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CN121159455A - Amino ester compounds and their use as P2X7 antagonists - Google Patents

Amino ester compounds and their use as P2X7 antagonists

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Publication number
CN121159455A
CN121159455A CN202510820922.5A CN202510820922A CN121159455A CN 121159455 A CN121159455 A CN 121159455A CN 202510820922 A CN202510820922 A CN 202510820922A CN 121159455 A CN121159455 A CN 121159455A
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China
Prior art keywords
alkyl
compound
independently selected
formula
substituted
Prior art date
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Pending
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CN202510820922.5A
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Chinese (zh)
Inventor
张学军
贾一民
李金平
李杨
张鑫利
宋小波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Original Assignee
Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Application filed by Humanwell Healthcare Group Co ltd, Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co filed Critical Humanwell Healthcare Group Co ltd
Publication of CN121159455A publication Critical patent/CN121159455A/en
Pending legal-status Critical Current

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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D498/04—Ortho-condensed systems

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Abstract

本发明提供了式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药；该化合物可用作P2X7受体拮抗剂， This invention provides a compound of formula (I), its stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs; this compound can be used as a P2X7 receptor antagonist.

Description

Amino ester compounds and their use as P2X7 antagonists
PRIORITY INFORMATION
The present application requests the priority and rights of patent application 202410789810.3 submitted to the China national intellectual property office at 18/6/2024, patent application 202410931486.4 submitted to the China national intellectual property office at 11/7/2024 and patent application 202411596682.7 submitted to the China national intellectual property office at 8/2024, and is incorporated herein by reference in its entirety.
Technical Field
The invention belongs to the field of medicines, in particular relates to amino ester compounds, and more particularly relates to amino ester compounds and application thereof as P2X7 antagonists.
Background
The P2 receptor is a cell membrane receptor combined with extracellular nucleotides (such as ATP, ADP and the like), and the receptors are divided into two major families of ligand-gated ion channel receptors P2X and G protein coupled receptors P2Y, wherein the P2X receptor is divided into 7 subtypes (P2X 1-7). The P2X7 receptor is closely related to the development and progression of most diseases. Activation of the P2X7 receptor opens ion channels (sodium, calcium and potassium influx) on the cell membrane, activates various intracellular signaling pathways, releases various inflammatory cytokines, damages the nervous system and induces pain. In the nervous system, activation of the P2X7 receptor mainly activates microglia, releasing inflammatory cytokines, damaging the nervous system. In addition, up-regulation of P2X7 receptor expression can activate immune cells, promote inflammatory responses, increase tissue damage, and exacerbate pain. There are studies that find over-expression of the P2X7 receptor in a variety of tumors, closely related to tumor progression, metastasis and angiogenesis. Therefore, antagonizing the P2X7 receptor can effectively prevent and treat various diseases such as pain, central diseases, immune diseases and inflammatory diseases, and has important clinical application value.
Disclosure of Invention
The invention aims to provide an amino ester compound serving as a P2X7 antagonist, and a preparation method and application thereof.
In a first aspect of the invention, the invention provides a compound of formula (I), a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof:
Wherein:
R 1 is selected from the group consisting of 6-15 membered aryl, 5-10 membered heteroaryl substituted with p R a, p is an integer selected from 0,1, 2,3 and 4;
R 2、R3 is each independently selected from hydrogen, deuterium and C 1-6 alkyl substituted by q R b, q is an integer selected from 0,1, 2,3, R b is each independently selected from halogen, -OH, -CN, -NH 2, oxo (=O), C 1-6 alkyl and-O-C 1-6 alkyl;
Or one of R 2 and R 3 is hydrogen, deuterium or is absent, and the other forms a 3-7 membered ring with R 1 substituted by j R c;
R a and R c are each independently selected from halogen, -OH, -CN, C 1-6 alkyl, -O-C 1-6 alkyl, halogenated C 1-6 alkyl, -O-halogenated C 1-6 alkyl, C 3-7 cycloalkyl, -O-C 3-7 cycloalkyl, -S (O) R-R a1、-SF5、-NRa1Ra2, R a1 and R a2 are each independently selected from hydrogen, C 1-6 alkyl, R is an integer selected from 0,1, 2;
r 4 is selected from hydrogen, deuterium, fluorine;
R 5 is selected from the group consisting of hydrogen, deuterium, halogen, -OH, -CN, and groups substituted with k R d C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, - (C=O) -R 51、-(C＝O)-NR51R52, and-NR 51R52, k is an integer selected from 0,1, 2,3, and 4, R 51 and R 52 are each independently selected from the group consisting of hydrogen, -OH, C 1-6 alkyl, C 1-6 alkyl substituted with hydroxy, R d is selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl, and-O-C 1-6 alkyl;
R 6 and R 7 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted with hydroxy and/or halogen;
Or R 6、R7 may form a 3-7 membered heterocyclic ring with the N atom to which it is commonly attached, said 3-7 membered heterocyclic ring being substituted with u R e, u being selected from 0, 1, 2, 3,4, 5 and 6, said R e each being independently selected from halogen, -OH, oxo (=O), C 1-6 alkyl, -O-C 1-6 alkyl, halogenated C 1-6 alkyl, -O-halogenated C 1-6 alkyl;
m is selected from 0 and 1, and n is selected from 0,1 and 2.
The alkyl group comprises a linear alkyl group and a branched alkyl group;
the halogen is selected from fluorine, chlorine, bromine and iodine, preferably the halogen is selected from fluorine and chlorine.
According to certain embodiments of the present invention, there is provided a compound of formula (I), stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs thereof:
Wherein:
R 1 is selected from the group consisting of 6-15 membered aryl, 5-10 membered heteroaryl substituted with p R a, p is an integer selected from 0,1, 2,3 and 4;
R 2、R3 is independently selected from hydrogen or C 1-6 alkyl substituted by q R b, q is an integer selected from 0,1, 2,3, R b is independently selected from halogen, -OH, -CN, -NH 2, oxo (=O), C 1-6 alkyl and-O-C 1-6 alkyl;
Or one of R 2 and R 3 is hydrogen or is absent, and the other forms a 3-7 membered ring with R 1 substituted by j R c;
R a and R c are each independently selected from halogen, -OH, -CN, C 1-6 alkyl, -O-C 1-6 alkyl, halogenated C 1-6 alkyl, -O-halogenated C 1-6 alkyl, C 3-7 cycloalkyl, -O-C 3-7 cycloalkyl, -S (O) R-R a1、-SF5、-NRa1Ra2, R a1 and R a2 are each independently selected from hydrogen, C 1-6 alkyl, R is an integer selected from 0,1, 2;
r 4 is selected from hydrogen, deuterium, fluorine;
R 5 is selected from the group consisting of hydrogen, halogen, -OH, -CN, and C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl, 3-to 6-membered heterocycloalkyl, - (C=O) -R 51、-(C＝O)-NR51R52, and-NR 51R52 substituted with k R d, k is an integer selected from 0, 1,2, 3, and 4, R 51 and R 52 are each independently selected from the group consisting of hydrogen, -OH, C 1-6 alkyl, C 1-6 alkyl substituted with hydroxy, R d is selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl, and-O-C 1-6 alkyl;
R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with hydroxy and/or halogen;
Or R 6、R7 may form a 3-7 membered heterocyclic ring with the N atom to which it is commonly attached, said 3-7 membered heterocyclic ring being substituted with u R e, u being selected from 0, 1, 2, 3,4, 5 and 6, said R e each being independently selected from halogen, -OH, oxo (=O), C 1-6 alkyl, -O-C 1-6 alkyl, halogenated C 1-6 alkyl, -O-halogenated C 1-6 alkyl;
m is selected from 0 and 1, and n is selected from 0,1 and 2.
The alkyl group comprises a linear alkyl group and a branched alkyl group;
the halogen is selected from fluorine, chlorine, bromine and iodine, preferably the halogen is selected from fluorine and chlorine.
According to some embodiments of the invention, in the compound shown in the formula (I), in R 1, the hetero atom of the 5-10 membered heteroaryl is selected from 1 or 2 in N, O, S, the hetero atom number is 1,2 or 3, and undefined groups are as described in any one of the schemes of the invention.
According to some embodiments of the invention, in the compound of formula (I), R 1 is selected from thienyl, thiazolyl, isoxazolyl, pyrazolyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl, and the undefined group is as defined in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 1, the 6-15 membered aryl is selected from phenyl, indenyl, naphthyl and azulenyl, and the undefined groups are as described in any of the embodiments of the present invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 1, R a, each independently selected from fluorine, chlorine, -OH, -CN, C 1-6 alkyl, -SF 5、-O-C1-6 alkyl, halogenated C 1-6 alkyl, -O-halogenated C 1-6 alkyl, C 3-7 cycloalkyl, -O-C 3-7 cycloalkyl, -S (O) R-R a1、-NRa1Ra2, R a1 and R a2, each independently selected from hydrogen, C 1-6 alkyl, R is an integer selected from 0,1, 2, C 1-6 alkyl, alone or as part of another group, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and C 3-7 cycloalkyl, alone or as part of another group, each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, an undefined group as described in any of the schemes of the present invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 1 is selected from R a and p are as defined in any one of the preceding claims, and the undefined groups are as defined in any one of the preceding claims.
According to certain embodiments of the present invention, in the compounds of formula (I), R 1 is selected from R a and p are as defined in any one of the preceding claims, and the undefined groups are as defined in any one of the preceding claims.
