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CN118255760A - A pyrimidine compound and its preparation method and medical use - Google Patents

A pyrimidine compound and its preparation method and medical use Download PDF

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Publication number
CN118255760A
CN118255760A CN202211714390.XA CN202211714390A CN118255760A CN 118255760 A CN118255760 A CN 118255760A CN 202211714390 A CN202211714390 A CN 202211714390A CN 118255760 A CN118255760 A CN 118255760A
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alkyl
heterocyclyl
cycloalkyl
heteroaryl
aryl
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CN202211714390.XA
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Inventor
王铁林
宋海峰
肖璐
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Shanghai Yahong Pharmaceutical Technology Co ltd
Jiangsu Yahong Pharmaceutical Technology Co ltd
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Shanghai Yahong Pharmaceutical Technology Co ltd
Jiangsu Yahong Pharmaceutical Technology Co ltd
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Priority to CN202211714390.XA priority Critical patent/CN118255760A/en
Priority to PCT/CN2023/139755 priority patent/WO2024140319A1/en
Priority to CN202380083590.6A priority patent/CN120303260A/en
Publication of CN118255760A publication Critical patent/CN118255760A/en
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to a pyrimidine compound, a preparation method and medical application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as an ATR kinase inhibitor in treating ATR kinase mediated diseases. The definition of each group in the general formula (I) is the same as that in the specification.

Description

Pyrimidine compound, preparation method and medical application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a pyrimidine compound serving as an ATR inhibitor, a preparation method thereof, a pharmaceutical composition containing the pyrimidine compound and application of the pyrimidine compound in treating ATR kinase mediated diseases, such as cancer treatment.
Background
DNA can be continually damaged by various factors in the external environment or within the cell. If unrepaired or abnormally repaired, these lesions may lead to cell death and even cause deleterious mutations in the gene. To ensure the stability and integrity of the cell genome, cells have formed a complex network of signal pathways, collectively known as the DNA Damage Response (DDR). DDR is responsible for coordinating early detection of DNA damage and signaling cell cycle checkpoints and DNA repair pathways, pausing the cell cycle to initiate repair, or initiating cell death when damage is too severe. It was found that healthy cells exist in a variety of DDR mechanisms, and that these repair mechanisms can compensate each other during DNA repair. Many cancer cells have defects in various DNA repair pathways, and thus exhibit greater dependence on intact DNA repair pathways.
Ataxia telangiectasia mutated gene Rad3 related kinase (ATR) belongs to serine-threonine kinase in phosphatidylinositol 3-kinase (PIKK) family, and after ATR kinase is activated at DNA damage, cell biological processes can be regulated by various signals including cell cycle arrest, inhibition of replication origin, promotion of deoxynucleotide synthesis, initiation of replication fork and repair of DNA double strand break, thereby avoiding apoptosis. The DNA damage repair system in most tumor cells is abnormal, usually lacking certain repair pathways (such as mutations in p53 or ATM), making it more dependent on ATR for survival. In normal cells, however, inhibition of ATR kinase alone does not have a major effect due to its robust and complete repair pathway. Thus, inhibition of ATR may have a more pronounced effect on cancer treatment, while interfering less with normal cells, making ATR a promising cancer therapeutic target.
ATR inhibitors may be used alone or as sensitizers for DNA damage chemotherapy or radiotherapy, other DDR inhibitors and immune checkpoint inhibitors. The combination therapies that are widely used include antimetabolites (e.g., gemcitabine), DNA crosslinkers (e.g., cisplatin, carboplatin), alkylating agents (e.g., temozolomide), topoisomerase inhibitors (e.g., camptothecine, topotecan, irinotecan), other DDR inhibitors (PARP inhibitors), and the like. The combination therapy inhibits ATR at elevated levels of replicative stress, thereby inhibiting the ability of cancer cells to repair damaged DNA, resulting in a greatly enhanced therapeutic effect on cancer.
