CN115867552A - Imidazolopyrimidine derivative, preparation method thereof and application thereof in medicines - Google Patents
Imidazolopyrimidine derivative, preparation method thereof and application thereof in medicines Download PDFInfo
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- CN115867552A CN115867552A CN202180045897.8A CN202180045897A CN115867552A CN 115867552 A CN115867552 A CN 115867552A CN 202180045897 A CN202180045897 A CN 202180045897A CN 115867552 A CN115867552 A CN 115867552A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The disclosure relates to imidazopyrimidine derivatives, a preparation method thereof and application thereof in medicines. Specifically, the disclosure relates to an imidazopyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, especially application of the derivative as an ATR kinase inhibitor and application of the derivative in preparation of drugs for treating or preventing hyperproliferative diseases.
Description
The disclosure belongs to the field of medicines, and relates to an imidazopyrimidine derivative shown as a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular application of the derivative as an ATR kinase inhibitor and application of the derivative in preparing medicines for treating and preventing hyperproliferative diseases.
DNA damage occurs millions of times a day, both in normal and tumor cells. This makes DNA damage repair a crucial role in maintaining genomic stability and cell survival. Tumor cells are subject to greater replicative stress, carry more endogenous DNA damage, and often suffer from the loss of one or more DNA damage repair pathways compared to normal cells. This makes the survival of tumor cells more dependent on the successful repair of DNA damage.
Homologous recombination repair is the main repair mode of DNA double-strand break, and takes the homologous sequence of undamaged sister chromatid as the template for repair to replicate the DNA sequence at the damaged part and precisely repair the DNA. This repair occurs primarily in the G2 and S phases of the cell. ATR is a key enzyme in the homologous recombination repair pathway and belongs to the PIKK family. When the ATR/ATRIP complex is combined with damaged DNA covered with Replication Protein A (RPA), ATR is activated and regulates each check point of a cell cycle by phosphorylating downstream proteins Chk1, SMARCAL and the like to cause cell cycle arrest, ensure the stability of damaged DNA, improve the concentration of dNTP and promote the repair of DNA damage. Repair of DNA damage occurring during the S phase of the cell cycle is mainly accomplished by the ATR pathway, suggesting that ATR is important to ensure cell proliferation. Analysis of clinical tumor samples indicates that elevated ATR expression levels are observed in a variety of tumor tissues, such as gastric, liver, colorectal, ovarian, pancreatic cancer, and the like. And in ovarian, pancreatic cancer patients, high levels of ATR tend to be associated with lower survival rates. It follows that ATR is an important target for tumor therapy.
Patent applications for ATR inhibitors that have been disclosed include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889, and WO2014140644, among others.
Disclosure of Invention
The purpose of the present disclosure is to provide a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
R 0 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups and cycloalkylalkyl groups;
R 1 and R 2 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroarylSubstituted with a plurality of substituents;
R 3 selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 the same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5 selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, and cycloalkylalkyl;
n is 0, 1,2 or 3.
In some embodiments of the present disclosure, the compound of formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (I-a) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein R is 0 、R 1 、R 2 、R 3 、R 4 And n is as defined in formula (I).
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 2 Is heteroaryl, optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, and cycloalkyl.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 2 Is a five membered heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy and halo C 1-6 One or more substituents in the alkyl group.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 2 Selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, said pyrazolyl, imidazolyl, pyrrolyl and triazolyl being optionally selected from halogen, C 1-6 Alkyl and halo C 1-6 Alkyl is substituted by one or more substituents.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 2 Is composed of
Preferably, it is
R 2a Selected from hydrogen atoms, C 1-6 Alkyl and halo C 1-6 An alkyl group; preferably, R 2a Is methyl or ethyl.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Is heteroaryl, said heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro and cycloalkyl.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Is a five membered heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy and halo C 1-6 One or more substituents in the alkyl group.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 3 Selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, which is optionally selected from halogen, C 1-6 Alkyl and halo C 1-6 Alkyl is substituted by one or more substituents.
In some embodiments of the disclosure, the compound of formula (I) or (I-a) or a tautomer thereof,A meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Is composed of
Preferably, it is
R 3a Selected from hydrogen atoms, C 1-6 Alkyl and halo C 1-6 An alkyl group; preferably, R 3a Is a hydrogen atom.
In some embodiments of the present disclosure, the compound of formula (I) or (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:
R 6 the same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 7 the same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
p and q are the same or different and are each independently selected from 0, 1,2 or 3;
R 0 、R 1 、R 4 and n is as defined in formula (I).
In some embodiments of the present disclosure, the compound of formula (I), (I-a), or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 0 Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cyano groups; preferably, R 0 Selected from hydrogen atoms, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano; more preferably a hydrogen atom or C 1-6 An alkyl group.
In some embodiments of the present disclosure, the compound of formula (I), (I-a), or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 1 Selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein said alkyl, alkoxy, heterocyclyloxy and cycloalkyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro;
preferably, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halo C 1-6 An alkyl group;
more preferably, R 1 Is a hydrogen atom.
In some embodiments of the disclosure, the compound of formula (I), (I-a), or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 4 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, and cycloalkyl group; wherein said alkyl, alkoxy and ringEach alkyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, and nitro;
preferably, R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halo C 1-6 An alkyl group;
more preferably, R 4 Is a hydrogen atom.
In some embodiments of the disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 5 Is alkyl or haloalkyl; preferably C 1-6 An alkyl group; more preferably methyl.
In some embodiments of the disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 6 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group and nitro group; preferably, R 6 Identical or different, each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and halo C 1-6 An alkyl group; more preferably C 1-6 An alkyl group; more preferably methyl.
In some embodiments of the disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 7 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group and nitro group; preferably, R 7 Identical or different, each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and halo C 1-6 An alkyl group; more preferably a hydrogen atom.
