CN109575022B - Compound and application thereof - Google Patents

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CN109575022B
CN109575022B CN201811586632.5A CN201811586632A CN109575022B CN 109575022 B CN109575022 B CN 109575022B CN 201811586632 A CN201811586632 A CN 201811586632A CN 109575022 B CN109575022 B CN 109575022B
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azabicyclo
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heteroaryl
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CN109575022A (en
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黄浩喜
刘冠锋
任俊峰
易守兵
陈垌珲
何权鸿
吴鲜财
李英富
苏忠海
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Chengdu Beite Pharmaceutical Co Ltd
Scinnohub Pharmaceutical Co Ltd
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CHENGDU BRILLIANT PHARMACEUTICAL CO LTD
Chengdu Highbred Pharmaceutical Co ltd
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The present invention provides novel compounds having certain inhibitory activity against the oxidoreductase indoleamine 2, 3-dioxygenase (IDO) or their use in the treatment of diseases associated therewith, including cancer and immune-related diseases.

Description

Compound and application thereof
The present invention is a subsequent application of the prior application having application number CN201711423562.7, and the present invention claims priority from the prior application, and the contents described in the prior application can be used as a supplement to the present invention.
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a compound and application thereof.
Background
IDO full name indoleamine 2,3 dioxygenase is a heme-containing monomer enzyme, is also a rate-limiting enzyme of human tryptophan metabolism, and is also a key immunosuppressive enzyme for regulating tumor immune response, like PD-1. IDO is in a silent state in most tissues, but is expressed continuously in many tumor cells, so that tryptophan levels in cells are reduced, a series of metabolites are produced, and system functions such as immune nerves are further influenced.
ID0 acts to break down tryptophan to kynurenine, depletion of tryptophan and its metabolites lead to strong suppression of the immune response, IDO1 acts as a novel immune checkpoint and induces T cell immune tolerance by three aspects: one is to arrest the proliferation of tryptophan-dependent T cells by degrading tryptophan to create a tryptophan-deficient microenvironment; secondly, some metabolites of tryptophan have the function of inhibiting T cells. And thirdly, the expansion of regulatory T cells is induced, and the up-regulation of the regulatory T cells is an important obstacle of tumor immunotherapy. In addition, hyperactive IDO also promotes direct inhibition and resistance by dendritic cells to T cells that elicit an antigenic response and T cell recognition of the antigen. Thus, both in tumor tissues that overexpress IDO and in tumor draining lymph nodes, an immunosuppressive tumor microenvironment is created, such that T cells are inhibited as soon as they enter the tumor tissue.
Tumor cells usually over-express IDO, inducing the immune system of the human body to develop immune tolerance to IDO, thereby escaping from the surveillance and killing of the immune system of the human body. At present, over-expression of ID O is found in a plurality of tumor cells such as prostatic cancer, pancreatic cancer, breast cancer, gastric cancer and the like.
BMS-986205 is a novel IDO inhibitor and is in the second stage of clinical research, but the pharmacodynamic and pharmacokinetic properties of the inhibitor still have great room for improvement.
Disclosure of Invention
The present invention relates to compounds that modulate IDO, as well as corresponding uses, combinations, methods of making, and the like.
Specifically, the invention provides a novel compound, which has a structure shown in a formula (I) or an isomer, a pharmaceutically acceptable hydrate, a pharmaceutically acceptable solvate or a salt thereof:
Figure BDA0001918189360000011
wherein Ar is3Comprises the following steps:
Figure BDA0001918189360000012
or Ar3Comprises the following steps: a substituted or unsubstituted monocyclic, bicyclic or tricyclic heteroaryl;
when Ar is3Is composed of
Figure BDA0001918189360000013
When R is1、R2、R3、R4Independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, amido, ether, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 haloalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl; or R1、R2Carbon bound thereto together forming C ═ Z1Wherein Z is1Selected from O, S; or R3Or/and R4Z attached thereto together
Figure BDA0001918189360000014
Wherein Z2Or Z2' are each independently selected from absent, O or S, but both are not absent at the same time; ar (Ar)1Is substituted or unsubstituted monocyclic aryl or heteroaryl, bicyclic or tricyclic fused ring aryl or fused ring heteroaryl, wherein the substituent is selected from nitro, hydroxyl, amino, mercapto, halogen, cyano, ester, carboxyl, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-to 6-membered aryl or heteroaryl;
when Ar is3When the aryl is substituted or unsubstituted monocyclic, bicyclic or tricyclic heteroaryl, the substituent is selected from nitro, hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, amido, substituted or unsubstitutedSubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-to 6-membered aryl or heteroaryl;
B. y is independently selected from carbon or nitrogen;
d is selected from a bond, oxygen, -CH2-, -CO-, -CH (OH) -, nitrogen, sulfur, sulfone, or sulfoxide;
x is selected from a bond, O, -NH-;
z is selected from C or S;
q is selected from CR9R10、N-R11O, S, S (O) or S (O)2；R9、R10、R11Independently selected from H, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl;
m、n1、n2independently 0, 1, 2,3 or 4;
Ar2the structure of (d) can be represented as:
Figure BDA0001918189360000021
wherein A is1、A2、A3、A4Each independently selected from C, N or O;
R5、R6、R7、R8independently selected from H, nitro, hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, amido, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 heteroalkyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C3-10 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic or tricyclic aryl, and substituted or unsubstituted monocyclic or bicyclic or tricyclic heteroaryl; or R5、R6The atoms connected with the aryl or heteroaryl group form substituted or unsubstituted C5-12 cycloalkyl or heterocycloalkyl, 5-6-membered aryl or heteroaryl; or R6、R7The atoms connected with the aryl form substituted or unsubstituted C5-12 cycloalkyl or heterocycloalkyl, 5-6 membered aryl orA heteroaryl group; or R7、R8The atoms connected with the aryl or heteroaryl group form substituted or unsubstituted C5-12 cycloalkyl or heterocycloalkyl, 5-6-membered aryl or heteroaryl.
“Ar1In the substituted or unsubstituted monocyclic aryl or heteroaryl group ", the substituent on the substituted monocyclic aryl or heteroaryl group may be bonded to the monocyclic aryl or heteroaryl group to form a bicyclic or tricyclic structure.
Further, the compound has a structure shown in formula (II) or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000022
wherein Ar is3Comprises the following steps:
Figure BDA0001918189360000023
or Ar3Comprises the following steps: substituted or unsubstituted monocyclic, bicyclic or tricyclic heteroaryl:
when Ar is3Is composed of
Figure BDA0001918189360000024
When R is1、R2、R3、R4Independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, amido, ether, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C1-6 haloalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl; or R1、R2Carbon bound thereto together forming C ═ Z1Wherein Z is1Selected from O, S; or R3Or/and R4Z attached thereto together
Figure BDA0001918189360000031
Wherein Z2Or Z2' are each independently selected from none, O orS, but the two can not be simultaneously absent; ar (Ar)1Is substituted or unsubstituted monocyclic aryl or heteroaryl, bicyclic or tricyclic fused ring aryl or fused ring heteroaryl, wherein the substituent is selected from nitro, hydroxyl, amino, mercapto, halogen, cyano, ester, carboxyl, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-to 6-membered aryl or heteroaryl;
when Ar is3When the aryl is a substituted or unsubstituted monocyclic, bicyclic or tricyclic heteroaryl, the substituent is selected from nitro, hydroxyl, amino, mercapto, halogen, cyano, ester, carboxyl, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl;
b is selected from carbon or nitrogen;
d is selected from a bond, oxygen, -CH2-, -CO-, -CH (OH) -, nitrogen, sulfur, sulfone, or sulfoxide;
z is selected from C or S;
q is selected from CR9R10、N-R11O, S, S (O) or S (O)2；R9、R10、R11Independently selected from H, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl;
m、n1、n2independently 0, 1, 2,3 or 4;
A1、A2、A3、A4each independently selected from C, N or O;
R5、R6、R7、R8independently selected from H, nitro, hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, amido, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 heteroalkyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstitutedC3-10 heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic or tricyclic aryl, substituted or unsubstituted monocyclic or bicyclic or tricyclic heteroaryl; or R5、R6The atoms connected with the aryl or heteroaryl group form substituted or unsubstituted C5-12 cycloalkyl or heterocycloalkyl, 5-6-membered aryl or heteroaryl; or R6、R7The atoms connected with the aryl or heteroaryl group form substituted or unsubstituted C5-12 cycloalkyl or heterocycloalkyl, 5-6-membered aryl or heteroaryl; or R7、R8The atoms connected with the aryl or heteroaryl group form substituted or unsubstituted C5-12 cycloalkyl or heterocycloalkyl, 5-6-membered aryl or heteroaryl.
In the above compounds, when m is not 0, (Q)mThe naphthenic base connected with the heterocyclic ring forms a bridge ring structure; namely (Q)mWhen both ends of (a) are connected with different carbon atoms on the cycloalkyl, a bridged ring is formed; (Q)mThe basic requirement for forming bridge ring can be met.
The term "one bond" as used herein means only one bond, and may be understood as "none".
Further, m is not 0.
Further, a compound of the structure shown in formula (I):
Ar3comprises the following steps:
Figure BDA0001918189360000032
or Ar3Comprises the following steps: a substituted or unsubstituted monocyclic, bicyclic or tricyclic heteroaryl;
when Ar is3Is composed of
Figure BDA0001918189360000033
When R is1、R2、R3、R4Independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and arylmethyl containing carboxylic acid structure; or R1、R2Carbon attached thereto together form C ═ O; or R3、R4Carbon attached thereto together form C ═ O;
Ar1is a substituted or unsubstituted monocyclic aryl or heteroaryl group, whereinThe substituent is selected from hydroxyl, amino, halogen, cyano, ester group, amido, phenoxy, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl;
when Ar is3When the aryl is a substituted or unsubstituted monocyclic, bicyclic or tricyclic heteroaryl, the substituent is selected from hydroxyl, amino, halogen, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-to 6-membered aryl or heteroaryl;
B. y is independently selected from C or N;
d is selected from a bond, O and-CH2-, -CO-, -CH (OH) -, -NH-, S, sulfone;
q is selected from CH2、-CH2NR22CH2-，R22Selected from H, C1-6 alkyl;
m、n1、n2independently 0, 1, 2,3, 4;
A1、A2、A3、A4each independently selected from C, N, and A1、A2、A3、A4At least one is selected from N;
R5、R6、R7、R8are respectively and independently selected from H, substituted or unsubstituted C1-10 alkyl; or R5、R6The atoms connected with the aryl or the heteroaryl form substituted or unsubstituted 5-to 6-membered aryl or heteroaryl; or R6、R7The atoms connected with the aryl or the heteroaryl form substituted or unsubstituted 5-to 6-membered aryl or heteroaryl; or R7、R8The atoms connected with the aryl or the heteroaryl form substituted or unsubstituted 5-to 6-membered aryl or heteroaryl.
Further, Ar2Selected from the group consisting of substituted or unsubstituted heteroaryl groups as follows:
Figure BDA0001918189360000041
the substituent is selected from halogen, methyl and methoxy.
Further, it has a structure shown in formula (III) or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000042
further, it has a structure represented by formula (III') or an isomer, a pharmaceutically acceptable hydrate, solvate or salt thereof:
Figure BDA0001918189360000043
in the formula (III'), in the presence of a catalyst,
Figure BDA0001918189360000044
the amidine functional group connected with the amidine functional group forms a substituted or unsubstituted monocyclic heteroaryl, bicyclic or tricyclic fused ring heteroaryl, and the substituent is selected from nitro, hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl.
The amidine functional group refers to the structure:
Figure BDA0001918189360000051
wherein R is1、R2Can be respectively and independently selected from H, C1-6 alkyl or heteroalkyl, in particular C-6 heteroalkyl containing O, N, hydroxyl, halogen, -CH2-O-R19An arylmethyl or heteroarylmethyl group containing a carboxylic acid structure, R19Selected from H or C1-6 alkyl or heteroalkyl.
Further, in the arylmethyl group or the heteroarylmethyl group having a carboxylic acid structure, the carboxylic acid is not directly bonded to the aromatic ring.
Further, said R1、R2Not H at the same time. IntoIn one step, R1、R2Are respectively and independently selected from H, C1-C3 alkyl and-CH2-O-R21，R21Selected from H or C1-3 alkyl, further, R1、R2Are independently selected from H or methyl.
Further, Z in the formula (III)2Is O.
Further, A1、A2、A3、A4Containing at least one heteroatom, i.e. constituting a heteroaryl group.
Further, A1、A2、A3、A4Contains only one heteroatom.
Wherein the heteroatom is selected from N. Further, A1、A2、A4Is C, A3Is N.
Further, R5、R6Independently selected from hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, amido, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 heteroalkyl, or R5、R6The atoms connected with the aryl or the heteroaryl form substituted or unsubstituted 5-to 6-membered aryl or heteroaryl.
Further, R7、R8Independently selected from H, substituted or unsubstituted C1-10 alkyl or substituted or unsubstituted C1-10 heteroalkyl.
In the present invention, the C1-10 alkyl or heteroalkyl group may be further selected from C1-6 lower alkyl or lower heteroalkyl group.
Further, it has a structure represented by formula (IV) or (IV'), or an isomer, a pharmaceutically acceptable hydrate, solvate or salt thereof:
Figure BDA0001918189360000052
R1selected from H, C1-6 alkyl;
R2selected from H, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, aryl containing carboxylic acid structureMethyl and carboxylic acid is not directly connected with aromatic ring, and the substituent is selected from halogen, hydroxyl, nitro, amino, sulfydryl, cyano, ester group and amido;
R3、R4each independently selected from H, C1-6 alkyl;
in the formula (IV'), E is selected from CH or N,
Figure BDA0001918189360000061
the substituted or unsubstituted monocyclic heteroaryl, bicyclic or tricyclic fused ring heteroaryl is selected from amino, halogen, cyano, ester, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl.
Further, in the formulae (IV), (IV'), (IV "):
R1selected from H, methyl;
R2selected from H, F, methyl, -CH2CF3、
Figure BDA0001918189360000062
R1、R2Not H at the same time;
R3selected from H, R4Is selected from methyl;
Ar1selected from substituted or unsubstituted phenyl, pyridyl, 2-thiazolyl, the substituent is selected from hydroxy, amino, halogen, cyano, -CF3、-CF2H、-COOCH3、-CONH2-OPh, methoxy,
Figure BDA0001918189360000063
Or Ar1In the case of phenyl, two adjacent substitution sites on the phenyl group are replaced by
Figure BDA0001918189360000064
Substitution;
Figure BDA0001918189360000065
a substituted or unsubstituted heteroaryl selected from:
Figure BDA0001918189360000066
Figure BDA0001918189360000067
Figure BDA0001918189360000068
the substituents being selected from
Figure BDA0001918189360000069
Figure BDA00019181893600000610
Amino, halogen, cyano, -COOCH3、-CONH24-chlorophenyl group and 4-pyridyl group.
Further, in the formulae (IV), (IV'), (IV "): m is selected from 0, 1, 2 and 3; n is1And n2Not simultaneously 0; further, the air conditioner is provided with a fan,
Figure BDA00019181893600000611
the structure shown is selected from the following structures:
Figure BDA00019181893600000612
Figure BDA00019181893600000613
Figure BDA0001918189360000071
Figure BDA0001918189360000072
further, it has a structure shown in formula (V) or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000073
further, it has a structure shown in formula (V') or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000074
in the above-mentioned result of formula (V) or (V'), R12、R13、R14、R15Independently selected from H, nitro, hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, ether group, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C3-6 heterocycloalkyl.
Further, R12、R13、R14、R15Independently selected from H, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl.
Further, it has a structure shown in formula (VI) or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000075
further, it has a structure shown in formula (VI') or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000081
further, in each of the foregoing compounds, Q is selected from CR9R10、N-R11O or S.
Wherein, R is9、R10、R11Each independently selected from H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl.
Further, (Q)mBoth ends of (a) are in phase C ortho to B on the ring in which B is locatedAnd (4) connecting. Namely, form a bridge ring (Q)mBoth ends of the C are respectively connected with two C adjacent to the B; further, m is selected from 1-3. Of course, the value of m is chosen in relation to the structure of Q. For example, if (Q)mIs selected from-CH2CH2-, Q and m have two combinations, one is that Q is-CH2-, m is 2 and the other is Q is-CH2CH2-, m is 1.
In one embodiment of the present invention, (Q)mIs selected from-CH2-、-CH2CH2-、-CH2CH2CH2-。
Further, n1、n2Independently is 1.
In the present invention, when n is1、n2Independently is 1, (Q)mWhen both ends of (B) are bonded to two C's in the ortho-position to B, respectively, in each of the above-mentioned compounds
Figure BDA0001918189360000082
This construction is further that
Figure BDA0001918189360000083
Further, it has a structure shown in formula (VII) or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000084
further, it has a structure shown in formula (VII') or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000091
further, Ar in the formula (VII)1Is a substituted or unsubstituted monocyclic aryl or heteroaryl group. Further, it may be selected from 5-to 6-membered aryl or heteroaryl.