Although a variety of ATR kinase inhibitors have been disclosed (e.g., M6620, WO2011154737, WO2016020320, WO2010071837, WO2014089379, WO 2020087170, WO2020049017, etc.), no ATR inhibitors have been marketed so far and therefore it is still necessary to find more potent and safe ATR inhibitors.
Disclosure of Invention
Through intensive research, the invention designs and synthesizes a new pyrimidine compound which can be used as an ATR kinase inhibitor for treating diseases received by ATR kinase such as cancers.
It is therefore an object of the present invention to provide a compound of the general formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, said alkyl, alkenyl, alkynyl optionally substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkoxy, halohydroxyalkyl, alkenyl, alkynyl;
or R 1 is
Wherein:
L is selected from the group consisting of bond, alkylene, alkenylene, alkynylene, -C (O) -, -S (O) 2-、-C(O)NH-、-S(O)NH-、-S(O)2 NH-, -C (O) O-;
Ring a is selected from aryl, heteroaryl, cycloalkyl, or heterocyclyl, optionally substituted with one or more Q groups;
q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc), said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc;
r 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, said alkyl, alkenyl, alkynyl optionally substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl;
Or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group, which is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH 2)qNRaRb);
R 3 is selected from alkyl, haloalkyl or cycloalkyl;
Each R 4 is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkoxy, halohydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
m is 0,1, 2 or 3;
p is 0, 1 or 2;
q is an integer from 0 to 6.
In one embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
R 1 is
Wherein:
L is selected from the group consisting of bond, alkylene, alkenylene, alkynylene, -C (O) -, -S (O) 2-、-C(O)NH-、-S(O)NH-、-S(O)2 NH-, -C (O) O-; preferably selected from the group consisting of bond, alkylene, -C (O) -;
Ring a is selected from aryl, heteroaryl, preferably C 6-10 aryl or 5-10 membered heteroaryl; the aryl, heteroaryl groups are optionally substituted with one or more Q groups;
Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc), said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is 0, 1 or 2;
q is an integer from 0 to 6.
In a specific embodiment, a compound of formula (I) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of:
Preferably is Ring a is optionally further substituted with Q, Q being as defined in formula (I).
In a preferred embodiment, the compound of formula (I) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2 is hydrogen or C 1-6 alkyl;
l is selected from-CH 2 -, -C (O) -;
Ring a is selected from phenyl or a 5 to 6 membered heteroaryl, preferably phenyl; ring a is optionally further substituted with- (CH 2)qNRaRb;
q is 1 or 2, preferably 1;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl.
In another embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
L is selected from the group consisting of a bond, an alkylene, -C (O) -; preferably a bond;
Each X 1、X2、X3、X4 is independently selected from CH or N;
Q 1 is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc), said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc;
Each Q 2 is independently selected from hydrogen, halogen, alkyl, haloalkyl, - (CH 2)qC(O)NRaRb), said alkyl optionally further substituted with NR aRb;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is 0, 1 or 2;
R 2、R3、R4, m, p and q are defined as in general formula (I).
In another embodiment, the compound of formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Q 1 is-NR aRb;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRd(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl, preferably a 4-6 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 aryl, and 5-to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3-to 6-membered heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is 1 or 2;
q is an integer of 0 to 6, preferably an integer of 1 to 6, more preferably an integer of 1 to 4.
In another embodiment, the compound of formula (I) or formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2、X3、X4 is independently selected from CH or N; preferably, X 1 is N and X 2、X3、X4 is CH, or X 2 is N and X 1、X3、X4 is CH, or X 1、X2、X3、X4 is CH;
Y is selected from NR 5、CR5R6 or SO 2;
R 5 is selected from hydrogen, halogen, amino, oxo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、C(O)Rf、C(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-S(O)pRf、-S(O)pNRdRe、-NRdC(O)Rf; said C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R 6 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
Or R 5 and R 6 together with the carbon atom to which they are attached form a 3-to 12-membered heterocyclyl, preferably a 3-to 6-membered heterocyclyl; the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is 1 or 2;
q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;
n is 0, 1 or 2;
s is 1 or 2; preferably 1;
t is 1 or 2; preferably 1;
R 2、R3、R4 and m are defined as general formula (I); q 2 is as defined in formula (II).
