane (v/v) ═ 1: 99 to 1: 19) to give the title compound 4-piperidinyl N- [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamate (5F), as a white solid (1.2g, 42% yield).
1H NMR(400MHz，CDCl3)8.01(d，1H)，7.50(d，2H)，7.46-7.30(m，5H)，7.23-7.03(m，4H)，6.54(s，1H)，5.23(s，2H)，4.94-4.87(m，1H)，4.34(s，1H)，3.22-3.06(m，2H)，2.98-2.85(m，2H)，2.15-1.97(m，2H)，1.90-1.70(m，2H)。
LCMS m/z＝437.1[M+1]。
The fourth step: 4-piperidinyl N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5G)
4-piperidyl N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate
Figure GPA0000231962000000391
4-piperidyl N- [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamate (5F) (0.860G, 1.97mmol) was dissolved in methanol (20m L), o-dichlorobenzene (1.45G, 9.84mmol) was added, 10% (w/w) palladium on carbon (0.3G) was added, hydrogen gas was replaced, and the reaction mixture was reacted at room temperature for 4 hours under a hydrogen atmosphere, and the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1: 99 to 1: 9) to give the title compound 4-piperidyl N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5G) as a pale yellow solid (0.700G, yield 103%).
1H NMR(400MHz，DMSO-d6)10.32(s，1H)，8.84(s，1H)，7.37-7.24(m，5H)，7.14(dd，1H)，7.04(d，1H)，4.81-4.68(m，1H)，3.17(s，1H)，3.05(s，4H)，1.93(s，2H)，1.70(d，2H)。
LCMS m/z＝347.0[M+1]。
The fifth step: [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5H)
[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate
Figure GPA0000231962000000392
6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (intermediate 1) (0.520G, 2.25mmol) was dissolved in 2-methyltetrahydrofuran (10m L), 4-piperidyl N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5G) (0.780G, 2.25mmol) was added, triethylamine (0.455G, 4.50mmol) was added, microwave reaction was performed at 100 ℃ for 1 hour, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1: 1 to 1: 0, methanol/dichloromethane (v): 3: 97) to give the title compound [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5H) in a yellow solid (1.25G, 96.1%).
1H NMR(400MHz，CDCl3)10.32(s，1H)，8.02(d，1H)，7.95(s，1H)，7.64(s，1H)，7.38-7.29(m，2H)，7.19-7.08(m，4H)，6.53(s，1H)，4.84(s，1H)，4.14(dd，2H)，3.91(s，3H)，3.16(d，2H)，3.01(s，2H)，2.89(d，4H)，2.60(s，2H)，2.10(s，2H)，1.88(s，2H)。
LCMS m/z＝578.1[M+1]。
And a sixth step: [1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5I)
[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate
Figure GPA0000231962000000401
Dissolving [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5H) (0.500g, 0.865mmol) in dichloromethane (10m L) and methanol (10m L), adding (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinoline-2 (1H) -one (1D) (0.318g, 0.951mmol), reacting at room temperature for 1 hour, adding sodium triacetoxyborohydride (0.553g, 2.59mmol), reacting at room temperature for 3 hours, adding dichloromethane (20m L) to the reaction solution, adding a saturated aqueous sodium bicarbonate solution (20m L), extracting the aqueous phase with dichloromethane (20m L× 1), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating the filtrate by silica gel chromatography (ethyl acetate/silica gel column chromatography) (1 v) (-1H) -1 g, purifying the title compound by ethyl-4-piperidinyl ] N- [2- (3-phenyl) N- [2- (3-4-piperidinyl ] N- [2- (3-4-phenyl) phenyl ] carbamate (0.42g, and purifying the title compound by ethyl-5H- [ [ -phenyl) as a yellow solid.
1H NMR(400MHz，CD3OD)8.15(d，1H)，7.68(s，1H)，7.39(d，1H)，7.28-7.14(m，5H)，7.07(dd，1H)，6.99(d，1H)，6.93-6.80(m，3H)，6.43(d，1H)，5.05(t，1H)，4.61(d，1H)，4.08(t，2H)，3.64-3.54(m，5H)，3.09-2.94(m，2H)，2.88-2.81(m，2H)，2.78-2.63(m，6H)，2.50(s，2H)，1.84(s，2H)，1.65(s，2H)，0.84-0.75(m，9H)，-0.00(s，3H)，-0.25(d，3H)。
LCMS m/z＝448.8[M/2+1]。
The seventh step: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (Compound 5)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate
Figure GPA0000231962000000411
[1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5I) (0.420g, 0.468mmol) was dissolved in tetrahydrofuran (5m L), triethylamine trihydrofluoride (0.755g, 4.68mmol) was added, reaction was carried out at room temperature for 24 hours, 10% methanol/dichloromethane (v/v ═ 1/10, 50m L) solution was added to the reaction solution, saturated bicarbonate solution was added to adjust pH to around 8, extraction was carried out, aqueous phase was extracted with 10% methanol/dichloromethane (v/v ═ 1/10, 50m L×), organic phase was combined with saturated sodium chloride aqueous solution (20m 461), filtrate was washed with anhydrous sodium sulfate, filtered, and the title compound was concentrated with 3-hydroxy-phenyl ] quinoline (3-oxo-2- [ 3-4-phenyl ] carbamate (3-hydroxy-phenyl) as a yellow solid, yield after-2-3-phenyl-4-phenyl ] indole-2H-7-phenyl ] carbamate was concentrated under reduced pressure to obtain a yellow syrup.
1H NMR(400MHz，CD3OD)8.18(d，1H)，7.86(s，1H)，7.48(d，1H)，7.37-7.31(m，2H)，7.28(dd，2H)，7.21(d，1H)，7.16(dd，1H)，7.09(s，1H)，7.00(dd，2H)，6.58(d，1H)，5.33-5.24(m，1H)，4.70(s，1H)，4.19(t，2H)，4.00(s，2H)，3.79(s，3H)，3.13(dd，2H)，3.09-3.02(m，2H)，2.92(t，2H)，2.86-2.73(m，4H)，2.57(s，2H)，1.93(s，2H)，1.75(s，2H)。
LCMS m/z＝391.8[M/2+1]。
Example 6: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-3H-1, 3-benzothiazol-7-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate bistrifluoroacetate salt (Compound 6)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1，3-benzothiazol-7-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate
Figure GPA0000231962000000412
[1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5H) (0.420g, 0.727mmol) was dissolved in dichloromethane (10m L) and methanol (10m L), 7- [ (1R) -2-amino-1-hydroxy-ethyl ] -4-hydroxy-3H-1, 3-benzothiazol-2-one (6A, ref Bioorganic & Medicinal Chemistry L ethyl, (21), 4612-.
1H NMR(400MHz，DMSO-d6)7.24(d，1H)，6.68(s，1H)，6.54(d，4H)，6.40(d，2H)，6.19(d，2H)，5.95(dd，1H)，4.18(dd，2H)，3.51-3.34(m，4H)，3.09(s，3H)，2.95-2.66(m，4H)，2.45-2.33(m，4H)，2.32-2.20(m，4H)，1.51-1.00(m，4H)。
LCMS m/z＝394.7[M/2+1]。
Example 7: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 7)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1，4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroaceticacid
Figure GPA0000231962000000421
Dissolving [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.400g, 0.758mmol) in tetrahydrofuran (2m L) and methanol (10m L), adding 8- [ (1R) -2-amino-1-hydroxy-ethyl ] -5-hydroxy-4H-1, 4-benzoxazin-3-one (7A, prepared with reference to WO2009098448a 1) (0.170g, 0.758mmol), adding anhydrous zinc chloride (0.413g, 3.03mmol), reacting at 55 ℃ for 1 hour, adding sodium cyanoborohydride (0.143g, 2.27mmol), reacting at 55 ℃ for 2 hours, adding dichloromethane (50m L), adding saturated aqueous sodium bicarbonate solution (50m L), extracting the aqueous phase with methanol/dichloromethane (1/10, 30m ═ L×%, extracting the aqueous phase with methanol/dichloromethane (5631 g, L×%) to obtain a white solid, purifying the compound by filtration using a column chromatography column (0.7g, 3-oxo-propylindolin-4-piperidinyl), purifying the title compound (0.7) by column chromatography) to obtain a white solid, purifying by column chromatography, eluting with dichloromethane (0.8 [ -2-phenyl-4-piperidinyl) to obtain a 3-phenyl-4-phenyl-ethyl-4-piperidinyl), purifying the title compound (TFA).