Further, the air conditioner is provided with a fan,
Figure BDA0001918189360000092
the amidine functional group attached thereto constitutes the following structure:
Figure BDA0001918189360000093
wherein A is5Selected from C or N;
R17、R18independently selected from H, nitro, hydroxyl, amino, sulfydryl, halogen, cyano, ester group, carboxyl, amido, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl;
or, R17、R18And atoms connected with the aryl or heteroaryl form a substituted or unsubstituted 5-to 10-membered monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl, fused ring aryl or heteroaryl.
Further, R17、R18Each independently selected from substituted or unsubstituted 5-to 6-membered aryl or heteroaryl; or, R17、R18And atoms connected with the aryl or the heteroaryl form substituted or unsubstituted 5-6-membered aryl or heteroaryl.
Still further, the heteroaryl group contains N or/and O; further, the heteroaryl group contains N.
Further, in the present invention,
Figure BDA0001918189360000094
the amidine functional group attached thereto constitutes the following structure:
Figure BDA0001918189360000095
wherein R is20Selected from halogen, hydroxy, cyano; n5 is selected from 0-4.
Further, R20Selected from halogens。
Further, n5Is 1.
Wherein R is17、R18Wherein the substituents are independently selected from halogen, amino, ether, oxygen, amide, C1-6 alkyl or C1-6 heteroalkyl.
Further, it has a structure shown in formula (VIII) or an isomer, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:
Figure BDA0001918189360000101
wherein R is16Selected from the group consisting of no, nitro, hydroxyl, amino, mercapto, halogen, cyano, ether, ester, carboxyl, amide, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 heterocycloalkyl, substituted or unsubstituted 5-to 6-membered aryl or heteroaryl;
n3is 0, 1, 2,3, 4 or 5.
Further, R16Selected from halogen, cyano, acylamino, hydroxyl, nitro, ether, C1-6 alkyl or heteroalkyl, and halogen-substituted C1-6 alkyl.
Further, n3Is 1 or 2.
Further, n is3Is 1, R16Taking amino para position.
Further, D in the compounds of the present invention is selected from O and-CH2-, -CO-, -CH (OH) -; still further, D is selected from O.
Further, B in the compounds of the present invention is selected from N.
Further, in the compounds of the present invention, R12、R14、R15Is selected from H.
The research of the invention finds that the compound with the following structure has better effect:
Figure BDA0001918189360000102
alternatively, compounds of the following structure also have good results:
Figure BDA0001918189360000103
in the present invention, further, R1Selected from H, C1-C3 alkyl.
Further, R13Selected from halogens.
Further, R16Selected from halogen, hydroxy, cyano; further, R16Selected from halogen and cyano.
Further, (Q) m is selected from- (CH)2)n4-, in which n41 to 3; further, n is4Is 2 or 3.
Wherein when n is42, then (Q)mIs namely-CH2CH2-。
Wherein when n is4Not 3, then, (Q)mIs namely-CH2CH2CH2-。
Further, R20May be selected from halogen, hydroxy, cyano; further, R20Selected from halogens.
In one embodiment of the present invention, there is provided a compound having the structure shown below or an isomer, a pharmaceutically acceptable hydrate, solvate or salt thereof:
Figure BDA0001918189360000111
Figure BDA0001918189360000121
Figure BDA0001918189360000131
Figure BDA0001918189360000141
in one embodiment of the invention, D, (Q)m、R1Having the following chiral conformation
Figure BDA0001918189360000142
In one embodiment of the invention, D, (Q)m、R1Having the following chiral conformation
Figure BDA0001918189360000143
In one embodiment of the invention, D, (Q)m、R1Having the following chiral conformation
Figure BDA0001918189360000144
In one embodiment of the invention, D, (Q)m、R1Having the following chiral conformation
Figure BDA0001918189360000145
The invention also provides a medicinal composition, wherein the active ingredient of the medicinal composition is selected from one or the combination of more than two of the compounds or the stereoisomer, the solvate, the hydrate, the pharmaceutically acceptable salt or the eutectic crystal thereof.
The pharmaceutical composition may include, in addition to the aforementioned compounds, at least one additional therapeutic agent. The additional therapeutic agent may be selected from immunomodulators, cancer chemotherapeutics, anti-infectives, and the like. Such cancer chemotherapeutic agents include, but are not limited to, alkylating agents (e.g., nitrogen mustards), nucleoside analogs (e.g., gemcitabine), nitrosoureas (e.g., carmustine), platinum-based drugs (e.g., cisplatin), DN a blockers (e.g., bleomycin), antimetabolites (folic acid antagonists such as methotrexate, pyrimidine antagonists such as fluorouracil, purine antagonists such as pentostatin, etc.), tubulin-interacting agents (e.g., vincristine, docetaxel, etc.), hormones, and the like.
The invention also provides application of the compound or a stereoisomer, a solvate, a hydrate, a pharmaceutically acceptable salt or a eutectic crystal thereof in preparing an indoleamine 2, 3-dioxygenase (IDO) inhibitor or a tryptophan-2, 3-dioxygenase (TDO) inhibitor.
Wherein the inhibitor is used for the treatment of at least one of the following diseases: cancer, autoimmune disorders, viral infections, depression, AIDS, myelodysplastic syndrome, anxiety, cataracts.
Further, the cancer is selected from breast cancer, cervical cancer, colon cancer, rectal cancer, liver cancer, stomach cancer, rectal cancer, ovarian cancer, pancreatic cancer, testicular cancer, bladder cancer, solid tumor, mesothelial intimal cancer, melanoma, myeloma, non-small cell lung cancer, leukemia, lymphoma, melanoma, esophageal cancer, connective tissue cancer, mesothelial cancer, prostate cancer, bone cancer, and renal cancer.
Wherein the use of the compound or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof for the manufacture of a medicament for the treatment of a disease resulting in the overexpression of indoleamine 2, 3-dioxygenase (IDO) or/and tryptophan-2, 3-dioxygenase (TDO).
Wherein, the compound or the stereoisomer, the solvate, the hydrate, the pharmaceutically acceptable salt or the eutectic crystal thereof is used for preparing the medicine for treating diseases caused by the overexpression of indoleamine 2, 3-dioxygenase (IDO) or/and tryptophan-2, 3-dioxygenase (TDO).
The use of such inhibitors requires administering to the individual an effective amount of the aforementioned compounds. The effective amount is sufficient to effectively reverse or stop IDP-or TDO-mediated diseases.
The present invention also provides a method of treating a disease mediated at least in part by IDO or TDO, comprising administering to a subject in need thereof an effective amount of the aforementioned compound.
Such diseases include, but are not limited to, cancer, autoimmune disorders, viral infections, depression, aids, myelodysplastic syndrome, anxiety, cataracts, and the like.
The pharmaceutical composition containing the compound of the invention or the stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof can contain pharmaceutically acceptable auxiliary materials.
As used herein, "pharmaceutically acceptable" is meant to include any material that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the host to which it is administered.
The pharmaceutically acceptable auxiliary materials are general names of all the additional materials except the main medicine in the medicine, and the auxiliary materials have the following properties: (1) no toxic effect on human body and few side effects; (2) the chemical property is stable and is not easily influenced by temperature, pH, storage time and the like; (3) has no incompatibility with the main drug, and does not influence the curative effect and quality inspection of the main drug; (4) does not interact with the packaging material. The auxiliary materials in the invention include, but are not limited to, a filler (diluent), a lubricant (glidant or anti-adhesion agent), a dispersing agent, a wetting agent, an adhesive, a regulator, a solubilizer, an antioxidant, a bacteriostatic agent, an emulsifier, a disintegrating agent and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises superfine silica gel powder, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; the disintegrating agent comprises starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone or microcrystalline cellulose, etc.; the wetting agent comprises sodium lauryl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulfite, sodium pyrosulfite, dibutylbenzoic acid, etc.; the bacteriostatic agent comprises 0.5% of phenol, 0.3% of cresol, 0.5% of chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate, and buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate); the emulsifier comprises polysorbate-80, sorbitan fatty acid, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc.
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. The acid base is a generalized Lewis acid base. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils, or mixtures of such materials, and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention can likewise be used in injectable preparations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to impression tablet or machine pressing tablet prepared by aseptic operation method of medicine, and is dissolved with water for injection for subcutaneous or intramuscular injection when in use).
Wherein the powder for injection contains at least an excipient in addition to the above compound. The excipients, which are components intentionally added to a drug in the present invention, should not have pharmacological properties in the amounts used, however, the excipients may aid in the processing, dissolution or dissolution of the drug, delivery by a targeted route of administration, or stability.
"alkyl" refers to an aliphatic hydrocarbon group and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain or branched chain alkyl.
The C1-n used in the invention comprises C1-2 and C1-3. n is an integer greater than one. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
"alkenyl" means that the first two atoms of an alkyl group form a double bond, i.e., alkenyl is-c (R) ═ c (R) -R, where R means the remainder of the alkenyl group and each R may be the same or different. Alkenyl groups may be optionally substituted, including but not limited to-CH ═ CH2、-C(C H3)＝CH2、-CH＝CHCH3、-C(CH3)＝CHCH3、-CH＝CHCH2-and so on.
"alkynyl" means that the two atoms from which the alkyl group originates form a triple bond, i.e., the alkynyl group is-C.ident.C-R, where R means the remainder of the alkynyl group and each R may be the same or different. Alkynyl groups may be optionally substituted and include, but are not limited to, -c.ident.CH, -C.ident.C-CH3、 -C≡C-CH2CH3- -C.ident.C- -and- -C.ident.C- -CH2-and so on.
"amide" is a chemical structure having the formula-C (O) NHR or-NHC (O) R, wherein R is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
"ester" means having the formula-COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
In the 5-or 6-membered ring of the invention with
Figure BDA0001918189360000171
This structure indicates that the 5-or 6-membered ring is aromatic.
"Ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aryls (e.g., aryl or heteroaryl), nonaromatic (e.g., cycloalkyl or heterocycloalkyl). The rings may be optionally substituted, and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings.
"element" means the number of skeleton atoms constituting a ring. Typical 5-membered rings may include cyclopentyl, pyrrole, imidazole, thiazole, furan, thiophene, and the like; typical 6-membered rings include cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like. Wherein, the skeleton atom contains the ring of heteroatom, namely is the heterocycle; aryl consisting of a heterocycle is heteroaryl; the nonaromatic group consisting of a heterocycle is a heterocycloalkyl group.
"heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from O, S, N, Si or P, but are not limited thereto.
"heteroalkyl" refers to an alkyl group containing a heteroatom, including, but not limited to O, S, N, P, and the like; alkoxy, thioalkyl, aminoalkyl and the like are all intended to be heteroalkyl.
The term "arylmethyl group or heteroarylmethyl group" in arylmethyl group or heteroarylmethyl group having carboxylic acid structure means that H in methyl group is substituted with aryl group or heteroaryl group, and the structural formula thereof can be represented by
Figure BDA0001918189360000172
Wherein Ar is aryl or heteroaryl.
Typical heterocycloalkyl groups include, but are not limited to:
Figure BDA0001918189360000173
typical heteroaryl or heteroaryl groups include, but are not limited to:
Figure BDA0001918189360000174
a "fused ring" is a polycyclic organic compound formed by two or more carbocyclic or heterocyclic rings sharing a ring edge. Typical common fused ring aromatic compounds are naphthalene, anthracene, phenanthrene, and the like; examples of the fused ring heterocyclic compound include indole, quinoline, purine and the like.
"aryl" means a planar ring having a delocalized pi-electron system and containing 4n +2 pi electrons, where n is an integer. An aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. Aromatic groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, indenyl, and the like.
"cycloalkyl" refers to a monocyclic or polycyclic group containing approximately carbon and hydrogen, which may be saturated or unsaturated. Typical cycloalkyl structures include, but are not limited to:
Figure BDA0001918189360000181
"halogen" or "halo" includes fluorine, chlorine, bromine or iodine. "haloalkyl" means an alkyl group wherein at least one hydrogen is replaced by a halogen atom.
The amino, ester and amide groups described herein may be unsubstituted amino, ester and amide groups, or substituted amino, ester and amide groups.
Hereinbefore, except where already indicated, "substituted" in said "substituted or unsubstituted" means that the mentioned groups may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, carboxy, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, alkylThio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, and the like, with additional groups including, but not limited to, the following: F. cl, Br, I, methyl, ethyl, propyl, hydroxy, mercapto, nitro, -CN,
Figure BDA0001918189360000182
Figure BDA0001918189360000183
"inhibitor" refers to a substance that decreases the activity of an enzyme.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The foregoing aspects of the present invention are explained in further detail below with reference to specific embodiments. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
To further illustrate the present invention, the compounds of the present invention which are useful as oxidoreductase indoleamine 2, 3-dioxygenase (IDO) inhibitors, as well as methods for their preparation and use, are described in detail in the examples which follow.
The following abbreviations have the meanings indicated below:
DMF means N, N-dimethylformamide;
DMSO represents dimethyl sulfoxide;
DME represents ethylene glycol dimethyl ether;
NIS represents N-iodosuccinimide;
DCM represents dichloromethane;
DCE represents 1, 2-dichloroethane;
TEA represents triethylamine;
THF represents tetrahydrofuran;
TFA represents trifluoroacetic acid;
TFAA represents trifluoroacetic anhydride;
EA represents ethyl acetate;
PE represents petroleum ether;
MeOH for methanol;
MeCN represents acetonitrile;
HBTU represents benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate;
TLC means thin layer chromatography;
KOAc represents potassium acetate;
Pd(dppf)Cl2represents [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride;
T3p represents propylphosphoric acid tricyclic anhydride;
STAB represents sodium triacetoxyborohydride;
LiHMDS represents lithium hexamethyldisilazide;
t-BuOK represents potassium tert-butoxide;
LDA represents lithium diisopropylamide
CDI represents carbonyldiimidazole;
PDC denotes pyridine dichromate;
m-CPBA represents m-chloroperoxybenzoic acid;
DIAD represents diisopropyl azodicarboxylate;
PPh3represents triphenylphosphine;
synthesis method
The patent also provides a synthetic method of the compound, and the synthetic method of the invention is mainly prepared from a preparation method reported in a chemical literature or a relevant synthesis method by taking a commercially available chemical reagent as a starting material.
Method 1
Figure BDA0001918189360000191
Method 1 gives a synthesis of a series of compounds as shown in formula 5.
Wherein, in step 1, when D is N, a halo-hetero compound may be usedAryl radicals, starting from e.g. t-BuOK, NaH, Cs2C O3An isobase is a deprotonating reagent, and an intermediate 2 is obtained through substitution reaction in a solvent such as THF, MeCN, DMF and the like; or taking the reports in related documents as references, using halogenated heteroaryl as raw material, and carrying out Buchwald coupling, Ullmann coupling and other methods. When D is O, in addition to the method, heteroaryl phenol can be used as a raw material to obtain an intermediate 2 through a mitsunobu reaction; when D is a bond, E in the starting material is C ═ O, deprotonated with e.g. LDA, LiHMDS and reacted with N-phenylbis (trifluoromethanesulfonyl) imide or similar reagents to give triflate, which is then reduced by Miyaura boronation, Suzuki coupling, hydrogenation to give intermediate 2, again as reported in the relevant literature.
Wherein, in step 2, when B is N, this step is a deprotection step, and different methods correspond to different protecting groups, such as (without limitation): boc is removed by hydrochloric acid, trifluoroacetic acid and other acidic conditions, acyl is removed by potassium carbonate, potassium hydroxide, sodium hydroxide and other alkaline conditions, Cbz is removed by catalytic hydrogenation; when B is C ═ O, the protecting group ketal (cyclohexal ketal, cyclopentyl ketal, methyl/ethyl ketal, etc.) is removed by acidic conditions such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.
Wherein, in step 3, when B is N, the alpha-substituted/unsubstituted alpha-haloacetate analog is used as a starting material, such as t-BuOK, NaH, Cs2CO3Bases such as triethylamine, diisopropylethylamine and the like are deprotonating reagents and are completed through substitution reaction in solvents such as DCM, TH F, MeCN, DMF and the like; when B is C ═ O, alpha substituted/unsubstituted witting reagent is used as raw material to obtain acrylate compound, and double bond is hydrogenated and reduced to obtain the product.
Wherein, the step 4 is a conventional hydrolysis reaction, and the corresponding acid (trifluoroacetic acid, etc.)/alkali (sodium hydroxide, etc.) hydrolysis method can be selected according to different esters.
Wherein, in step 5, a conventional condensing agent such as T can be used3P, HBTU and the like, and the substituted/unsubstituted heteroaromatic amine is used as a raw material; or preparing acid chloride from acid such as thionyl chloride, and synthesizing the series of compounds under alkaline conditions such as triethylamine5。
Method 2
Figure BDA0001918189360000201
Method 2 the corresponding compounds were prepared by analogous procedures as in method 1, in a different synthetic sequence.
Wherein, when D is N, D is used as a raw material with a protecting group, and a deprotection step is added between the step 3 and the step four, and the method for removing the protecting group is consistent with the corresponding step in the method 1.
Method 3
Figure BDA0001918189360000202
Method 3 gives a general synthetic approach to the imidazo substituted/unsubstituted aryl or heteroaryl fused ring structures.