According to certain embodiments of the invention, in the compounds of formula (I), R 2、R3, the C 1-6 alkyl, alone or as part of another group, is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, an undefined group being as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 2、R3 are each independently selected from hydrogen, deuterium, methyl, ethyl, undefined groups as described in any of the schemes of the present invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 2、R3 are each independently selected from hydrogen, methyl, ethyl, undefined groups as described in any of the schemes of the present invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, the 3-7 membered ring is selected from the group consisting of 3-7 membered cycloalkenyl and 3-7 membered heterocycloalkenyl, the 3-7 membered heterocycle includes 1,2, or 3 heteroatoms selected from N, O and S, and the undefined groups are as described in any one of the embodiments of the present invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, a groupSelected from the group consisting ofRepresents a single bond or a double bond, X 1、X2 and X 3 are each independently selected from CH, CH 2, N, NH, O, S, t1 and t2 are each independently selected from 0,1 and 2;R a、Rc, p, j and other undefined groups as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, a groupSelected from the group consisting ofX 1、X2 and X 3 are each independently selected from CH 2, NH, O, S, t1 and t2 are each independently selected from 0,1 and 2;R a、Rc, p, j and other undefined groups as described in any one of the embodiments of the present invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, a groupSelected from the group consisting ofX 1、X2 and X 3 are each independently selected from CH 2, NH, O, S, and at least one of X 1、X2 and X 3 is selected from NH, O, and S, t1 and t2 are each independently selected from 0,1 and 2;R a、Rc, p, and j are as defined in claim 1, and R a、Rc, p, j, and other undefined groups are as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, a groupSelected from the group consisting ofX 1 is independently selected from NH, O, S, X 2 and X 3 are each independently selected from CH 2, t1 is 1, t2 is 1;R a、Rc, p, j and other undefined groups are as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, a groupSelected from the group consisting ofX 1 is independently selected from NH, O, S, X 2 and X 3 are each independently selected from CH 2, t1 is 1, t2 is 1;R a is independently selected from halogen, p is selected from 1 and 2;j is 0, and undefined groups are as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 2 or R 3 and R 1 form a 3-7 membered ring substituted with j R c, a groupSelected from the group consisting ofX 1 is independently selected from CH 2、NH、O、S;Ra、Rc, j and other undefined groups as described in any of the embodiments of the invention.
According to certain embodiments of the present invention, R 5 is selected from the group consisting of hydrogen, halogen, -OH, and C 1-6 alkyl substituted with k R d, k is selected from the group consisting of 0, 1,2, 3, and 4, R d is selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl, and-O-C 1-6 alkyl, and undefined groups are described in any of the embodiments of the present invention.
According to some embodiments of the invention, R 5 is selected from hydrogen, fluoro, chloro, -OH, methyl and ethyl in the compounds of formula (I), the undefined groups being as described in any one of the embodiments of the invention.
According to certain embodiments of the invention, in the compounds of formula (I), R 6、R7, the C 1-6 alkyl, alone or as part of another group, is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, an undefined group being as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 6、R7 are each independently selected from hydrogen, methyl, ethyl, undefined groups as described in any of the schemes of the present invention.
According to some embodiments of the invention, in the compound shown in the formula (I), when R 6、R7 and the N atom which is jointly connected with the compound form a 3-7 membered heterocyclic ring, the 3-7 membered heterocyclic ring is a saturated ring, and undefined groups are as described in any scheme of the invention.
According to some embodiments of the invention, in the compound shown in formula (I), when R 6、R7 and the N atom to which R 6、R7 is commonly connected form a 3-7 membered heterocyclic ring, the 3-7 membered heterocyclic ring is a saturated ring containing only 1N atom, and undefined groups are as described in any one of the embodiments of the invention.
According to some embodiments of the invention, in the compounds of formula (I), when R 6、R7 and the N atom to which it is jointly attached form a 3-7 membered heterocyclic ring, said 3-7 membered heterocyclic ring is substituted by u R e, u is selected from 0,1, 2 and 3, each R e is independently selected from halogen, -OH, oxo (=O), C 1-3 alkyl, halogenated C 1-3 alkyl, -O-C 1-3 alkyl, -O-halogenated C 1-3 alkyl, and the undefined groups are as described in any one of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), when R 6、R7 forms a 3-to 7-membered heterocyclic ring with the N atom to which it is commonly attached, a groupSelected from the group consisting ofUndefined groups are as described in any of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), R 1 is selected fromUndefined groups are as described in any of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), the radicalsSelected from the group consisting of
Undefined groups are as described in any of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), the radicalsSelected from the group consisting of
Undefined groups are as described in any of the embodiments of the invention.
According to certain embodiments of the present invention, in the compounds of formula (I), the radicalsSelected from the group consisting of-NH 2,Undefined groups are as described in any of the embodiments of the invention.
According to certain embodiments of the invention, the compound is selected from the following structures:
R 1、R2、R3、R4、R5、R6、R7, m and n are as defined in any one of the embodiments of the first aspect of the invention.
According to certain embodiments of the invention, the compound is selected from the following structures:
R a、R2、R3、R4、R5、R6、R7, m, n and p are as defined in any one of the embodiments of the first aspect of the invention.
According to certain embodiments of the invention, the compound is selected from the following structures:
Wherein:
p is an integer selected from 0, 1, 2;
R 2、R3 is each independently selected from hydrogen, deuterium, and C 1-6 alkyl substituted with q R b, q is an integer selected from 0, 1, 2, 3, R b is each independently selected from halogen and C 1-6 alkyl;
R a is each independently selected from halogen, -OH, -CN, C 1-6 alkyl;
r 4 is selected from fluorine;
R 5 is selected from the group consisting of hydrogen, deuterium, halogen, -OH and C 1-6 alkyl substituted with k R d, k is an integer selected from 0,1, 2, 3 and 4, R d is selected from the group consisting of halogen, -OH and C 1-6 alkyl;
R 6 and R 7 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted with hydroxy and/or halogen;
n is selected from 0, 1 and 2.
According to certain embodiments of the invention, the compound is selected from the following structures:
Wherein:
Each R 2、R3 is independently selected from hydrogen and deuterium;
r a are each independently selected from fluorine and chlorine;
R 5 is selected from halogen, -OH and C 1-6 alkyl;
R 6 and R 7 are each independently selected from hydrogen, deuterium, C 1-6 alkyl.
According to some embodiments of the present invention, among the compounds of formula (VI-1), formula (VI-2), formula (VI-3), and formula (VI-4),
Radicals (C)Selected from the group consisting of
According to certain embodiments of the present invention, R 5 is selected from fluorine and-OH in the compounds of formula (I), formula (II), formula (III), formula (IV 1), formula (IV 2), formula (V1), formula (V2), formula (VI-1), formula (VI-2), formula (VI-3), and formula (VI-4).
According to certain embodiments of the present invention, a group in a compound of formula (I), formula (II), formula (III), formula (IV 1), formula (IV 2), formula (V1), formula (V2), formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4)Selected from the group consisting of-NH 2 and
According to certain embodiments of the present invention, there is provided a compound of the formula, or a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof:
According to certain embodiments of the present invention, the compound of formula (I) comprises:
According to certain embodiments of the present invention, the compound of formula (I) comprises:
In a second aspect of the present invention, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) according to the first aspect of the present invention or a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I).
In the pharmaceutical composition, the compound of formula (I), or a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I) may be in a therapeutically effective dose.
In a third aspect of the present invention, there is also provided the use of a compound of formula (I) as described in the first aspect of the present invention, or a stereoisomer, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I), or a pharmaceutical composition as described in the second aspect of the present invention, comprising
Antagonizing P2X7 receptor activity;
And/or preventing and/or treating a condition or disorder mediated by P2X7 receptor antagonistic activity;
and/or preparing a medicament, pharmaceutical composition or formulation for antagonizing P2X7 receptor activity, and/or preventing and/or treating a condition or disorder mediated by P2X7 receptor antagonizing activity.
According to certain embodiments of the invention, the condition or disorder is selected from pain, a central disease, an immune disease, inflammation and an inflammation-related disorder in the use according to the third aspect of the invention.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control.
Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectrometry and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present application. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, CH 2 O is equivalent to OCH 2.
The terms "comprising" or "including" are used in an open-ended fashion, i.e., including the elements recited in the present invention, and not excluding other elements, unless expressly stated otherwise.
Where a range of values recited in the specification and claims is understood to be an "integer," it is understood that both ends of the range and each integer within the range are recited. For example, an "integer of 1 to 6" should be understood to describe each integer of 0, 1,2, 3, 4, 5, and 6. When a numerical range is understood as a "number," it is understood that both endpoints of the range are noted, as well as each integer within the range, and each fraction within the range. For example, a "number of 1 to 10" should be understood to describe not only each integer of 1,2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.
The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers. The stereochemical definitions and conventions used in the present invention are generally defined as S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. Many geometric isomers of olefins, c=n double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, such double bonds include E and Z geometric isomers unless specified otherwise. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.
By straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the stereogenic centers, for example: Represented as One of the configurations ofThen this is indicated as the remaining alternative configuration. In a similar manner to that described above,Respectively represent One of the configurations of (a).
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a stereogenic center.
When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985,62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key.
Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. The compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of the racemic mixture of the compounds may be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active salified organic acid. Suitable resolving agents for use in the fractional recrystallisation process are, for example, D and L forms of optically active acids such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulphonic acids such as β -camphorsulphonic acid. Other resolving agents suitable for the fractional crystallization process include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methyl ephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Resolution of the racemic mixture may also be carried out by eluting on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC) may be used. The choice of the particular method and elution conditions, choice of chromatographic column can be selected by one skilled in the art based on the structure of the compound and the results of the assay. Further, any enantiomer or diastereomer of a compound described herein may also be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
For a drug or pharmacologically active agent, the terms "effective dose", "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.