1H NMR(400MHz，CD3OD)7.99(s，1H)，7.57(s，1H)，7.50-7.28(m，8H)，7.19(s，1H)，7.04(d，1H)，6.59(d，1H)，5.14(dd，1H)，4.93(s，1H)，4.40(dd，2H)，4.28-4.09(m，4H)，3.83(s，3H)，3.77-3.49(m，4H)，3.24-2.99(m，8H)，2.25-1.70(m，4H)。
19F NMR(376MHz，CD3OD)-75.45。
LCMS m/z＝368.6[M/2+1]。
Example 8: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 8)
[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000431
The first step is as follows: (1R) -2-amino-1- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) ethanol (8B)
(1R)-2-amino-1-(2，2-dimethyl-4H-1，3-benzodioxin-6-yl)ethanol
Figure GPA0000231962000000432
(5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxol-6-yl) oxazolidin-2-one (8A) (2.0g, 8.0mmol) was dissolved in ethanol (10m L) and water (10m L), sodium hydroxide (0.64g, 16mmol) was added, reflux reaction was performed at 90 ℃ for 2 hours, dichloromethane (30m L) and water (30m L) were added to the reaction solution, extraction was performed, the aqueous phase was extracted with dichloromethane (30m L× 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1R) -2-amino-1- (2, 2-dimethyl-4H-1, 3-benzodioxol-6-yl) ethanol (8B), a yellow solid (1.6g, 89% yield).
1H NMR(400MHz，CDCl3)7.11(dd，1H)，6.99(d，1H)，6.79(d，1H)，4.82(d，2H)，4.53(dd，1H)，2.94(dd，1H)，2.77(dd，1H)，2.04(s，3H)，1.53(d，6H)。
The second step is that: [1- [3- [5- [ [ [ (2R) -2- (2, 2-dimethyl-4H-1, 3-benzodioxol-6-yl) -2-hydroxy-ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (8C)
[1-[3-[5-[[[(2R)-2-(2，2-dimethyl-4H-1，3-benzodioxin-6-yl)-2-hydroxy-ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000441
[1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.400g, 0.758mmol) was dissolved in tetrahydrofuran (2m L) and methanol (10m L), (1R) -2-amino-1- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) ethanol (8B) (0.203g, 0.910mmol) was added, (0.413g, 3.03mmol) was added, 55 ℃ was reacted for 1 hour, (0.143g, 2.27mmol) sodium cyanoborohydride (0.143g, 55 ℃ was reacted for 2 hours), (30m L) was added to the reaction solution, water (30m L) was added to the aqueous phase, dichloromethane (30m L× 1) was extracted, the organic phase was combined with sodium sulfate, the filtrate was filtered, the residue was concentrated by silica gel column chromatography (1 v) ([ (3-phenyl) -3-oxo-propyl ] -4-piperidinyl ] compound (1B) (0.203g, 0.3H-phenyl) was purified to obtain the title compound (3-phenyl-amino-1H-1-phenyl-1H-1, 3-piperidinyl).
LCMS m/z＝368.4[M/2+1]。
The third step: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 8)
[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000442
[1- [3- [5- [ [ [ (2R) -2- (2, 2-dimethyl-4H-1, 3-benzodioxol-6-yl) -2-hydroxy-ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (8C) (0.220g, 0.299mmol) was dissolved in dichloromethane (15m L), trifluoroacetic acid (0.0683g, 0.599mmol) was added, the reaction liquid was reacted at room temperature for 2 hours, a saturated aqueous sodium bicarbonate solution (15m L) was added to the reaction liquid, the aqueous phase was extracted with dichloromethane (20m L× 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was isolated and purified by a liquid phase preparative column preparative (liquid phase preparative conditions: C18 reverse phase preparative column, mobile phase was deionized water containing 0.05% TFA, acetonitrile (B), elution equal degree B: 25%, elution time: 20 min. [ (2R) -3-hydroxy-propyl ] -4-piperidinyl ] carbamate (1g), the title compound was obtained as a white solid.
1H NMR(400MHz，CD3OD)8.04(s，1H)，7.57(d，1H)，7.49-7.28(m，9H)，7.26(s，1H)，7.15(dd，1H)，6.80(d，1H)，4.91(dd，2H)，4.65(s，2H)，4.25(s，2H)，4.20(t，2H)，3.91(s，3H)，3.75-3.45(m，4H)，3.25-3.00(m，8H)，2.25-1.75(m，4H)。
19F NMR(376MHz，CD3OD)-75.35。
LCMS m/z＝348.3[M/2+1]。
Example 9: [1- [3- [6- [ [ [ (2R) -2-hydroxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 9)
[1-[3-[6-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1，4-benzoxazin-8-yl)ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000451
Dissolving [1- [3- (6-formyl-7-methoxy-3, 4-dihydro-2H-quinolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (4F) (0.300g, 0.554mmol) in methanol (15m L), adding 8- [ (1R) -2-amino-1-hydroxy-ethyl ] -5-hydroxy-4H-1, 4-benzoxazin-3-one (7A) (0.124g, 0.554mmol), adding anhydrous zinc chloride (0.302g, 2.22mmol), reacting at 55 ℃ for 1 hour, adding sodium cyanoborohydride (0.104g, 1.66mmol), reacting at 55 ℃ for 2 hours, adding dichloromethane (50m L) and saturated aqueous sodium bicarbonate solution (50m L), extracting the aqueous phase with methanol/dichloromethane (v/v ═ 1/10, 30m L× mmol), combining the organic phase, preparing a white filtrate by filtration using anhydrous column, preparing the title compound under reduced pressure, purifying with ethyl-phenyl-4H-phenyl-quinoline-1-yl-4-ethyl-1-oxoethyl-1-phenyl) as a white solid, eluting with sodium hydrogen carbonate (0.2-2-ethyl-4-phenyl-4H-4-phenyl-4-oxo-4-piperidinyl), purifying the title compound under reduced pressure conditions of ethyl-phenyl-4-phenyl-7-phenyl-4-ethyl-4-phenyl-4-7-4-ethyl-phenyl-4-phenyl-7-4-7-one, and 0-phenyl-7-4-ethyl.
1H NMR(400MHz，CD3OD)7.57(s，1H)，7.50-7.25(m，9H)，7.14(s，1H)，7.05(d，1H)，6.60(d，1H)，5.16(d，1H)，4.93(s，1H)，4.50-4.30(m，2H)，4.29-4.18(m，2H)，3.91-3.75(m，5H)，3.75-3.43(m，4H)，3.25-2.93(m，6H)，2.76(t，2H)，2.25-1.73(m，6H)。
19F NMR(376MHz，CD3OD)-75.37。
LCMS m/z＝375.8[M/2+1]。
Example 10: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate bistrifluoroacetate salt (Compound 10)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000461
The first step is as follows: 4-piperidinyl N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10A)
4-piperidyl N-[2-(4-hydroxyphenyl)phenyl]carbamate
Figure GPA0000231962000000462
4-piperidyl N- [2- (3-chloro-4-hydroxyphenyl) phenyl ] carbamate (5G) (0.600G, 1.73mmol) was dissolved in methanol (10m L), 10% palladium on carbon (2.0G) was added to replace hydrogen, and the reaction mixture was reacted at room temperature under a hydrogen atmosphere for 24 hours, the reaction mixture was suction-filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1: 99 to 1: 9) to give the title compound 4-piperidyl N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10A) as a yellow oil (0.47G, yield 87%).