In some embodiments of the present disclosure, the compound of formula (I), (I-a), or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, preferably 1.
In some embodiments of the disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.
In some embodiments of the present disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1, preferably 1.
In some embodiments of the disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 0 Selected from hydrogen atom, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano; r 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halo C 1-6 An alkyl group; r 2 Is a five membered heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy and halogeno C 1-6 Substituted by one or more substituents in the alkyl group; r 3 Is a five membered heteroaryl group optionally substituted by a group selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy and halogeno C 1-6 Substituted by one or more substituents in the alkyl group; r is 4 Is a hydrogen atom; r 5 Is C 1-6 An alkyl group; n is 0 or 1. In some embodiments of the disclosure, the compound of formula (I-a) or a tautomer, mesomer, or racemate thereofIn the form of a isomer, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atom, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano; r 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halo C 1-6 An alkyl group; r 2 Is composed of
R 2a Selected from hydrogen atom, C 1-6 Alkyl and halo C 1-6 An alkyl group; r 3 Is composed of
R 3a Selected from hydrogen atom, C 1-6 Alkyl and halo C 1-6 An alkyl group; r 4 Is a hydrogen atom; n is 0 or 1.
In some embodiments of the disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is 0 Is a hydrogen atom or C 1-6 An alkyl group; r is 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halo C 1-6 An alkyl group; r 4 Is a hydrogen atom; r is 6 Identical or different, each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and halo C 1-6 An alkyl group; r 7 Identical or different, each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and halo C 1-6 An alkyl group; n is 0 or 1; p is 1; q is 1.
Table a typical compounds of the present disclosure include, but are not limited to:
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
Another aspect of the present disclosure relates to compounds of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;
R 0 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups and cycloalkylalkyl groups;
R 1 and R 2 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, ammoniaAlkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5 selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, and cycloalkylalkyl;
n is 0, 1,2 or 3.
Another aspect of the present disclosure relates to a compound of formula (I-aA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;
R 0 、R 1 、R 2 、R 4 and n is as defined in formula (I-a).
Another aspect of the present disclosure relates to a compound of formula (IIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;
R 0 、R 1 、R 4 、R 6 n and p are as defined in formula (II).
Typical intermediate compounds of the present disclosure include, but are not limited to:
another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
coupling a compound of formula (IA) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (IB) to obtain a compound of formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Br;
y is
R is a hydrogen atom or an alkyl group;
R 0 、R 1 、R 2 、R 3 、R 4 、R 5 and n is as defined in formula (I).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (I-a), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
a compound of the general formula (I-aA) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and a compound of the general formula (IB) are subjected to a coupling reaction to obtain a compound of the general formula (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Br;
y is
R is a hydrogen atom or an alkyl group;
R 0 、R 1 、R 2 、R 3 、R 4 and n is as defined in formula (I-a).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
the compound of the general formula (IIA) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof and the compound of the general formula (IIB) are subjected to coupling reaction to obtain the compound of the general formula (II) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Br;
y is
R is a hydrogen atom or an alkyl group;
R 0 、R 1 、R 4 、R 6 、R 7 n, p and q are as defined in formula (II).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (I-a), (II), or table a of the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present disclosure further relates to the use of a compound of formula (I), (I-a), (II) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting ATR kinase.
The present disclosure further relates to the use of a compound of general formula (I), (I-a), (II) or table a, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment or prevention of a hyperproliferative disease.
The present disclosure further relates to the use of a compound of general formula (I), (I-a), (II) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment or prevention of a tumor.
The present disclosure further relates to the use of a compound of general formula (I), (I-a), (II) or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of a tumor.
The present disclosure also relates to a method of inhibiting ATR kinase comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), (I-a), (II), or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure also relates to a method of treating or preventing a hyperproliferative disease comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I), (I-a), (II), or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure also relates to a method of treating or preventing a tumor comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I), (I-a), (II), or table a, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to a compound of general formula (I), (I-a), (II) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
The present disclosure also relates to compounds of general formula (I), (I-a), (II) or table a or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as ATR kinase inhibitors.
The present disclosure also relates to compounds of general formula (I), (I-a), (II) or table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a hyperproliferative disease.
The present disclosure further relates to compounds of general formula (I), (I-a), (II) or table a or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment of tumors.
The tumor described in the present disclosure is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.
The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.
As a general guide, the active compounds of the present disclosure are preferably administered in unit doses, or in such a way that the patient can self-administer the compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be from 0.1 to 1000mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickening agent. Sweetening agents and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion, in which the active ingredient is dissolved in the oil phase, the injection solution or microemulsion being injectable in the bloodstream of a patient by local bolus injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be used to prepare injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Description of the terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2, 3, 4,5,6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1,2, 3, 4,5,6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 -), 1-ethylene (-CH (CH) 3 ) -), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) -), 1, 2-propylene (-CH) 2 CH(CH 3 ) -), 1, 3-propylene (-CH) 2 CH 2 CH 2 -), 1, 4-butylene (-CH) 2 CH 2 CH 2 CH 2 -) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxyOne or more substituents selected from the group consisting of alkyl, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.
The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from one or more substituents of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.
The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from one or more substituents of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 3, 4,5,6, 7, and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, according to the number of spiro atoms shared between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring includes cycloalkyl as described above (including monocyclic, spiro)Rings, fused rings, and bridged rings) to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the rings joined together with the parent structure are cycloalkyl, non-limiting examples of which include
And the like; preferably a
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 (e.g. 1,2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (e.g., 3, 4,5,6, 7 and 8), wherein 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclyl groups include:
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulphur, which may optionally be oxo (i.e. form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected and which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:
The heterocyclyl group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5,6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived from the parent ring atom by the removal of one hydrogen atom, or those derived from the parent ring atom by the removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".