In a preferred embodiment, the compound of formula (III) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: x 1 is N; x 2、X3、X4 is CH.
In a preferred embodiment, the compound of formula (III) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: y is selected from NR 5;
R 5 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl (e.g., oxetane, azetidine, pyrrolidinyl, furanyl, piperidinyl, piperazinyl, pyranyl), phenyl, 5-6 membered heteroaryl (e.g., pyridinyl, oxazolyl), -C (O) R f; the C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R f is selected from C 1-6 alkyl, C 1-6 haloalkyl.
In another preferred embodiment, the compound according to the invention of formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: y is selected from CR 5R6;
R 5 is selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (e.g., imidazolyl) )、-(CH2)qNRdRe、-C(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-S(O)pNRdRe、-NRdC(O)Rf;
R 6 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R d is selected from hydrogen, C 1-6 alkyl;
R e is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 4 to 6 membered heterocyclyl (e.g., pyranyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl), phenyl, 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 4 to 6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (e.g., pyridinyl, thiazolyl, imidazolyl, pyrazolyl) optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl;
R d and R e together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl (e.g., azetidine, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, azacyclooctane), said 3-8 membered heterocyclyl optionally being further substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl (e.g., oxetane, piperazinyl, piperidinyl, morpholinyl), said C 3-6 cycloalkyl, 3-6 membered heterocyclyl optionally being further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is hydrogen or C 1-6 alkyl;
p is 1 or 2, preferably 2;
q is 0, 1 or 2.
In another preferred embodiment, the compound according to the invention of formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: y is selected from CR 5R6;
R 5 is selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl 、-(CH2)qNRdRe、-NRdC(O)Rf、-S(O)pNRdRe;
R 6 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R d is selected from hydrogen, C 1-6 alkyl;
r e is selected from hydrogen, C 1-6 alkyl;
R f is hydrogen or C 1-6 alkyl;
p is 2;
q is 0 or 1;
In another preferred embodiment, the compound according to the invention of formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: y is selected from CR 5R6;
R 5 is selected from cyano, C 1-6 alkyl, C 1-6 haloalkyl 、-(CH2)qNRdRe、-NRdC(O)Rf、-S(O)pNRdRe;
R 6 is selected from hydrogen;
R d is selected from hydrogen, C 1-6 alkyl;
r e is selected from hydrogen, C 1-6 alkyl;
R f is hydrogen or C 1-6 alkyl;
p is 2;
q is 0 or 1;
in another preferred embodiment, the compound according to the invention of formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: y is selected from SO 2.
In another preferred embodiment, the compound according to the invention of formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from CR 5R6;
R 5 and R 6 together with the carbon atom to which they are attached form azetidinyl, pyrrolidinyl, tetrahydroimidazolyl; the azetidinyl, pyrrolidinyl, tetrahydroimidazolyl are optionally further substituted with oxo.
In another embodiment, the compound of formula (I), formula (II) or formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIA) or formula (IIIB) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2 is independently selected from CH or N;
Y 1 is selected from N or CR 6;
R 6 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, - (CH 2)qNRdRe) wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 6 membered heterocyclyl;
R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;
Or R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, preferably a 6 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, a 3-8 membered heterocyclyl, wherein the C 3-6 cycloalkyl, 3-8 membered heterocyclyl is optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl are optionally further substituted with one or more substituents selected from halogen;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl;
q is an integer from 1 to 4, preferably 1 or 2;
n is 0, 1 or 2;
R 2、R3、R4 and m are defined as general formula (I); q 2 is as defined in formula (II).