1H NMR(400MHz，DMSO-d6)9.58(s，1H)，9.24(s，1H)，9.14(s，1H)，8.65(s，1H)，7.36(t，1H)，7.32-7.27(m，1H)，7.18(d，2H)，6.83(d，2H)，4.74(s，1H)，3.02(s，4H)，1.94(s，2H)，1.72(s，2H)。
LCMS m/z＝313.1[M+1]。
The second step is that: [1- [3- (5-formyl-6-methoxy-indol-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10B)
[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate
Figure GPA0000231962000000471
6-methoxy-1-propyl-2-enoyl-indole-5-carbaldehyde (intermediate 1) (0.348g, 1.50mmol) was dissolved in 2-methyltetrahydrofuran (10m L), 4-piperidyl N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10A) (0.470g, 1.50mmol) was added, triethylamine (0.304g, 3.01mmol) was added, the reaction was microwave-reacted at 100 ℃ for 1 hour, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 1 to 1: 0) to give the title compound [1- [3- (5-formyl-6-methoxy-indol-1-yl) -3-oxo-propyl ] -4-piperidyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10B), a yellow solid (0.580g, yield 70.9%).
1H NMR(400MHz，CDCl3)10.31(s，1H)，8.02(d，1H)，7.93(s，1H)，7.63(s，1H)，7.36-7.29(m，1H)，7.20-7.08(m，4H)，6.99(d，2H)，6.65(s，1H)，4.85(s，1H)，4.14(t，2H)，3.90(s，3H)，3.17-3.11(m，4H)，2.96(d，4H)，2.72(s，2H)，2.14(s，2H)，1.92(s，2H)。
LCMS m/z＝544.3[M+1]。
The third step: [1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10C)
[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate
Figure GPA0000231962000000472
Dissolving [1- [3- (5-formyl-6-methoxy-indol-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10B) (0.250g, 0.460mmol) in methanol (10m L), (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.318g, 0.951mmol) was added, (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) was added, (R) -anhydrous zinc chloride (0.251g, 1.84mmol) was added, (R) -sodium cyanoborohydride (0.0867g, 1.38mmol) was added at 55 ℃ for 2H. (R) -dichloromethane (30m L) was added to the reaction mixture, water (30m L) was added, (R) -the aqueous phase was extracted with dichloromethane (30m L× 1), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was added to the reaction mixture under reduced pressure (20 m.2), the filtrate was added to the filtrate, (R) -2-N- [ 3-piperidinyl ] ethyl ] carbamate (1g, the filtrate, the title compound was purified by chromatography (R) -5-4-1H) -1-4-phenyl ] ethyl bicarbonate, the yellow organic phase was purified by silica gel chromatography (1-ethyl-1 g, the yellow silica gel (1-6-2-ethyl-1 g, the yellow silica gel (1-1H) was obtained as an oil phase, the title compound, the yellow silica gel yield [ ((R) -5-2-6-phenyl) was extracted with silica gel, the yellow silica gel was separated, the yellow silica-2-6-4-2-ethyl-4-phenyl) was extracted with the title compound.
LCMS m/z＝431.9[M/2+1]。
The fourth step: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate bistrifluoroacetate salt (Compound 10)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000481
[1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10C) (0.200g, 0.232mmol) was dissolved in tetrahydrofuran (5m L), triethylamine trihydrofluoride salt (0.374g, 2.32mmol) was added, reaction was carried out at room temperature for 24 hours, dichloromethane (50m L) was added to the reaction solution, saturated aqueous sodium bicarbonate solution was added to adjust pH to around 8, extraction was carried out, the aqueous phase was extracted with dichloromethane (50m L× 2), the organic phases were combined, washed with saturated aqueous sodium chloride solution (20m L× 1), sodium sulfate was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified with a liquid phase preparative column (liquid phase preparative conditions: C18 reverse phase preparative column, mobile phase containing 0.5% of acetonitrile-hydroxy-phenyl-propyl ] -2-ethyl ] carbamate [ (3-hydroxy-2-phenyl ] acetate ] 0.5% and the title compound was eluted at room temperature for 24 hours, and the time of the title compound was obtained.
1H NMR(400MHz，CD3OD)7.97(d，1H)，7.81(s，1H)，7.57(s，1H)，7.39-7.17(m，6H)，7.06(d，2H)，6.93-6.79(m，2H)，6.53(d，1H)，5.41(dd，1H)，4.96(s，1H)，4.26-4.06(m，4H)，3.77(s，3H)，3.70-3.45(m，4H)，3.30-2.98(m，8H)，2.35-1.85(m，4H)。
LCMS m/z＝374.8[M/2+1]。
Example 11: 1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (4-hydroxy-2-oxo-3H-1, 3-benzothiazol-7-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] -N- (2-phenylphenyl) carbamate (Compound 11)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1，3-benzothiazol-7-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000491
1- [3- (5-formyl-6-methoxyindolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] -N- (2-phenylphenyl) carbamic acid (1B) (0.35g, 0.66mmol) and 7- [ (1R) -2-amino-1-hydroxy-ethyl ] -4-hydroxy-3H-1, 3-benzothiazol-2-one (6A) (0.57g, 2.5mmol) were dissolved in a mixed solvent of dichloromethane (5m L) and methanol (5m L), stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (0.42g, 2.0mmol) was added, reaction was carried out at room temperature for 2 hours, dichloromethane (10m L) was added, washing was carried out with a saturated sodium bicarbonate solution (20m L× 2), a saturated brine (20m L× 1) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure using silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1: 100 ═ 1: 1 ═ 4-piperidinyl ] -N- (2-phenyl) carbamic acid ester (1, 3H-phenyl-4-dihydro-2-phenyl-2-oxo-2-4H-phenyl-one (6A) was obtained, yield).
1H NMR(400MHz，CD3OD)7.82(s，1H)，7.57(d，1H)，7.47-7.24(m，8H)，7.00(s，1H)，6.88(d，1H)，6.71(d，1H)，4.74-4.71(m，1H)，4.69-4.59(m，1H)，4.17(t，2H)，3.78-3.64(m，5H)，3.13(t，2H)，2.88-2.67(m，8H)，2.41(t，2H)，1.87(s，2H)，1.67(s，2H)。
LCMS m/z＝739.1[M+1]。
Example 12: [ [1- [4- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -4-oxobutyl ] -4-piperidinyl ] -N- (2-phenylphenyl) carbamate (Compound 12)
[1-[4-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000492
The first step is as follows: 1- (4-bromobutyl) -6-methoxyindoline-5-carbaldehyde (12A)
1-(4-bromobutanoyl)-6-methoxy-indoline-5-carbaldehyde
Figure GPA0000231962000000501
Tetrabromobutyric acid (2g, 10mmol) was dissolved in anhydrous dichloromethane (20m L), oxalyl chloride (3g, 30mmol) was added dropwise after cooling to 0 ℃, stirring at low temperature for 30 minutes, concentration was performed, dichloromethane (10m L) was added to obtain reaction solution 1, 6-methoxyindoline-5-carbaldehyde (1f) (0.8g, 5mmol) and triethylamine (1g, 10mmol) were added to dichloromethane (20m L), cooling to 0 ℃, reaction solution 1 was added dropwise after reaction at low temperature for 0.5 hour, dichloromethane (50m L) and water (50m L) were added to the reaction solution, extraction was performed by layers, the organic phase was washed with a saturated sodium chloride solution (50m L× 1), dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v): 0: 1 to 1: 2), to obtain the title compound 1- (4-bromobutyl) -6-methoxyindoline-5-carbaldehyde (12A), light red solid (yield 0.8g, 50%).
1HNMR(400MHz，CDCl3)10.32(d，1H)，8.00(s，1H)，7.65(s，1H)，3.93(d，3H)，3.59(t，2H)，3.16(dd，2H)，2.67(dd，2H)，2.51(m，4H)。
LCMSm/z＝326.0[M+1]。
The second step is that: [1- [4- (5-formyl-6-methoxyindolin-1-yl) -4-oxobutyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (12B)
[1-[4-(5-formyl-6-methoxy-indolin-1-yl)-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000502
1- (4-bromobutyl) -6-methoxyindoline-5-carbaldehyde (12A) (0.8g, 2mmol) and 4-piperidinyl-N- (2-phenylphenyl) carbamate (1A) (0.7g, 2mmol) were dissolved in a mixed solvent of acetonitrile/tetrahydrofuran (v/v) ═ 2/1 (15m L), then triethylamine (0.5g, 5mmol), tetrabutylammonium iodide (0.2g, 0.2mmol) were added, stirring was carried out in a microwave reactor for 7 hours, concentration was carried out, ethyl acetate (50m L) was added to the residue to be dissolved, water (50m L× 1) and a saturated sodium chloride solution (50m L× 1) were successively, the organic phase was dried over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0: 1 to 5: 95) to give the title compound [1- [4- (5-formyl-6-methoxyindoline-1-piperidinyl ] -4-oxophenyl carbamate (0.8g, 12 g yellow B) yield.