The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged during the reaction at other parts of the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The term "hydroxy-protecting group" is a suitable group known in the art for hydroxy-protection, see the literature ("Protective Groups in Organic Synthesis", 5) Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C) 1-10 Alkyl or aryl) 3 Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C 1-10 Alkyl or substituted alkyl, preferably alkoxy-substituted alkyl or arylSubstituted alkyl, more preferably C 1-6 Alkoxy-substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy-substituted C 1-4 Alkyl groups, for example: methyl, tert-butyl, benzyl, methoxymethyl (MOM), ethoxyethyl; may be (C) 1-10 Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C) 1-6 Alkyl or C 6-10 Aryl) sulfonyl; or (C) 1-6 Alkoxy or C 6-10 Aryloxy) carbonyl.
The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to the heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.
The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.
The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to-OH.
The term "mercapto" refers to-SH.
The term "amino" refers to the group-NH 2 。
The term "cyano" refers to — CN.
The term "nitro" means-NO 2 。
The term "oxo" or "oxo" means "= O".
The term "carbonyl" refers to C = O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl, cycloalkyl are as defined above.
The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the disclosure except for replacing hydrogen with "deuterium" or "tritium", or with 18 F-fluorine labeling: ( 18 Isotope of F) instead of fluorine, or with 11 C-、 13 C-, or 14 C-enriched carbon (C) 11 C-、 13 C-, or 14 C-carbon labeling; 11 C-、 13 c-, or 14 C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The 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, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.
The term "pharmaceutically acceptable" as used herein refers 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 patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.
Synthesis of the compounds of the present disclosure
In order to achieve the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure:
scheme one
The preparation method of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof comprises the following steps:
a compound of the general formula (IA) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof and a compound of the general formula (IB) are subjected to a coupling reaction in the presence of a catalyst under basic conditions to obtain a compound of the general formula (I) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Br;
y is
R is a hydrogen atom or an alkyl group;
R 0 、R 1 、R 2 、R 3 、R 4 、R 5 and n is as defined in formula (I).
Scheme two
Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (I-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
a compound of the general formula (I-aA) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof and a compound of the general formula (IB) are subjected to a coupling reaction in the presence of a catalyst under basic conditions to obtain the compound of the general formula (I-a) or the tautomer, the meso form, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Br;
y is
R is a hydrogen atom or an alkyl group;
R 0 、R 1 、R 2 、R 3 、R 4 and n is as defined in formula (I-a).
Scheme three
The preparation method of the compound shown in the general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof comprises the following steps:
a compound of the general formula (IIA) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof and a compound of the general formula (IIB) are subjected to a coupling reaction in the presence of a catalyst under basic conditions to obtain a compound of the general formula (II) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
x is halogen; preferably Br;
y is
R is a hydrogen atom or an alkyl group;
R 0 、R 1 、R 4 、R 6 、R 7 n, p and q are as defined in formula (II).
The reagents providing basic conditions in the above synthesis schemes include organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium acetate, sodium t-butoxide, potassium t-butoxide, and sodium N-butoxide, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, and lithium hydroxide, preferably sodium carbonate or anhydrous sodium carbonate.
Catalysts described in the above synthetic schemes include, but are not limited to, palladium on carbon, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, bis (dibenzylideneacetone) palladium, chlorine (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) ] palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, 1' -bis (dibenzylideneacetone) dipalladium, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex.
The above reaction is preferably carried out in a solvent including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water or N, N-dimethylformamide.
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 or Bruker AVANCE NEO 500M NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
For MS measurement, agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: agilent, MS model: 6110/6120 Quadrupole MS) is used; waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector); THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC analytical determination Agilent 1260 DAD HPLC was used.
High performance liquid preparative chromatography preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281.
Chiral preparative chromatography was performed using Shimadzu LC-20AP preparative chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).
The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.
Average inhibition rate of kinase and IC 50 The values were determined with a NovoStar microplate reader (BMG, germany).
Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shao Yuan Chemical technology (Accela ChemBio Inc), darril Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.
The hydrogenation reaction is usually carried out by vacuum pumping, hydrogen filling and repeated operation for 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds, and a system of developing solvents for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: in the petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can also be added for adjustment.
Example 1
(R) -3-methyl-4- (6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) morpholine 1
First step of
N- ((4, 6-dioxo-1, 4,5, 6-tetrahydropyrimidin-2-yl) methyl) acetamide 1c
Malonamide 1a (8.6 g,84.2mmol, obtained after Shanghai, N.H.), ethyl acetylglycinate 1b (12.9g, 88.87mmol), and sodium methoxide (11.2g, 207.3 mmol) were added to methanol (150 mL) under argon, refluxed for 14 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1c (12 g), which was used in the next reaction without purification.
MS m/z(ESI)：184.1[M+1]。
Second step of
2, 4-dichloro-6-methylimidazo [1,5-a ] pyrimidine 1d
The crude compound 1c (12g, 65.5 mmol) was dissolved in toluene (50 mL), phosphorus oxychloride (36mL, 393.1mmol) was added, N-diisopropylethylamine (33mL, 196.5 mmol) was added slowly, and the reaction was carried out at 90 ℃ for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, dichloromethane (500 mL) was added and stirred for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1d (8 g), which was used in the next reaction without purification.
MS m/z(ESI)：202.1[M+1]。
The third step
(R) -4- (2-chloro-6-methylimidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 1f
The crude compound 1d (8g, 39.59mmol) was dissolved in 80mL of acetonitrile, N-diisopropylethylamine (232.12mmol, 39mL) and (R) -3-methylmorpholine (1 e) (8g, 79.0mmol, obtained after Shanghai) were added, and reacted at 75 ℃ for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, extracted with water (150 mL), extracted with ethyl acetate (80 mL. Times.2), and purified by silica gel column chromatography with eluent system C to give the title compound 1f (500 mg, yield: 4.7%).