The term "solvate" refers to a compound of the invention or a salt thereof that includes a stoichiometric or non-stoichiometric solvent that binds with non-covalent intermolecular forces, and when the solvent is water, is a hydrate.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as deuterium (2 H), tritium (3 H), iodine-125 (125 I) or C-14 (14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "oxo" refers to = O. When oxo is substituted on the carbon chain, the two hydrogens on the methylene group are substituted with oxygen, which together form a carbonyl moiety [ -C (=o) - ], and when oxo is substituted on the ring, one or more atoms on the ring are substituted with =o, e.g., carbon, nitrogen and sulfur heteroatoms may optionally be oxo (i.e., C (=o), NO and S (O) p, p being 1 or 2), e.g., 2-pyridonyl.
The term "C 1-6 alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. In particular, the groups have 1,2 or 3 carbon atoms ("C 1-C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.
The term "C 3-7 cycloalkyl" denotes a saturated monocyclic or bicyclic ring having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentane, bicyclo [3.1.0] hexane.
The term "3-7 membered ring" substituent is understood to mean a monocyclic or bicyclic ring system having 3 to 7 ring atoms, wherein the bicyclic ring system includes spiro, fused and bridged rings, and the tricyclic ring system includes fused rings, any of which rings may be aromatic or non-aromatic, for example, may be aryl, heteroaryl, may be saturated "3-7 membered cycloalkyl or C 3-7 cycloalkyl", "3-7 membered heterocycloalkyl", and may also be unsaturated "3-7 membered cycloalkenyl", and "3-7 membered heterocycloalkenyl".
The term "3-7 membered heterocyclic ring" is understood to mean a saturated or unsaturated mono-or bicyclic ring system having 3 to 7 ring atoms, wherein 1,2 or 3 ring atoms are selected from the group consisting of N, O and S. Unless otherwise indicated, a "3-7 membered heterocyclic ring" may be attached to the remainder of the molecule through carbon or nitrogen. "3-7 membered heterocycle" includes "3-7 membered heterocycloalkyl" and "3-7 membered heterocycloalkenyl".
The term "m-n membered heterocycloalkyl" is understood to mean a saturated mono-, bi-or tricyclic ring system having m to n ring atoms, wherein part of the ring atoms are selected from N, O and S. "m-to n-membered heterocycloalkyl" may be attached to the remainder of the molecule through carbon or nitrogen. It will be appreciated that when the total number of S and O atoms in the heterocycloalkyl group exceeds 1, these heteroatoms are not adjacent to each other. One non-limiting example is "3 to 6 membered heterocycloalkyl" or "3 to 7 membered heterocycloalkyl" representing a saturated mono-or bi-cyclic ring having 3 to 6 ring atoms or 3 to 7 ring atoms, wherein 1,2 or 3 ring atoms are selected from N, O and S.
The term "m-n membered heterocycloalkenyl" is understood to mean a monocyclic, bicyclic or tricyclic ring system having m to n ring atoms and comprising at least one carbon-carbon double bond (c=c), wherein bicyclic ring systems include spiro, fused and bridged rings, tricyclic ring systems include fused rings, wherein part of the ring atoms are selected from N, O and S, the remainder being carbon atoms, and heteroatoms may occupy the attachment position of the heterocycloalkenyl to the remainder of the molecule. Any ring of this system is non-aromatic. One non-limiting example is "3-7 membered heterocycloalkenyl", meaning a monocyclic or bicyclic ring system having 3-7 ring atoms and containing at least one carbon-carbon double bond (c=c), wherein the bicyclic ring system includes spiro, fused and bridged rings, wherein 1,2 or 3 ring atoms are heteroatoms independently selected from O, S and N. Further, the 3-7 membered heterocycloalkenyl group includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered heterocycloalkenyl groups and the like. Examples of 3-to 7-membered heterocycloalkenyl groups include, but are not limited to, dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3, 4-dihydro-2H-pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl and dihydrotetrazolyl, or isomers and stereoisomers thereof.
The term "6-15 membered aryl" is understood to mean a monocyclic, bicyclic or tricyclic aromatic ring radical having 6 to 15 ring atoms.
The term "5-10 membered heteroaryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 10 ring atoms, in particular 5 or 6 carbon atoms, and comprising 1 to 5 heteroatoms independently selected from N, O and S. Preferably 1 to 3-monovalent monocyclic, bicyclic or tricyclic aromatic ring groups independently selected from the heteroatoms of N, O and S, and additionally may be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The term "halo" or "halogen" is fluoro, chloro, bromo and iodo.
"Haloalkyl" is meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v=1 to 3,w =1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
The term "amino" means the substituent-NH 2.
Advantageous effects
According to a specific example of the present invention, the compound of formula (I) of the present invention has a good antagonism against P2X7 as a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
According to a specific example of the present invention, the compounds of the present invention have good antagonism against P2X7 and excellent pharmacokinetic properties.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Embodiments of the present invention provide compounds of formula (I), stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, methods and intermediates for preparing compounds of formula (I), or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the invention in the manufacture of a medicament.
The reaction solvent used in each of the reaction steps described in the present invention is not particularly limited, and any solvent which dissolves the starting materials to some extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention.
Abbreviations for the present invention are defined as follows:
Symbol or unit:
IC 50 represents half inhibition concentration, which means concentration at half maximum inhibition effect, M represents mol/L of N-butyllithium (14.56 mL,29.1mmol,2.5M N-hexane solution) as N-butyllithium in molar concentration of 2.5mol/L, N represents equivalent concentration as 2N hydrochloric acid represents 2mol/L hydrochloric acid solution
Reagent:
DCM: meOH: N, N-dimethylformamide HATU:2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate TEA: triethylamine
AD-mix-α:
SFC supercritical fluid chromatography
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift was 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).
Liquid Mass Spectrometry (LC-MS) method one was determined by Waters acquisition H-class Uplc-QDA or Aglient 1260IIPrime iQ mass spectrometer and monitored using ACQUITY UPLCBEH C, 2.1 x 50mm,1.7 μm column chromatography. Gradient elution conditions were 95-5% solvent A1 and 5-95% solvent B1 at a flow rate of 1.0mL/min, then 95% B1 and 5% A1 were maintained for 0.5min as a percentage of the volume of a certain solvent to the total solvent volume. Wherein the solvent A1 is 0.1% formic acid aqueous solution, and the solvent B1 is 0.1% formic acid acetonitrile or ethanol solution. The percentage is the volume percentage of solute in the solution.
Liquid chromatography-mass spectrometry (LC-MS) method two, as determined by Aglient1260IIPRIMEIQ mass spectrometer, using a YMCC18EXRS2.1 x 33mm,3um column. Gradient elution conditions were 95-5% solvent A1 and 5-95% solvent B1 in 1.1min at a flow rate of 1.2mL/min, then 95% B1 and 5% A1 were maintained for 0.4min, with A1 95% and B1 5% at 1.51 min. The percentage is the volume percentage of a certain solvent to the total solvent volume. Wherein, solvent A1 is 0.1% formic acid aqueous solution, and solvent B1 is 0.1% formic acid acetonitrile or ethanol solution. The percentage is the volume percentage of solute in the solution.
EXAMPLE 1 preparation of Compound I-1
N- ((2, 4-dichlorobenzylcarbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamic acid methyl ester (target compound I-1)
The synthetic route for the target compound I-1 is shown below:
first step, synthesis of N- (2, 4-dichlorobenzyl) -5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-1B)
5-Fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-1A) (160 mg,0.8 mmol) was dissolved in N, N-dimethylformamide (8.0 mL), then triethylamine (236 mg,2.3 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (360 mg,0.9 mmol) and 2, 4-dichlorobenzene methylamine (0.2 g,0.8 mmol) were added, and the reaction was stirred at 25℃for 8 hours. After the disappearance of the starting material, the reaction solution was diluted with water (20.00 mL), then extracted with ethyl acetate (30.0 ml×2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified on a silica gel plate (petroleum ether: ethyl acetate (V/V) =2:1) to give the compound N- (2, 4-dichlorobenzyl) -5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-1B).
LC-MS,M/Z(ESI):365.1[M+H]+
Second step, synthesis of N- (2, 4-dichlorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-1C)
N- (2, 4-dichlorobenzyl) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-1B) (157.0 mg, 430. Mu. Mol) was dissolved in methanol (2.0 mL), tert-butanol (2.0 mL) and water (2.0 mL), then AD-mix- α (1.0 g,2.1 mmol) was added and the reaction stirred at 25℃for 8 hours. After the disappearance of the starting material, the reaction solution was quenched with 1.00M aqueous sodium sulfite (20.0 mL), then extracted with dichloromethane (20.0 ml×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound N- (2, 4-dichlorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-1C).
LC-MS,M/Z(ESI):399.1[M+H]+
Third step, synthesis of N- ((2, 4-dichlorophenyl methyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl- (2, 2-trichloroacetyl) carbamate (I-1D)
N- (2, 4-Dichlorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-1C) (97 mg, 244. Mu. Mol) was dissolved in dichloromethane (1.0 mL), then 2, 2-trichloroacetyl isocyanate (50.7 mg, 269. Mu. Mol) was added dropwise at 0℃and the reaction stirred at 0℃for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain the compound N- ((2, 4-dichlorobenzylmethyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl- (2, 2-trichloroacetyl) carbamate (I-1D) which was directly used in the next step.