LCMSm/z＝542.1[M+1]。
The third step: [1- [4- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -4-oxobutyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (12C)
[1-[4-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000511
[1- [4- (5-formyl-6-methoxyindolin-1-yl) -4-oxobutyl ] -4-piperidinyl ] -N- (2-phenyl) carbamate (12B) (0.11g, 0.20mmol) and 5- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -8-hydroxy-1H-quinolin-2-one (1D) (0.10g, 0.30mmol) were dissolved in a mixed solvent (10m L) of methanol/dichloromethane (v/v ═ 1/1), after stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.25g, 1.2mmol) was added, the reaction was continued for 2 hours, dichloromethane (50m L) and water (50m L) were added to the reaction liquid, the organic phase was washed with a saturated sodium chloride solution (50m L× 1), anhydrous sodium sulfate was dried, filtered and concentrated under reduced pressure to give the title compound [1- [4- [5- [ 2R) -2- [ tert-butyl (dimethyl) oxy ] piperidinyl ] -8-hydroxy-1H-quinolin-2-one (1D) (0.10g, 3mmol), yield).
LCMSm/z＝430.8[1/2M+1]。
The fourth step: [ [1- [4- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -4-oxobutyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (Compound 12)
[1-[4-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000512
[1- [4- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -4-oxobutyl ] -4-piperidinyl ] -N- (2-phenylphenyl) carbamate (12C) (0.11g, 0.13mmol) was dissolved in dichloromethane (10m L), triethylamine trihydrofluoride salt (0.21g, 1.3mmol) was added, reaction was allowed to stand overnight at room temperature, the reaction liquid was adjusted to alkali with saturated sodium bicarbonate, extracted with 8% methanol/dichloromethane (v/v) (50m L× 1) and washed with saturated sodium chloride solution (10m L), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was chromatographed on a silica gel column (methanol/dichloromethane (v/v) (-1 to 1: 9) to give the title compound [ [1- [4- [5- [ 2R) -2-hydroxy-2- (2H-oxobutyl) -2-piperidinyl ] -N- (8-hydroxy-2-phenyl) indole-4-phenyl ] carbamate as a solid in a yield of [1- [4- [ 5R ] - ] 3 g.
1HNMR(400MHz，DMSO-d6)8.61(m，1H)，8.14(m，1H)，7.85(m，1H)，7.39(m，8H)，7.06(m，2H)，6.93(m，1H)，6.49(m，1H)，5.05(s，1H)，4.46(s，1H)，4.11(t，2H)，3.72(s，3H)，3.66(s，2H)，3.46(dd，2H)，3.05(d，2H)，2.70(m，2H)，2.61(s，2H)，2.46(d，2H)，2.33(t，2H)，2.13(d，2H)，1.74(d，4H)。
LCMSm/z＝373.8[1/2M+1]。
Example 13: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2-hydroxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxyindoline-1-carboxylate (Compound 13)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1，4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000521
The first step is as follows: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxyindoline-1-carboxylate (13B)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1，4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000522
Dissolving 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5-formyl-6-methoxy-indole-1-carboxylate (3C) (0.200g, 0.368mmol) in dry methanol (6m L), adding dichloromethane (3m L), adding 8- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -5-hydroxy-4H-1, 4-benzoxazin-3-one (13A) (0.125g, 0.368mmol), stirring at room temperature for 1 hour, adding sodium triacetoxyborohydride (0.234g, 1.10mmol), reacting at room temperature for 2 hours after completion of addition, adding dichloromethane (30m L), washing with saturated aqueous sodium bicarbonate solution (10m L× 3), washing with saturated aqueous sodium chloride solution (10m L× 1), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (dichloromethane methanol (v/v) ═ 1-piperidinyl ] ethyl 5-formyl-6-methoxy-indole-1-carboxylate (3C) (0.200g, 0.368mmol), obtaining title compound (2- [ (2R-phenyl-methoxy-2-piperidinyl ] -2-indole-1-carboxylate (0.19g, 13H-dihydro-2-1-ethyl-2-phenyl-1-one (13%).
1HNMR(400MHz，CDCl3)8.09(d，1H)，7.57(s，1H)，7.50-7.46(m，2H)，7.44-7.33(m，4H)，7.21(dd，1H)，7.15-7.10(m，1H)，7.06-7.03(s，1H)，6.77(d，1H)，6.59(s，1H)，6.17(d，1H)，5.16-5.10(m，1H)，4.78-4.70(m，1H)，4.52-4.38(m，2H)，4.36-4.28(m，2H)，4.06-3.89(m，3H)，3.83(s，3H)，3.13-2.90(m，4H)，2.84-2.68(m，4H)，2.44-2.34(m，2H)，1.96-1.92(m，2H)，1.76-1.66(m，2H)，0.85(s，9H)，0.00(s，3H)，-0.10(s，3H)。
LCMSm/z＝433.7[M/2+1]。
The second step is that: 2- [4- [ (2-Phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2-hydroxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxyindoline-1-carboxylate (Compound 13)
2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1，4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate
Figure GPA0000231962000000531
Dissolving 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxyindoline-1-carboxylate (13B) (0.19g, 0.22mmol) in dichloromethane (3m L), adding triethylamine trihydrofluoride (0.71g, 4.4mmol), heating to 30 ℃ after completion of addition, reacting for 6 hours, adding dichloromethane (20m L), adjusting pH to 9 with saturated aqueous sodium bicarbonate solution, separating, extracting with dichloromethane (20m L× 3), combining organic layers, washing with saturated aqueous sodium chloride (10m L× 1), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying with silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1: 0: 7), to obtain the title compound 2- [4- [ (2-piperidinyl) amino ] ethyl ] -6-methoxyindoline-1-carboxylate (13 g, 4H-phenyl-piperidinyl) -2- [ 4-phenyl ] amino ] ethyl ] -6-methoxyindoline-1-carboxylate (13H, yield: 8).
1HNMR(400MHz，CD3OD)7.44(d，2H)，7.34-7.19(m，7H)，7.19-7.12(m，2H)，6.93(s，1H)，6.79(d，1H)，6.41(d，1H)，4.95-4.91(m，1H)，4.56-4.47(m，1H)，4.34(s，2H)，4.28-4.20(m，2H)，3.94(t，2H)，3.76-3.62(m，5H)，2.95(t，2H)，2.78-2.70(m，2H)，2.70-2.60(m，5H)，2.32-2.28(m，2H)，1.80-1.72(s，3H)，1.58-1.50(s，4H)。
LCMSm/z＝376.7[M/2+1]。
Example 14: [1- [3- [6- [ [ [ (2R) -2-hydroxy- (4-hydroxy-2-oxo-3H-1, 3-benzothiazol-7-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 14)
[1-[3-[6-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1，3-benzothiazol-7-yl)ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000541
The first step is as follows: [1- [3- [6- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- [4- [ tert-butyl (dimethyl) silyl ] oxy-2-oxo-3H-1, 3-benzothiazol-7-yl ] ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (14A)
[1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2-oxo-3H-1，3-benzothiazol-7-yl]ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000542
[1- [3- (6-formyl-7-methoxy-3, 4-dihydro-2H-quinolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (4F) (0.550g, 1.02mmol) was dissolved in methanol (10m L), 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2) (0.600g, 1.32mmol) was added, anhydrous zinc chloride (0.554g, 4.06mmol) was added, reaction was carried out at 55 ℃ for 1 hour, sodium cyanoborohydride (0.191g, 3.05mmol) was added, reaction was carried out at 55 ℃ for 2 hour, dichloromethane (50m L) and water (20m L) were added to the reaction solution, extraction of the aqueous phase with dichloromethane (30m L× 1) was carried out, the organic phase was combined with sodium sulfate, the organic phase was dried, the filtrate was filtered under reduced pressure, and the title compound was concentrated under reduced pressure to give [1- [ 3H ] -7- [ 3-phenyl ] N- [ 3H-oxo-piperidinyl ] carbamate (intermediate 2-1H-1, 1H-phenyl) as a yellow solid (intermediate 2-oxo-phenyl).