MS m/z(ESI)：267.2[M+1]。
The fourth step
(R) -3-methyl-4- (6-methyl-2- (1-methyl-1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) morpholine 1g
Compound 1f (40mg, 0.15mmol), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-diboronocyclopent-2-yl) -1H-pyrazole (56mg, 0.44mmol, obtained after finishing Shanghai) were dissolved in a mixed solution of 4mL dioxane and water (v: v = 3). After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system C to obtain 1g (40 mg, yield: 85.3%) of the title compound.
MS m/z(ESI)：313.1[M+1]。
The fifth step
(R) -4- (8-bromo-6-methyl-2- (1-methyl-1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 1H
Compound 1g (40mg, 0.13mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, cooled to-78 deg.C, N-bromosuccinimide (23mg, 0.13mmol) was added, and the mixture was stirred for 10 minutes. The reaction was warmed to room temperature, 3mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and concentrated under reduced pressure to give the crude title product 1h (40 mg, yield: 79.2%) which was used in the next reaction without purification.
MS m/z(ESI)：391.1[M+1]。
The sixth step
(R) -3-methyl-4- (6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) morpholine 1
The crude compound 1H (40mg, 0.102mmol) was dissolved in a mixed solution of 4mL dioxane and water (v: v = 3. Cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution: ammonium bicarbonate, acetonitrile, water) to give the title product 1 (6 mg, yield: 15.6%).
MS m/z(ESI)：379.2[M+1]。
1 H NMR(400MHz,CDCl 3 ):δ7.77(s,1H),7.57(s,1H),6.89(s,1H),6.71(s,1H),6.49(s,1H),4.43(s,3H),4.01(d,2H),3.93(s,1H),3.44-3.40(m,2H),3.23(d,1H),3.00(s,3H),2.95-2.92(m,1H),1.25(d,3H)。
Example 2
(R) -4- (6-ethyl-2- (1-methyl-1H-pyrazol-5-yl) -8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 2
First step of
N- ((4, 6-dioxo-1, 4,5, 6-tetrahydropyrimidin-2-yl) methyl) propionamide 2b
Compound 1a (5 g,48.9mmol, obtained after finishing shanghai), compound 2a (8.5g, 53.4mmol, prepared by the method disclosed in intermediate 3 on page 76 of the specification of the patent application "WO 2015095788"), and sodium methoxide (6.6 g, 122.16mmol) were added to methanol (25 mL) under argon, refluxed for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2b (9.6 g), which was used in the next reaction without purification.
MS m/z(ESI)：198.0[M+1]。
Second step of
2, 4-dichloro-6-ethylimidazo [1,5-a ] pyrimidine 2c
The crude compound 2b (9.6 g,48.6 mmol) was dissolved in toluene (80 mL), phosphorus oxychloride (27mL, 292.1 mmol) was added, N-diisopropylethylamine (33mL, 194.7 mmol) was added slowly, and the reaction was carried out at 90 ℃ for 3 hours. The reaction was concentrated under reduced pressure, dichloromethane (500 mL) was added and stirred for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2c (10 g), which was used in the next reaction without purification.
MS m/z(ESI)：216.1[M+1]。
The third step
(R) -4- (2-chloro-6-ethylimidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 2d
Crude compound 2c (10g, 46.3mmol) was dissolved in 80mL of acetonitrile, and N, N-diisopropylethylamine (185.12mmol, 32mL) and compound 1e (23g, 227.4mmol) were added and reacted at 75 ℃ for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, extracted with water (150 mL), extracted with ethyl acetate (80 mL. Times.2), and purified by silica gel column chromatography with eluent system C to give the title compound 2d (1.3 g, yield: 10%).
MS m/z(ESI)：281.2[M+1]。
The fourth step
(R) -4- (6-Ethyl-2- (1-methyl-1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 2e
Compound 2d (300mg, 1.07mmol), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-diboronocyclopent-2-yl) -1H-pyrazole (555mg, 2.67mmol, obtained after shanghai) were dissolved in a mixed solution of 6mL dioxane and water (v: v =5: 1), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (135mg, 0.16mmol) and anhydrous sodium carbonate (339mg, 3.19mmol) were added and reacted at 100 ℃ for 2 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 2e (300 mg, yield: 86%).
MS m/z(ESI)：327.1[M+1]。
The fifth step
(R) -4- (8-bromo-6-ethyl-2- (1-methyl-1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 2f
Compound 2e (300mg, 919.13. Mu. Mol) was dissolved in 10mL of anhydrous tetrahydrofuran, cooled to-78 ℃ and N-bromosuccinimide (114mg, 640.51. Mu. Mol) was added thereto, and stirred for 10 minutes. The reaction was warmed to room temperature, 3mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and concentrated under reduced pressure to give the crude title compound 2f (240 mg) which was used in the next reaction without purification.
MS m/z(ESI)：405.1[M+1]。
The sixth step
(R) -4- (6-ethyl-2- (1-methyl-1H-pyrazol-5-yl) -8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 2
Crude compound 2f (370mg, 912.9. Mu. Mol) was dissolved in 10mL of 1, 4-dioxane and 2mL of water under an argon atmosphere, and compound 1i (204mg, 1.82mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (116mg, 137. Mu. Mol) and sodium carbonate (193mg, 1.82mmol) were added in this order and stirred at 90 ℃ for 4 hours. The reaction solution was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution: ammonium bicarbonate, acetonitrile, water) to give the title compound 2 (98 mg, yield: 27.3%).