In a preferred embodiment, the compound of formula (IIIA) or (IIIB) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: x 1 is N and X 2 is CH.
In another preferred embodiment, the compound according to the invention of formula (IIIA) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is selected from CR 6;
r 6 is selected from hydrogen, halogen, amino and C 1-6 alkyl.
In another preferred embodiment, the compound of formula (IIIA) or (IIIB) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
y 1 is selected from N.
In another preferred embodiment, the compound according to the invention of formula (IIIA) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl (e.g., oxetanyl, azetidinyl, pyranyl, furanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), phenyl, 5-6 membered heteroaryl (e.g., thiazolyl, imidazolyl, pyrazolyl, pyridinyl), - (CH 2)qNRdRe), wherein the C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl;
R 8 is selected from hydrogen, C 1-6 alkyl;
r d is selected from C 1-6 alkyl;
r e is selected from C 1-6 alkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclylheterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);
q is 2.
In another preferred embodiment, the compound according to the invention of formula (IIIA) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), preferably a 6 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, di C 1-6 alkylamino, C 3-6 cycloalkyl, a 3-8 membered heterocyclyl (e.g., oxetanyl, piperidinyl, piperazinyl, morpholinyl), wherein the C 3-6 cycloalkyl, 3-8 membered heterocyclyl is optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl.
In another preferred embodiment, the compound according to the invention of formula (IIIB) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl.
In another embodiment, the compound of formula (I), formula (II) or formula (III) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIC) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2 is independently selected from CH or N;
Y 2 is selected from NR 11、CR11R12、SO2;
R 12 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R 11 is substituted with one or more substituents selected from hydrogen, halogen, oxo, thioxo, cyano, hydroxy, mercapto, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、-C(O)NRdRe、-S(O)pNRdRe, and-NR dC(O)Rf; the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
Or R 11 and R 12 together with the carbon atom to which they are attached form a 3-to 12-membered heterocyclyl, preferably a 3-to 6-membered heterocyclyl; the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl;
r f is selected from C 1-6 alkyl;
p is 1 or 2;
q is an integer from 0 to 4, preferably an integer from 0 to 2;
R 2、R3、R4 and m are defined as general formula (I); q 2 and n are defined as general formula (II).
In another embodiment, the compound of formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Q 1 is selected from NR aRb;
R a is selected from hydrogen and C 1-6 alkyl;
R b is selected from C 1-6 alkyl, said C 1-6 alkyl optionally further substituted with a substituent selected from-NR dRe、-NRdC(O)Rf、-C(O)NRdRe;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl (e.g. pyrrolidinyl), said 5-6 membered heterocyclyl optionally being further substituted with a substituent selected from halogen, amino, oxo, C 1-6 alkyl;
r f is selected from C 1-6 alkyl.
In another embodiment, the compound of formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
L is a bond;
Q 1 is selected from NR aRb;
R a is selected from hydrogen and C 1-6 alkyl;
r b is selected from C 1-6 alkyl, preferably C 1-4 alkyl, optionally further substituted with a substituent selected from-NR dRe、-NRdC(O)Rf、-C(O)NRdRe;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl (e.g. pyrrolidinyl), said 5-6 membered heterocyclyl being optionally further substituted with a substituent selected from halogen, amino, oxo, C 1-6 alkyl, preferably oxo;
r f is selected from C 1-6 alkyl.
In another embodiment, the compound of formula (I) or formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2 is independently selected from CH or N;
y 3、Y4、Y5、Y6 are each independently selected from CH or N, preferably both CH, or one of them is N, the others are CH, or two of them are N, the others are CH;
Each R 13a is independently selected from hydrogen, halogen, C 1-6 alkyl; s is 0,1, 2, 3 or 4, preferably 0,1 or 2;
R 13b is selected from hydrogen, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C (O) NR dRe、-C(O)NRf(CH2)qNRdRe;
R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl being optionally further substituted with a substituent selected from halogen, amino, oxo, C 1-6 alkyl, 5-6 membered heterocyclyl;
r f is selected from hydrogen and C 1-6 alkyl;
q is an integer from 1 to 4, preferably 1 or 2;
R 2、R3、R4 and m are defined as general formula (I); q 2 and n are defined as general formula (II).