LC-MS,M/Z(ESI):586.0[M+H]+
Fourth step methyl N- ((2, 4-dichlorobenzylcarbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamate (target compound I-1)
N- (2, 4-Dichlorobenzyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl (2, 2-trichloroacetyl) carbamate (I-1D) (146 mg, 250. Mu. Mol) was dissolved in methanol (2.0 mL), and then an aqueous potassium carbonate solution (2M, 313. Mu.L) was added dropwise at 0℃and the reaction was stirred at 0℃for 1 hour. After the reaction was completed, the reaction solution was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 ml×3), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by high performance liquid chromatography (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: a=water+0.05 volume formic acid (99%), b=acetonitrile; gradient: 25% -55%,15 min) and then the compound N- ((2, 4-dichlorobenzylcarbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamic acid methyl ester (target compound I-1) was obtained.
LC-MS,M/Z(ESI):442.3[M+H]+。
1H NMR(400MHz,CDCl3)δ8.55(d,1H),7.95(s,1H),7.60–7.47(m,1H),7.32(s,1H),7.29–7.19(m,1H),7.15(d,1H),4.46(d,2H),4.36(s,1H),4.20(dd,1H),2.65–2.42(m,1H),2.37–2.03(m,3H).
EXAMPLE 2 preparation of Compound I-2
N- ((2-chloro-4-fluorobenzyl carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamic acid methyl ester (target compound I-2)
The synthetic route for the target compound I-2 is shown below:
First step, synthesis of N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-2B)
5-Fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-1A) (1.0 g,5 mmol) was dissolved in N, N-dimethylformamide (20.0 mL), then triethylamine (1.5 g,15 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.1 g,5.5 mmol) and 2-chloro-4-fluorobenzylamine (0.8 g,5 mmol) were added and the reaction was stirred at 25℃for 8 hours. After the disappearance of the starting material, the reaction solution was diluted with water (20.00 mL), then extracted with ethyl acetate (30.0 ml×2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified on silica gel plates (petroleum ether: ethyl acetate (V/V) =2:1) to give the compound N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-2B).
LC-MS,M/Z(ESI):349.1[M+H]+
Second step, synthesis of N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-2C)
N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-1B) (0.7 g,2 mmol) was dissolved in methanol (5.0 mL), t-butanol (10.0 mL) and water (10.0 mL), then AD-mix- α (6.2 g,8 mmol) was added and the reaction stirred at 25℃for 8 hours. After the disappearance of the starting material, the reaction solution was quenched with 1.00M aqueous sodium sulfite (20.0 mL), then extracted with dichloromethane (20.0 ml×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give the compound N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-2C).
LC-MS,M/Z(ESI):383.1[M+H]+
Third step, N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-2C 1) & (I-2C 2) & (I-2C 3) & (I-2C 4) synthesis
The compound N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-2C) (55.0 mg) was isolated and purified by chiral preparation by (column: DAICEL CHIRALPAK AD (250 mm x 30mm,10 um); mobile phase: [ a=co 2,B＝EtOH(0.1％NH3·H2 O) ];: B%:28%, isobaric elution mode) giving compound (I-2C 1) with retention time of 1.656min.LC-MS,M/Z(ESI):383.1[M+H]+.1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.57(d,1H),7.39–7.29(m,1H),7.27–7.20(m,1H),7.18(td,2H),7.00(td,1H),4.65–4.53(s,2H),4.00(s,1H),3.85(d,1H),3.75–3.71(m,2H),2.51–2.42(m,3H),2.06–2.01(m,1H).
(I-2C 2) retention time of 2.048min.LC-MS,M/Z(ESI):383.1[M+H]+.1H NMR(400MHz,CDCl3)δ8.55(d,1H),7.55(d,1H),7.44–7.43(m,1H),7.27–7.21(m,1H),7.19(td,2H),7.00(td,1H),5.00(d,1H),4.68–4.59(m,2H),4.00(d,1H),3.69(t,2H),2.94–2.85(m,1H),2.22–2.01(m,3H).
(I-2C 3) retention time of 1.588min.LC-MS,M/Z(ESI):383.1[M+H]+.1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.57(d,1H),7.39–7.29(m,1H),7.27–7.20(m,1H),7.18(td,2H),7.00(td,1H),4.65–4.53(s,2H),4.01(s,1H),3.85(d,1H),3.77–3.73(m,2H),2.51–2.42(m,3H),2.06–2.01(m,1H).
(I-2C 4) retention time of 1.866min.LC-MS,M/Z(ESI):383.1[M+H]+.1H NMR(400MHz,CDCl3)δ8.55(d,1H),7.55(d,1H),7.44–7.43(m,1H),7.27–7.21(m,1H),7.19(td,2H),7.00(td,1H),5.00(d,1H),4.68–4.58(m,2H),3.99(d,1H),3.70(t,2H),2.96–2.81(m,1H),2.22–2.03(m,3H).
Fourth step Synthesis of N- ((2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl- (2, 2-trichloroacetyl) carbamate (I-2D 4)
N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-2C 4) (382.1 mg,1 mmol) was dissolved in dichloromethane (5.0 mL) and then 2, 2-trichloroacetyl isocyanate (224.4 mg, 1.2. Mu. Mol) was added dropwise at 0℃and the reaction stirred at 0℃for 1 hour. After the reaction is completed, the reaction solution is concentrated to obtain a compound N- ((2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl- (2, 2-trichloroacetyl) carbamate (I-2D 4) which is directly used in the next step.
LC-MS,M/Z(ESI):586.0[M+H]+
Fifth step methyl N- ((2-chloro-4-fluorobenzyl carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamate (target compound I-2)
N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl (2, 2-trichloroacetyl) carbamate (I-2D 4) (150 mg, 263. Mu. Mol) was dissolved in methanol (5.0 mL), and then an aqueous potassium carbonate solution (2M, 400. Mu.L) was added dropwise at 0℃and the reaction was stirred at 0℃for 1 hour. After the reaction was completed, the reaction solution was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 ml×3), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by high performance liquid chromatography (column: phenomenex luna C18.150 x 25mm x 10 μm; mobile phase: a=water+0.05 volume formic acid (99%), b=acetonitrile; gradient: 25% -55%,15 min), then the compound N- ((2-chloro-4-fluorobenzyl carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamic acid methyl ester (target compound) I-2).LC-MS,M/Z(ESI):326.1[M+H]+.1H NMR(400MHz,dmso)δ9.14(s,1H),8.63(d,1H),7.58(d,1H),7.49–7.30(m,2H),7.24(td,1H),6.39(s,1H),5.36(s,1H),4.62–4.28(m,3H),4.21(d,1H),2.72–2.49(m,1H),2.30–2.03(m,2H),1.92(d,J＝13.9Hz,1H).
EXAMPLE 3 preparation of target Compounds I-3P1 and I-3P2
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (target compound I-3P 1)
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (target compound I-3P 2)
The synthetic routes for the target compounds I-3P1 and I-3P2 are shown below:
first step, synthesis of 5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 2)
The compound 5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-1A) (2.50 g,12.1 mmol) was isolated and purified by chiral preparation (column: DAICEL CHIRALPAK IC (250 mm x 30mm,10 μm; solvent: a = carbon dioxide, B = ammonia (0.1%) +ethanol; gradient: 20% -20%, 10 min) to give the following compounds:
5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 1). The retention time was 1.835min.
5-Fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 2). The retention time was 1.974min.
Second step (2-chloro-4-fluorophenyl) methane-d 2-amine (I-3B) synthesis
2-Chloro-4-fluorobenzonitrile (I-3A) (2.00 g,12.8 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to 0℃in an ice-water bath, then deuterated lithium aluminum hydride (1.62 g,38.5 mmol) was slowly added and the reaction stirred at 65℃for 9 hours and then at 25℃for 1 hour. After the reaction was completed, the reaction solution was cooled to 0 ℃, slowly dropwise added with water (2.00 mL), aqueous sodium hydroxide solution (15.0%, 2.00 mL) and water (6.00 mL) under nitrogen protection to quench the reaction, then tetrahydrofuran (100 mL) was added to dilute the reaction solution, the reaction solution was filtered, the filtrate was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was isolated and purified by high performance liquid chromatography (chromatographic column: waters Xbridge 150 x 25mm x 5um; solvent: a=water+0.05 volume of aqueous ammonia (30%), b=acetonitrile; gradient: 22% -52%,11 min) to obtain compound (2-chloro-4-fluorophenyl) methane-d 2-amine (I-3B) (2.00 g, crude product) directly used in the next step.
LC-MS,M/Z(ESI):162.1[M+H]+
Third step Synthesis of N- ((2-chloro-4-fluorophenyl) methyl-D2) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-3D)
5-Fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 2) (520 mg,2.51 mmol) was dissolved in dichloromethane (20.0 mL), then O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphate (1.15 g,3.01 mmol), triethylamine (768mg, 7.53mmol,1.05 mL) was added, the reaction was stirred at 25℃for 0.5 hours, then (2-chloro-4-fluorophenyl) methane-d 2-amine (I-3B) (506.95 mg,3.14 mmol) was added, and the reaction was stirred at 25℃for 1 hour. After the reaction was completed, the reaction solution was diluted with water (20.0 mL), then extracted with dichloromethane (10.0 ml×3), and the organic phases were combined, washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel plate (petroleum ether: ethyl acetate (V/V) =3:1) to give compound N- ((2-chloro-4-fluorophenyl) methyl-D2) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-3D).