Wherein, substituted/non-substituted aryl or heteroaryl diamine can be used as raw material, compound 9 can be obtained by the procedure consistent with the relevant steps in the method 1, and then the series of compound 10 can be synthesized by cyclization in acidic atmosphere such as hydrochloric acid, acetic acid, sulfuric acid and the like; compound 10 can also be obtained directly from intermediate 4 and substituted/unsubstituted aryl or heteroaryl diamine in the next step in the presence of a halophosphorous reagent.
Method 4
Figure BDA0001918189360000211
Method 4 gives a general synthetic method for substituted/unsubstituted imidazole structures.
Wherein step 1 may be carried out by a procedure consistent with the relevant steps in method 1; step two, under the participation of different ammonia sources (acetamide, formamide, ammonium acetate, ammonium formate, ammonia various solutions and the like), R18The ortho carbonyl forms imine and then reacts with Z to form ring to obtain the series of compounds 12.
Example 1: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000212
step 1: preparation of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate
TEA (30.4g, 300.0mmol) was added dropwise to a mixed solution of nortropinone hydrochloride (16.2g, 100.0mmol) and DCM (300mL) at room temperature, controlling the system temperature below 30 ℃. After the addition, the (Boc) was added to the reaction system in portions2O (24.0g, 110.0mmol), and after the addition was complete, the reaction was stirred at room temperature for 6 h. TLC showed that the starting material was reacted completely, and the reaction solution was treated once with 1M diluted hydrochloric acid and saturated Na2CO3The aqueous solution and the saturated brine were washed with water. Anhydrous Na for organic phase2SO4Drying and concentration under reduced pressure gave 22.1g (yield: 98%) of the title compound as a colorless oil.
Step 2: preparation of 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
At 0-10 deg.c, adding 3-oxo-8-azabicyclo [3.2.1]]To a solution of tert-butyl octane-8-carboxylate (22.0g, 97.6 mmol) in 300mL MeOH was added NaBH in portions4(7.4g, 195.3mmol) and TLC indicated completion of the reaction after the reaction mixture was stirred at 0-10 ℃ for 30 min. The reaction was poured into 1000mL of saturated aqueous ammonium chloride solution, extracted with EA (500 mL. times.3), and the organic phase was washed twice with saturated brine and anhydrous Na2SO4After sufficiently drying, concentration under reduced pressure gave 22.5g (yield: 101%) of the objective compound as a colorless oil.
And step 3: preparation of tert-butyl 3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate
Under the protection of nitrogen and at room temperature, 3-hydroxy-8-azabicyclo [3.2.1] is reacted]To a 300mL DMSO solution of tert-butyl octane-8-carboxylate (22.0g, 96.8 mmol) was added t-BuOK (16.3g, 145.2mmol) in portions. Cooling the reaction system to 10-25 ℃, and then adding 4-chloro-6 in batches-fluoroquinoline (26.4g, 145.2mmol), temperature controlled not higher than 25 ℃. After the addition was complete the reaction mixture was stirred at 25 ℃ overnight and TLC showed the reaction was complete. The reaction was poured into 1000mL of water and extracted with EA (500 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After sufficiently drying, concentration was performed under reduced pressure, and the residue was purified by column chromatography (PE: EA: 3: 1) to obtain 25.3g (yield: 69%) of the objective compound as a pale yellow solid.
And 4, step 4: preparation of 4- ((8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline dihydrochloride
A solution of tert-butyl 3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (25.0g, 67.1mmol) in 300mL 4M HCl/EA was stirred at room temperature for 6 h. TLC showed that the reaction was directly concentrated under reduced pressure after completion of the reaction to give 23.5 g (yield: 101%) of the objective compound as a pale yellow solid.
And 5: preparation of ethyl 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) propionate
At room temperature to 4- ((8-azabicyclo [ 3.2.1)]To a 300mL solution of MeCN of oct-3-yl) oxy) -6-fluoroquinoline dihydrochloride (23.0g, 66.6mmol) was added TEA (27.0g, 266.5mmol) with the system temperature controlled below 30 ℃. Ethyl 2-bromoacetate (14.5g, 79.9mmol) was added. The reaction mixture was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 1000mL of water and extracted with EA (500 mL. times.3). The organic phase was washed twice with saturated brine and anhydrous Na2SO4After sufficiently drying, concentration was performed under reduced pressure, and the residue was purified by column chromatography (PE: EA: 1) to obtain 20.0g (yield: 81%) of the objective compound as a pale yellow solid.
Step 6: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) propionic acid
To (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [ 3.2.1)]Octane-8-yl) propionic acid ethyl ester (20.0g, 53.7mmol) in 400mL MeOH/H2NaOH (4.3g, 107.4mmol) was added to the O (1/1) solution, the temperature of the system was controlled to be lower than 30 ℃ and the reaction system was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using concentrated hydrochloric acid, and concentrating under reduced pressure.To the resulting residue was added 200mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined and concentrated under reduced pressure to give 19.0g (yield: 103% containing a small amount of inorganic salt) of the objective compound as a pale yellow solid.
And 7: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propanamide
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (344mg, 1.0mmol) in 5mL of THF was added pyridine (400mg, 5.0mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 1272mg, 2.0mmol) and 4-chloroaniline (192mg, 1.5 mmol). The reaction mixture was stirred at 70 ℃ overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the residue by column chromatography (DCM: MeOH ═ 20: 1) gave 260mg (yield: 57%) of the title compound as a white solid.
1H NMR(400MHz，d6-DMSO)δ1.27-1.31(3H，m)，1.82-2.10(7H，m)，2.21-2.41(1H，m)， 3.13-3.21(1H，m)，3.30-3.40(1H，m)，3.47(1H，brs)，4.97-5.00(1H，m)，6.97(0.6H，d，J＝5.2Hz)， 7.23(0.4H，d，J＝5.6Hz)，7.35-7.38(2H，m)，7.63-7.81(4H，m)，7.99-8.05(1H，m)，8.69-8.71(1H， m)，9.84(1H，s).
EM (calculated): 453.2; MS (ESI) M/e (M + H)+：454.2
Example 2: preparation of endo-R-N- (4-chlorophenyl) -2- ((1R, 3R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
The synthesis steps are as follows:
Figure BDA0001918189360000231
note: the synthesis of the three isomers endo-S (example 62), exo-R (example 63) and exo-S (example 64) was carried out in accordance with example 2.
Step 1: preparation of endo-4- (((1R, 3R, 5S) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (3.7g, 10.0mmol) in 50mL of 4M HCl/EA was stirred at room temperature for 6 h. TLC shows that after the reaction is finished, the reaction system is directly decompressed and concentrated, the obtained solid is dissolved in 50mL of water, and the pH value is adjusted to be alkaline by NaOH. The resulting system was extracted with EA (50 mL. times.5), and the organic phase was back-washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by column chromatography (DCM: MeOH: 10: 1) as the exo-product (1.2g, yield: 44% as a pale yellow solid); the lower point was an endo-product (1.4g, yield: 52% as a pale yellow solid).
Step 2: preparation of endo-ethyl-R-2- ((1R, 3R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) propionate
Endo-form-4- (((1R, 3R, 5S) -8-azabicyclo [ 3.2.1) at room temperature]To a solution of oct-3-yl) oxy) -6-fluoroquinoline (544mg, 2.0mmol) and TEA (404mg, 4.0mmol) in 10mL of MeCN was added ethyl (S) -2- ((methylsulfonyl) oxy) propionate (431mg, 2.2 mmol). The reaction was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 40mL of water and extracted with EA (30 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure gave 680mg (yield: 91%) of the title compound as a yellow solid.
And step 3: preparation of endo-R-2- ((1R, 3R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) propionic acid
endo-R-2- ((1R, 3R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]Octane-8-yl) propionic acid ethyl ester (372mg, 1.0mmol) in 10mL MeOH/H2NaOH (160mg, 4.0mmol) was added to the O (1/1) solution, the temperature of the system was controlled to be lower than 30 ℃ and the reaction system was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using concentrated hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 50mL DCM/MeOH (20/1) andstirring for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined, and concentrated under reduced pressure to give 350mg (yield: 102% containing a small amount of inorganic salt) of the objective compound as a pale yellow solid.
And 4, step 4: preparation of endo-R-N- (4-chlorophenyl) -2- ((1R, 3R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
inward-form-R-2- ((1R, 3R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (344mg, 1.0mmol) in 5mL of THF was added pyridine (400mg, 5.0mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 1272mg, 2.0mmol) and 4-chloroaniline (192mg, 1.5 mmol). The reaction mixture was stirred at 70 ℃ overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by column chromatography (DCM: MeOH ═ 20: 1) to give 285mg (yield: 63%) of the objective compound as a white solid.
1H NMR(400MHz，d6-DMSO)δ1.27(3H，d，J＝6.8Hz)，1.89-2.02(6H，m)，2.27-2.30(1H，m)，2.33-2.35(1H，m)，3.13-3.14(1H，m)，3.21(1H，brs)，3.44(1H，brs)，4.97(1H，brs)，6.97(1H，d， J＝5.2Hz)，7.36-7.39(2H，m)，7.67-7.74(4H，m)，8.03(1H，dd，J＝9.2Hz，5.6Hz)，8.70(1H，d，J ＝5.2Hz)，9.84(1H，s).
EM (calculated): 453.2; MS (ESI) M/e (M + H)+：454.2
Example 3: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000241
step 1: preparation of tert-butyl 3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Nitrogen protectionProtected towards 3-amino-8-azabicyclo [3.2.1]]To a 30mL DMSO solution of octane-8-carboxylic acid tert-butyl ester (2.3g, 10.2mmol) and 4-chloro-6-fluoroquinoline (1.8g, 9.9mmol) was added CuI (0.2g, 1.0 mol). After the addition was complete, the reaction mixture was stirred at 100 ℃ for 6h under nitrogen. The reaction was poured into 200mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After sufficiently drying, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA: 1) to give 1.1g (yield: 30%) of the objective compound as a yellow solid.
Step 2: preparation of N- (8-azabicyclo [3.2.1] oct-3-yl) -6-fluoroquinolin-4-amine trihydrochloride
A solution of tert-butyl 3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (1.0g, 2.7mmol) in 20mL 4M HCl/EA was stirred at room temperature for 6 h. TLC showed that after the reaction was completed, the reaction system was directly concentrated under reduced pressure, and the crude product was slurried once with 5mL of EA to give 1.0g (yield: 98%) of the title compound as a yellow solid.
And step 3: preparation of ethyl 2- (3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionate
To N- (8-azabicyclo [3.2.1] at room temperature]To a solution of oct-3-yl) -6-fluoroquinolin-4-amine trihydrochloride (1.0g, 2.6mmol) in 15mL of MeCN was added TEA (1.6g, 15.8mmol) and the temperature of the system was controlled below 30 ℃. Ethyl 2-bromoacetate (0.5g, 2.8mmol) was added. The reaction mixture was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 50mL of water and extracted with EA (30 mL. times.3). The organic phase was washed twice with saturated brine and anhydrous Na2SO4After drying sufficiently, concentration was performed under reduced pressure, and the residue was purified by column chromatography (DCM: EA: 5: 1) to obtain 0.8g (yield: 82%) of the objective compound as a pale yellow solid.
And 4, step 4: preparation of 2- (3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionic acid
To 2- (3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1]Octane-8-yl) propionic acid ethyl ester (371mg, 1.0mmol) in 10mL MeOH/H2Adding NaOH (160mg, 4.0mmol) into O (1/1) solution, controlling the temperature of the system to be lower than 30 ℃, and reacting the systemStir at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using concentrated hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 20mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined and concentrated under reduced pressure to give 350mg (yield: 102%, containing a small amount of inorganic salts) of the objective compound as an off-white solid.
And 5: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] oct-8-yl) propanamide
To 2- (3- ((6-fluoroquinolin-4-yl) amino) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (100mg, 0.3mmol) in 2mL of THF was added pyridine (120mg, 1.5mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 382mg, 0.6mmol) and 4-chloroaniline (64mg, 0.5 mmol). The reaction mixture was stirred at 70 ℃ overnight. TLC showed that after the reaction was complete, the reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the residue by column chromatography (DCM: MeOH 15: 1) gave 47mg (yield: 36%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.25-1.30(3H，m)，1.64-2.08(8H，m)，3.16-3.21(1H，m)， 3.33-3.45(3H，m)，6.08-6.10(0.5H，m)，6.15-6.16(0.5H，m)，6.54(1H，brs)，7.37(2H，d，J＝8.8 Hz)，7.49-7.53(2H，m)，7.73(2H，d，J＝8.8Hz)，8.00-8.09(1H，m)，9.02-9.04(1H，m)，9.86(1H， s).
EM (calculated): 452.2; MS (ESI) M/e (M + H)+：453.2
Example 4: preparation of N- (4-chlorophenyl) -2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) propionamide the synthesis procedure is as follows:
Figure BDA0001918189360000251
step 1: preparation of 8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-one
To a solution of nortropinone hydrochloride (1.6g, 9.9mmol), 4-chloro-6-fluoroquinoline (1.8g, 9.9mmol) and TEA (2.0g, 20.0mmol) in 20mL of DMSO, GuI (0.2g, 1.0mol) was added under nitrogen. After the addition was complete, the reaction mixture was stirred at 100 ℃ for 6h under nitrogen. The reaction was poured into 200mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After sufficiently drying, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA: 2: 1) to give 0.7g (yield: 26%) of the objective compound as a yellow solid.
Step 2: preparation of 8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-ol
At 0-10 ℃, to 8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1 ℃]To a solution of oct-3-one (540mg, 2.0mmol) in 10mL MeOH was added NaBH in portions4(152mg, 4.0mmol) and TLC indicated completion of the reaction after the reaction mixture was stirred at 0-10 ℃ for 30 min. The reaction was poured into 30mL of saturated aqueous ammonium chloride solution, extracted with EA (20 mL. times.3), and the organic phase was washed twice with saturated brine and anhydrous Na2SO4After being sufficiently dried, concentration under reduced pressure gave 500mg (yield: 92%) of the objective compound as a pale yellow oil.
And step 3: preparation of ethyl 2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] octan-3-yl) oxy) propionate
To a mixture of 8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-ol (272mg, 1.0mmol) and t-BuOK (224mg, 2.0mmol) in 5mL of MeCN at room temperature was added ethyl 2-bromoacetate (181mg, 1.0 mmol). The reaction mixture was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction system was directly filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography (PE: EA: 1) to give 240mg (yield: 65%) of the objective compound as an off-white solid.
And 4, step 4: preparation of 2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] octan-3-yl) oxy) propanoic acid
To 2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [ 3.2.1)]Octane-3-yl) oxy) propionic acid ethyl ester (100mg, 0.3mmol) in 5mL MeOH/H2O (1/1) solutionNaOH (43mg, 1.1mmol) was added thereto, the temperature of the system was controlled to be lower than 30 ℃ and the reaction system was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using concentrated hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 10mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined and concentrated under reduced pressure to give 90mg (yield: 98%, containing a small amount of inorganic salts) of the objective compound as an off-white solid.
And 5: preparation of N- (4-chlorophenyl) -2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) propanamide
To 2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] under nitrogen protection]Octane-3-yl) oxy) propionic acid (70mg, 0.2mmol) in 2mL THF was added pyridine (80mg, 1.0mmol), followed by dropwise addition of T in that order at room temperature3P (50% in EA, 254mg, 0.4mmol) and 4-chloroaniline (38mg, 0.3 mmol). The reaction mixture was stirred at 70 ℃ overnight. TLC showed that after the reaction was complete, the reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 20: 1) to obtain 35mg (yield: 38%) of the objective compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.25-1.30(3H，m)，1.58-2.01(8H，m)，3.13-3.23(1H，m)， 3.33-3.45(1H，m)，4.76-5.78(1H，m)，4.96-5.00(1H，m)，6.24(0.6H，d，J＝5.2Hz)，6.31(0.4H，d， J＝5.2Hz)，7.39(2H，d，J＝8.8Hz)，7.44-7.51(2H，m)，7.73(2H，d，J＝8.8Hz)，8.00-8.09(1H，m)， 8.88-8.90(1H，m)，9.90(1H，s).
EM (calculated): 453.2; MS (ESI) M/e (M + H)+：454.2
Example 5: preparation of N- (4-chlorophenyl) -2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-yl) amino) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000271
step 1: preparation of tert-butyl (1- ((4-chlorophenyl) amino) -1-oxoprop-2-yl) carbamate
To a solution of t-butoxycarbonylalanine (189mg, 1.0mmol) in 5mL of THF under nitrogen, TEA (303mg, 3.0mmol), HBTU (569mg, 1.5mmol) and 4-chloroaniline (192mg, 1.5mmol) were added in that order. The reaction mixture was stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (PE: EA: 3: 1) to obtain 230mg (yield: 77%) of the objective compound as a white solid.
Step 2: preparation of 2-amino-N- (4-chlorophenyl) propanamide
A solution of tert-butyl (1- ((4-chlorophenyl) amino) -1-oxoprop-2-yl) carbamate (210mg, 0.7mmol) in 5mL 4M HCl/EA was stirred at room temperature for 6 h. TLC shows that after the reaction is finished, the reaction system is directly decompressed and concentrated, the obtained solid is dissolved in 10mL of water, and the pH value is adjusted to be alkaline by NaOH. The resulting system was extracted with EA (10 mL. times.5), and the organic phase was back-washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure gave 110mg (yield: 79%) of the title compound as a pale yellow oil.