In a preferred embodiment, the compound of formula (IV) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y 3、Y4、Y5、Y6 is CH.
In another preferred embodiment, the compound of formula (IV) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is CH.
In another preferred embodiment, the compound of formula (IV) according to the invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 13b is selected from the group consisting of-C (O) NR dRe
R d is selected from hydrogen, C 1-6 alkyl;
R e is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; the C 3-6 cycloalkyl group is optionally further substituted with halogen;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), said 5-6 membered heterocyclyl being optionally further substituted with a 5-6 membered heterocyclyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl).
In another preferred embodiment, the compound of formula (IV) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 13b is selected from-C (O) NR f(CH2)qNRdRe;
R d is selected from hydrogen, C 1-6 alkyl, preferably C 1-6 alkyl;
r e is selected from C 1-6 alkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);
r f is selected from hydrogen and C 1-6 alkyl, preferably hydrogen;
q is an integer from 1 to 4, preferably 2.
In another embodiment, the compound of formula (I) or formula (II) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from the group consisting of 8-10 membered fused heterocyclyl, preferably Which is optionally further substituted with a substituent selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl.
In another embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
R 1 is
L is selected from a bond, alkylene, or-C (O) -;
Ring a is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, preferably phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyridopyrrolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl; optionally substituted with one or more Q groups;
Q is selected from halogen, hydroxy, mercapto, cyano, C 1-6 alkyl, C 1-6 haloalkyl, - (CH 2)qNRaRb);
R a and R b are each independently selected from hydrogen and C 1-6 alkyl;
q is an integer from 0 to 4, preferably an integer from 0 to 2.
In another embodiment, the compound of formula (I), formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein R 2 is selected from hydrogen and C 1-6 alkyl.
In another embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, preferably an 8-10 membered heterocyclyl, more preferablyWhich is optionally further substituted with one or more substituents selected from halogen, amino, cyano, hydroxy, mercapto, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, - (CH 2)qNRaRb);
q is an integer from 1 to 4, preferably 1 or 2;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl.
In another embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclyl selected from:
Preferably is The heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, cyano, hydroxy, mercapto, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, - (CH 2)qNRaRb);
q is an integer from 1 to 4, preferably 1 or 2;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl.
In another embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclyl selected from: The heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy, C 1-6 haloalkoxy, - (CH 2)qNRaRb);
q is 1 or 2;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl.
In another specific embodiment, a compound according to the invention of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2 is hydrogen;
wherein:
l is selected from-CH 2 -, -C (O) -;
Ring a is selected from phenyl optionally further substituted with- (CH 2)qNRaRb;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl;
q is 1.
In another specific embodiment, a compound according to the invention of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2 is hydrogen;
wherein:
L is a bond;
Ring a is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, preferably 5 to 10 membered heteroaryl; the C 6-10 aryl or 5 to 10 membered heteroaryl is optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, - (CH 2)qNRaRb);
R a and R b are each independently selected from hydrogen or C 1-6 alkyl;
q is 1.
In another specific embodiment, a compound according to the invention of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
R 2 is hydrogen;
wherein:
L is a bond;
Ring A is selected from Ring a is optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, - (CH 2)qNRaRb);
R a and R b are each independently selected from hydrogen or C 1-6 alkyl;
q is 1.