LC-MS,M/Z(ESI):351.1[M+H]+
Fourth step Synthesis of N- ((2-chloro-4-fluorophenyl) methyl-d 2) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-3E)
N- ((2-chloro-4-fluorophenyl) methyl-D2) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-3D) (600 mg,1.71 mmol) was dissolved in methanol (10.0 mL), t-butanol (10.0 mL) and water (30.0 mL), then AD-mix- α (3.00 g,8.55 mmol) was added and the reaction stirred at 25℃for 10 hours. After the completion of the reaction, the reaction solution was quenched with saturated aqueous sodium sulfite (200 mL), then extracted with methylene chloride (50.0 ml×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1-0:1) to give the compound N- ((2-chloro-4-fluorophenyl) methyl-d 2) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-3E).
LC-MS,M/Z(ESI):385.1[M+H]+
Fifth step (Synthesis of 5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl (2, 2-trichloroacetyl) carbamate (I-3F)
N- ((2-chloro-4-fluorophenyl) methyl-d 2) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-3E) (550 mg,1.43 mmol) was dissolved in dichloromethane (10.0 mL) and then 2, 2-trichloroacetyl isocyanate (298 mg,1.57 mmol) was added dropwise at 0℃and the reaction stirred at 0℃for 1 hour. After completion of the reaction, the reaction solution was concentrated to give the compound (5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl (2, 2-trichloroacetyl) carbamate (I-3F) (820 mg, crude product) which was directly used in the next step.
LC-MS,M/Z(ESI):572.1[M+H]+
Sixth step Synthesis of 5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (I-3G)
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl (2, 2-trichloroacetyl) carbamate (I-3F) (820 mg,1.43 mmol) was dissolved in dichloromethane (10.0 mL) and then neutral alumina (3.65 g,35.8 mmoles) was added at 0℃and the reaction stirred at 25℃for 10 hours. After the completion of the reaction, the reaction solution was diluted with methanol (20.0 mL), then filtered, and the cake was washed with dichloromethane (20.0 mL) and methanol (20.0 mL), and the filtrates were combined and concentrated to give a crude product. The crude product was isolated and purified by high performance liquid chromatography (column: phenomenex luna C18:150×40mm×15um; solvent: a=water+0.05 volume formic acid (99%), b=acetonitrile; gradient: 18% -48%,15 min) to give compound 5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (I-3G).
LC-MS,M/Z(ESI):428.1[M+H]+
Seventh step Synthesis of 5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (target Compound I-3P 1) and 5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (target Compound I-3P 2)
The compound 5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methylcarbamate (I-3G) (350 mg,818 μmol) was isolated and purified by chiral preparation (column: DAICEL CHIRALPAK IG (250 mm. Times.30 mm,10um; solvent: a = carbon dioxide, B = ammonia (0.1%) + acetonitrile/ethanol; gradient: 50%. About.50%. About.3 min) to give the compound:
5- (((2-chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl carbamate (I-3P 1). Retention time of 1.512min.LC-MS,M/Z(ESI):428.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.61-8.68(m,1H),7.51(d,1H),7.39-7.45(m,1H),7.29(d,1H),7.19-7.26(m,2H),6.98-7.07(m,1H),4.26-4.38(m,2H),4.19(s,1H),2.72-2.99(m,1H),2.17-2.44(m,3H).
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl carbamate (I-3P 2). Retention time of 1.740min.LC-MS,M/Z(ESI):428.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.64(dt,1H),7.50-7.58(m,1H),7.39-7.45(m,1H),7.28-7.32(m,1H),7.20(dd,1H),7.10-7.16(m,1H),7.00(td,1H),4.55-4.75(m,2H),4.34-4.55(m,2H),3.43(s,1H),2.55-2.72(m,1H),2.16-2.41(m,3H).
EXAMPLE 4 preparation of target Compounds I-4P1 and I-4P2
5- ((2-Chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (target compound I-4P 1)
5- ((2-Chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (target compound I-4P 2)
The synthetic routes for the target compounds I-4P1 and I-4P2 are shown below:
first step, synthesis of 5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 2)
The compound 5-fluoro-8-methylidene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-1A) (2.50 g,12.1 mmol) was isolated and purified by chiral preparation (column: DAICEL CHIRALPAK IC (250 mm x 30mm,10 μm; solvent: a = carbon dioxide, B = ammonia (0.1%) +ethanol; gradient: 20% -20%, 10 min) to give the following compounds:
5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 1). The retention time was 1.835min.
5-Fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 2). The retention time was 1.974min.
Second step, synthesis of N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4A)
5-Fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxylic acid (I-3C 2) (180 mg, 869. Mu. Mol) was dissolved in methylene chloride (2.00 mL), then O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethylurea hexafluorophosphate (396 mg,1.04 mmol), N, N-diisopropylethylamine (337 mg,2.61mmol, 454. Mu. L) and 2-chloro-4-fluorobenzylamine (139 mg, 869. Mu. Mol) were added, and the reaction was stirred at 25℃for 1 hour. After the reaction was completed, the reaction solution was diluted with water (10.0 mL), then extracted with dichloromethane (10.0 ml×3), the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =20:1-5:1) to give the compound N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4A).
Third step, the synthesis of N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-oxo-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4B)
N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-methylene-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4A) (750 mg,2.15 mmol) was dissolved in methanol (5.00 mL) and methylene chloride (5.00 mL), then cooled to-70℃and ozone gas was introduced at-70℃for 15 minutes, then nitrogen gas was introduced for 15 minutes to remove excess ozone, and dimethyl sulfide (670 mg,10.8 mmol) was slowly added dropwise to the reaction solution at-70℃and the reaction was stirred at 25℃for 3 hours. After the reaction is completed, the reaction solution is concentrated to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1-0:1) to give the compound N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-oxo-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4B).
LC-MS,M/Z(ESI):351.1[M+H]+
Fourth step, synthesis of N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8-methyl-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4C)
(R) -N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-oxo-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4B) (250 mg, 713. Mu. Mo) was dissolved in tetrahydrofuran (5.00 mL), then methyl magnesium bromide (3.00M, 356. Mu.L) was added dropwise at-70℃under nitrogen protection, and the reaction was stirred at-70℃for 3 hours, then at 25℃for 10 hours. After the completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride (20.0 mL), then extracted with ethyl acetate (20.0 ml×3), and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by high performance liquid chromatography (column: waters Xbridge 150 x 25mm x 5um; solvent: a=water+0.05 volume ammonia (30%), b=acetonitrile; gradient: 26% -56%,11 min) to give the compound N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8-methyl-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4C).
LC-MS,M/Z(ESI):367.1[M+H]+。
Fifth step Synthesis of 5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-yl (2, 2-trichloroacetyl) carbamate (I-4D)
N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8-methyl-5, 6,7, 8-tetrahydroquinoline-5-carboxamide (I-4C) (30.0 mg, 81.8. Mu. Mol) was dissolved in dichloromethane (2.00 mL), then 2, 2-trichloroacetyl isocyanate (17.0 mg, 90.0. Mu. Mol) was added dropwise at 0℃and the reaction stirred at 0℃for 2 hours. After the completion of the reaction, the reaction solution was concentrated to give the compound 5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-yl (2, 2-trichloroacetyl) carbamate (I-4D) (crude product) which was directly used in the next step.
LC-MS,M/Z(ESI):554.2[M+H]+
Sixth step Synthesis of 5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (target Compound I-4P 1) and 5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (target Compound I-4P 2)
5- ((2-Chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-yl (2, 2-trichloroacetyl) carbamate (I-4D) (45.0 mg, 81.1. Mu. Mol) was dissolved in dichloromethane (3.00 mL) and then neutral alumina (124 mg,1.22 mmol) was added dropwise at 0℃and the reaction stirred at 25℃for 10 hours. After the completion of the reaction, the reaction mixture was diluted with methanol (10.0 mL), then filtered, and the cake was washed with dichloromethane (10.0 mL) and methanol (10.0 mL), and the filtrate was concentrated to give a crude product. The crude product was isolated and purified by high performance liquid chromatography (column: waters Xbridge 150 x 25mm x 5 μm; solvent: a=water+0.05 volume ammonium bicarbonate (99%), b=acetonitrile; gradient: 25% -55%,9 min) to give the compound:
5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (I-4P 1), retention time ：0.911min.LC-MS,M/Z(ESI):410.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.61-8.67(m,1H),7.40-7.48(m,2H),7.29-7.35(m,1H),7.17-7.24(m,2H),7.01(td,1H),4.44-4.76(m,4H),3.13(td,1H),2.48-2.67(m,1H),2.30-2.42(m,1H),2.12-2.23(m,1H),1.74(s,3H).
5- ((2-Chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (I-4P 2), retention time ：0.937min.LC-MS,M/Z(ESI):410.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.65-8.69(m,1H),7.72(dd,1H),7.33-7.41(m,1H),7.29-7.32(m,1H),7.20-7.26(m,1H),7.09(dd,1H),6.92(td,1H),4.37-4.75(m,4H),2.84-2.96(m,1H),2.56-2.70(m,1H),2.13-2.30(m,2H),1.79(s,3H).
EXAMPLE 5 preparation of the target Compound I-5
5- ((2-Chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl carbamate (target compound I-5)
The synthetic route for the target compound I-5 is shown below:
First step Synthesis of 4-nitrophenylmethyl carbamate (I-5B)
Methylamine hydrochloride (335 mg,4.96 mmol) was dissolved in dichloromethane (10.0 mL), then triethylamine (1.51 g,14.9mmol,2.07 mL) and p-nitrophenyl chloroformate (I-5A) (1.00 g,4.96 mmol) were added dropwise at 0 ℃ and the reaction stirred at 0 ℃ for 1 hour. After the completion of the reaction, the reaction mixture was diluted with methylene chloride (20.0 mL), then washed with water (20.0 ml×3), and the organic phase was dried over sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =50:1-3:1) to give compound 4-nitrophenylmethyl carbamate (I-5B).