LCMS m/z＝490.9[M/2+1]。
The second step is that: [1- [3- [6- [ [ [ (2R) -2-hydroxy- (4-hydroxy-2-oxo-3H-1, 3-benzothiazol-7-yl) ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 14)
[1-[3-[6-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1，3-benzothiazol-7-yl)ethyl]amino]methyl]-7-methoxy-3，4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000551
[1- [3- [6- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- [4- [ tert-butyl (dimethyl) silyl ] oxy-2-oxo-3H-1, 3-benzothiazol-7-yl ] ethyl ] amino ] methyl ] -7-methoxy-3, 4-dihydro-2H-quinolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (14A) (1.0g, 1.0mmol) was dissolved in tetrahydrofuran (5m L), triethylamine trihydrofluoride (1.6g, 10mmol) was added and reacted at room temperature for 24 hours, dichloromethane (20m L) was added to the reaction solution, a saturated sodium bicarbonate solution was added to adjust pH to around 8, extraction was performed, the aqueous phase was extracted with dichloromethane (20m L×), the organic phases were combined, the organic phase was washed with a saturated brine (20m L×), anhydrous drying was performed, sodium sulfate was filtered, the filtrate was concentrated, the residue was prepared by liquid phase preparative separation (column preparative) under reduced pressure (column preparative conditions: 3-4% aqueous phase, 3-dihydroxy-3-phenyl-ethyl ] carbamate (0% strength) and the title compound was obtained as a white solid.
1H NMR(400MHz，CD3OD)7.57(s，1H)，7.49-7.27(m，9H)，7.20(s，1H)，7.00(d，1H)，6.78(d，1H)，5.02-4.88(m，2H)，4.28(dd，2H)，3.91(s，3H)，3.87-3.73(m，2H)，3.72-3.44(s，4H)，3.17(s，4H)，3.11-3.04(m，2H)，2.77(t，2H)，2.25-1.73(m，6H)。
19F NMR(376MHz，CD3OD)-76.93。
LCMS m/z＝376.7[M/2+1]。
Example 15: [1- [3- [7- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 15)
[1-[3-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-2，3-dihydro-1，4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate；2，2，2-trifluoroacetic acid
Figure GPA0000231962000000561
The first step is as follows: 6-methoxy-4H-1, 4-benzoxazine-3-one (15B)
6-methoxy-4H-1，4-benzoxazin-3-one
Figure GPA0000231962000000562
2-amino-4-methoxy-phenol (15A) (8.5g, 61.1mmol) was dissolved in acetonitrile (100m L), chloroacetyl chloride (8.28g, 73.3mmol) was added at 0 deg.C, followed by potassium carbonate (22g, 159mmol), and the mixture was stirred at reflux for 3 hours at elevated temperature, ethyl acetate (200m L) and water (150m L) were added to the reaction mixture, extraction was performed, the aqueous phase was extracted with ethyl acetate (100m L× 1), the organic phases were combined, the organic phase was dried with saturated brine (200m L× 2), anhydrous sodium sulfate was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-4H-1, 4-benzoxazin-3-one (15B) as a brown solid (9.8g, 90% yield).
11H NMR(400MHz，CDCl3)8.86(s，1H)，6.89(d，1H)，6.51(dd，1H)，6.41(d，1H)，4.56(s，2H)，3.76(s，3H)。
LCMS m/z＝180.2[M+1]。
The second step is that: 6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15C)
6-methoxy-3，4-dihydro-2H-1，4-benzoxazine
Figure GPA0000231962000000571
6-methoxy-4H-1, 4-benzoxazine-3-one (15B) (9.8g, 55mmol) was dissolved in tetrahydrofuran (100m L) under nitrogen, lithium aluminum hydride (1.1g, 71mmol) was added at 0 deg.C, reacted at 60 deg.C for 3 hours, cooled to 0 deg.C, and quenched with water carefully, ethyl acetate (200m L) was added, celite was filtered, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15C) as a brown oil (6.0g, 66% yield).
1H NMR(400MHz，CDCl3)6.68(d，1H)，6.21(dd，1H)，6.16(d，1H)，4.18(dd，2H)，3.71(s，3H)，3.39(dd，2H)。
LCMS m/z＝166.2[M+1]。
The third step: 7-bromo-6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15D)
7-bromo-6-methoxy-3，4-dihydro-2H-1，4-benzoxazine
Figure GPA0000231962000000572
6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15C) (5.5g, 33mmol) was dissolved in ethyl acetate (50m L), 1, 3-dibromo-5, 5-dimethylhydantoin (4.88g, 17mmol) was added at 0 ℃, and reacted at 0 ℃ for 2 hours.15% potassium carbonate solution (100m L) was added to the reaction solution, followed by stirring well, ethyl acetate (50m L) was added, extraction, drying of the organic phase with anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 0: 1 to 1: 9) to give the title compound 7-bromo-6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15D) as a brown oil (1.6g, 20% yield).
LCMS m/z＝244.1[M+1]。
The fourth step: 6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15E)
6-methoxy-3，4-dihydro-2H-1，4-benzoxazine-7-carbaldehyde
Figure GPA0000231962000000573
Dissolving 7-bromo-6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15D) (1.6g, 6.6mmol) in tetrahydrofuran (30M L), adding 2M isopropyl magnesium chloride in tetrahydrofuran (3.6M L, 7.2mmol) at-10 ℃, heating to 0 ℃ for 1 hour, -25 ℃ and adding 2.5M N-butyl lithium in N-hexane (13M L, 33mmol), reacting at 10 ℃ for 30 minutes, -10 ℃ and adding N, N-dimethylformamide (4.8g, 66mmol), gradually heating to room temperature for 0.5 hour, adding 5g citric acid (5.0g) to water (50M L), pouring the reaction solution into it, adding ethyl acetate (50M L), extracting the aqueous phase with ethyl acetate (50M L× 1), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating the residue with silica gel column (1 v/v), purifying the title compound with ethyl dihydrobenzoxazine (1-4H-2H-4-15 mg) to obtain yellow benzoxazine compound (1-4H-15H).
1H NMR(400MHz，CDCl3)10.13(s，1H)，7.25(s，1H)，6.06(s，1H)，4.20-4.12(m，2H)，3.80(s，3H)，3.55-3.37(m，2H)。
LCMS m/z＝194.1[M+1]。
The fifth step: 6-methoxy-4-prop-2-enoyl-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15F)
6-methoxy-4-prop-2-enoyl-2，3-chhydro-1，4-benzoxazine-7-carbaldehyde
Figure GPA0000231962000000581
6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15E) (0.42g, 2.2mmol) was dissolved in ethyl acetate (30m L), triethylamine (1.6g, 16mmol) was added, nitrogen was protected, acrylic acid (0.39, 5.4mmol) was added dropwise, the mixture was raised to 40 ℃ and 1-propylphosphoric anhydride (1.7, 5.4mmol) was added dropwise, the reaction was reacted at 80 ℃ for 4 hours, ethyl acetate (20m L) and water (20m L) were added to the reaction solution, the organic phase was extracted, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-4-prop-2-enoyl-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15F), a yellow solid (0.54g, 100% yield).