In another embodiment, the compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
ring M is selected from 5-6 membered heterocyclyl, preferably 6 membered heterocyclyl;
Y 7 is selected from NR 13、CR13R14、SO2;
R 14 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R 13 is substituted with one or more substituents selected from hydrogen, halogen, oxo, thioxo, cyano, hydroxy, mercapto, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、-C(O)NRdRe、-S(O)pNRdRe, and-NR dC(O)Rf; the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
Or R 13 and R 14 together with the carbon atom to which they are attached form a 3-to 12-membered heterocyclyl, preferably a 3-to 6-membered heterocyclyl; the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl;
r f is selected from C 1-6 alkyl;
p is 1 or 2;
q is an integer from 0 to 4, preferably an integer from 0 to 2;
R 2、R3、R4 and m are defined as general formula (I); q 2 and n are defined as general formula (II).
In a preferred embodiment, the compounds of the general formula (V) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring M is
In a preferred embodiment, the compound of formula (V) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y 7 is CR 13R14;
R 14 is selected from hydrogen or C 1-6 alkyl, preferably hydrogen;
R 13 is selected from-C (O) NR dRe;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl.
In another embodiment, the compound of formula (I), formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV), formula (V), or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl or C 1-6 haloalkyl, particularly methyl, ethyl, n-propyl, isopropyl.
In another embodiment, the compound of formula (I), formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV), or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl; m is 0 or 1.
In another embodiment, the compound of formula (I), formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV), or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or C 1-6 alkyl, preferably hydrogen.
In another embodiment, the compound of formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV), or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each Q 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, (CH 2)qC(O)NRaRb), said C 1-6 alkyl optionally being further substituted with NR aRb;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl;
q is an integer from 0 to 6;
n is an integer from 0 to 4, preferably an integer from 0 to 2.
In another embodiment, the compound of formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV), or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each Q 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, -C (O) NR aRb、-CH2-NRaRb;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl.
In another embodiment, the compound of formula (II), formula (III), (IIIA), (IIIB), (IIIC), formula (IV) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, preferably 1.
Typical compounds of the invention include, but are not limited to:
The invention also relates to a preparation method of the compound shown in the general formula (I) or stereoisomers, tautomers, meso forms, racemates, enantiomers, diastereomers or mixture thereof or pharmaceutically acceptable salts thereof, which comprises the following steps:
Under alkaline condition, in the presence of condensing agent, the compound of general formula (IA) and the compound of general formula (IB) undergo condensation reaction to obtain the compound of general formula (I);
The alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP (4-dimethylaminopyridine), triethylamine and DIPEA (diisopropylethylamine);
The condensing agent is preferably EDCI (N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N, N' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate);
the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
Wherein: r 1、R2、R3、R4 and m are defined as general formula (I).
The invention also relates to a preparation method of the compound shown in the general formula (II) or stereoisomers, tautomers, meso forms, racemates, enantiomers, diastereomers or mixture thereof or pharmaceutically acceptable salts thereof, which comprises the following steps:
Under alkaline conditions, in the presence of a condensing agent, carrying out condensation reaction on a compound shown in a general formula (IA) and a compound shown in a general formula (IIB) to obtain a compound shown in a general formula (II);
The alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP (4-dimethylaminopyridine), triethylamine and DIPEA (diisopropylethylamine);
The condensing agent is preferably EDCI (N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N, N' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate);
the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
Wherein: r 2、R3、R4、L、X1～X4、Q1、Q2, m and n are defined as in the general formula (II).
The invention also relates to a preparation method of the compound shown in the general formula (III) or stereoisomers, tautomers, meso forms, racemates, enantiomers, diastereomers or mixture thereof or pharmaceutically acceptable salts thereof, which comprises the following steps:
Under alkaline conditions, in the presence of a condensing agent, carrying out condensation reaction on the compound shown in the general formula (IA) and the compound shown in the general formula (IIIb) to obtain a compound shown in the general formula (III);
The alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP (4-dimethylaminopyridine), triethylamine and DIPEA (diisopropylethylamine);
The condensing agent is preferably EDCI (N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N, N' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate);
the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
Wherein: r 2、R3、R4、X1～X4、Y、Q2, m and n are defined as in the general formula (III).