LC-MS,M/Z(ESI):197.1[M+H]+
Second step Synthesis of 5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl carbamate (target Compound I-5)
N- (2-chloro-4-fluorobenzyl) -5-fluoro-8-hydroxy-8- (hydroxymethyl) -5,6,7, 8-tetrahydroquinoline-5-carboxamide (I-2C 4) (100 mg, 261. Mu. Mol) was dissolved in dichloromethane (5.00 mL) and then 1.8-diazabicyclo [5.4.0] undec-7-ene (99.4 mg, 653. Mu. Mol, 98.4. Mu. L) and 4-nitrophenylmethylcarbamate (I-5B) (56.4 mg, 287. Mu. Mol) were added dropwise at 0℃and the reaction was stirred at 25℃for 10 hours. After the reaction, the reaction mixture was concentrated and the crude product was purified by high performance liquid chromatography (column: waters Xbridge 150 x 25mm x 5 μm; solvent: a=water+0.05 volume ammonia (30%), b=acetonitrile; gradient: 22% -52%,11 min) to give 5- ((2-chloro-4-fluorobenzyl) carbamoyl) -5-fluoro-8-hydroxy-5, 6,7, 8-tetrahydroquinolin-8-yl) methyl carbamate (I-5).
LC-MS,M/Z(ESI):440.2[M+H]+。
1H NMR(400MHz,CDCl3)δ8.57-8.69(m,1H),7.53(dt,1H),7.38-7.44(m,1H),7.24-7.27(m,1H),7.19(dd,1H),7.09-7.17(m,1H),7.00(td,1H),4.53-4.76(m,3H),4.36-4.52(m,2H),3.36-3.49(m,1H),2.79(d,3H),2.55-2.70(m,1H),2.15-2.45(m,3H).
EXAMPLE 6 preparation of target Compounds I-6P1 and I-6P2
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (target compound I-6P 1)
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-ylcarbamate (target compound I-6P 2)
Synthetic routes for the target compounds I-6P1 and I-6P2 referring to the synthesis of the compounds I-4P1 and I-4P2, 2-chloro-4-fluorobenzylamine was replaced with (2-chloro-4-fluorophenyl) methane-d 2-amine (I-3B).
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-yl carbamate (target compound I-6P 1) retention time ：0.923min.LC-MS,M/Z(ESI):410.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.61-8.67(m,1H),7.40-7.48(m,2H),7.29-7.35(m,1H),7.17-7.24(m,2H),7.01(td,1H),4.44-4.76(m,2H),3.13(td,1H),2.48-2.67(m,1H),2.30-2.42(m,1H),2.12-2.23(m,1H),1.74(s,3H).
5- (((2-Chloro-4-fluorophenyl) methyl-d 2) carbamoyl-5-fluoro-8-methyl-5, 6,7, 8-tetrahydroquinolin-8-yl carbamate (target compound I-6P 2) retention time ：0.957min.LC-MS,M/Z(ESI):410.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.65-8.69(m,1H),7.72(dd,1H),7.33-7.41(m,1H),7.29-7.32(m,1H),7.20-7.26(m,1H),7.09(dd,1H),6.92(td,1H),4.37-4.75(m,2H),2.84-2.96(m,1H),2.56-2.70(m,1H),2.13-2.30(m,2H),1.79(s,3H).
EXAMPLE 7 preparation of the target Compound I-8
(N- ((2-chloro-4-fluorobenzyl carbamoyl) -5, 8-difluoro-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamic acid methyl ester (target compound I-8)
The synthetic route for the target compound I-8 is shown below:
Compound I-2C4 (400 mg,0.9 mmol) was dissolved in dichloromethane (10.0 mL), and diethylaminosulfur trifluoride (DAST) (320 mg,2.0 mmol) was added at-20℃and stirred for 8 hours. The reaction solution was diluted with water (20.00 mL), then extracted with ethyl acetate (30.0 ml×2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by high performance liquid chromatography (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: a=water+0.05 volume formic acid (99%), b=acetonitrile; gradient: 25% -55%,15 min) and then the compound methyl (N- ((2-chloro-4-fluorobenzyl carbamoyl) -5, 8-difluoro-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamate (target compound I-8) was obtained.
LC-MS,M/Z(ESI):444.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.85(s,1H),7.60–7.47(m,1H),7.32(s,1H),7.29–7.29(m,1H),7.15(d,1H),4.46(d,2H),4.36(s,2H),2.68–2.52(m,2H),2.37–2.13(m,2H).
EXAMPLE 8 preparation of the target Compound I-9
(N- ((2, 4-dichloro-benzylcarbamoyl) -5, 8-difluoro-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamic acid methyl ester (target compound I-9)
The synthetic route for the target compound I-9 is shown below:
Compound I-1 (440 mg,1.0 mmol) was dissolved in dichloromethane (10.0 mL), and diethylaminosulfur trifluoride (DAST) (320 mg,2.0 mmol) was added at-20℃and stirred for 8 hours. The reaction solution was diluted with water (20.00 mL), then extracted with ethyl acetate (30.0 ml×2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by high performance liquid chromatography (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: a=water+0.05 volume formic acid (99%), b=acetonitrile; gradient: 25% -55%,15 min) and then the compound methyl (N- ((2, 4-dichloro-benzylcarbamoyl) -5, 8-difluoro-5, 6,7, 8-tetrahydroquinolin-8-yl) carbamate (target compound I-9) was obtained.
LC-MS,M/Z(ESI):444.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.55(d,1H),7.95(s,1H),7.60–7.47(m,1H),7.32(s,1H),7.29–7.19(m,1H),7.15(d,1H),4.46(d,2H),4.36(s,2H),2.68–2.42(m,2H),2.37–2.03(m,2H).
Test example 1 FLIPR method for determining antagonistic Activity of Compounds against hP2X7
The measurement of the inhibition effect of compounds on hP2X7 Calcium flux was performed in HEK293 stably transformed cells overexpressing the human P2X7 receptor, and the Calcium flux signal was detected using the FLIPR Calcium 6Assay Kit (Molecular Devices, R8191) and FLIPR TETRA system (Molecular Devices). Stable cells cultured in 37 ℃,5% CO 2 incubator, cells were isolated and counted using TrypLE TM Express (cell viability > 85%), seeded into 384 well plates at 20000 cells/well density, 30 μl system per well, and incubated overnight in incubator. 2 Xdye buffer was prepared by diluting dye with Assay buffer (1 XHBSS, pH 7.4 containing 20mM HEPES) and adding probenecid at a final concentration of 5 mM. The cell culture plates were removed from the incubator and the medium was removed, and 10. Mu.L of Assay buffer and 10. Mu.L of 2 Xdye were added to each well. The cell plates were placed on a shaker and incubated at 600rpm for 2 minutes. Followed by incubation at 37 ℃ for 2 hours and then at 25 ℃ for a further 15 minutes. Test compounds were formulated as 10mM stock solutions in DMSO and serially diluted in 384 well plates. Different concentrations of compounds were transferred to new 384 well plates using an Echo sonic pipetting system (Labcyte), 90nL per well. To the 384-well plate, 30. Mu.L/well of dilution buffer was added to give a 3X compound solution. The compound plate was placed on a shake plate shaker and shaken for 2 minutes.
The cell plate, compound plate and tip were placed in a FLIPR instrument, which transferred a 3 Xcompound solution into the cell plate at a volume of 10. Mu.L/well. Plates were then read for 160 seconds, 1 second apart, to obtain agonist mode data, and then the plates were stored at 25 ℃ protected from light for 30 minutes. EC 80 was calculated using data of control agonist (BzATP). BzATP at a concentration of 4 XEC 80 was formulated in Assay buffer and added to the new 384-well compound plate at a volume of 30. Mu.L/well. After incubation at 25 ℃ for 30 minutes in the dark, the cell plates, compound plates containing BzATP and tips were placed in a FLIPR instrument. The FLIPR instrument transferred 4 xec 80 concentration BzATP into the cell plate at a volume of 10 μl/well. The plate was then read for 160 seconds, 1 second apart, to obtain antagonistic mode data. The inhibition ratio is calculated as follows, inhibition ratio (%) =100- (test value-low control mean)/(high control mean-low control mean) ×100. Wherein the low control group is BzATP with EC 80 added and the highest concentration positive control (JNJ-47965567), and the high control group is BzATP with EC 80 only added. IC 50 values were calculated from the inhibition ratios of the compounds at the different concentrations after curve fitting with XLift.
Experimental results show that the compound shows excellent antagonistic activity on human P2X 7.
TABLE 1 test of antagonistic Activity of Compounds against hP2X7
Numbering of compounds hP2X7 IC50(nM)
Compound I-1 21.4
Compound I-2 10.6
Compound I-3P2 8.69
Compound I-4P2 21.62
Compound I-6P2 15.4
Compound I-7 11.80
Compound I-8 18.6
Compound I-9 11.45
Test example 2 pharmacokinetic test in mice
The pharmacokinetic test of mice is carried out by taking 3 male ICR mice, 20-30g, and orally and parenterally administering 10mg/kg overnight. Blood was collected 5, 15, 30 minutes and 1,2, 4, 6, 8, 24 hours before and after dosing. Blood samples were centrifuged at 6000 g/min at 2-8℃for 3 min and plasma was collected and stored at-20 ℃. Plasma at each time point was taken, 10 times of 50% methanol acetonitrile solution containing an internal standard was added and mixed, vortex mixing was performed for 5 minutes, centrifugation was performed for 10 minutes at 4000 rpm and 4 ℃, the supernatant was taken and mixed with 1 time of water, and a proper amount of the mixed solution was taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.