And step 3: preparation of N- (4-chlorophenyl) -2- ((8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-3-yl) amino) propanamide
To 2-amino-N- (4-chlorophenyl) propanamide (100mg, 0.5mmol) and 8- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] at room temperature]To a solution of oct-3-one (135mg, 0.5mmol) in 5mL of DCE was added 0.5mL of acetic acid. The system was stirred at room temperature for 1h and STAB (212mg, 1.0mmol) was added. The reaction mixture was continued to stir at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and the pH was adjusted to basic with NaOH (1M aq). The resulting compound was extracted with DCM (10mL x 3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the residue by chromatography on silica gel (DCM: MeOH ═ 20: 1) gave 95mg (yield: 42%) of the title compound as a white solid。
1H NMR(400MHz，d6-DMSO)δ1.27-1.32(3H，m)，1.58-2.01(7H，m)，2.33-2.38(1H，m)， 3.05-3.07(1H，m)，3.28-3.39(3H，m)，5.44(1H，brs)，6.25-6.33(1H，m)，7.37(2H，d，J＝8.8Hz)， 7.44-7.49(2H，m)，7.71(2H，d，J＝8.8Hz)，8.05-8.09(1H，m)，8.89-8.91(1H，m)，9.65(1H，s).
EM (calculated): 452.2; MS (ESI) M/e (M + H)+：453.2
Example 6: preparation of N- (4-chlorophenyl) -2- (3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide the synthetic procedure was as follows:
Figure BDA0001918189360000281
step 1: preparation of tert-butyl 3- (((trifluoromethyl) sulfonyl) oxy) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate
Under the protection of nitrogen, 3-oxo-8-azabicyclo [3.2.1] is reacted]A solution of tert-butyl octane-8-carboxylate (1.2g, 5.3mmol) in 15mL of THF was cooled to-70 ℃. LDA (1M in THF, 8mL, 8.0mmol) was added dropwise with stirring, and the system temperature was controlled at about-70 ℃. After stirring the system for 1h N-phenylbis (trifluoromethanesulfonyl) imide (1.9g, 5.3mmol) was added in portions. After the addition, the system was allowed to warm naturally with stirring and stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 100mL saturated ammonium chloride solution and extracted with EA (50 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product with a chromatography column (PE: EA 20: 1) gave 1.5g (yield: 79%) of the title compound as a white solid.
Step 2: preparation of tert-butyl 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate
To 3- (((trifluoromethyl) sulfonyl) oxy) -8-azabicyclo [3.2.1] under nitrogen]20m of tert-butyl oct-2-ene-8-carboxylate (714mg, 2.0mmol), pinacol diboron (508mg, 2.0mmol) and KOAc (392mg, 4.0mmol)Adding Pd (dppf) Cl into the L1, 4-dioxane solution2(73mg, 0.1 mmol). The reaction mixture was stirred at 90 ℃ for 6h under nitrogen and TLC showed the reaction was complete. The reaction was poured into 100mL of water and extracted with EA (50 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After sufficiently drying, it was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA: 20: 1) to give 520mg (yield: 78%) of the objective compound as a pale yellow solid.
And step 3: preparation of 3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester
To 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -8-azabicyclo [3.2.1] under nitrogen]Oct-2-ene-8-carboxylic acid tert-butyl ester (500mg, 1.5mmol), 4-chloro-6-fluoroquinoline (270mg, 1.5mmol) and K2CO3(410mg, 3.0mmol) of 10mL of 1, 4-dioxane/water (5/1) was added Pd (dppf) Cl2(73mg, 0.1 mmol). The reaction mixture was stirred at 90 ℃ for 6h under nitrogen and TLC showed the reaction was complete. The reaction was poured into 50mL of water and extracted with EA (20 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After sufficiently drying, it was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA: 10: 1) to give 310mg (yield: 59%) of the objective compound as a pale yellow solid.
And 4, step 4: preparation of 3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-8-carboxylic acid tert-butyl ester
To a solution of tert-butyl 3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (280mg, 0.8mmol) in 10mL MeOH at room temperature was added Pd/C (10%, 50mg), and the reaction mixture was stirred overnight at room temperature under an atmosphere of hydrogen at about two atmospheres. TLC showed that after the reaction was completed, the reaction system was directly filtered, and the filtrate was concentrated under reduced pressure to give 270mg (yield: 96%) of the objective compound as a pale yellow solid.
And 5: preparation of 4- (8-azabicyclo [3.2.1] oct-3-yl) -6-fluoroquinoline dihydrochloride
A solution of tert-butyl 3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] octa-8-carboxylate (250mg, 0.7mmol) in 3mL 4M HCl/EA was stirred at room temperature for 6 h. TLC showed that after the reaction was completed, the reaction was directly concentrated under reduced pressure, and the crude product was slurried with 2mL EA to give 220mg (yield: 95%) of the title compound as a pale yellow solid.
Step 6: preparation of ethyl 2- (3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionate
To 4- (8-azabicyclo [3.2.1] at room temperature]To a solution of oct-3-yl) -6-fluoroquinoline dihydrochloride (200mg, 0.6mmol) and TEA (242mg, 2.4mmol) in 5mL of MeCN was added ethyl 2-bromoacetate (110mg, 0.6 mmol). The reaction was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and slurrying of the crude product with 3mL EA/PE (1/10) afforded 190mg (yield: 88%) of the title compound as a pale yellow solid.
And 7: preparation of 2- (3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl) propionic acid
To 2- (3- (6-fluoroquinolin-4-yl) -8-azabicyclo [ 3.2.1)]Octane-8-yl) propionic acid ethyl ester (180mg, 0.5mmol) in 5mL MeOH/H2NaOH (80mg, 2.0mmol) was added to the O (1/1) solution, and the reaction was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using dilute hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 10mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined and concentrated under reduced pressure to give 160mg (yield: 98%, containing a small amount of inorganic salts) of the objective compound as an off-white solid.
And 8: preparation of N- (4-chlorophenyl) -2- (3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
To 2- (3- (6-fluoroquinolin-4-yl) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (100mg, 0.3mmol) in 3mL of THF was added pyridine (120mg, 1.5mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 318mg, 0.5mmol) and 4-chloroaniline (64mg, 0.5 mmol). The reaction mixture was stirred at 70 ℃ overnight. TLC showed that after the reaction was complete, the reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). Organic phase is saturatedWashing with salt solution, anhydrous Na2SO4After drying, concentration under reduced pressure was carried out, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 20: 1) to give 64mg (yield: 48%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.27-1.33(3H，m)，1.62-2.02(7H，m)，2.34-2.37(1H，m)， 3.19-3.24(2H，m)，3.33-3.42(2H，m)，6.99-7.02(0.7H，m)，7.15-7.18(0.3H，m)，7.35(2H，d，J＝ 8.8Hz)，7.51-7.55(2H，m)，7.71(2H，d，J＝8.8Hz)，8.04-8.08(1H，m)，8.67-8.69(1H，m)，9.84 (1H，s).
EM (calculated): 437.2, respectively; MS (ESI) M/e (M + H)+：438.2
Example 7: preparation of N- (4-chlorophenyl) -2- (3- ((2-methylpyridin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000291
step 1: preparation of ethyl 2- (3-oxo-8-azabicyclo [3.2.1] octan-8-yl) propionate
To a solution of nortropinone hydrochloride (8.1g, 50.0mmol) and TEA (20.0g, 200.0mmol) in 100mL MeCN at room temperature was added ethyl 2-bromoacetate (10.0g, 55.0 mmol). The reaction was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 500mL of water and extracted with EA (200 mL. times.3). The organic phase was washed twice with saturated brine and anhydrous Na2SO4After drying, concentration under reduced pressure gave 9.8g (yield: 87%) of the title compound as a pale yellow oil.
Step 2: preparation of 2- (3-oxo-8-azabicyclo [3.2.1] octan-8-yl) propionic acid
To 2- (3-oxo-8-azabicyclo [3.2.1]]Octane-8-yl) propionic acid ethyl ester (9.0g, 40.0mmol) in 150mL MeOH/H2NaOH (6.4g, 160.0mmol) was added to the O (1/1) solution, and the reaction was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using dilute hydrochloric acid, and concentrating under reduced pressure. To the residue was added 100mL DCM/MeOH(20/1) and stirring for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined and concentrated under reduced pressure to give 7.5g (yield: 95% containing a small amount of inorganic salt) of the objective compound as an off-white solid.
And step 3: preparation of N- (4-chlorophenyl) -2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) propanamide
To 2- (3-oxo-8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl propionic acid (5.9g, 30.0mmol) in 100mL of THF was added pyridine (12.0g, 150.0mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 31.8g, 50.0mmol) and 4-chloroaniline (6.4g, 50.0 mmol). The reaction mixture was stirred at 70 ℃ overnight. TLC showed that after the reaction was complete, the reaction was poured into 300mL of water and extracted with EA (100 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 50: 1) to give 6.5g (yield: 71%) of the title compound as a pale yellow solid.
And 4, step 4: preparation of N- (4-chlorophenyl) -2- (3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl) propanamide
Adding N- (4-chlorophenyl) -2- (3-oxo-8-azabicyclo [3.2.1] at 0-10 deg.C]Oct-8-yl) propionamide (6.1g, 20.0mmol) in 100mL MeOH was added portionwise to the NaBH4(1.5g, 40.0mmol) and TLC indicated completion of the reaction after the reaction mixture was stirred at 0-10 ℃ for 30 min. The reaction was poured into 300mL of saturated aqueous ammonium chloride solution, followed by extraction with EA (200 mL. times.3), and the organic phase was washed twice with saturated brine, anhydrous Na2SO4After being sufficiently dried, concentration under reduced pressure gave 6.1g (yield: 99%) of the objective compound as a pale yellow solid.
And 5: n- (4-chlorophenyl) -2- (3- ((2-methylpyridin-4-yl) oxy) -8-azabicyclo [3.2.1]Preparation of Oct-8-yl) propionamide N- (4-chlorophenyl) -2- (3-hydroxy-8-azabicyclo [3.2.1] under nitrogen blanket at room temperature]Oct-BuOK (56mg, 0.5mmol) was added portionwise to a 2mL DMSO solution of oct-8-yl) propionamide (90mg, 0.3 mmol). Cooling the reaction system to 10-25 ℃, then adding 4-chloro-2-methylpyridine (63mg, 0.5mmol) in batches, and controlling the temperature to be not higher than 2 DEG C5 ℃ is adopted. After the addition was complete the reaction mixture was stirred at 25 ℃ overnight and TLC showed the reaction was complete. The reaction was poured into 10mL of water and extracted with EA (5 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After drying sufficiently, it was concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 15: 1) to give 37mg (yield: 31%) of the title compound as an off-white solid.
1H NMR(400MHz，CDCl3)δ1.35-1.37(3H，m)，1.75-2.22(8H，m)，2.50(3H，s)，3.07-3.26 (1.4H，m)，3.37-3.61(1.6H，m)，4.61-4.68(1H，m)，6.54-6.64(2H，m)，7.30(2H，d，J＝8.8Hz)，7.52-7.55(2H，m)，8.29-8.32(1H，m)，9.21-9.26(1H，m).
EM (calculated): 399.2, respectively; MS (ESI) M/e (M + H)+：400.2
Example 8: preparation of N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) -3, 9-diazabicyclo [3.3.1] nonan-9-yl) propanamide
The synthesis steps are as follows:
Figure BDA0001918189360000311
step 1: preparation of N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) -3, 9-diazabicyclo [3.3.1] nonan-9-yl) propanamide
The starting material for this step was prepared in the same manner as in example 7 using the corresponding commercial reagents.
Reacting 9- (1- ((4-chlorophenyl) amino) -1-oxopropan-2-yl) -7- ((6-fluoroquinolin-4-yl) oxy) -3, 9-diazabicyclo [3.3.1]A solution of tert-butyl nonane-3-carboxylate (57mg, 0.1mmol) in 2mL of 4M HCl/EA was stirred at room temperature for 6 h. TLC shows that the reaction system is directly decompressed and concentrated after the reaction is finished, the obtained solid is dissolved in 5mL of water, Na2CO3The pH value is adjusted to be alkaline. The resulting system was extracted with EA (5mL x 5), and the organic phase was back-washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by silica gel plate chromatography (DCM: MeOH 10: 1) gives 40mg (yield:85%) target compound as a white solid.
1H NMR(400MHz，d6-DMSO)δ1.25-1.32(3H，m)，1.87-2.04(4H，m)，2.99-3.20(4H，m)，3.32-3.46(2H，m)，3.47(1H，brs)，4.97-4.99(1H，m)，5.66(1H，brs)，6.89(0.65H，d，J＝5.2Hz)， 7.10(0.35H，d，J＝5.6Hz)，7.36-7.38(2H，m)，7.69-7.81(4H，m)，8.01-8.05(1H，m)，8.69-8.72(1H， m)，9.79(1H，s).
EM (calculated): 468.2, respectively; MS (ESI) M/e (M + H)+：469.2
Example 9: preparation of N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) -3-methyl-3, 9-diazabicyclo [3.3.1] nonan-9-yl) propionamide
The synthesis steps are as follows:
Figure BDA0001918189360000312
step 1: preparation of N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) -3-methyl-3, 9-diazabicyclo [3.3.1] nonan-9-yl) propionamide
N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) -3, 9-diazabicyclo [3.3.1] at room temperature]Nonan-9-yl) propionamide (30mg, 0.06mmol) and 5mg of anhydrous formaldehyde in 1mL of DCE were stirred at room temperature for 0.5h and STAB (21mg, 0.1mmol) was added. The reaction mixture was continued to stir at room temperature overnight. TLC shows that after the reaction is finished, the reaction system is poured into 5mL of water and Na is added2CO3(1M aqueous solution) to adjust the pH to alkaline. The resulting compound was extracted with DCM (5 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was carried out, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 18mg (yield: 58%) of the title compound as a white solid.
1H NMR(400MHz，d6-DMSO)δ1.22-1.28(3H，m)，1.87-2.04(4H，m)，2.1-2.26(3H，m)， 2.68-2.80(4H，m)，3.33-3.42(2H，m)，3.48-3.49(1H，m)，4.98-4.99(1H，m)，6.87(0.65H，d，J＝5.2 Hz)，7.10(0.35H，d，J＝5.6Hz)，7.35-7.38(2H，m)，7.69-7.80(4H，m)，8.01-8.05(1H，m)， 8.68-8.72(1H，m)，9.82(1H，s).
EM (calculated): 482.2; MS (ESI) M/e (M + H)+：482.2
Example 10: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) thio) -8-azabicyclo [3.2.1] oct-8-yl) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000321
step 1: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) thio) -8-azabicyclo [3.2.1] oct-8-yl) propanamide
To N- (4-chlorophenyl) -2- (3-hydroxy-8-azabicyclo [3.2.1] at room temperature]Oct-8-yl) propionamide (309mg, 1.0mmol), 6-fluoroquinoline-4-thiol (179mg, 1.0mmol) and PPh3(393mg, 1.5mmol) in 5mL THF was added DIAD (303mg, 1.5mmol) dropwise. After the addition, the system was stirred at room temperature for 6 h. TLC showed the reaction was complete and the reaction was directly concentrated under reduced pressure and the residue was purified by column chromatography (DCM: MeOH ═ 10: 1) to give 260mg (yield: 55%) of the title compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.32(3H，m)，1.80-2.07(7H，m)，2.23-2.42(1H，m)， 3.15-3.21(1H，m)，3.33-3.40(1H，m)，3.45-3.47(1H，m)，3.53-3.55(1H，m)，6.42-6.45(0.6H，m)， 6.67-6.70(0.4H，m)，7.35(2H，d，J＝8.8Hz)，7.49-7.51(2H，m)，7.73(2H，d，J＝8.8Hz)，8.05-8.09 (1H，m)，9.02-9.04(1H，m)，9.73(1H，s).
EM (calculated): 469.1, respectively; MS (ESI) M/e (M + H)+：470.1
Example 11: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) sulfonyl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
The synthesis steps are as follows:
Figure BDA0001918189360000322
step 1: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) sulfonyl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
To N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) thio) -8-azabicyclo [3.2.1] at room temperature]To a solution of oct-8-yl) propionamide (100mg, 0.2mmol) in 3mL DCM was added m-CPBA (69mg, 0.4mmol) and stirred at room temperature for 6 h. TLC showed the reaction was complete and diluted with 10mL DCM. The resulting solution was washed once with an aqueous sodium sulfite solution, an aqueous sodium carbonate solution and a saturated brine. Anhydrous Na for organic phase2SO4After drying, concentration under reduced pressure was carried out, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 65mg (yield: 61%) of the title compound as a white solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.31(3H，m)，1.82-2.11(7H，m)，2.21-2.39(1H，m)， 3.16-3.21(1H，m)，3.33-3.40(1H，m)，3.48(1H，brs)，4.97-5.02(1H，m)，7.10(0.6H，d，J＝5.2Hz)， 7.32(0.4H，d，J＝5.6Hz)，7.36-7.38(2H，m)，7.70-7.76(2H，m)，7.85-8.05(3H，m)，8.93-8.96(1H， m)，9.91(1H，s).