1H NMR(400MHz，CDCl3)10.34(s，1H)，7.39(s，1H)，7.08(s，1H)，6.74(dd，1H)，6.52(dd，1H)，5.88(dd，1H)，4.35-4.21(m，2H)，4.04-3.93(m，2H)，3.85(s，3H)。
LCMS m/z＝248.1[M+1]。
And a sixth step: [1- [3- (7-formyl-6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl) -3-oxo-propyl ] 4-piperidinyl ] N- (2-phenylphenyl) carbamate (15G)
[1-[3-(7-formyl-6-methoxy-2，3-dihydro-1，4-benzoxazin-4-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000582
6-methoxy-4-prop-2-enoyl-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15F) (0.540G, 2.18mmol) was dissolved in 2-methyltetrahydrofuran (10m L), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (0.647G, 2.18mmol) was added, triethylamine (0.442G, 4.37mmol) was added, microwave reaction was performed at 100 ℃ for 1 hour, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1: 1 to 1: 0, methanol: dichloromethane (v/v) ═ 3: 97) to give the title compound [1- [3- (7-formyl-6-methoxy-2, 3-dihydro-1, 4-benzoxazin-yl) -3-oxo-propyl ] 4-piperidinyl ] N- (2-phenyl) carbamate (15G) in a yellow solid yield (0.48%).
1H NMR(400MHz，CDCl3)10.34(s，1H)，8.08(d，1H)，7.52-7.33(m，8H)，7.22(dd，1H)，7.16-7.10(m，1H)，6.59(s，1H)，4.76(s，1H)，4.31-4.21(m，2H)，3.91(dd，2H)，3.88(s，3H)，2.87(s，4H)，2.74(s，2H)，2.40(s，2H)，1.97(s，2H)，1.73(s，2H)。
LCMS m/z＝544.3[M+1]。
The seventh step: [1- [3- [7- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (15H)
[1-[3-[7-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-2，3-dihydro-1，4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000591
[1- [3- (7-formyl-6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl) -3-oxo-propyl ] 4-piperidinyl ] N- (2-phenylphenyl) carbamate (15G) (0.300G, 0.552mmol) was dissolved in methanol (10m L), and (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.222G, 0.662mmol) was added, (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) was added, (R) -anhydrous zinc chloride (0.301G, 2.21mmol) was added, reaction was carried out at 55 ℃ for 1 hour, (R) -cyanoborohydride (0.104G, 1.66mmol) was added, reaction was carried out at 55 ℃ for 2 hours, dichloromethane (30m L) and saturated aqueous sodium bicarbonate solution (20m L) was added to the extraction aqueous phase, dichloromethane (30m L× 1) was combined, the organic phases were dried over sodium sulfate, the filtrate was filtered, the filtrate was concentrated under reduced pressure to give the title compound [1- [ 3-methoxy-4-phenyl ] -4-piperidinyl ] N- (2H ] -1H ] -4-phenyl ] carbamate (1H) -6-phenyl) as a yellow solid, yield.
LCMS m/z＝431.8[M/2+1]。
Eighth step: [1- [3- [7- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 15)
[1-[3-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-2，3-dihydro-1，4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate2，2，2-trifluoroacetic acid
Figure GPA0000231962000000601
Dissolving [1- [3- [7- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (15H) (0.450g, 0.522mmol) in tetrahydrofuran (5m L), adding triethylamine trihydrofluoride (0.841g, 5.22mmol), reacting at room temperature for 24 hours, adding a solution of methanol/dichloromethane (v/v ═ 1/10, 50m L) to the reaction solution, adjusting pH to about 8 by adding a saturated sodium bicarbonate solution, extracting the aqueous phase with methanol/dichloromethane (v ═ 1/10, 20m L×), combining the organic phases, drying the organic phases with a saturated brine (20m L×), preparing a filtrate, purifying the title compound by column chromatography, purifying the aqueous phase with a column under reduced pressure to obtain a white liquid phase [ (3- [7 ═ N-phenyl ] ethyl ] carbamate (0.7 ═ 2-phenyl) and (7 ═ 2-phenyl) to obtain a-phenyl) solid, purifying the title compound (0.5-phenyl-4-phenyl) under reduced pressure, 3-propyl-4-phenyl-piperidine-4-phenyl) yield, and the title compound.
1H NMR(400MHz，CD3OD)8.07(s，2H)，7.55(s，1H)，7.48-7.22(m，9H)，7.03(d，1H)，6.88(s，1H)，6.58(d，1H)，5.40(dd，1H)，4.91(s，1H)，4.34-4.09(m，4H)，3.91(s，2H)，3.77(s，3H)，3.72-3.45(m 4H)，3.28-3.04(m，6H)，2.25-1.70(m，4H)。
19F NMR(376MHz，CD3OD)-75.44.
LCMS m/z＝374.8[M/2+1]。
Example 16: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (Compound 16)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000602
The first step is as follows: 4-hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (16B)
tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate
Figure GPA0000231962000000611
N-tert-Butoxycarbonyl-4-piperidone (16A) (4g, 20mmol) was dissolved in anhydrous tetrahydrofuran (20M L), cooled to 0 deg.C, 1.0M solution of methylmagnesium bromide in tetrahydrofuran (40M L) was added dropwise, allowed to react at room temperature for 2 hours, cooled to 0 deg.C, then saturated ammonium chloride solution was slowly added, ethyl acetate (200M L) and water (200M L) were added, extracted, the organic phase was washed with saturated sodium chloride solution (200M L× 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound tert-butyl 4-hydroxy-4-methyl-piperidine-1 carboxylate (16B) as a pale yellow oil (4.0g, 92.5% yield).
1H NMR(400MHz，CDCl3)3.87(t，2H)，3.71(dd，2H)，3.21(m，4H)，1.53(m，3H)，1.49(s，9H)。
LCMS m/z＝238.1[M+23]。
The second step is that: 4-methyl-4- [ (2-phenylphenyl) carbamoyloxy ] piperidine-1-carboxylic acid tert-butyl ester (16C)
tert-butyl 4-methyl-4-[(2-phenylphenyl)carbamoyloxy]piperidine-1-carboxylate
Figure GPA0000231962000000612
O-phenylamine (3.4g, 20mmol) and triphosgene (3.0g, 10mmol) were dissolved in anhydrous toluene (50m L), warmed to 110 ℃ for 3 hours, concentrated, then tetrahydrofuran (50m L) was added, tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate (16B) (3.5g, 16mmol) and triethylamine (4.0g, 40mmol) were warmed to reflux for 3 hours the reaction liquid was cooled to room temperature, ethyl acetate (100m L) and sodium chloride solution (120m L) were added, the separated layers were extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound tert-butyl 4-methyl-4- [ (2-phenylphenyl) carbamoyloxy ] piperidine-1-carboxylate (16C), yellow (6.6g, 100% oily yield).
LCMS m/z＝433.3[M+23]。
The third step: (4-methyl-4-piperidine) N- (2-phenylphenyl) carbamate (16D)
(4-methyl-4-piperidyl)N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000613
Tert-butyl 4-methyl-4- [ (2-phenylphenyl) carbamoyloxy ] piperidine-1-carboxylate (16C) (6.6g, 16mmol) was dissolved in dichloromethane (40m L), trifluoroacetic acid (18g, 160mmol) was added, the reaction was carried out at room temperature for 5 hours, the temperature was cooled to 0 ℃, pH was adjusted to more than 7 with a saturated sodium bicarbonate solution, dichloromethane (50m L) and water (50m L) were added, the layers were separated by extraction, the organic phase was washed with a saturated sodium chloride solution (50m L× 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0: 1 to 1: 9) to give the title compound (4-methyl-4-piperidine) N- (2-phenylphenyl) carbamate (16D) as a yellow oil (0.77g, 15% yield).
1H NMR(400MHz，CDCl3)7.97(s，1H)，7.51(dd，2H)，7.42(m，1H)，7.36(m，3H)，7.24(m，1H)，7.16(td，1H)，6.59(s，1H)，3.20(d，2H)，3.02(m，2H)，2.45(d，2H)，1.88(td，2H)，1.56(m，3H)。
LCMS m/z＝311.2[M+1]。
The fourth step: [1- [3- (5-formyl-6-methoxyindolin-1-yl) -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16E)
[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000621
(4-methyl-4-piperidine) N- (2-phenylphenyl) carbamate (16D) (0.77g, 2.5mmol) and 6-methoxy-1-propene-2-acyl-indoline-5-carbaldehyde (intermediate 1) (0.57g, 2.5mmol) were dissolved in 2-methyltetrahydrofuran (20m L), triethylamine (0.50g, 5.0mmol) was added, the mixture was placed in a microwave reactor and heated to 100 ℃ to react for 1 hour, the reaction liquid was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0: 1 to 1: 9) to give the title compound [1- [3- (5-formyl-6-methoxyindolin-1-yl) -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16E), a pale yellow solid (0.77g, 57% yield).