Experimental results show that the compound has good pharmacokinetic properties on mice.
Test example 3 pharmacokinetic test in rats
Rat pharmacokinetic experiments were performed using 3 male SD rats, 180-240g, overnight fasted, and 10mg/kg administered orally by gavage. Blood was collected 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours before and after dosing. Blood samples were centrifuged at 8000 rpm at 4℃for 6 minutes and plasma was collected and stored at-20 ℃. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.
Experimental results show that the compound has good pharmacokinetic properties on rats.
TABLE 3 results of pharmacokinetic experiments in rats
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (17)

1.式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药：1. The compound of formula (I), its stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs: 其中：in: R1选自被p个Ra取代的以下基团：6-15元芳基、5-10元杂芳基；p为选自0、1、2、3和4的整数； R1 is selected from the following groups substituted by p Ra : 6-15 aryl, 5-10 heteroaryl; p is an integer selected from 0, 1, 2, 3 and 4; R2、R3各自独立地选自氢、氘和被q个Rb取代的C1-6烷基；q为选自0、1、2、3的整数，Rb各自独立地选自卤素、-OH、-CN、-NH2、氧代(＝O)、C1-6烷基和-O-C1-6烷基； R2 and R3 are each independently selected from hydrogen, deuterium, and C1-6 alkyl groups substituted by q Rb ; q is an integer selected from 0, 1, 2, 3, and Rb are each independently selected from halogen, -OH, -CN, -NH2 , oxo (=O), C1-6 alkyl, and -OC1-6 alkyl; 或者，R2与R3中，一个为氢、氘或不存在，另一个与R1形成被j个Rc取代的3-7元环；j为选自0、1、2和3；Alternatively, of R2 and R3 , one is hydrogen, deuterium, or absent, and the other forms a 3-7 membered ring with R1 , which is substituted by j Rc ; j is selected from 0, 1, 2, and 3; Ra和Rc各自独立地选自卤素、-OH、-CN、C1-6烷基、-O-C1-6烷基、卤代C1-6烷基、-O-卤代C1-6烷基、C3-7环烷基、-O-C3-7环烷基、-S(O)r-Ra1、-SF5、-NRa1Ra2；所述Ra1和Ra2各自独立地选自氢、C1-6烷基，r为选自0、1、2的整数； Ra and Rc are each independently selected from halogens, -OH, -CN, C1-6 alkyl, -OC1-6 alkyl, haloC1-6 alkyl, -O- haloC1-6 alkyl, C3-7 cycloalkyl, -OC3-7 cycloalkyl, -S(O) rRa1 , -SF5 , -NRa1Ra2 ; wherein Ra1 and Ra2 are each independently selected from hydrogen and C1-6 alkyl, and r is an integer selected from 0, 1, and 2 ; R4选自氢、氘、氟； R4 is selected from hydrogen, deuterium, and fluorine; R5选自氢、氘、卤素、-OH、-CN和被k个Rd取代的以下基团：C1-6烷基、-O-C1-6烷基、C3-6环烷基、3至6元杂环烷基、-(C＝O)-R51、-(C＝O)-NR51R52和-NR51R52；k为选自0、1、2、3和4的整数，R51和R52各自独立地选自氢、-OH、C1-6烷基、被羟基取代的C1-6烷基，Rd选自卤素、-OH、-CN、C1-6烷基和-O-C1-6烷基； R5 is selected from hydrogen, deuterium, halogen, -OH, -CN, and the following groups substituted with k Rd : C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclic alkyl, -(C=O) -R51 , -(C=O) -NR51R52 , and -NR51R52 ; k is an integer selected from 0, 1 , 2, 3 , and 4; R51 and R52 are each independently selected from hydrogen, -OH, C1-6 alkyl, and C1-6 alkyl substituted with hydroxyl; Rd is selected from halogen, -OH, -CN, C1-6 alkyl, and -OC1-6 alkyl. R6和R7各自独立地选自氢、氘、C1-6烷基、被羟基和/或卤素取代的C1-6烷基； R6 and R7 are each independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkyl substituted with hydroxyl and/or halogen; 或者，R6、R7可以与其共同连接的N原子形成3-7元杂环，所述3-7元杂环被u个Re取代；u选自0、1、2、3、4、5和6，所述Re各自独立地选自卤素、-OH、氧代(＝O)、C1-6烷基、-O-C1-6烷基、卤代C1-6烷基、-O-卤代C1-6烷基；Alternatively, R6 and R7 can form a 3-7 membered heterocycle with the N atom they are connected to, wherein the 3-7 membered heterocycle is substituted by u Re atoms ; u is selected from 0, 1, 2, 3, 4, 5 and 6, and each Re atom is independently selected from halogen, -OH, oxo (=O), C1-6 alkyl, -OC1-6 alkyl, haloC1-6 alkyl, -O- haloC1-6 alkyl; m选自0和1；n选自0、1和2。m is selected from 0 and 1; n is selected from 0, 1 and 2. 2.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R1中，所述5-10元杂芳基的杂原子选自N、O、S中的1种或2种，杂原子数为1、2或3个；2. The compound of formula (I) as claimed in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, characterized in that, in R1 , the heteroatom of the 5-10 member heteroaryl group is selected from one or two of N, O, and S, and the number of heteroatoms is 1, 2 or 3. 和/或，R1中，所述5-10元杂芳基选自噻吩基、噻唑基、异噁唑基、吡唑基、四唑基、呋喃基、吡咯基、咪唑基、噁唑基、异噻唑基、三唑基、噻二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基和三嗪基；And/or, in R 1 , the 5-10 heteroaryl group is selected from thienyl, thiazolyl, isoxazolyl, pyrazolyl, tetrazolyl, furanyl, pyrrolithyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl; 和/或，R1中，所述6-15元芳基选自苯基、茚基、萘基和薁基；And/or, in R1 , the 6-15 aryl group is selected from phenyl, indene, naphthyl, and azulel; 和/或，R1中，所述Ra各自独立地选自氟、氯、-OH、-CN、C1-6烷基、-SF5、-O-C1-6烷基、卤代C1-6烷基、-O-卤代C1-6烷基、C3-7环烷基、-O-C3-7环烷基、-S(O)r-Ra1、-NRa1Ra2；所述Ra1和Ra2各自独立地选自氢、C1-6烷基，r为选自0、1、2的整数；单独的或作为其他基团的一部分的所述C1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，单独的或作为其他基团的一部分的所述C3-7环烷基各自独立地为环丙基、环丁基、环戊基、环己基；And/or, in R1 , each Ra is independently selected from fluorine, chlorine, -OH, -CN, C1-6 alkyl, -SF5 , -OC1-6 alkyl, haloC1-6 alkyl, -O- haloC1-6 alkyl, C3-7 cycloalkyl, -OC3-7 cycloalkyl, -S(O) rRa1 , -NRa1Ra2 ; Ra1 and Ra2 are each independently selected from hydrogen and C1-6 alkyl , where r is an integer selected from 0, 1, 2; the C1-6 alkyl group, alone or as part of other groups, is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; and the C3-7 cycloalkyl group, alone or as part of other groups, is each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 和/或，R1选自 And/or, R1 is selected from 和/或，R1选自 And/or, R1 is selected from 3.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R2、R3中，单独的或作为其他基团的一部分的所述C1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基；3. The compound of formula (I) as claimed in claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that, in R2 and R3 , the C1-6 alkyl group, alone or as part of other groups, is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 和/或，R2、R3各自独立地选自氢、氘、甲基、乙基；And/or, R2 and R3 are each independently selected from hydrogen, deuterium, methyl, and ethyl; 和/或，当R2或R3与R1形成被j个Rc取代的3-7元环时，所述3-7元环选自3-7元环烯基和3-7元杂环烯基，所述3-7元杂环包括1、2或3个杂原子，所述杂原子选自N、O和S。And/or, when R2 or R3 forms a 3-7 membered ring with R1 that is substituted by j Rc , the 3-7 membered ring is selected from 3-7 membered cyclic alkenyl and 3-7 membered heterocyclic alkenyl, the 3-7 membered heterocycle comprising 1, 2 or 3 heteroatoms selected from N, O and S. 4.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，4. The compound of formula (I) as claimed in claim 1, wherein its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that, 当R2或R3与R1形成被j个Rc取代的3-7元环时，基团选自表示单键或双键，X1、X2和X3各自独立地选自CH、CH2、N、NH、O、S；t1和t2各自独立地选自0、1和2；Ra、Rc、p和j的定义如权利要求1所述；When R2 or R3 forms a 3-7 membered ring with R1 , which is substituted by j Rc , the group Selected from The terms X1 , X2 , and X3 are each independently selected from CH, CH2 , N, NH, O, and S; t1 and t2 are each independently selected from 0, 1, and 2; Ra , Rc , p, and j are defined as described in claim 1. 和/或，当R2或R3与R1形成被j个Rc取代的3-7元环时，基团选自X1、X2和X3各自独立地选自CH2、NH、O、S；t1和t2各自独立地选自0、1和2；Ra、Rc、p和j的定义如权利要求1所述；And/or, when R2 or R3 forms a 3-7 membered ring with R1 substituted by j Rc , the group Selected from X1 , X2 , and X3 are each independently selected from CH2 , NH, O, and S; t1 and t2 are each independently selected from 0, 1, and 2; Ra , Rc , p, and j are defined as described in claim 1; 和/或，当R2或R3与R1形成被j个Rc取代的3-7元环时，基团选自X1、X2和X3各自独立地选自CH2、NH、O、S，且X1、X2和X3中至少有一个选自NH、O和S；t1和t2各自独立地选自0、1和2；Ra、Rc、p和j的定义如权利要求1所述；And/or, when R2 or R3 forms a 3-7 membered ring with R1 substituted by j Rc , the group Selected from X1 , X2 , and X3 are each independently selected from CH2 , NH, O, and S, and at least one of X1 , X2 , and X3 is selected from NH, O, and S; t1 and t2 are each independently selected from O, 1, and 2; Ra , Rc , p, and j are defined as described in claim 1; 和/或，当R2或R3与R1形成被j个Rc取代的3-7元环时，基团选自X1独立地选自NH、O、S，X2和X3各自独立地选自CH2；t1为1，t2为1；Ra、Rc、p和j的定义如权利要求1所述；And/or, when R2 or R3 forms a 3-7 membered ring with R1 substituted by j Rc , the group Selected from X1 is independently selected from NH, O, and S; X2 and X3 are each independently selected from CH2 ; t1 is 1, t2 is 1; Ra , Rc , p, and j are defined as described in claim 1; 和/或，当R2或R3与R1形成被j个Rc取代的3-7元环时，基团选自X1独立地选自NH、O、S，X2和X3各自独立地选自CH2；t1为1，t2为1；Ra各自独立地选自卤素，p选自1和2；j为0；And/or, when R2 or R3 forms a 3-7 membered ring with R1 substituted by j Rc , the group Selected from X1 is independently selected from NH, O, and S; X2 and X3 are each independently selected from CH2 ; t1 is 1, t2 is 1; Ra is each independently selected from halogens; p is selected from 1 and 2; j is 0. 