MS m/z(ESI)：393.0[M+1]。
1H NMR(500MHz,CD 3 OD):δ7.65(s,1H),7.56(d,1H),7.09-6.97(m,1H),6.90(d,2H),4.39(d,3H),4.10-3.73(m,4H),3.62-3.37(m,4H),2.95(ddd,1H),1.44(t,3H),1.13-1.02(m,3H)。
Example 3
(R) -4- (2- (1-ethyl-1H-pyrazol-5-yl) -6-methyl-8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 3
First step of
(R) -4- (2- (1-ethyl-1H-pyrazol-5-yl) -6-methylimidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 3b
Compound 1f (100mg, 0.37mmol) and 1-ethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (3 a) (166mg, 0.75mmol, obtained from shanghai) were dissolved in a mixed solution of 4mL dioxane and water (v: v = 3), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (47mg, 0.055mmol) and anhydrous sodium carbonate (119mg, 1.21mmol) were added and reacted at 100 ℃ for 2 hours. Cooled to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 3b (100 mg, yield: 81.7%).
MS m/z(ESI)：327.3[M+1]。
Second step of
(R) -4- (8-bromo-2- (1-ethyl-1H-pyrazol-5-yl) -6-methylpyrazolo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 3c
Compound 3b (100mg, 0.3mmol) was dissolved in 2mL of anhydrous tetrahydrofuran, cooled to-78 deg.C, N-bromosuccinimide (27mg, 0.15mmol) was added, and stirred for 20 minutes. The reaction solution was warmed to room temperature, 3mL of a saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and concentrated under reduced pressure to give the crude title compound 3c (100 mg, yield: 80%) which was used in the next reaction without purification.
MS m/z(ESI)：405.0[M+1]。
The third step
(R) -4- (2- (1-ethyl-1H-pyrazol-5-yl) -6-methyl-8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 3
Compound 3c (100mg, 0.247mmol) was dissolved in 4mL of a mixed solution of dioxane and water (v: v = 3) and compound 1i (55mg, 0.491mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium chloromethane complex (31mg, 0.04mmol) and anhydrous sodium carbonate (78mg, 0.74mmol) were added and stirred at 90 ℃ for 2 hours. Cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, and the obtained residue was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution system: ammonium hydrogencarbonate, acetonitrile, water) to give compound 3 (30 mg, yield: 30.9%).
MS m/z(ESI):393.0[M+1]。
1 H NMR(500MHz,CD 3 OD):δ7.85-7.45(m,2H),7.03(s,1H),6.95-6.43(m,2H),4.91(d,2H),4.20-3.56(m,4H),3.55-3.33(m,2H),3.01(s,4H),1.50(t,3H),1.05(d,3H)。
Example 4
(R) -3-methyl-4- (2- (1-methyl-1H-pyrazol-5-yl) -8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) morpholine 4
First step of
2, 4-Dihydroxyimidazo [1,5-a ] pyrimidine-8-carboxylic acid methyl ester 4b
Dimethyl malonate (700mg, 5.3 mmol), methyl 5-amino-1H-imidazole-4-carboxylate (4 a) (500mg, 3.5mmol, hanhan hong of Shanghai), cesium carbonate (2.3 g, 7.08mmol) were added to N, N-dimethylformamide (15 mL) under an argon atmosphere and stirred at 110 ℃ for 15 hours. The reaction was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the title product 4b (1.2 g), which was used in the next reaction without purification.
MS m/z(ESI)：210.1[M+1]。
Second step of
2, 4-Dichloroimidazo [1,5-a ] pyrimidine-8-carboxylic acid methyl ester 4c
The crude compound 4b (1.0 g, 4.78mmol) was dissolved in toluene (20 mL), phosphorus oxychloride (3 mL, 35.1mmol) was added, and the reaction was carried out at 100 ℃ for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, dichloromethane (500 mL) was added and stirred for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure to give the title product 4c (3.2 g), which was used in the next reaction without purification.
MS m/z(ESI)：246.0[M+1]。
The third step
(R) -2-chloro-4- (3-methylmorpholine) imidazo [1,5-a ] pyrimidine-8-carboxylic acid methyl ester 4d
The crude compound 4c (1.0g, 1.6mmol) was dissolved in 20mL of acetonitrile, and N, N-diisopropylethylamine (1.05g, 8.0mmol) and compound 1e (822mg, 8mmol) were added to react at 75 ℃ for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and purified by silica gel column chromatography with eluent system C to give the title compound 4d (120 mg), yield: 23.7 percent.
MS m/z(ESI)：311.1[M+1]。
The fourth step
(R) -2- (1-methyl-1H-pyrazol-5-yl) -4- (3-methylmorpholine) imidazo [1,5-a ] pyrimidine-8-carboxylic acid methyl ester 4e
Compound 4d (100mg, 0.39mmol) and 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (160mg, 0.772mmol) were dissolved in a mixed solution of 4mL dioxane and water (v: v = 3). After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system C to give the title compound 4e (40 mg, yield: 87.2%).
MS m/z(ESI)：357.3[M+1]。
The fifth step
(R) -2- (1-methyl-1H-pyrazol-5-yl) -4- (3-methylmorpholine) imidazo [1,5-a ] pyrimidine-8-carboxylic acid 4f
Compound 4e (120mg, 0.336mmol) was dissolved in 4mL of a mixed solution of methanol and water (v: v = 3). The reaction solution was concentrated under reduced pressure, diluted with 5mL of water, adjusted to pH =5 with 1N hydrochloric acid, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and concentrated under reduced pressure to give a crude title product 4f (60 mg, yield: 52.1%) which was used in the next reaction without purification.