1H NMR(400MHz，CDCl3)10.32(s，1H)，8.00(m，2H)，7.65(s，1H)，7.51(t，2H)，7.39(m，4H)，7.23(d，1H)，7.16(t，1H)，6.54(s，1H)，4.13(t，2H)，3.92(s，3H)，3.16(t，2H)，2.87(s，6H)，2.44(d，4H)，1.85(s，2H)，1.57(s，3H)。
LCMS m/z＝542.2[M+1]。
The fifth step: [1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16F)
[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000631
[1- [3- (5-formyl-6-methoxyindolin-1-yl) -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16E) (0.25g, 0.46mmol) and (R) -5- (2-amino-1- ((tert-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.10g, 0.30mmol) were dissolved in a methanol/dichloromethane (v/v ═ 1: 1, 10m L) solution, after 1 hour of reaction at room temperature, sodium triacetoxyborohydride (0.2g, 0.9mmol) was added, reaction was continued for 2 hours, dichloromethane (50m L) and water (50m L) were added to the reaction solution, the layers were extracted, the organic phase was washed with a saturated sodium chloride solution (50m L× 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/dichloromethane (v) ═ 1 ═ 2-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenyl) carbamate (1H) -8-hydroxyquinolin-2 (1H) -one (1H) solution, the title compound was obtained in a yield [ (-6H) solution, and the title compound (3 g-phenyl) was purified.
LCMS m/z＝430.8[M/2+1]。
And a sixth step: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (Compound 16)
[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure GPA0000231962000000632
[1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16F) (0.11g, 0.13mmol) was dissolved in tetrahydrofuran (5m L), triethylamine trihydrofluoride (0.10g, 0.65mmol) was added, the reaction was left overnight at room temperature, the reaction solution was filtered, the filter cake was dissolved with 8% (v/v) methanol/dichloromethane solution (50m L), then saturated aqueous sodium bicarbonate was added to adjust the pH to basic, the layers were extracted, the organic phase was washed with saturated sodium chloride solution (50m L× 1), anhydrous sodium sulfate was dried, the filtrate was filtered, and concentrated under reduced pressure to give the title compound- [ [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-1-oxo-1-yl) quinoline-1-yl ] methyl-4-phenyl ] carbamate (0.11g, 3-phenyl) yellow solid yield.
1H NMR(400MHz，DMSO-d6)7.26(d，1H)，6.93(s，1H)，6.47(m，10H)，6.27(d，1H)，6.10(m，2H)，5.64(d，1H)，4.32(t，1H)，3.26(t，2H)，3.01(d，2H)，2.85(s，3H)，2.21(t，2H)，2.09(d，2H)，1.98(t，2H)，1.86(m，4H)，1.53(d，2H)，1.30(m，2H)，0.77(t，2H)，0.55(d，3H)。
LCMS m/z＝373.7[M/2+1]。
Biological test example
Test example 1: inhibitory Activity on human muscarinic M3 receptor
CHO cells (PerkinElmer) stably expressing human muscarinic receptor 3(hM3) and apo-Aequorin were cultured in Ham' S F12 medium (Invitrogen12500-062) containing 10% Fetal Bovine Serum (FBS) (Gibico 10099-141), 400. mu.g/m L G418(sigma G5013) and 250. mu.g/m L Zeocin (Invitrogen ant-zn-5p) at 37 ℃ with 5% CO2Culturing under the condition to achieve 90-100% fusion. Washing with PBS/5mM EDTA to separate cells, centrifuging, collecting, resuspending and counting the cells in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-6cells/m L. Add 15ml of cell suspension to a 50m L centrifuge tube, add Coelenterazine-h (promega S2011) to a final concentration of 5. mu.M, wrap with tinfoil to protect from light, incubate for 4 hours at 20 ℃ on a rotary shaker, dilute the cells with 0.1% BSA/phenol-free Red Ham' S F12 medium to a final concentration of 5.0 × 105cells/m L, cells were placed on a rotary shaker at low rotation speed and incubated at room temperature for at least 1 hour the inhibitors of the examples were formulated in DMSO as 10mM stock, 0.1% BSA/phenol red free Ham's F12 medium gradient dilution (log (M): 7, -8, -9, -10, -11), 96-well plates were added at 50 μ L per well 50 μ L cell suspension (25000 cells/well) was added per well and incubated at room temperature for 15 minutes the 96-well plates were placed in a microplate reader (Perkin Elmer, Envision), acetylcholine chloride (SigmaA6625) solution was added at 112.92nM (hM3) by a microplate reader, luminescence was recorded for 20 seconds, IC was calculated and analyzed using origin7.550. Inhibitory Activity of the Compounds of the invention at human muscarinic receptors the IC determined by the above assay50The values are given in table 1 below.
Table 1 results of the inhibitory activity of the test compounds on human muscarinic M3 receptor
Figure GPA0000231962000000641
And (4) conclusion: the compound has obvious inhibitory activity on human muscarinic M3 receptor.
Test example 2 agonistic Activity on human adrenergic β 2 receptor
Agonist activity of the compounds of the examples on human adrenergic receptors was determined by L ANCE Ultra cAMP Assay.
CHO cells (PerkinElmer) stably expressing human adrenergic receptor (h β 2) were cultured in MEM-alpha medium (Invitrogen 12561-056) containing 10% Fetal Bovine Serum (FBS) (Gibico 10099-141) and 250. mu.g/m L Zeocin (InvivGen ant-zn-5p) at 37 ℃ and 5% CO2Culturing under conditions to achieve 90-100% fusion and detecting the agonism of cAMP in the examples using L ANCEULTra cAMP Assay kit (PerkinElmer TRF0263) cells were separated with PBS/5mM EDTA, harvested by centrifugation, resuspended in Stimulation Buffer (1 XHBSS, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH7.4), and adjusted to 6X105cells/ml. the inhibitors of the examples were prepared as 10mM stock solutions in DMSO, diluted in a Ststimulation Buffer gradient and added to 384 well plates at 5. mu.l per well.5. mu. L cell suspension (3000 cells/well) was added per well, and after incubation for 30 minutes at room temperature, 5. mu.l 4 x Eu-cAMP tracer working solution was added per well, followed by 5. mu.l 4 x Ulight-anti-cAMP working solution per well and incubation for 1 hour at room temperature.TR-FRET was detected in 384 well plates using a microplate reader (Perkin Elmer, Envision), and EC was calculated and analyzed using origin7.550. The agonistic activity of the compound of the present invention on human adrenergic receptors was determined by the above experiment, and the EC was measured50The values are shown in Table 2:
table 2 results of testing the agonist activity of the compounds at the human adrenergic β 2 receptor
Figure GPA0000231962000000651
The conclusion is that the compound of the invention has obvious activation activity on β 2 adrenergic receptors.