和/或，当R2或R3与R1形成被j个Rc取代的3-7元环时，基团选自X1独立地选自CH2、NH、O、S；Ra、Rc和j的定义如权利要求1所述。And/or, when R2 or R3 forms a 3-7 membered ring with R1 substituted by j Rc , the group Selected from X1 is independently selected from CH2 , NH, O, S; Ra , Rc , and j are defined as described in claim 1. 5.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R5选自氢、卤素、-OH和被k个Rd取代的C1-6烷基；k选自0、1、2、3和4，Rd选自卤素、-OH、-CN、C1-6烷基和-O-C1-6烷基；5. The compound of formula (I) as claimed in claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that R5 is selected from hydrogen, halogens, -OH and C1-6 alkyl groups substituted with k Rd ; k is selected from 0, 1, 2, 3 and 4, and Rd is selected from halogens, -OH, -CN, C1-6 alkyl groups and -OC1-6 alkyl groups; 和/或，R5选自氢、氟、氯、-OH、甲基和乙基。And/or, R5 is selected from hydrogen, fluorine, chlorine, -OH, methyl and ethyl. 6.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R6、R7中，单独的或作为其他基团的一部分的所述C1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基；6. The compound of formula (I) as claimed in claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that, in R6 and R7 , the C1-6 alkyl group, alone or as part of other groups, is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 和/或，R6、R7各自独立地选自氢、甲基、乙基；And/or, R6 and R7 are each independently selected from hydrogen, methyl, and ethyl; 和/或，当R6、R7与其共同连接的N原子形成3-7元杂环时，所述3-7元杂环为饱和环；And/or, when R6 , R7 and the N atom they are connected to form a 3-7 membered heterocycle, the 3-7 membered heterocycle is a saturated ring; 和/或，当R6、R7与其共同连接的N原子形成3-7元杂环时，所述3-7元杂环为仅含有1个N原子的饱和环；And/or, when R6 , R7 and the N atom they are connected to form a 3-7 membered heterocycle, the 3-7 membered heterocycle is a saturated ring containing only one N atom; 和/或，当R6、R7与其共同连接的N原子形成3-7元杂环时，所述3-7元杂环被u个Re取代；u选自0、1、2和3，所述Re各自独立地选自卤素、-OH、氧代(＝O)、C1-3烷基、卤代C1-3烷基、-O-C1-3烷基、-O-卤代C1-3烷基；And/or, when R6 , R7 and the N atom they are connected to form a 3-7 membered heterocycle, the 3-7 membered heterocycle is replaced by u Re atoms ; u is selected from 0, 1, 2 and 3, and each Re is independently selected from halogen, -OH, oxo (=O), C1-3 alkyl, halo- C1-3 alkyl, -OC1-3 alkyl, -O-halo- C1-3 alkyl; 和/或，当R6、R7与其共同连接的N原子形成3至7元杂环时，基团选自 And/or, when R6 , R7 and the N atom they are jointly attached to form a 3- to 7-membered heterocycle, the group Selected from 7.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的式(I)所示化合物满足下述条件中的一种或多种：7. The compound of formula (I) as claimed in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound of formula (I) satisfies one or more of the following conditions: (1)R1选自 (1) R 1 is selected from (2)基团选自 (2) Group Selected from (3)基团选自-NH2、 (3) Group Selected from -NH 2 , 8.如权利要求1所述的化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：8. The compound of claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that the compound is selected from the following structures: R1、R2、R3、R4、R5、R6、R7、m和n具有权利要求1所述的定义。 R1 , R2 , R3 , R4 , R5 , R6 , R7 , m, and n have the definitions described in claim 1. 9.如权利要求1所述的化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：9. The compound of claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that the compound is selected from the following structures: Ra、R2、R3、R4、R5、R6、R7、m、n和p具有权利要求1所述的定义。 Ra , R2 , R3 , R4 , R5 , R6 , R7 , m, n, and p have the definitions described in claim 1. 10.如权利要求1所述的化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：10. The compound of claim 1, wherein the stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that the compound is selected from the following structures: 其中：in: p为选自0、1、2的整数；p is an integer selected from 0, 1, and 2; R2、R3各自独立地选自氢、氘和被q个Rb取代的C1-6烷基；q为选自0、1、2、3的整数，Rb各自独立地选自卤素和C1-6烷基； R2 and R3 are each independently selected from hydrogen, deuterium and C1-6 alkyl groups substituted with q Rb ; q is an integer selected from 0, 1, 2 and 3, and Rb are each independently selected from halogens and C1-6 alkyl groups; Ra各自独立地选自卤素、-OH、-CN、C1-6烷基； Ra is independently selected from halogens, -OH, -CN, and C1-6 alkyl groups; R4选自氟； R4 is selected from fluorine; R5选自氢、氘、卤素、-OH和被k个Rd取代的以下基团：C1-6烷基；k为选自0、1、2、3和4的整数，Rd选自卤素、-OH和C1-6烷基；R 5 is selected from hydrogen, deuterium, halogen, -OH and the following groups substituted by k R d : C 1-6 alkyl; k is an integer selected from 0, 1, 2, 3 and 4, and R d is selected from halogen, -OH and C 1-6 alkyl; R6和R7各自独立地选自氢、氘、C1-6烷基、被羟基和/或卤素取代的C1-6烷基； R6 and R7 are each independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkyl substituted with hydroxyl and/or halogen; n选自0、1和2。n is selected from 0, 1, and 2. 11.如权利要求1所述的化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述化合物选自如下结构：11. The compound of claim 1, wherein the stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that the compound is selected from the following structures: 其中：in: R2、R3各自独立地选自氢和氘； R2 and R3 are each independently selected from hydrogen and deuterium; Ra各自独立地选自氟和氯； Ra is independently selected from fluorine and chlorine; R5选自卤素、-OH和C1-6烷基； R5 is selected from halogens, -OH, and C1-6 alkyl groups; R6和R7各自独立地选自氢、氘、C1-6烷基。 R6 and R7 are each independently selected from hydrogen, deuterium, and C1-6 alkyl groups. 12.如权利要求11所述的化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，12. The compound of claim 11, wherein its stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug, is characterized in that, 基团选自 Group Selected from 和/或，R5选自氟和-OH；And/or, R5 is selected from fluorine and -OH; 和/或，基团选自-NH2和 and/or, groups Selected from -NH 2 and 13.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，式(I)所示化合物选自如下结构：13. The compound of formula (I) as claimed in claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that the compound of formula (I) is selected from the following structures: 14.如权利要求1所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，式(I)所示化合物选自如下结构：14. The compound of formula (I) as claimed in claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that the compound of formula (I) is selected from the following structures: 15.一种药物组合物，其特征在于，包含有效剂量的权利要求1～14中任一项所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药。15. A pharmaceutical composition, characterized in that it comprises an effective dose of the compound of formula (I) according to any one of claims 1 to 14, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug. 16.权利要求1～14中任一项所述的式(I)所示化合物，其立体异构体、溶剂化物、药学上可接受的盐或前药，或权利要求15所述的药物组合物的用途，其特征在于，所述用途包括：16. Use of the compound of formula (I) according to any one of claims 1 to 14, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 15, characterized in that the use comprises: 拮抗P2X7受体活性；Antagonizes P2X7 receptor activity; 和/或，预防和/或治疗由P2X7受体拮抗活性介导的病症或紊乱；And/or, prevent and/or treat conditions or disorders mediated by P2X7 receptor antagonistic activity; 和/或，制备用于拮抗P2X7受体活性，和/或预防和/或治疗由P2X7受体拮抗活性介导的病症或紊乱的药物、药物组合物或制剂。And/or, to prepare a medicine, pharmaceutical composition or preparation for antagonizing P2X7 receptor activity, and/or for preventing and/or treating conditions or disorders mediated by P2X7 receptor antagonistic activity. 17.如权利要求16所述的用途，其特征在于，所述病症或紊乱选自疼痛、中枢疾病、免疫疾病、炎症及炎症相关疾病。17. The use as described in claim 16, wherein the symptom or disorder is selected from pain, central nervous system diseases, immune diseases, inflammation, and inflammation-related diseases.
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