EM (calculated): 501.2; MS (ESI) M/e (M + H)+：502.2
Example 12: preparation of 4- ((8- (1- (5-chloro-1H-benzo [ d ] imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
The synthesis steps are as follows:
Figure BDA0001918189360000331
step 1: preparation of N- (2-amino-4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (172mg, 0.5mmol) in 3mL of THF was added pyridine (198mg, 2.5mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 636mg, 1.0mmol) and 4-chloroaniline (127mg, 1.0 mmol). The reaction mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 20: 1) to give 90mg (yield: 38%) of the objective compound as a pale yellow solid.
Step 2: preparation of 4- ((8- (1- (5-chloro-1H-benzo [ d ] imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
To N- (2-amino-4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] at room temperature]To a solution of oct-8-yl) propionamide (100mg, 0.2mmol) in 1mL of 1, 4-dioxane was added dilute hydrochloric acid (6M, 1 mL). The reaction mixture was stirred at 95 ℃ overnight. The reaction was poured into 10mL of water and Na was added2CO3After adjusting the pH to basic, extract with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give the endo/exo two isomer compounds (upper point, 35mg, yield: 39% as off-white solid, No. example 12A; lower point, 25mg, yield: 28% as off-white solid, No. example 12B).
Example 12A:
1H NMR(400MHz，d6-DMSO)δ1.43(3H，d，J＝6.4Hz)，1.82-2.03(8H，m)，3.25-3.33(2H，m)，4.07-4.15(1H，m)，4.96-5.05(1H，m)，7.11-7.23(2H，m)，7.45-7.52(1H，m)，7.53-7.59(1H，m)， 7.63-7.68(1H，m)，7.78(1H，dd，J＝9.6Hz，2.8Hz)，8.01(1H，dd，J＝9.2Hz，5.2Hz)，8.68(1H，d， J＝5.2Hz)，12.45-12.50(1H，m).
EM (calculated): 450.2 of the total weight of the mixture; MS (ESI) M/e (M + H)+：451.2
Example 12B:
1H NMR(400MHz，d6-DMSO)δ1.42(3H，d，J＝5.6Hz)，1.79-1.90(2H，m)，2.00(4H，s)， 2.22-2.37(2H，m)，3.12(1H，brs)，3.31-3.34(1H，m)，3.96-3.97(1H，m)，5.00-5.02(1H，m)，6.98 (1H，d，J＝5.2Hz)，7.17(1H，brs)，7.45-7.72(4H，m)，8.02(1H，dd，J＝9.2Hz，5.2Hz)，8.70(1H，d， J＝5.2Hz)，12.39-12.46(1H，m).
EM (calculated): 450.2 of the total weight of the mixture; MS (ESI) M/e (M + H)+：451.2
Example 13: preparation of 6-chloro-2- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) quinazolin-4 (1H) -one
The synthesis steps are as follows:
Figure BDA0001918189360000341
step 1: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propanamide
2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of ethyl octane-8-yl) propionate (186mg, 0.5mmol) in 5mL aqueous ammonia/MeOH (1/1) was stirred at 50 deg.C overnight. The reaction was poured into 20mL of water, adjusted to pH 10 with NaOH and extracted with EA (10 mL. times.3). The organic phase was washed with saturated sodium carbonate and saturated brine in this order, and anhydrous Na2SO4After drying, concentration under reduced pressure gave 130mg (yield: 76%) of the title compound as a white solid.
Step 2: preparation of 6-chloro-2- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) quinazolin-4 (1H) -one
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of oct-8-yl) propionamide (100mg, 0.3mmol), 2-bromo-5-chlorobenzonitrile (63mg, 0.3mmol) and NaOH (14mg, 0.3mmol) in 2mL of NMP was added CuI (6mg, 0.03 mmol). The reaction mixture was stirred at 120 ℃ overnight. The reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to obtain 30mg (yield: 21%) of the objective compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.24-1.31(3H，m)，1.82-2.12(7H，m)，2.21-2.39(1H，m)， 3.13-3.20(1H，m)，3.33-3.40(1H，m)，3.45(1H，brs)，4.97-5.02(1H，m)，6.95(0.6H，d，J＝5.2Hz)， 7.23(0.4H，d，J＝5.6Hz)，7.56-7.59(1H，m)，7.60-7.83(4H，m)，7.99-8.02(1H，m)，8.69-8.70(1H， m)，12.41(1H，brs).
EM (calculated): 478.2, respectively; MS (ESI) M/e (M + H)+：479.2
Example 14: preparation of 2- ((8- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -9H-purin-2-yl) oxy) ethan-1-ol
The synthesis steps are as follows:
Figure BDA0001918189360000351
step 1: preparation of 2- ((8- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -9H-purin-2-yl) oxy) ethan-1-ol
The starting materials for this step were prepared in the same manner as in example 12 using the corresponding commercial reagents.
Reacting 4- ((8- (1- (2-chloro-9H-purin-8-yl) ethyl) -8-azabicyclo [3.2.1]A mixture of oct-3-yl) oxy) -6-fluoroquinoline (45mg, 0.1mmol), ethylene glycol (62mg, 1.0mmol) and potassium carbonate (55mg, 0.4mmol) in 2mL of MeCN was stirred at 80 ℃ overnight. TLC showed the reaction was poured into 10mL water and extracted with EA (5mL x 3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to obtain 35mg (yield: 73%) of the objective compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.33-1.36(3H，m)，1.80-2.09(7H，m)，2.21-2.30(1H，m)， 3.13-3.19(1H，m)，3.33-3.38(1H，m)，3.45-3.47(1H，m)，3.83-3.88(2H，m)，4.45-4.50(2H，m)， 4.97-5.12(2H，m)，6.98(0.6H，d，J＝5.2Hz)，7.19(0.4H，d，J＝5.6Hz)，7.60-7.83(2H，m)， 7.99-8.03(1H，m)，8.68-8.70(1H，m)，8.86-8.88(1H，m)，12.41-12.45(1H，m).
EM (calculated): 478.2, respectively; MS (ESI) M/e (M + H)+：479.2
Example 15: preparation of 4- ((8- (1- (4- (4-chlorophenyl) -1H-imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
The synthesis steps are as follows:
Figure BDA0001918189360000352
step 1: preparation of N- (2- (4-chlorophenyl) -2-oxoethyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]TEA (303mg, 3.0mmol), HBTU (569mg, 1.5mmol) and 2-amino-1- (4-chlorophenyl) ethan-1-one (250mg, 1.5mmol) were added sequentially to a solution of octane-8-yl) propionic acid (344mg, 1.0mmol) in 5mL THF. The reaction mixture was stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the residue by column chromatography (DCM: MeOH ═ 20: 1) gave 350mg (yield: 71%) of the title compound as a white solid.
Step 2: preparation of 4- ((8- (1- (4- (4-chlorophenyl) -1H-imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
Reacting N- (2- (4-chlorophenyl) -2-oxoethyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of oct-8-yl) propionamide (100mg, 0.2mmol) and ammonium acetate (77mg, 1.0mmol) in 2mL acetic acid was stirred at 140 deg.C overnight. The reaction was poured into 10mL of aqueous sodium carbonate and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the residue by chromatography on silica gel (DCM: MeOH ═ 10: 1) gave 15mg (yield: 16%) of the desired compoundMaterial as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.27-1.32(3H，m)，1.82-2.09(7H，m)，2.21-2.33(1H，m)， 3.14-3.20(1H，m)，3.36-3.40(1H，m)，3.42(1H，brs)，4.95-5.01(1H，m)，6.93(0.6H，d，J＝5.2Hz)， 7.22(0.4H，d，J＝5.6Hz)，7.31-7.35(2H，m)，7.43-7.46(1H，m)，7.62-7.85(4H，m)，7.99-8.03(1H， m)，8.67-8.70(1H，m)，11.92(1H，brs).
EM (calculated): 476.2; MS (ESI) M/e (M + H)+：477.2
Example 16: preparation of 4- ((8- (1- (1H-tetrazol-5-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline the synthetic procedure was as follows:
Figure BDA0001918189360000361
step 1: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
At room temperature to 4- ((8-azabicyclo [ 3.2.1)]To a solution of oct-3-yl) oxy) -6-fluoroquinoline dihydrochloride (345mg, 1.0mmol) in 5mL of MeCN was added TEA (505mg, 5.0mmol) while controlling the system temperature below 30 ℃. Additional 2-bromopropionitrile (147mg, 1.1mmol) was added. The reaction mixture was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed twice with saturated brine and anhydrous Na2SO4After sufficiently drying, it was concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography (PE: EA: 1) to give 220mg (yield: 68%) of the objective compound as a pale yellow solid.
Step 2: preparation of 4- ((8- (1- (1H-tetrazol-5-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of octane-8-yl) propionitrile (195mg, 0.6mmol), ammonium chloride (318mg, 6.0mmol) and sodium azide (390mg, 6.0mmol) in 5mL of DMF was stirred at 140 ℃ overnight. The reaction was poured into 20mL of aqueous solution and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 40mg (yield: 18%) of the objective compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.25-1.30(3H，m)，1.85-2.09(7H，m)，2.24-2.33(1H，m)， 3.14-3.19(1H，m)，3.35-3.45(2H，m)，4.95-5.02(1H，m)，6.59(1H，brs)，6.93(0.6H，d，J＝5.2Hz)，7.21(0.4H，d，J＝5.6Hz)，7.69-7.85(2H，m)，7.99-8.02(1H，m)，8.68-8.70(1H，m).
EM (calculated): 368.2, respectively; MS (ESI) M/e (M + H)+：369.2
Example 17: preparation of 6-fluoro-4- ((8- (1- (3- (pyridin-4-yl) -1H-1, 2, 4-triazol-5-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) quinoline
The synthesis steps are as follows:
Figure BDA0001918189360000371
step 1: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) propanehydrazide
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]To a solution of octane-8-yl) propionic acid ethyl ester (372mg, 1.0mmol) in 5mL MeOH was added 2mL hydrazine hydrate. The reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of aqueous solution and extracted with EA (10 mL. times.5). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure gave 260mg (yield: 73%) of the title compound as a pale yellow solid.
Step 2: preparation of 6-fluoro-4- ((8- (1- (3- (pyridin-4-yl) -1H-1, 2, 4-triazol-5-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) quinoline
2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]Octane-8-yl) propylhydrazide (179mg, 0.5mmol), 4-cyanopyridine (104mg, 1.0mmol) and sodium methoxide (54mg, 1.0mmol) in 3mL of DMF was stirred at 120 deg.COvernight. The reaction was poured into 20mL of aqueous solution and extracted with EA (10 mL. times.5). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 85mg (yield: 38%) of the objective compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.32(3H，m)，1.89-2.11(7H，m)，2.24-2.31(1H，m)， 3.16-3.19(1H，m)，3.37-3.45(2H，m)，4.96-5.02(1H，m)，6.89(0.6H，d，J＝5.2Hz)，7.20(0.4H，d， J＝5.6Hz)，7.71-7.85(2H，m)，7.92-8.02(3H，m)，8.65-8.73(3H，m)，14.21(1H，brs).
EM (calculated): 444.2, respectively; MS (ESI) M/e (M + H)+：445.2
Example 18: preparation of 4- (2- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-imidazol-4-yl) morpholine
The synthesis steps are as follows:
Figure BDA0001918189360000372
step 1: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propanal
Under the protection of nitrogen, and at the temperature of-40 ℃, 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] is reacted]DiBAL-H (1M in THF, 1.0mL, 1.0mmol) was added dropwise to a solution of ethyl octane-8-yl) propionate (372mg, 1.0mmol) in 5mL THF. The reaction mixture was stirred at-40 ℃ for 1 h. TLC showed that after the reaction was complete, the reaction was poured into 20mL saturated ammonium chloride and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was carried out, and the residue was purified by column chromatography (PE: EA: 1) to give 280mg (yield: 85%) of the objective compound as a white solid.
Step 2: preparation of 4- ((8- (1- (1H-imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) -6-fluoroquinoline
2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo[3.2.1]Oct-8-yl) propanal (262mg, 0.8mmol) and glyoxal (93mg, 1.6mmol) in 5mL NH3the/MeOH (4M) solution was stirred at 60 ℃ overnight. The reaction system was directly concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM: MeOH ═ 20: 1) to give 185mg (yield: 63%) of the title compound as a pale yellow solid.
And step 3: preparation of 6-fluoro-4- ((8- (1- (5-iodo-1H-imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) quinoline
To 4- ((8- (1- (1H-imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1]To a solution of oct-3-yl) oxy) -6-fluoroquinoline (183mg, 0.5mmol) in 5mL of DCM was added NIS (225mg, 1.0 mmol). The reaction mixture was stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water, 1g of sodium sulfite was added and stirred at room temperature for 2 h. Extract with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by column chromatography (DCM: MeOH ═ 20: 1) gave 120mg (yield: 49%) of the title compound as a pale yellow solid.
And 4, step 4: preparation of 4- (2- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-imidazol-4-yl) morpholine
To 6-fluoro-4- ((8- (1- (5-iodo-1H-imidazol-2-yl) ethyl) -8-azabicyclo [3.2.1] under nitrogen protection]Oct-3-yl) oxy) quinoline (100mg, 0.2mmol) and morpholine (35mg, 0.4mmol) in 2mL DMF was added CuI (4mg, 0.02 mmol). The reaction mixture was stirred at 100 ℃ overnight. The reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 45mg (yield: 50%) of the objective compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.231-1.35(3H，m)，1.83-2.02(7H，m)，2.28-2.32(1H，m)， 3.17-3.22(1H，m)，3.29-3.47(6H，m)，3.80-3.85(4H，m)，4.96-5.02(1H，m)，6.92(0.6H，d，J＝5.2 Hz)，7.05(1H，s)，7.21(0.4H，d，J＝5.6Hz)，7.67-7.82(2H，m)，7.98-8.02(1H，m)，8.68-8.70(1H， m)，12.80(1H，brs).
EM (calculated): 451.2 of the total weight of the mixture; MS (ESI) M/e (M + H)+：452.2
Example 19: preparation of 5- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-pyrazol-3-amine the synthetic procedure was as follows:
Figure BDA0001918189360000381
step 1: preparation of 4- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -3-oxopentanenitrile
Under the protection of nitrogen, 2- ((1R, 5S) -3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]To a solution of octane-8-yl) propionic acid ethyl ester (372mg, 1.0mmol) and acetonitrile (205mg, 5.0mmol) in 5mL THF was added NaH (60%, 120mg, 3.0mmol) in portions. The reaction mixture was stirred at 70 ℃ overnight. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by column chromatography (DCM: MeOH ═ 20: 1) to give 105mg (yield: 29%) of the objective compound as a pale yellow solid.
Step 2: preparation of 5- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-pyrazol-3-amine
Reacting 4- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of oct-8-yl) -3-oxovaleronitrile (100mg, 0.27mmol) and hydrazine hydrate (100mg, 1.0mmol) in 5mL THF was stirred at 70 deg.C overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 25mg (yield: 24%) of the objective compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.27-1.31(3H，m)，1.88-2.05(7H，m)，2.27-2.33(1H，m)， 3.15-3.19(1H，m)，3.38-3.45(2H，m)，4.99-5.04(1H，m)，6.10(2H，brs)，6.52(1H，s)，6.95(0.6H，d， J＝5.2Hz)，7.21(0.4H，d，J＝5.6Hz)，7.69-7.83(2H，m)，7.97-8.00(1H，m)，8.69-8.71(1H，m)， 11.97(1H，brs).
EM (calculated): 381.2, respectively; MS (ESI) M/e (M + H)+：382.2
Example 20: preparation of 5- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-pyrazole-3-carboxamide
The synthesis steps are as follows:
Figure BDA0001918189360000391
step 1: preparation of 3- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) butan-2-one
At room temperature to 4- ((8-azabicyclo [ 3.2.1)]To a solution of oct-3-yl) oxy) -6-fluoroquinoline dihydrochloride (345mg, 1.0mmol) in 5mL of MeCN was added TEA (404mg, 4.0mmol) while controlling the system temperature below 30 ℃. 3-bromo-2-butanone (166mg, 1.1mmol) was added. The reaction mixture was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 20mL of water and extracted with EA (20 mL. times.3). The organic phase was washed twice with saturated brine and anhydrous Na2SO4After drying sufficiently, concentration was performed under reduced pressure, and the residue was purified by column chromatography (DCM: EA: 10: 1) to give 320mg (yield: 94%) of the objective compound as a pale yellow solid.
Step 2: preparation of ethyl 5- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) -2, 4-dioxohexanoate
To a solution of sodium tert-butoxide (260mg, 2.7mmol) in 5mL of THF under nitrogen at 0 deg.C was added dropwise 3- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]Octane-8-yl) butan-2-one (310mg, 0.9mmol) and diethyl oxalate (263mg, 1.8mmol) in 3mL THF. The reaction mixture was stirred at room temperature overnight. The reaction was poured into 40mL of water and extracted with EA (20 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the residue by column chromatography (DC)M MeOH 20: 1) to 220mg (yield: 55%) target compound as light yellow solid.