MS m/z(ESI)：343.1[M+1]。
The sixth step
(R) -4- (8-bromo-2- (1-methyl-1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) -3-methylmorpholine 4g
The crude compound 4f (60mg, 0.175mmol) was dissolved in 4mL of N, N-dimethylformamide, cooled to-78 deg.C, and anhydrous sodium bicarbonate (30mg, 0.35mmol) and N-bromosuccinimide (35mg, 0.184mmol) were added and stirred for 10 minutes. The reaction solution was warmed to room temperature, 10mL of a saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and concentrated under reduced pressure to give 4g (30 mg, yield: 45.4%) of the crude title product, which was used in the next reaction without purification.
MS m/z(ESI)：377.2[M+1]。
Seventh step
(R) -3-methyl-4- (2- (1-methyl-1H-pyrazol-5-yl) -8- (1H-pyrazol-5-yl) imidazo [1,5-a ] pyrimidin-4-yl) morpholine 4
Crude compound 4g (30mg, 0.079mmol) was dissolved in 4mL of a mixed solution of dioxane and water (v: v = 3) and compound 1i (27mg, 0.238mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (10mg, 0.02mmol) and anhydrous sodium carbonate (27mg, 0.26mmol) were added and stirred at 90 ℃ for 2 hours. Cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution: ammonium bicarbonate, acetonitrile, water) to give the title product 4 (5 mg, yield: 17.2%).
MS m/z(ESI):365.2[M+1]。
1 H NMR(400MHz,CDCl 3 ):δ7.75(s,1H),7.52(s,1H),7.13(s,2H),7.02(s,1H),6.90(s,1H),4.23(s,3H),4.03(d,2H),3.95(s,1H),3.66-3.64(m,2H),3.53(d,1H),3.39(d,1H),1.33(d,3H)。
Test example:
biological evaluation
Test example 1 inhibitory Activity of the Compounds of the present disclosure on ATR enzyme
The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on ATR enzyme.
The experimental method is briefly described as follows:
1. experimental materials and instruments
1. ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M)
2. GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)
3. 384 orifice (Thermo Scientific, 267462)
4. U type bottom 96-well plate (Corning, 3795)
5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08 KAE)
6. anti-GST antibody linked to d2 (cisbio, 61 GSTDLF)
7. ATP solution (Promega, V916B)
8、EDTA(Thermo Scientific，AM9260G)
9、HEPES(Gibco，15630-080)
10. Enzyme mark instrument (BMG, PHERASta)
2. Experimental procedure
1nM ATR enzyme, 50nM P53 protein, 7.435. Mu.M ATP and varying concentrations (first concentration 1. Mu.M, 11 concentrations of 3-fold dilution gradient) of a compound of the present disclosure were mixed, incubated at room temperature for 2 hours, then mixed with stop buffer (12.5 mM HEPES,250mM EDTA) and mixed with 0.42 ng/well of europium cryptate anti-phosphorylated P53 protein antibody and 25 ng/well of d 2-linked anti-GST antibody. After overnight incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software.
3. Experimental data
The inhibitory activity of the disclosed compounds against ATR enzyme can be determined by the above assay. Blank test wells without ATR enzyme addition were set to 100% inhibition by the formula 100 × [1- (compound signal-background signal)/(DMSO well signal-background signal)]The inhibition rate of the compound was calculated. Measured IC 50 Values and maximum inhibition rates are given in table 1 below.
TABLE 1 IC inhibition of ATR enzyme by the compounds of this disclosure 50
| Example numbering | IC 50 /nM | Maximum inhibition ratio (%) |
| 1 | 8 | 99 |
| 2 | 3 | 100 |
| 3 | 13 | 99 |
| 4 | 101 | 96 |
And (4) conclusion: the disclosed compound has good inhibitory activity to ATR enzyme.
Test example 2 selectivity test of the compounds of the present disclosure for ATR enzyme
The following methods measure the inhibitory activity of the compounds of the present disclosure against ATM enzyme, DNA-PK enzyme and PI3K enzyme, respectively, to illustrate the selectivity of the compounds of the present disclosure for ATR enzyme.
The experimental method is briefly described as follows:
inhibition of ATM enzymes by compounds of the disclosure
1. Experimental materials and instruments
1. ATM enzyme (Eurofins Pharma Discovery Services, 14-933-M)
2. GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)
3. 384 orifice (Thermo Scientific, 267462)
4. U type bottom 96-well plate (Corning, 3795)
5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08 KAE)
6. anti-GST antibody linked to d2 (cisbio, 61 GSTTDLF)
7. ATP solution (Promega, V916B)
8、EDTA(Thermo Scientific，AM9260G)
9、HEPES(Gibco，15630-080)
10. Enzyme mark instrument (BMG, PHERASta)
2. Experimental procedure
1nM ATM enzyme, 30nM P53 protein, 11. Mu.M ATP and different concentrations (10. Mu.M initial concentration, 3-fold gradient dilution 11 concentrations) of a compound of the present disclosure were mixed and incubated for 2 hours at room temperatureIn this case, stop solution (12.5 mM HEPES,250mM EDTA) was added thereto and mixed, and then 0.42 ng/well of europium cryptate-labeled anti-phosphorylated P53 protein antibody and 25 ng/well of anti-GST antibody linked to d2 were added. After overnight incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software. Inhibition of ATM enzymes by compounds of the disclosure IC 50 The values are given in Table 2 below.
(II) inhibition of DNA-PK enzyme by the disclosed compounds
1. Experimental materials and instruments
1. DNA-PK enzyme (Eurofins Pharma Discovery Services, 14-950-M)
2. GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)
3. 384 orifice (Thermo Scientific, 267462)
4. U type bottom 96-well plate (Corning, 3795)
5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08 KAE)
6. anti-GST antibody linked to d2 (cisbio, 61 GSTTDLF)
7. ATP solution (Promega, V916B)
8、EDTA(Thermo Scientific，AM9260G)
9、HEPES(Gibco，15630-080)
10. Enzyme mark instrument (BMG, PHERASta)
2. Experimental procedure
0.02nM DNA-PK enzyme, 50nM P53 protein, 7.3. Mu.M ATP and various concentrations of compounds of the present disclosure (first concentration 10. Mu.M, 11 concentrations by 3-fold gradient dilution) were mixed, incubated at room temperature for 1 hour, mixed with stop solution (12.5 mM HEPES,250mM EDTA), and added with 0.42 ng/well of the europium cryptate anti-phosphorylated P53 protein antibody and 25 ng/well of the anti-GST antibody linked to d 2. After overnight incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software. Inhibition of DNA-PK enzymes by the compounds of the disclosure 50 The values are given in Table 2 below.