Claims (14)

1. A compound shown in a general formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure FDA0002291100780000011
wherein:
a is selected from 0, 1, 2, 3, 4 or 5;
b is selected from 0, 1, 2, 3 or 4;
R1each independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano, -OR1a、-C(O)OR1b、-SR1c、-S(O)R1d、-S(O)2R1eor-NR1fR1g；
R2Each independently selected from F, Cl, Br, I, CF3、C1-4Alkyl, cyano, -OR1a、-C(O)OR1b、-SR1c、-S(O)R1d、-S(O)2R1eor-NR1fR1g；
R1a、R1b、R1c、R1d、R1e、R1fAnd R1gEach independently selected from H or C1-4An alkyl group;
alternatively, R1f、R1gA 5-to 6-membered heterocyclic ring formed with the nitrogen atom to which it is attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S;
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group;
c is selected from 0, 1, 2, 3 or 4;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, C1-4Alkyl or C1-4An alkoxy group;
R4is selected from C1-6Alkylene radical, C2-6Alkenylene or C2-6Alkynylene, said alkylene, alkenylene or alkynylene being optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4Substituted by a substituent of alkylene;
x is selected from-C (O) -or-OC (O) -;
d is selected from 0, 1, 2 or 3;
R5selected from F, Cl, Br, I, OH、NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl, -C (O) O-C1-4Alkyl, -OC (O) -C1-4Alkyl or-C (O) NH2The alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, NH2and-C (O) NH2Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-；
Ya、YbEach independently selected from H or C1-4An alkyl group; or Ya、YbTogether with the carbon atom to which they are attached form a 3-to 6-membered carbocyclic ring;
n is 0, 1 or 2;
e is selected from 0, 1, 2, 3 or 4;
R6selected from F, Cl, Br, I, cyano, C1-4Alkyl or C1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CH2F、CHF2、CF3Or a cyano group;
alternatively, two R6May form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R7is selected from C1-6Alkylene optionally further substituted with 0 to 5 substituents selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4An alkylene group;
alternatively, two R7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R8、R9each independently selected from H or C1-4An alkyl group;
Figure FDA0002291100780000021
represents a group capable of binding to β -adrenoceptor;
b is selected from
Figure FDA0002291100780000022
Figure FDA0002291100780000023
Wherein Q is selected from-CH ═ CH-, -CH2CH2-, -O-, -S-or-CH2O-。
2. A compound according to claim 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from 0, 1 or 2;
b is selected from 0, 1 or 2;
R1each independently selected from F, Cl, Br, I, CF3Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio;
R2each independently selected from preferably F, Cl, Br, I, CF3Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio;
c is selected from 0, 1 or 2;
R3each independently selected from F, Cl, Br, I, CF3OH, cyano, methyl, ethyl, methoxy or ethoxy,
R4is selected from C1-6Alkylene optionally further substituted by 0 to 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl radical, C1-4Alkoxy, phenyl or phenyl-C1-4Substituted by a substituent of alkylene;
R5selected from F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C2-4Alkynyl, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl or-C (O) O-C1-4Alkyl, said alkyl, alkoxy, cycloalkyl and NH2Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent;
R7is selected from C1-4Alkylene optionally further substituted with 0 to 5 substituents selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy or phenyl;
alternatively, two R7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy.
3. A compound according to claim 2 or a stereoisomer, or a pharmaceutically acceptable salt thereof,
b is selected from
Figure FDA0002291100780000031
Figure FDA0002291100780000032
W is-O-or-N (W)a)-；
WaSelected from H, methyl or ethyl;
R4selected from methylene, ethylene, propylene or butylene, said methylene, ethylene, propylene or butylene being optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R5selected from F, Cl, Br, CH2F、CHF2、NH2Cyano, nitro, OCH2F、OCHF2、OCF3Methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyloxy, ethynyl, propynyl, -S (O)2CH3、-C(O)CH3、-C(O)OCH3or-C (O) OCH2CH3；
Y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-；
Ya、YbEach independently selected from H, methyl or ethyl; or Ya、YbMay each independently form a 3-to 6-membered carbocyclic ring with the carbon atom to which it is attached;
e is 0, 1 or 2;
R6selected from F, Cl, Br, cyano, methyl, ethyl, methoxy or ethoxy;
R7selected from methylene, ethylene, propylene or butylene, said methylene, ethylene, propylene or butylene being optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R8、R9each independently selected from H, methyl or ethyl.
4. The compound according to claim 1, wherein the compound is selected from compounds represented by the general formula (II):
Figure FDA0002291100780000041
w is-O-or-N (W)a)-；
WaIs selected from H or C1-4An alkyl group;
R4is selected from C1-4Alkylene optionally further substituted by 0 to 5 groups selected from F, Cl, Br, I, OH, cyano, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
x is selected from-C (O) -or-OC (O) -;
R5selected from F, Cl, Br, I, OH, NH2Carboxy, cyano, nitro, C1-4Alkyl radical, C1-4Alkoxy, -OC3-6Cycloalkyl radical, C1-4Alkylthio, -S (O) -C1-4Alkyl, -S (O)2-C1-4Alkyl, -C (O) -C1-4Alkyl or-C (O) O-C1-4Alkyl, said alkyl, alkoxy, cycloalkyl and NH2Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF3、C1-4Alkyl radical, C1-4Alkoxy or-C (O) -C1-4Alkyl is substituted by a substituent;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-；
Ya、YbEach independently selected from H or C1-4An alkyl group; or Ya、YbTogether with the carbon atom to which they are attached form a 3-to 6-membered carbocyclic ring;
R6selected from F, Cl, Br, cyano, C1-4Alkyl or C1-4An alkoxy group;
alternatively, two R6May form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R7is selected from C1-4Alkylene optionally further substituted with 0 to 5 substituents selected from R7aSubstituted with the substituent(s);
R7aselected from F, Cl, Br, I, cyano, OH, C1-4Alkyl radical, C1-4Alkoxy or phenyl;
alternatively, two R7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R8、R9each independently selected from H or C1-4An alkyl group;
b is selected from
Figure FDA0002291100780000051
Figure FDA0002291100780000052
Q is selected from-CH ═ CH-, -CH2CH2-, O, S or-CH2O-。
5. The compound according to claim 4, or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
w is-O-or-N (W)a)-；
WaSelected from H, methyl or ethyl;
c is 0;
R4selected from methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
x is selected from-C (O) -or-OC (O) -;
R5selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;
y is selected from-CYaYb-、-NYa-, -O-, -S-, -S (O) -or-S (O)2-；
Ya、YbEach independently selected from H, methyl or ethyl; or Ya、YbMay each independently form a 3-to 6-membered carbocyclic ring with the carbon atom to which it is attached;
e is 0, 1 or 2;
R6selected from F, Cl, Br, cyano, methyl, ethyl, methoxy or ethoxy;
R7selected from methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R8、R9each independently selected from H, methyl or ethyl;
b is selected from
Figure FDA0002291100780000061
Figure FDA0002291100780000062
6. A compound or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:
Figure FDA0002291100780000071
Figure FDA0002291100780000081
7. a compound according to any one of claims 1 to 5, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, maleate, hydroxymaleate, glutarate, fumarate, tartrate, succinate, benzenesulfonate, p-toluenesulfonate, benzoate, salicylate, phenylacetate, cinnamate, lactate, malonate, pivalate, malate, mandelate, oxalate, gallate, gluconate, laurate, palmitate, pectate, picrate, citrate, methanesulfonate, hexanesulfonate, saccharinate, or a combination thereof.
8. The compound of claim 6, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the salt is selected from the group consisting of a hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, maleate, hydroxymaleate, glutarate, fumarate, tartrate, succinate, benzenesulfonate, p-toluenesulfonate, benzoate, salicylate, phenylacetate, cinnamate, lactate, malonate, pivalate, malate, mandelate, oxalate, gallate, gluconate, laurate, palmitate, pectate, picrate, citrate, methanesulfonate, hexanesulfonate, saccharinate, or a combination thereof.
9. A compound according to any one of claims 1 to 5, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the salt is selected from the hydrochloride, sulfate, trifluoroacetate, fumarate, tartrate, succinate, oxalate, methanesulfonate, saccharinate or a combination thereof.
10. The compound of claim 6, or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein the salt is selected from the group consisting of a hydrochloride salt, a sulfate salt, a trifluoroacetate salt, a fumarate salt, a tartrate salt, a succinate salt, an oxalate salt, a mesylate salt, a saccharinate salt, or a combination thereof.
11. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 10, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; the composition may further comprise one or more additional therapeutic agents.
12. The pharmaceutical composition of claim 11, wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a β -adrenergic receptor agonist.
13. Use of a compound according to any one of claims 1 to 10 or a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 or 12, for the manufacture of a medicament for the treatment of an obstructive airways disease.
14. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 or 12, in the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
CN201680003424.0A 2015-03-27 2016-03-25 Heterocyclic derivative, preparation method and medical application thereof Expired - Fee Related CN107074816B (en)

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