And step 3: preparation of ethyl 5- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-pyrazole-3-carboxylate
A solution of ethyl 5- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) -2, 4-dioxohexanoate (220mg, 0.5mmol) and hydrazine hydrate (50%, 50mg, 0.5mmol) in 5mL of THF was stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: MeOH 15: 1) to give 90mg (yield: 41%) of the title compound as a pale yellow solid.
And 4, step 4: preparation of 5- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) ethyl) -1H-pyrazole-3-carboxamide
Reacting 5- (1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]]Oct-8-yl) ethyl) -1H-pyrazole-3-carboxylic acid ethyl ester (88 mg, 0.2mmol) and 0.2mL of aqueous ammonia in 2mL of THF were stirred at 70 deg.C overnight. TLC showed that after the reaction was completed, the reaction system was concentrated under reduced pressure, the residue was dissolved in 5mL of DCM, and washed twice with 1M aqueous sodium hydroxide solution and saturated brine in this order, and the organic phase was washed with anhydrous Na2SO4After drying, concentration under reduced pressure gave 60mg (yield: 73%) of the title compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.27-1.31(3H，m)，1.87-2.05(7H，m)，2.27-2.31(1H，m)， 3.13-3.19(1H，m)，3.38-3.45(2H，m)，4.98-5.04(1H，m)，6.67(1H，s)，6.95(0.6H，d，J＝5.2Hz)， 7.24(0.4H，d，J＝5.6Hz)，7.70-7.83(2H，m)，7.97-8.01(1H，m)，8.69-8.71(1H，m)，9.04(2H，brs)， 11.84(1H，brs).
EM (calculated): 409.2; MS (ESI) M/e (M + H)+：410.2
Example 21: preparation of 6-fluoro-4- ((8- (1- (3- (pyridin-4-yl) -1H-pyrazol-5-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) quinoline
The synthesis steps are as follows:
Figure BDA0001918189360000401
step 1: preparation of 4- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -1- (pyridin-4-yl) pentan-1, 3-dione
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (344mg, 1.0mmol) in 5mL THF was added CDI (162mg, 1.0mmol), and the reaction mixture was stirred at room temperature for 1h as system 1. Another reaction flask was taken and 4-acetylpyridine (121mg, 1.0mmol) in 1mL THF was added dropwise to a mixture of LDA (1M in THF, 1.1mL, 1.1mmol) and 5mL THF under nitrogen at-70 deg.C. After the reaction system was stirred at-70 ℃ for 1h, the resulting system 1 was added dropwise to the mixture and stirring was continued for 1 h. The system was allowed to warm to room temperature and stirred overnight. TLC showed that after the reaction was complete, the reaction was poured into 50mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure was performed, and the residue was purified by column chromatography (DCM: MeOH ═ 20: 1) to give 90mg (yield: 20%) of the objective compound as a pale yellow solid.
Step 2: preparation of 6-fluoro-4- ((8- (1- (3- (pyridin-4-yl) -1H-pyrazol-5-yl) ethyl) -8-azabicyclo [3.2.1] oct-3-yl) oxy) quinoline
A solution of 4- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -1- (pyridin-4-yl) pentan-1, 3-dione (90mg, 0.2mmol) and hydrazine hydrate (50%, 40mg, 0.4mmol) in 2mL of THF was stirred at room temperature overnight. TLC showed the reaction was complete and the reaction was concentrated under reduced pressure and the residue was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give 40mg (yield: 44%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.29-1.34(3H，m)，1.88-2.05(7H，m)，2.26-2.29(1H，m)， 3.15-3.19(1H，m)，3.34-3.41(2H，m)，4.98-5.04(1H，m)，6.55(1H，s)，6.95(0.6H，d，J＝5.2Hz)， 7.24(0.4H，d，J＝5.6Hz)，7.70-7.81(2H，m)，7.91-8.08(3H，m)，8.67-8.78(3H，m)，11.92(1H， brs).
EM (calculated): 443.2, respectively; MS (ESI) M/e (M + H)+：444.2
Example 22: preparation of N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) bicyclo [3.3.1] nonan-3-yl) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000411
step 1: preparation of spiro [ bicyclo [3.3.1] nonane-3, 2' - [1, 3] dioxolane ] -7-one
To bicyclo [3.3.1]To a solution of nonane-3, 7-dione (7.6g, 50.0mmol) and ethylene glycol (2.5g, 40.3mmol) in 50mL of toluene was added p-toluenesulfonic acid (0.3g, 1.7mmol), and the reaction mixture was refluxed overnight with a water separator. The reaction system was washed with 1M aqueous sodium hydroxide solution and saturated brine once each, and dried over anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by column chromatography (PE: EA: 10: 1) to give 2.8g (yield: 29%) of the objective compound as a colorless oil.
Step 2: preparation of ethyl 2- (spiro [ bicyclo [3.3.1] nonane-3, 2' - [1, 3] dioxolane ] -7-ylidene) propionate
To a solution of triethyl 2-phosphonopropyl ester (3.0g, 12.8mmol) in 30mL of THF under nitrogen at 0 deg.C was added NaH (60%, 0.6g, 15.0mmol) in portions, and after the addition was complete the system was stirred at 0 deg.C for 0.5 h. Then adding spiro [ bicyclo [3.3.1] in batches]Nonane-3, 2' - [1, 3]]Dioxolanes]-7-one (2.5g, 12.8 mmol). The reaction mixture was stirred at room temperature for 2h and the system was poured into 200mL saturated ammonium chloride and extracted with EA (100 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by column chromatography (PE: EA 8: 1) gave 2.9g (yield: 751%) of the title compound as a colorless oil.
And step 3: preparation of ethyl 2- (spiro [ bicyclo [3.3.1] nonane-3, 2' - [1, 3] dioxolan ] -7-yl) propionate
To a solution of ethyl 2- (spiro [ bicyclo [3.3.1] nonane-3, 2' - [1, 3] dioxolane ] -7-ylidene) propionate (2.8g, 10.0mmol) in 50mL of MeOH at room temperature was added Pd/C (10%, 0.5g), and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen at about two atmospheres overnight. TLC showed that the reaction was completed, the reaction system was directly filtered, and the filtrate was concentrated under reduced pressure to give 2.7g (yield: 96%) of the objective compound as a colorless oil.
And 4, step 4: preparation of 2- (spiro [ bicyclo [3.3.1] nonane-3, 2' - [1, 3] dioxolan ] -7-yl) propionic acid
To 2- (spiro [ bicyclo [3.3.1]]Nonane-3, 2' - [1, 3]]Dioxolanes]-7-yl) propionic acid ethyl ester (2.5g, 8.9mmol) in 40mL MeOH/H2NaOH (1.5g, 37.5mmol) was added to the O (1/1) solution, and the reaction was stirred at room temperature for 4 h. After the reaction is finished, adding 200mL of water for dilution, adjusting the pH value of the system to 5-6 by using dilute hydrochloric acid, and extracting by using EA (100mL x 3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure gave 2.0g (yield: 89%) of the title compound as a white solid.
And 5: preparation of N- (4-chlorophenyl) -2- (spiro [ bicyclo [3.3.1] nonane-3, 2' - [1, 3] dioxolane ] -7-yl) propionamide
Under the protection of nitrogen, to 2- (spiro [ bicyclo [3.3.1]]Nonane-3, 2' - [1, 3]]Dioxolanes](1.9g, 7.5mmol) of (7-yl) propionic acid in 30mL of THF was added pyridine (3.0g, 38.0mmol), followed by successive dropwise addition of T at room temperature3P (50% in EA, 7.2g, 11.3mmol) and 4-chloroaniline (1.5g, 11.8 mmol). The reaction mixture was stirred at 70 ℃ overnight. The reaction was poured into 150mL of water and extracted with EA (100 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration was performed under reduced pressure, and the residue was purified by column chromatography (PE: EA: 5: 1) to obtain 2.2g (yield: 81%) of the objective compound as a pale yellow solid.
Step 6: preparation of N- (4-chlorophenyl) -2- (7-oxobicyclo [3.3.1] nonan-3-yl) propionamide
Reacting N- (4-chlorophenyl) -2- (spiro [ bicyclo [3.3.1]]Nonane-3, 2' - [1, 3]]Dioxolanes]A solution of-7-yl) propionamide (2.0g, 5.5mmol) in 20mL 6M HCl and 20mL acetone is stirred at room temperature for 2 h. TLC shows that after the reaction is finished, the reaction system is diluted by adding 50mL of water, and the pH value is adjusted to be the same as that of NaOHAnd (3) alkalinity. The resulting system was extracted with EA (50 mL. times.3), and the organic phase was back-washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure gave 1.4g (yield: 79%) of the title compound as a pale yellow solid.
And 7: preparation of N- (4-chlorophenyl) -2- (7-hydroxybicyclo [3.3.1] nonan-3-yl) propanamide
Charging N- (4-chlorophenyl) -2- (7-oxobicyclo [3.3.1] at 0-10 deg.C]Nonan-3-yl) propionamide (200mg, 0.6mmol) in 5mL MeOH was added NaBH in portions4(46mg, 1.2mmol) and TLC indicated completion of the reaction after the reaction mixture was stirred at 0-10 ℃ for 30 min. The reaction was poured into 20mL of saturated aqueous ammonium chloride solution, extracted with EA (10 mL. times.3), and the organic phase was washed twice with saturated brine, anhydrous Na2SO4After drying sufficiently, concentration under reduced pressure gave 180mg (yield: 90%) of the objective compound as a colorless oil.
And 8: preparation of N- (4-chlorophenyl) -2- (7- ((6-fluoroquinolin-4-yl) oxy) bicyclo [3.3.1] nonan-3-yl) propionamide
Under the protection of nitrogen and at room temperature, adding N- (4-chlorphenyl) -2- (7-hydroxy bicyclo [3.3.1]]Nonan-3-yl) propionamide (100mg, 0.3mmol) in 2mL of DMSO was added t-BuOK (56mg, 0.5mmol) in portions. The reaction system is cooled to 10-25 ℃, and then 4-chloro-6-fluoroquinoline (91mg, 0.5mmol) is added in batches, and the temperature is controlled to be not higher than 25 ℃. After the addition was complete the reaction mixture was stirred at 25 ℃ overnight and TLC showed the reaction was complete. The reaction was poured into 10mL of water and extracted with EA (5 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After drying sufficiently, it was concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography (DCM: EA: 5: 1) to give 45mg (yield: 33%) of the objective compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.19-1.24(3H，m)，1.54-2.13(10H，m)，2.25-2.41(2H，m)， 3.28-3.40(1H，m)，3.47-3.49(1H，m)，4.86-4.92(1H，m)，6.95(0.6H，d，J＝5.2Hz)，7.21(0.4H，d， J＝5.6Hz)，7.36-7.39(2H，m)，7.67-7.78(4H，m)，7.98-8.03(1H，m)，8.64-8.8.68(1H，m)，9.87 (1H，s).
EM (calculated): 466.2; MS (ESI) M/e (M + H)+：467.2
Example 23: preparation of N- (4-chlorophenyl) -2- (7- (6-fluoroquinolin-4-yl) bicyclo [3.3.1] nonan-3-yl) propionamide the synthetic procedure is as follows:
Figure BDA0001918189360000421
step 1: 7- (1- ((4-chlorophenyl) amino) -1-oxoprop-2-yl) bicyclo [3.3.1]Preparation of non-2-en-3-yl-triflate N- (4-chlorophenyl) -2- (7-oxobicyclo [3.3.1] was reacted under nitrogen]A solution of nonan-3-yl) propionamide (320mg, 1.0mmol) in 5mL THF was cooled to-70 deg.C. LDA (1M in THF, 2.5mL, 2.5mmol) was added dropwise with stirring, and the system temperature was controlled at about-70 ℃. After the system was stirred for 1h, N-phenylbis (trifluoromethanesulfonyl) imide (393mg, 1.1mmol) was added in portions. After the addition, the system was allowed to warm naturally with stirring and stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL saturated ammonium chloride solution and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by means of a chromatography column (PE: EA 5: 1) yields 300mg (yield: 67%) of the title compound as a white solid.
Step 2: preparation of N- (4-chlorophenyl) -2- (7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) bicyclo [3.3.1] non-6-en-3-yl) propionamide
To 7- (1- ((4-chlorophenyl) amino) -1-oxoprop-2-yl) bicyclo [3.3.1 under the protection of nitrogen]To a solution of nonan-2-en-3-yl-trifluoromethanesulfonate (270mg, 0.6mmol), pinacol diboron (152mg, 0.6mmol) and KOAc (118mg, 1.2mmol) in 5mL of 1, 4-dioxane was added Pd (dppf) Cl2(37mg, 0.05 mmol). The reaction mixture was stirred at 90 ℃ for 6h under nitrogen and TLC showed the reaction was complete. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4Drying thoroughly, concentrating under reduced pressure, purifying the residue by column chromatography (PE: EA: 5: 1)180mg (yield: 70%) of the title compound are obtained as a pale yellow solid.
And step 3: preparation of N- (4-chlorophenyl) -2- (7- (6-fluoroquinolin-4-yl) bicyclo [3.3.1] non-6-en-3-yl) propionamide
To N- (4-chlorophenyl) -2- (7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) bicyclo [3.3.1] under the protection of nitrogen]Non-6-en-3-yl) propionamide (172mg, 0.4mmol), 4-chloro-6-fluoroquinoline (181mg, 0.5mmol) and K2CO3(110mg, 0.8mmol) of 5mL of 1, 4-dioxane/water (5/1) was added Pd (dppf) Cl2(29mg, 0.04 mmol). The reaction mixture was stirred at 90 ℃ for 6h under nitrogen and TLC showed the reaction was complete. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After sufficiently drying, concentration was performed under reduced pressure, and the residue was purified by column chromatography (PE: EA: 2: 1) to obtain 115mg (yield: 64%) of the objective compound as a pale yellow solid.
And 4, step 4: preparation of N- (4-chlorophenyl) -2- (7- (6-fluoroquinolin-4-yl) bicyclo [3.3.1] nonan-3-yl) propionamide
To a solution of N- (4-chlorophenyl) -2- (7- (6-fluoroquinolin-4-yl) bicyclo [3.3.1] non-6-en-3-yl) propionamide (90mg, 0.2mmol) in 5mL of MeOH at room temperature was added Pt/C (10%, 20mg), and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen at about two atmospheres overnight. TLC showed the reaction was complete, the reaction was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was slurried with PE/DCM (20/1) to give 60mg (yield: 67%) of the title compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO) δ 1.18-1.24(3H, m), 1.59-2.13(10H, m), 2.27-2.41(2H, m), 3.16-3.40(2H, m), 3.46-3.49(1H, m), 6.94(0.6H, d, J ═ 5.2Hz), 7.21(0.4H, d, J ═ 5.6Hz), 7.36-7.41(2H, m), 7.67-7.75(4H, m), 7.98-8.01(1H, m), 8.64-8.8.67(1H, m), 9.86(H, s). EM (calculated): 450.2 of the total weight of the mixture; MS (ESI) M/e (M +1H)+：450.2
Example 24: preparation of 2- ((4-chlorophenyl) amino) -1- (3- ((6-fluoroquinoline 4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propan-1-one
The synthesis steps are as follows:
Figure BDA0001918189360000431
step 1: preparation of ethyl (4-chlorophenyl) alanine
To a solution of 4-chloroaniline (254mg, 2.0mmol) and potassium carbonate (552mg, 4.0mmol) in 5mL of MeCN at room temperature was added ethyl 2-bromoacetate (398mg, 2.2 mmol). The reaction was stirred at 70 ℃ overnight and TLC showed the reaction was complete. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed once with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and slurrying of the crude product with 3mL EA/PE (1/10) gives 375mg (yield: 82%) of the title compound as a yellow solid.
Step 2: preparation of (4-chlorophenyl) alanine
To (4-chlorophenyl) alanine ethyl ester (228mg, 1.0mmol) in 5mL MeOH/H2NaOH (160mg, 4.0mmol) was added to the O (1/1) solution, the temperature of the system was controlled to be lower than 30 ℃ and the reaction system was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using concentrated hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 10mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined, and concentrated under reduced pressure to give 170mg (yield: 85%) of the objective compound as a yellow solid.
And step 3: preparation of 2- ((4-chlorophenyl) amino) -1- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propan-1-one
To a solution of (4-chlorophenyl) alanine (100mg, 0.5mmol) in 3mL of THF under nitrogen, TEA (303mg, 3.0mmol), HBTU (266mg, 0.7mmol) and 4- ((8-azabicyclo [3.2.1] were added sequentially]Oct-3-yl) oxy) -6-fluoroquinoline dihydrochloride (172mg, 0.5 mmol). The reaction mixture was stirred at room temperature overnight. TLC showed that after the reaction was complete, the reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4Drying, concentrating under reduced pressure to obtain residueThe material was purified by silica gel plate chromatography (DCM: MeOH ═ 10: 1) to give the endo/exo two isomer compounds (upper point, 45mg, yield: 33% as off-white solid, numbered example 26A; lower point, 35mg, yield: 26% as off-white solid, numbered example 26B). The absolute configuration of the two isomers is not determined.