(III) inhibition of PI3K enzymes by compounds of the disclosure
1. Experimental materials and instruments
1. PIK3CA/PIK3R1 (p 110alpha/p85 alpha) kinase (Invitrogen, PV 4788)
2. PIP2 PS Lipid substrate (Invitrogen, PV 5100)
3、DTT(Sigma，43815-1G)
4. Tris-HCl (1M, pH 7.5) (Beijing Tian Enze biotechnology, inc., 101205-100)
5. ATP solution (Promega, V916B)
6. Magnesium chloride hexahydrate (Sigma, M2393)
7. Sodium chloride (national drug group chemical agents Co., ltd., 10019318)
8、CHAPS(Sigma，C3023-5G)
9、HEPES(Gibco，15630-080)
10、ADP-Glo TM Kinase assay kit (Promega, V9102)
11. 384 orifice (Thermo Scientific, 267462)
12. U type bottom 96-well plate (Corning, 3795)
13. Enzyme-labeling instrument (BMG, PHERAstar)
2. Experimental procedure
The final concentration of PIK3CA/PIK3R1 (p 110alpha/p85 alpha) kinase is 0.625nM, and is mixed with the compound of the invention with different concentrations (initial concentration 10. Mu.M, 3 times gradient dilution 10 concentrations), and incubated at room temperature for 30 minutes, then PIP2: PS Lipid substrate (final concentration 50. Mu.M) and 1 xATP (final concentration 50. Mu.M) are added, mixed, incubated at 37 ℃ for 30 minutes, then added with detection reagent ADP-Glo (Promega, V9102) and mixed, and after incubation at room temperature for 40 minutes, ADP-Glo is added TM The detection reagent of the kinase assay kit (Promega, V9102) was incubated at room temperature for 40 minutes. Fluorescence signals were detected with PHERAstar and data were processed using GraphPad software. Inhibition IC of PI3K enzyme by the disclosed compounds 50 The values are given in Table 2 below.
TABLE 2 IC of inhibition of ATM enzyme, DNA-PK enzyme and PI3K enzyme by the compounds of this disclosure 50 Value of
And (4) conclusion: the disclosed compounds have weak inhibitory activity against ATM enzyme, DNA-PK enzyme and PI3K enzyme, and the compounds have selectivity to ATR enzyme as can be seen by comparing test examples 1 and 2.
Test example 3 cell proliferation assay of LoVo
The following method was performed by measuring intracellular ATP content based on IC 50 The effect of the disclosed compounds on inhibition of LoVo cell proliferation was evaluated.
The experimental method is briefly described as follows:
1. experimental materials and instruments
1. LoVo, human colon cancer tumor cell (Nanjing Kebai, CBP 60032)
2. Fetal bovine serum (GIBCO, 10091-148)
3. F-12K Medium (Gibco, 21127030)
4. CellTite-Glo reagent (Promega, G7573)
5. 96-well cell culture plate (corning, 3903)
6. Pancreatin (invitrogen, 25200-072)
7. Enzyme-linked immunosorbent assay (BMG, PHERAsta)
8. Cell counter (Shanghai Rui Yu biological technology company, IC 1000)
2. Experimental procedure
LoVo cells were cultured in F-12K medium containing 10% FBS, passaged 2 to 3 times a week at a passage ratio of 1. During passage, cells are digested by pancreatin and transferred to a centrifuge tube, centrifugation is carried out for 3 minutes at 1200rpm, the residual liquid of a supernatant culture medium is discarded, and a fresh culture medium is added to resuspend the cells. 90 μ L of cell suspension was added to a 96-well cell culture plate at a density of 3.88X 10 4 Cells/ml, 96-well plate periphery only 100. Mu.L of complete medium was added. Culturing the plate in an incubator for 24 hours (37 ℃,5% 2 )。
Test compounds were diluted to 2mM in DMSO and sequentially diluted 3-fold to 10 concentrations, and blank wells (no compound in cells) and control wells (no compound in cells) were set. Taking and matching5 μ L of the compound solution to be tested prepared into gradient concentration is added into 95 μ L of fresh culture medium to prepare the culture medium solution containing the compound. To the plate was added 10. Mu.L of the above drug-containing medium solution. Incubate the plates in the incubator for 3 days (37 ℃,5% CO) 2 ). In 96 hole cell culture plate, each hole is added with 50 u L CellTiter-Glo reagent, room temperature and light protection placed for 5-10 minutes, in the PHERAstar in the chemiluminescence signal value, the data using GraphPad software processing.
3. Experimental data
The inhibitory activity of the disclosed compounds on the proliferation of LoVo cells can be determined by the above assay. Blank wells were set for 100% inhibition by the formula 100 × [1- (compound signal-blank well signal)/(control well signal-blank well signal)]The inhibition rate of the compound was calculated. Measured IC 50 Values and maximum inhibition rates are given in table 3 below.
TABLE 3 IC of compounds of the present disclosure for inhibition of LoVo cell proliferation 50
| Example numbering | IC 50 /nM | Maximum inhibition ratio (%) |
| 1 | 47 | 84 |
| 2 | 9.4 | 95 |
| 3 | 40 | 94 |
And (4) conclusion: the compounds disclosed have good inhibitory activity on LoVo cell proliferation.