The present invention also relates to a method for preparing a compound of formula (IIIA) according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Under alkaline conditions, in the presence of a condensing agent, carrying out condensation reaction on a compound of a general formula (IIIAa) and a compound of a general formula (IIIAb) to obtain a compound of a general formula (IIIA);
The alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP (4-dimethylaminopyridine), triethylamine and DIPEA (diisopropylethylamine);
The condensing agent is preferably EDCI (N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N, N' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate);
the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
Wherein ：R2、R3、R4、R7、R8、X1、X2、Y1、Q2、m、n is defined as formula (IIIA).
The invention also relates to a method for preparing a compound shown in a general formula (IIIC) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof, which comprises the following steps:
Under alkaline conditions, in the presence of a condensing agent, carrying out condensation reaction on a compound of the general formula (IA) and a compound of the general formula (IIICb) to obtain a compound of the general formula (IIIC);
The alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP (4-dimethylaminopyridine), triethylamine and DIPEA (diisopropylethylamine);
The condensing agent is preferably EDCI (N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N, N' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate);
the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
wherein: r 2、R3、R4、X1、X2、Y2、Q2, m, n are as defined in formula (IIIC).
The invention also relates to a preparation method of the compound shown in the general formula (IV) or stereoisomers, tautomers, meso forms, racemates, enantiomers, diastereomers or mixture thereof or pharmaceutically acceptable salts thereof, which comprises the following steps:
Under alkaline conditions, in the presence of a condensing agent, carrying out condensation reaction on a compound shown in a general formula (IA) and a compound shown in a general formula (IVb) to obtain a compound shown in a general formula (IV);
The alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP (4-dimethylaminopyridine), triethylamine and DIPEA (diisopropylethylamine);
The condensing agent is preferably EDCI (N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N, N' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate);
the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
Wherein ：R2、R3、R4、R13a、R13b、X1、X2、Y3～Y6、Q2、m、n、s is as defined in formula (IV).
The invention further relates to a pharmaceutical composition comprising a compound according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
The invention further relates to the use of a compound according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or according to a pharmaceutical composition comprising the same, for the preparation of an ATR kinase inhibitor.
The invention further relates to the use of a compound according to the invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or according to a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of ATR kinase mediated diseases, preferably melanoma, brain tumor, oesophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non small cell lung cancer and bronchioloalveolar cancer), kidney cancer, bladder cancer, gall bladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck cancer, leukaemia (including Acute Lymphocytic Leukaemia (ALL), chronic Myelogenous Leukaemia (CML) and Acute Myelogenous Leukaemia (AML) and the like), multiple myeloma and lymphoma.
The invention also relates to compounds according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or according to pharmaceutical compositions comprising the same, for use as ATR kinase inhibitors.
The invention also relates to a compound according to the invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to comprising the same, for use in the treatment of ATR kinase mediated diseases, preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer), kidney cancer, bladder cancer, gall bladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck cancer, leukemia (including Acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML), etc.), multiple myeloma and lymphoma.
The present invention also relates to a method of inhibiting ATR kinase, comprising administering to a subject in need thereof an effective amount of a compound according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to comprising the same.
The present invention also relates to a method of treating ATR kinase mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or according to a pharmaceutical composition comprising the same, wherein the disease is preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer), kidney cancer, bladder cancer, gall bladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumor, leukemia (including Acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML), etc.), multiple myeloma and lymphoma.
The compounds of the present invention may form pharmaceutically acceptable acid addition salts with acids according to methods conventional in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like are particularly preferable.