Example 26A:
1H NMR(400MHz，d6-DMSO)δ1.25-1.40(3H，m)，1.62-2.02(6H，m)，2.28-2.31(2H，m)， 4.35-4.42(1H，m)，4.59-4.76(2H，m)，5.18-5.22(1H，m)，5.96-6.05(1H，m)，6.59-6.70(2H，m)， 7.07-7.09(2H，m)，7.29-7.31(1H，m)，7.62-7.76(2H，m)，7.99-8.02(1H，m)，8.71(1H，d，J＝5.2 Hz).
EM (calculated): 453.2; MS (ESI) M/e (M + H)+：453.2
Example 26B:
1H NMR(400MHz，d6-DMSO)δ1.24-1.33(3H，m)，1.80-1.99(1H，m)，2.07-2.33(7H，m)， 4.33-4.42(1H，m)，4.54-4.70(2H，m)，5.04-5.08(1H，m)，5.94-6.03(1H，m)，6.60-6.69(2H，m)， 6.99-7.03(1H，m)，7.08-7.12(2H，m)，7.66-7.75(2H，m)，8.01-8.06(1H，m)，8.72(1H，d，J＝5.2 Hz).
EM (calculated): 453.2; MS (ESI) M/e (M + H)+：453.2
Examples 25 to 90
Using the preparation method of the above examples, the following compounds, the structures of which and nuclear magnetic characterization data are shown in Table 1, were prepared using the corresponding commercial reagents as raw materials
TABLE 1
Figure BDA0001918189360000441
Figure BDA0001918189360000451
Figure BDA0001918189360000461
Figure BDA0001918189360000471
Figure BDA0001918189360000481
Figure BDA0001918189360000491
Figure BDA0001918189360000501
Figure BDA0001918189360000511
Figure BDA0001918189360000521
Figure BDA0001918189360000531
Figure BDA0001918189360000541
Figure BDA0001918189360000551
Figure BDA0001918189360000561
Figure BDA0001918189360000571
Figure BDA0001918189360000581
Figure BDA0001918189360000591
Figure BDA0001918189360000601
Figure BDA0001918189360000611
Example 91: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) pent-4-enamide
The synthesis steps are as follows:
Figure BDA0001918189360000612
step 1: preparation of N- (4-chlorophenyl) -2, 2, 2-trifluoro-N- (2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) acetyl) acetamide
To N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of oct-8-yl) acetamide (440mg, 0.5mmol) in 5mL THF was added NaH (60%, 56mg, 0.7mmol), and the reaction mixture was stirred at room temperature for 0.5h before adding TFAA (210mg, 0.5 mmol). The reaction was stirred for an additional 1 h. TLC showed that after the reaction was complete, the reaction was poured into 20mL saturated ammonium chloride and extracted with EA (10mL x 3). The organic phase was washed with saturated brine, anhydrous Na2SO4Drying, concentrating under reduced pressure, and precipitating the residue with silica gelPurification (DCM: MeOH: 20: 1) afforded 420mg (yield: 78%) of the title compound as a white solid.
Step 2: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -N- (2, 2, 2-trifluoroacetyl) pent-4-enamide
Under the protection of nitrogen, N- (4-chlorphenyl) -2, 2, 2-trifluoro-N- (2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of oct-8-yl) acetyl) acetamide (160mg, 0.3mmol) in 3mL THF was cooled to-70 deg.C. LiHMDS (1M in THF, 0.5mL, 0.5mmol) was added dropwise with stirring, with the system temperature controlled at about-70 ℃. After the system was stirred for 1h, bromopropene (36mg, 0.3mmol) was added dropwise. After the addition, the system was allowed to warm naturally with stirring and stirred at room temperature overnight. The reaction was poured into 20mL of saturated ammonium chloride solution and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by silica gel plate chromatography (DCM: MeOH ═ 20: 1) gave 50mg (yield: 29%) of the title compound as a pale yellow solid.
And step 3: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) pent-4-enamide
To N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] at room temperature]Oct-8-yl) -N- (2, 2, 2-trifluoroacetyl) pent-4-enamide (50mg, 0.09mmol) in 2mL MeOH/H2Adding Na into O (1/1) solution2CO3(38mg, 0.36mmol), the reaction was stirred at 70 ℃ overnight. TLC showed the reaction was complete, diluted with 10mL water and extracted with EA (100mL x 3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by silica gel plate chromatography (DCM: MeOH ═ 20: 1) gave 30mg (yield: 71%) of the title compound as a white solid.
1H NMR(400MHz，d6-DMSO)δ1.85-2.12(7H，m)，2.23-2.41(2H，m)，2.63-2.65(1H，m)， 3.16-3.21(1H，m)，3.32-3.40(1H，m)，3.47(1H，brs)，4.91-5.04(2H，m)，5.21(1H，d，J＝5.2Hz)， 5.94-5.97(1H，m)，6.96(0.6H，d，J＝5.2Hz)，7.23(0.4H，d，J＝5.6Hz)，7.33-7.38(2H，m)， 7.63-7.79(4H，m)，7.99-8.04(1H，m)，8.68-8.71(1H，m)，9.90(1H，s).
EM (calculated): 479.2, respectively; MS (ESI) M/e (M +1H)+：480.2
Example 92: preparation of 2- (4- (3- ((4-chlorophenyl) amino) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -3-oxopropyl) phenyl) propanoic acid
The synthesis steps are as follows:
Figure BDA0001918189360000621
step 1: preparation of methyl 2- (4- (3- (N- (4-chlorophenyl) -2, 2, 2-trifluoroacetylamino) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -3-oxopropyl) phenyl) propanoate
Under the protection of nitrogen, N- (4-chlorphenyl) -2, 2, 2-trifluoro-N- (2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]A solution of oct-8-yl) acetyl) acetamide (160mg, 0.3mmol) in 3mL THF was cooled to-70 deg.C. LiHMDS (1M in THF, 0.5mL, 0.5mmol) was added dropwise with stirring, with the system temperature controlled at about-70 ℃. After the system was stirred for 1h, tert-butyl 2- (4- (bromomethyl) phenyl) propionate (90mg, 0.3mmol) was added dropwise. After the addition, the system was allowed to warm naturally with stirring and stirred at room temperature overnight. The reaction was poured into 20mL of saturated ammonium chloride solution and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by silica gel plate chromatography (DCM: MeOH ═ 20: 1) gave 35mg (yield: 15%) of the title compound as a yellow solid.
Step 2: preparation of tert-butyl 2- (4- (3- ((4-chlorophenyl) amino) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -3-oxopropyl) phenyl) propionate
To 2- (4- (3- (N- (4-chlorophenyl) -2, 2, 2-trifluoroacetylamino) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] at room temperature]Oct-8-yl) -3-oxopropyl) phenyl) propionic acid methyl ester (35mg, 0.046mmol) in 2mL MeOH/H2O (1/1) solutionAdding Na2CO3(9mg, 0.23mmol), the reaction was stirred at 70 ℃ overnight. TLC showed the reaction was complete, diluted with 10mL water and extracted with EA (100mL x 3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure gives 20mg of the title compound as a yellow solid. The crude product was used directly in the next step.
And step 3: preparation of 2- (4- (3- ((4-chlorophenyl) amino) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -3-oxopropyl) phenyl) propanoic acid
A solution of tert-butyl 2- (4- (3- ((4-chlorophenyl) amino) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -3-oxopropyl) phenyl) propanoate (20mg, crude product from the previous step) in 1mL TFA/DCM (1/1) was stirred at room temperature for 4 h. TLC showed that after the reaction was complete the system was directly concentrated under reduced pressure and the residue was prepared in reverse phase with basic conditions (ammonium bicarbonate) to give 6mg (two-step yield: 21%) of the title compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.54-1.59(3H，m)，1.87-2.14(7H，m)，2.25-2.40(1H，m)， 3.14-3.25(2H，m)，3.37-3.49(3H，m)，3.91-3.95(1H，m)，4.91-5.02(1H，m)，6.95(0.6H，d，J＝5.2 Hz)，7.15-1.78(2H，m)，7.23(0.4H，d，J＝5.6Hz)，7.30-7.41(4H，m)，7.65-7.91(4H，m)，7.97-8.04 (1H，m)，8.67-8.69(1H，m)，9.82(1H，s)，13.20(1H，brs).
EM (calculated): 601.2; MS (ESI) M/e (M +1H)+：602.2
Example 93: preparation of N- (4-chloro-3- (2-hydroxyethoxy) phenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
The synthesis steps are as follows:
Figure BDA0001918189360000631
step 1: preparation of N- (4-chloro-3- (2-hydroxyethoxy) phenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
To a solution of N- (4-chloro-3- (2-hydroxyethoxy) phenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide (47mg, 0.1mmol) and potassium carbonate (28mg, 0.2mmol) in 2mL of MeCN at room temperature was added 2-bromoethanol (12mg, 0.1 mmol). The reaction was stirred at rt overnight, TLC showed the reaction was complete and the reaction was filtered directly, the filtrate was concentrated under reduced pressure and purified by silica gel plate chromatography (DCM: MeOH ═ 20: 1) to give 20mg (yield: 39%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.35(3H，m)，1.82-2.08(7H，m)，2.23-2.40(1H，m)， 3.14-3.21(1H，m)，3.32-3.40(1H，m)，3.48(1H，brs)，3.84-3.89(2H，m)，4.45-4.51(2H，m)， 4.97-5.10(2H，m)，6.95(0.6H，d，J＝5.2Hz)，7.23-7.29(1.4H，m)，7.46-4.51(1H，m)，7.60-7.81 (3H，m)，7.99-8.04(1H，m)，8.68-8.71(1H，m)，9.88(1H，s).
EM (calculated): 513.2; MS (ESI) M/e (M +1H)+：514.2
Example 94: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -N- (4- (2-hydroxyethoxy) phenyl) propanamide, the synthetic procedure was as follows:
Figure BDA0001918189360000632
step 1: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -N- (4- (2-hydroxyethoxy) phenyl) propanamide
To a solution of N- (4-hydroxyphenyl) -2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) propionamide (44mg, 0.1mmol) and potassium carbonate (28mg, 0.2mmol) in 2mL of MeCN at room temperature was added 2-bromoethanol (12mg, 0.1 mmol). The reaction was stirred at rt overnight, TLC showed the reaction was complete and the reaction was filtered directly, the filtrate was concentrated under reduced pressure and purified by silica gel plate chromatography (DCM: MeOH ═ 20: 1) to give 25mg (yield: 52%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.31(3H，m)，1.83-2.10(7H，m)，2.21-2.40(1H，m)， 3.15-3.21(1H，m)，3.30-3.39(1H，m)，3.4-3.48(1H，m)，3.88-3.93(2H，m)，4.41-4.47(2H，m)， 4.97-5.08(2H，m)，6.95-7.06(2.6H，m)，7.22(0.4H，d，J＝5.6Hz)，7.43-7.47(2H，m)，7.63-7.78 (2H，m)，7.98-8.05(1H，m)，8.70-8.73(1H，m)，9.81(1H，s).
EM (calculated): 479.2, respectively; MS (ESI) M/e (M +1H)+：480.2
Example 95: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -N- (4- (2-hydroxyethoxy) phenyl) propanamide
The synthesis steps are as follows:
Figure BDA0001918189360000641
step 1: preparation of diethyl 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) malonate
At room temperature to 4- ((8-azabicyclo [ 3.2.1)]To a solution of oct-3-yl) oxy) -6-fluoroquinoline dihydrochloride (345mg, 1.0mmol) in 5mL of MeCN was added TEA (505mg, 5.0mmol) while controlling the system temperature below 30 ℃. Diethyl bromomalonate (239mg, 1.0mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by column chromatography (PE: EA 1: 1) gives 180mg (yield: 42%) of the title compound as a pale yellow solid.
Step 2: preparation of ethyl 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) -3-hydroxypropionate
Charging 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] at 0-10 DEG C]Octane-8-yl) malonic acid diethyl ester (130mg, 0.3mmol) in 3mL MeOH and NaBH was added portionwise4(15mg, 0.4mmol), stirring the reaction mixture at 0-10 deg.C for 30min, pouring the reaction into 20mL saturated ammonium chloride aqueous solution, extracting with EA (10mL x3), and saturating the organic phase with EAWashed with brine and anhydrous Na2SO4And (5) fully drying. After concentration under reduced pressure, purification by silica gel plate chromatography (DCM: MeOH ═ 20: 1) gave 85mg (yield: 73%) of the title compound as a yellow solid.
And step 3: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] octan-8-yl) -3-hydroxypropionic acid
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1]2mL MeOH/H of Ethyl octane-8-yl) -3-hydroxypropionate (80mg, 0.2mmol)2NaOH (32mg, 0.8mmol) was added to the O (1/1) solution, and the reaction was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using dilute hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 10mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined, and concentrated under reduced pressure to give 65mg (yield: 87%) of the objective compound as a pale yellow solid.
And 4, step 4: preparation of 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] oct-8-yl) -N- (4- (2-hydroxyethoxy) phenyl) propanamide
To 2- (3- ((6-fluoroquinolin-4-yl) oxy) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) -3-hydroxypropionic acid (60 mg, 0.17mmol) in 2mL of THF was added pyridine (66mg, 0.83mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 127mg, 0.2mmol) and 4-chloroaniline (25mg, 0.2 mmol). The reaction mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water and extracted with EA (10 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by silica gel plate chromatography (DCM: MeOH 10: 1) gave 15mg (yield: 19%) of the title compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.87-2.12(7H，m)，2.24-2.41(1H，m)，3.13-3.19(1H，m)， 3.32-3.39(1H，m)，3.48(1H，brs)，3.92-3.96(1H，m)，4.27-2.33(1H，m)，4.97-5.12(2H，m)，6.96 (0.6H，d，J＝5.2Hz)，7.23(0.4H，d，J＝5.6Hz)，7.34-7.38(2H，m)，7.67-7.81(4H，m)，7.97-8.02 (1H，m)，8.70-8.72(1H，m)，9.89(1H，s).
EM (calculated): 469.2, respectively; MS (ESI) M/e (M +1H)+：470.2
Example 96: preparation of N- (4-chlorophenyl) -2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide the synthesis procedure is as follows:
Figure BDA0001918189360000651
step 1: preparation of 3-cyano-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
t-BuOK (4.5g, 40.2mmol) was added portionwise to a solution of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (4.5g, 20.0mmol) and p-toluenesulfonylmethylisonitrile (5.9g, 30.2mmol) in 50mL DME/EtOH (30/1) at 0 ℃ with the system temperature controlled below 10 ℃. After the addition, the system was stirred at room temperature for 0.5h, and then stirred at 40 ℃ for 2 h. After the reaction was completed, the reaction system was filtered, and the solid was washed with DME. The filtrates were combined and concentrated under reduced pressure, and the crude product was purified by column chromatography (PE: EA: 10: 1) to give 1.5g (yield: 32%) of the title compound as a yellow solid.
Step 2: preparation of 3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
Under nitrogen protection at-70 deg.C, n-butyllithium (1.6M in n-hexane, 3.9mL, 6.2mmol) was added dropwise to a solution of 4-bromo-6-fluoroquinoline (1.4g, 6.2mmol) in 20mL of THF, the reaction mixture was stirred at-70 deg.C for 30min, and then 3-cyano-8-azabicyclo [3.2.1] was added dropwise to the reaction system]Octane-8-carboxylic acid tert-butyl ester (1.4g, 5.6mmol) in 5mL THF. The system was stirred for 2h at-70 ℃. Poured into 100mL saturated aqueous ammonium chloride, then extracted with EA (50mL x3), and the organic phase washed with saturated brine, anhydrous Na2SO4And (5) fully drying. After concentration under reduced pressure, column chromatography (DCM: MeOH ═ 30: 1) afforded 1.1g (yield: 46%) of the title compound as a yellow solid.
And step 3: preparation of (8-azabicyclo [3.2.1] octan-3 yl) (6-fluoroquinolin-4-yl) methanone dihydrochloride
A solution of 3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (1.0g, 2.6mmol) in 20mL 4M HCl/EA was stirred at room temperature for 6 h. TLC showed that after completion of the reaction, the reaction was directly concentrated under reduced pressure, and the crude product was slurried with 10mL of EA to give 0.9g (yield: 97%) of the title compound as a pale yellow solid.
And 4, step 4: preparation of ethyl 2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] octan-8-yl) propionate
At room temperature to (8-azabicyclo [3.2.1]]To a solution of octane-3-yl) (6-fluoroquinolin-4-yl) methanone dihydrochloride (714mg, 2.0mmol) in 10mL of MeCN was added TEA (505mg, 5.0mmol) while controlling the system temperature below 30 ℃. Ethyl 2-bromoacetate (362mg, 2.0mmol) was added. The reaction mixture was stirred at room temperature overnight and TLC showed the reaction was complete. The reaction was poured into 50mL of water and extracted with EA (30 mL. times.3). The organic phase was washed twice with saturated brine and anhydrous Na2SO4After sufficiently drying, concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA: 3: 1) to give 560mg (yield: 73%) of the objective compound as a pale yellow solid.