Pharmacokinetic evaluation
Test example 4 pharmacokinetic testing of Compounds of the disclosure
1. Abstract
The drug concentrations in plasma of nude mice at different times after gavage administration of the compound of example 1 were determined by LC/MS/MS method using nude mice as test animals. The pharmacokinetic behavior of the compounds of the present disclosure in nude mice was studied and their pharmacokinetic profile was evaluated.
2. Test protocol
2.1 test specimens
The compound of example 1.
2.2 test animals
Healthy adult nude mice 9, female, were purchased from Witongliwa laboratory animals, inc.
2.3 sample preparation
A predetermined volume of the compound of example 1 was weighed, PEG400 (15% final volume, nanjing Will chemical Co., ltd.) was added thereto, ultrasonic agitation was performed with a stirrer until the sample was completely dissolved, and a predetermined volume (85% final volume) of the already prepared 1% HPMC K100LV solution (HPMC K100LV powder was purchased from Umbellifera DOW Co., ltd., and 1% HPMC K100LV solution was prepared internally) was added to prepare a 0.5mg/mL administration solution of the compound of example 1.
2.4 administration of drugs
The nude mice were fasted overnight and then administered by gavage at a dose of 10mg/kg and a volume of 0.2mL/10g.
3. Operation of
The compound of example 1 is administered to nude mice by gavage, 0.1mL of blood is collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours after administration, the blood is put into an EDTA-K2 anticoagulation test tube, centrifuged at 4 ℃ and 10000 rpm for 1 minute, plasma is separated within 1 hour, the blood is stored at-20 ℃ for testing, and the blood collection and centrifugation process are carried out under ice bath conditions.
Determining the content of the compound to be tested in the blood plasma of nude mice after the drug with different concentrations is administered by gastric gavage: mu.L of nude mouse plasma at each time point after administration was taken, 50. Mu.L of internal standard solution (100 ng/mL camptothecin) and 200. Mu.L of acetonitrile were added, vortex mixed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and 0.1. Mu.L of supernatant was taken from the plasma sample for LC/MS/MS analysis.
4. Pharmacokinetic parameter results
The pharmacokinetic parameters of the compounds of the present disclosure are shown in table 4 below.
Table 4 pharmacokinetic parameters of the Compounds of the disclosure
And (4) conclusion: the disclosed compound has good drug absorption and obvious pharmacokinetic advantage.
Claims (19)
- A compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:R 0 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups and cycloalkylalkyl groups;R 1 and R 2 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkenyl group, alkoxy group, heterocyclyloxy group, haloalkyl group, haloalkoxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, cycloalkyl group, heterocyclyl group, and aryl groupAnd a heteroaryl group; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;R 3 selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;R 4 the same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;R 5 selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, and cycloalkylalkyl;n is 0, 1,2 or 3. - The compound of formula (I) according to claim 1, wherein R is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 2 Is a five membered heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy and halogeno C 1-6 Alkyl is substituted by one or more substituents.
- The compound of formula (I) according to claim 1 or2, wherein R is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 3 Is a five membered heteroaryl group optionally substituted by a group selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy and halogeno C 1-6 Alkyl is substituted by one or more substituents.
- A compound of formula (I) according to any one of claims 1 to 3, which is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
wherein:R 6 the same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;R 7 the same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;p and q are the same or different and are each independently selected from 0, 1,2 or 3;R 0 、R 1 、R 4 and n is as followsAs defined in claim 1. - The compound of general formula (I) according to any one of claims 1 to 4, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 0 Is a hydrogen atom or C 1-6 An alkyl group.
- The compound of general formula (I) according to any one of claims 1 to 5, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 1 Is a hydrogen atom.
- The compound of general formula (I) according to any one of claims 1 to 6, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 4 Is a hydrogen atom.
- The compound of formula (I) according to any one of claims 1 to 3, 5 to 7, wherein R is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 5 Is methyl.
- The compound of general formula (I) according to any one of claims 4 to 8, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 6 Is C 1-6 An alkyl group.
- The compound of the general formula (I) according to any one of claims 4 to 9, or a tautomer, mesomer, racemate, enantiomer, or isomer thereof,Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 7 Is a hydrogen atom.
- A compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:
- a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:x is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;R 0 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups and cycloalkylalkyl groups;R 1 and R 2 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl；R 4 The same or different, each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;R 5 selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, and cycloalkylalkyl;n is 0, 1,2 or 3. - The compound of formula (IA) according to claim 12, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:
- a process for the preparation of a compound of formula (I) according to claim 1 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises:
coupling a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (IB) to provide a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,wherein:x is halogen;y is
R is a hydrogen atom or an alkyl group;R 0 、R 1 、R 2 、R 3 、R 4 、R 5 and n is as defined in claim 1. - A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
- Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the preparation of a medicament for inhibiting ATR kinase.
- Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the preparation of a medicament for the treatment or prevention of a hyperproliferative disease.
- Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the preparation of a medicament for the treatment or prevention of tumors.
- The use according to claim 18, wherein the tumor is selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.
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| PCT/CN2021/104227 WO2022002243A1 (en) | 2020-07-02 | 2021-07-02 | Imidazopyrimidine derivative, preparation method therefor and medical use thereof |
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| NZ731337A (en) * | 2012-12-07 | 2019-02-22 | Vertex Pharma | Compounds useful as inhibitors of atr kinase |
| CN110467610A (en) * | 2018-05-10 | 2019-11-19 | 四川科伦博泰生物医药股份有限公司 | A kind of substituted pyrimidines compound, preparation method and use |
| WO2020103897A1 (en) * | 2018-11-22 | 2020-05-28 | 上海迪诺医药科技有限公司 | Heterocyclic fused pyrimidine derivative, pharmaceutical composition thereof, and application thereof |
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