And 5: preparation of 2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] octan-8-yl) propionic acid
To 2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1]Octane-8-yl) propionic acid ethyl ester (538mg, 1.4mmol) in 10mL MeOH/H2NaOH (240mg, 6.0mmol) was added to the O (1/1) solution, and the reaction was stirred at room temperature overnight. And after the reaction is finished, adjusting the pH value of the system to 5-6 by using dilute hydrochloric acid, and concentrating under reduced pressure. To the resulting residue was added 30mL DCM/MeOH (20/1) and stirred for 10 min. Filtration and cake washing with DCM/MeOH (20/1) until no product remained. The filtrates were combined, and concentrated under reduced pressure to give 440mg (yield: 88%) of the objective compound as a pale yellow solid.
Step 6: preparation of N- (4-chlorophenyl) -2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
To 2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] under nitrogen protection]To a solution of octane-8-yl) propionic acid (356mg, 1.0mmol) in 5mL of THF was added pyridine (395mg, 5.0mmol), followed by dropwise addition of T in this order at room temperature3P (50% in EA, 954mg, 1.5mmol) and 4-chlorobenzeneAmine (254mg, 2.0 mmol). The reaction mixture was stirred at 70 ℃ overnight. The reaction was poured into 20mL of water and extracted with EA (20 mL. times.3). The organic phase was washed with saturated brine, anhydrous Na2SO4After drying, concentration under reduced pressure and purification of the crude product by column chromatography (DCM: MeOH 15: 1) gave 275mg (yield: 59%) of the title compound as a pale yellow solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.32(3H，m)，1.82-2.10(7H，m)，2.21-2.41(1H，m)， 3.10-3.21(2H，m)，3.30-3.40(1H，m)，3.47-3.50(1H，m)，6.95(0.6H，d，J＝5.2Hz)，7.18(0.4H，d， J＝5.6Hz)，7.33-7.36(2H，m)，7.63-7.81(4H，m)，7.97-8.03(1H，m)，8.69-8.71(1H，m)，9.80(1H， s).
EM (calculated): 465.2; MS (ESI) M/e (M + H)+：466.2
Example 97: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) (hydroxy) methyl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide
Charging N- (4-chlorophenyl) -2- (3- (6-fluoroquinoline-4-carbonyl) -8-azabicyclo [3.2.1] at 0-10 deg.C]To a solution of oct-8-yl) propionamide (93mg, 0.2mmol) in 3mL MeOH was added NaBH in portions4(15mg, 0.4mmol), stirring the reaction mixture at 0-10 deg.C for 30min, pouring the reaction into 20mL saturated aqueous ammonium chloride solution, extracting with EA (10mL x3), washing the organic phase with saturated brine, anhydrous Na2SO4And (5) fully drying. After concentration under reduced pressure, purification by silica gel plate chromatography (DCM: MeOH ═ 10: 1) gave 70mg (yield: 75%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.28-1.32(3H，m)，1.82-2.14(7H，m)，2.21-2.45(2H，m)，3.16-3.25(1H，m)，3.28-3.36(1H，m)，3.45-3.47(1H，m)，5.10-5.13(1H，m)，5.25(1H，brs)，7.03 (0.7H，d，J＝5.6Hz)，7.25(0.3H，d，J＝5.6Hz)，7.33-7.38(2H，m)，7.65-7.81(4H，m)，8.00-8.05 (1H，m)，8.69-8.71(1H，m)，9.84(1H，s).
EM (calculated): 467.2, respectively; MS (ESI) M/e (M + H)+：468.2
Example 98: preparation of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) methyl) -8-azabicyclo [3.2.1] oct-8-yl) propanamide
To a solution of N- (4-chlorophenyl) -2- (3- ((6-fluoroquinolin-4-yl) (hydroxy) methyl) -8-azabicyclo [3.2.1] oct-8-yl) propionamide (47mg, 0.1mmol) in 3mL MeOH at room temperature was added Pt/C (10%, 10mg), and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen at about two atmospheres for 6 h. After TLC indicated completion of the reaction, the reaction was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel plate chromatography (DCM: MeOH ═ 25: 1) to give 18mg (yield: 40%) of the title compound as an off-white solid.
1H NMR(400MHz，d6-DMSO)δ1.25-1.33(3H，m)，1.87-2.12(7H，m)，2.24-2.41(1H，m)， 3.13-3.19(1H，m)，3.32-3.39(1H，m)，3.48(1H，brs)，3.92-3.96(1H，m)，4.27-2.33(1H，m)， 4.97-5.12(1H，m)，6.96(0.6H，d，J＝5.2Hz)，7.23(0.4H，d，J＝5.6Hz)，7.34-7.38(2H，m)， 7.67-7.81(4H，m)，7.97-8.02(1H，m)，8.70-8.72(1H，m)，9.89(1H，s).
EM (calculated): 451.2: MS (ESI) M/e (M +1H)+：452.2
Biological assay
Test example one test for the inhibitory Effect of Compounds on the Activity of IDO1 on Hela cells
1: test materials:
RPMI 1640 (phenol red free) medium (Invitrogen Cat.No.11835030), fetal bovine serum (Invitrogen Cat.No. 10099141), streptomycin (Invitrogen Gibco Cat.No.15140-122), NFKGreen fluorescence detection kit (NTRC, Cat.No. NTRC-GSCell-1K), DMSO (Sigma, Cat.No. D2650), 384 wells compound plate (Greiner, Cat.No.781280), 384 wells cell microplate (Greiner, Cat.No.781090)
2: the experimental method comprises the following steps:
compound final test concentration:
test and reference compounds INCB024360 final test concentrations ranged from 10M to 0.51nM, 3-fold gradient dilution, 10 concentrations, double wells.
And (3) cytological detection:
HeLa cells were plated in 384-well cell culture plates at a number of 8,000 cells per well, and cultured in RPMI 1640 containing 10% fetal bovine serum. After adding the diluted test compound and 1 mu M L-tryptophan, the recombinant human interferon gamma with the final concentration of 100ng/mL activates IDO1 expression. The cells were cultured in a cell culture chamber at 37 ℃ enriched with 5% carbon dioxide for 2 days. Adding a detection reagent according to the operation instruction of the NFK Green fluorescence detection kit, reading by using an Envision plate reader (exciting light, 400/25; emitting light, 510/20), and detecting the content of the N-acetyl kynurenine. Data analysis and mapping were performed according to XLfit5 software.
TABLE 2
Figure BDA0001918189360000671
Figure BDA0001918189360000681
Test example two liver microsome stability test
1: materials and methods
A buffer solution;
1.100 mM potassium phosphate buffer, pH 7.4
2. 10mM MgCl2
Preparation of compound solution:
preparation of 1.100. mu.M working solution: mu.L of the stock solution (10mM) of the test or control group was diluted with 495. mu.L of methanol to give a compound concentration of 100. mu.M (99% MeOH).
Preparation of 2.10 μ M working solution: mu.L of 100. mu.M working solution was diluted with 450. mu.L of 100mM potassium phosphate buffer to give a compound concentration of 10. mu.M (9.9% MeOH).
Composition of NADPH (prototype coenzyme II) regeneration System (final concentration of isocitrate dehydrogenase in culture broth 1 unit/mL):
1.: β -nicotinamide adenine dinucleotide phosphate, supplier: sigma Aldrich (Sigma-Aldrich) cargo number: n0505
2. Isocitric acid, supplier: sigma Aldrich (Sigma-Aldrich) cargo number: i1252
3. Isocitrate dehydrogenase, supplier: sigma Aldrich (Sigma-Aldrich) cargo number: i2002
Composition of NADPH (prototype coenzyme II) regeneration System (final concentration of isocitrate dehydrogenase in culture broth 1 unit/mL):
1.: β -nicotinamide adenine dinucleotide phosphate, supplier: sigma Aldrich (Sigma-Aldrich) cargo number: n0505
2. Isocitric acid, supplier: sigma Aldrich (Sigma-Aldrich) cargo number: i1252
3. Isocitrate dehydrogenase, supplier: sigma Aldrich (Sigma-Aldrich) cargo number: i2002
Preparation of liver microsome solution (final concentration of 0.5mg protein/mL):
Figure BDA0001918189360000682
stopping liquid:
acetonitrile ice-cold solution containing 100ng/mL tolbutamide and 100ng/mL zamide as internal standard substance
The method comprises the following operation steps:
1. in addition to the blank matrix plate wells, 10 μ 0 working solution of test or control drug was added to each of the plate wells (T0, T5, T10, T20, T30, T60, and NCF 60).
2. The liver microsome solution was added in an amount of 680. mu.L/well, then 80. mu.L/well by Apricot, corresponding to a 96-well plate, and the solution containing the liver microsomes and the test substance was incubated at 37 ℃ for 10 minutes.
3. To each well of the NCF60 plate was added 10. mu.L of 100mM potassium phosphate buffer, the incubation temperature was 37 ℃, and timer 1 was started.
Figure BDA0001918189360000691
4. After preheating, NADPH (prototype coenzyme II) regenerating solution was added to a 96-well plate in an amount of 90. mu.L/well, and then the corresponding solution was added to a 96-well plate in an amount of 80. mu.L/well using Apricot, and the reaction was initiated.
5. The above 96-well plate was placed in a 37 ℃ incubator for incubation, and timer 2 was started.
Figure BDA0001918189360000692
6. The reaction was stopped by adding pre-cooled stop solutions (containing 100ng/mL tolbutamide and 100ng/mL albuterol) at 4 ℃ to each well.
7. The sample plate was then shaken on a shaking trigger for about 10 minutes.
8. The samples were centrifuged at 4000rpm for 20min at 4 ℃.
9. And adding 300 mu L of HPLC-grade water into each hole of another 96-hole plate, adding 100 mu L of supernate obtained by centrifugation into the corresponding hole position, and uniformly mixing the two for LC/MS/MS detection.
And (3) data analysis:
calculating t from first order elimination kinetics1/2And Clint(mic)Value of
The first order elimination kinetics equation is:
Figure BDA0001918189360000693
Figure BDA0001918189360000694
Figure BDA0001918189360000695
Figure BDA0001918189360000696
Figure BDA0001918189360000697
Figure BDA0001918189360000701
as can be seen from the research data, the compound of the invention has obvious inhibiting effect on IDO activity, the inhibiting activity on HeLa cells is obviously superior to that of NLG-919, Epacadostat and BMS-986205 in clinical stage, and the HeLa cell inhibiting activity is more than 100 times of NLG-919 and more than 4 times of BMS-986205 in some embodiments of the invention. From the aspect of stability of liver microsomes, the invention also has obvious drug properties, so the invention has wide application prospects in resisting malignant tumor diseases, autoimmune diseases, viral infection, depression, AIDS, myelodysplastic syndrome, anxiety, cataract and the like.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications, equivalent structures, or equivalent processes that may be made or used directly or indirectly in other related fields using the principles of the present invention and the contents of the specification are included in the scope of the present invention.

Claims (27)

1. A compound having a structure according to formula (V) or (V') or a stereoisomer, pharmaceutically acceptable salt thereof:
Figure 705227DEST_PATH_IMAGE001
R12、R13、R14、R15independently selected from H, nitro, hydroxyl, amino, sulfydryl, halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl;
d is selected from a bond, oxygen, -CH2-, -CO-, -CH (OH) -, nitrogen, sulfur；
B is independently selected from carbon or nitrogen;
m is selected from 1-3, (Q) m and the cycloalkyl connected with the m form a bridge ring structure, and Q is selected from CR9R10、N-R11；
The R is9、R10、R11Independently selected from H, halogen, alkyl, heteroalkyl, cycloalkyl, said heteroalkyl referring to alkyl containing a heteroatom selected from O, S, N, P;
n1、n2independently 0, 1, 2,3 or 4, and not simultaneously 0;
R1selected from H, C1-6 alkyl;
R2the substituent is selected from H, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and the substituent is selected from halogen, hydroxyl, nitro, amino, sulfydryl and cyano;
Z2is selected from O;
Figure 91209DEST_PATH_IMAGE002
the amidine functional group connected with the amidine functional group forms a substituted or unsubstituted monocyclic heteroaryl, bicyclic or tricyclic fused ring heteroaryl, and the substituent is selected from nitro, hydroxyl, amino, sulfydryl, halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, 5-6 membered aryl or heteroaryl;
Ar1is a monocyclic aryl or heteroaryl group, said heteroaryl group being selected from one of the following structures
Figure DEST_PATH_IMAGE003
。
2. The compound of claim 1, wherein:
R1selected from H, methyl;
R2selected from H, F, methyl, -CH2CF3、
Figure DEST_PATH_IMAGE004
；R1、R2Not H at the same time;
Ar1selected from phenyl, pyridyl and 2-thiazolyl.
3. The compound of claim 1, wherein:
Figure 526738DEST_PATH_IMAGE005
the structure shown is selected from the following structures:
Figure 390789DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
。
4. the compound of claim 1, wherein: r12、R13、R14、R15Independently selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl.
5. The compound of claim 1, wherein: the compound has a structure shown as a formula (VI) or (VI'), or a stereoisomer and a pharmaceutically acceptable salt thereof:
Figure 142845DEST_PATH_IMAGE008
。
6. the compound of claim 1 or 5, wherein: both ends of (Q) m are connected with C adjacent to B on the ring on which B is positioned.
7. The compound of claim 1 or 5, wherein: n is1、n2Independently is 1.
8. The compound of claim 1, wherein: the compound has a structure shown as a formula (VII) or (VII') or a stereoisomer and a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE009
。
9. the compound of any one of claims 1, 5, 8, wherein:
Figure 886679DEST_PATH_IMAGE010
the amidine functional group connected with the amidine functional group has the following structure:
Figure 622553DEST_PATH_IMAGE011
wherein A is5Selected from C or N;
R17、R18independently selected from H, nitro, hydroxyl, amino, sulfydryl, halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, 5-6 membered aryl or heteroaryl;
or, R17、R18And atoms connected with the aryl or heteroaryl form 5-10 membered monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
10. The compound of claim 9, wherein: r17、R18Each independently selected from 5-6 membered aryl or heteroaryl; or, R17、R18And atoms connected with the aryl or the heteroaryl form 5-6-membered aryl or heteroaryl.
11. The compound of claim 9, wherein: the heteroaryl group contains N or/and O.
12. The compound of claim 11, wherein: the heteroaryl group contains N.
13. The compound of claim 9, wherein: r17、R18Wherein the substituents are independently selected from halogen, amino, oxygen, C1-6 alkyl or C1-6 heteroalkyl.
14. The compound of any one of claims 1-13, wherein: the compound has a structure shown in a formula (VIII) or a stereoisomer and pharmaceutically acceptable salt thereof:
Figure 273983DEST_PATH_IMAGE012
wherein R is16Selected from the group consisting of none, nitro, hydroxy, amino, mercapto, halogen, cyano, C1-6 alkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, 5-6 membered aryl or heteroaryl;
n3is 0, 1, 2,3 or 4.
15. The compound of claim 14, wherein: r16Selected from halogen, cyano, hydroxyl, nitro, C1-6 alkyl, and C1-6 heteroalkyl.
16. The compound of claim 14 or 15, wherein: n is3Is 1 or 2.
17. A compound according to any one of claims 14 or 16, wherein: n is3Is 1, R16Taking amino para position.
18. The compound of any one of claims 1, 5, 8, 14, wherein: d is selected from O and-CH2-、-CO-、-CH(OH)-。
19. The compound of any one of claims 1, 5, 8, 14, wherein: b is selected from N.
20. A compound according to any one of claims 1 to 19, wherein: r12、R14、R15Is selected from H.
21. A compound characterized by: the compound has the following structure or a stereoisomer and a pharmaceutically acceptable salt thereof:
Figure 752571DEST_PATH_IMAGE002
Figure 873909DEST_PATH_IMAGE014
Figure 532308DEST_PATH_IMAGE004
Figure 193096DEST_PATH_IMAGE006
Figure 812259DEST_PATH_IMAGE016
Figure DEST_PATH_IMAGE017
。
22. a pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition is selected from the compounds of any one of claims 1-21 or one or more of stereoisomers and pharmaceutically acceptable salts thereof.
23. Use of a compound according to any one of claims 1 to 21, or a stereoisomer or pharmaceutically acceptable salt thereof, for the preparation of an indoleamine 2, 3-dioxygenase (IDO) inhibitor or/and a tryptophan-2, 3-dioxygenase (TDO) inhibitor.
24. The use according to claim 23, wherein the inhibitor is used for the treatment of at least one of the following diseases: cancer, autoimmune disorders, viral infections, depression, AIDS, myelodysplastic syndrome, anxiety, cataracts.
25. The use according to claim 24, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, rectal cancer, liver cancer, stomach cancer, ovarian cancer, pancreatic cancer, testicular cancer, bladder cancer, myeloma, non-small cell lung cancer, leukemia, lymphoma, melanoma, esophageal cancer, connective tissue cancer, mesothelial cancer, prostate cancer, bone cancer, renal cancer.
26. Use according to claim 23 or 24, characterized in that: the use of said compounds or stereoisomers, pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a disease which results in the over-expression of indoleamine 2, 3-dioxygenase (IDO) or/and tryptophan-2, 3-dioxygenase (TDO).
27. Use according to claim 23 or 24, characterized in that: the application of the compound or the stereoisomer and the pharmaceutically acceptable salt thereof in preparing the medicines for treating diseases caused by over-expression of indoleamine 2, 3-dioxygenase (IDO) or/and tryptophan-2, 3-dioxygenase (TDO).
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