The compounds of the general formula of the present invention may be combined with a base to form pharmaceutically acceptable base addition salts according to methods conventional in the art to which the present invention pertains. The base includes inorganic bases and organic bases, acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like, and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. 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, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to 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. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol such as heptadecaethyleneoxycetyl alcohol (heptadeca ethyl eneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing-paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used 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 an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
The compounds of the present invention 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 will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
It is well known to those skilled in the art that the amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The invention can contain the compound of the general formula and pharmaceutically acceptable salt, hydrate or solvate thereof as active ingredients, and is mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and is prepared into clinically acceptable dosage forms. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not exert other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or in combination with other therapeutic agents. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.
Description of the terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention each include their isotopes, i.e., the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C、13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as heavy hydrogen), the isotopes of oxygen include 16O、17 O and 18 O, the isotopes of sulfur include 32S、33S、34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, an alkyl group containing from 1 to 4 carbon atoms, or an alkyl group containing from 1 to 3 carbon atoms. 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 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. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.
The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having from 1 to 20 (e.g., 1,2, 3,4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a C 1-20 alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., a C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., a C 1-6 alkylene group), still more preferably an alkylene group having 1 to 4 carbon atoms (i.e., a C 1-6 alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), 1-ethylene (-CH (CH 3) -), 1, 2-ethylene (-CH 2CH2 -), 1-propylene (-CH (CH 2CH3) -), 1, 2-propylene (-CH 2CH(CH3) -), 1, 3-propylene (-CH 2CH2CH2 -), 1, 4-butylene (-CH 2CH2CH2CH2 -), and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
The term "alkenyl" refers to a monovalent hydrocarbon radical consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably alkenyl radicals containing 2 to 4 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "alkynyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or an alkynyl group preferably containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
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 from 3 to 12 carbon atoms, more preferably from 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 polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms 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 monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
The term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 7 to 12 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as a spiro atom) shared between 5-to 20-membered monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 12 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl 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 the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 12 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl 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, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 12 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
Etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be 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, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The above alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "alkenylene", "alkynylene", "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".
The term "cycloalkoxy" refers to-O- (cycloalkyl), wherein cycloalkyl is as defined above.
The term "heterocycloalkoxy" refers to-O- (heterocyclyl), wherein heterocyclyl 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 "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "hydroxy" refers to-OH.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2.
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2.
The term "oxo" refers to = O.
The term "thio" refers to = S.
The term "carboxy" refers to-C (O) OH.
The term "mercapto" refers to-SH.
The term "ester group" refers to a-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
The term "acyl" refers to compounds of the group-C (O) R, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
"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 group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" is meant a salt of a compound of the invention which is safe and effective when used in a mammal, and which has the desired biological activity.
"Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not negate the biological activity and properties of the compound being administered.
Detailed Description
The compounds of the present invention and their preparation are further understood by the examples which illustrate some methods of making or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.
The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferential reaction conditions are given in the present invention, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But other reaction conditions can be adopted unless specifically stated. The optimization conditions may vary with the particular reactants or solvents used, but in general, both the reaction optimization steps and conditions can be determined.
In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, T.W.Greene and G.M.Wuts in organic preparation of protecting groups (3 rd edition, wiley, new York,1999 and literature citations) describe in detail the protection or deprotection of a large number of protecting groups.
The separation and purification of the compounds and intermediates may be carried out by any suitable method or procedure depending on the particular needs, such as filtration, extraction, distillation, crystallization, column chromatography, thin layer chromatography, high performance liquid chromatography or a combination thereof. The specific methods of use thereof may be found in the examples described herein. Of course, other similar isolation and purification means may be employed. It can be characterized using conventional methods, including physical constants and spectral data.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift is given in units of 10 -6 (ppm). NMR was performed using a WNMR-I-400MHz nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) as the measurement solvent, and Tetramethylsilane (TMS) as the internal standard.
The MS was measured using an LC (Agilent 1260 Informance)/MS (G6125B) mass spectrometer (manufacturer: agilent).
Preparation liquid chromatography was performed using a GX-281 high performance liquid chromatograph (manufacturer: GILSON). The chromatographic column is5 Μm EVO C18 100 (100 mm. Times.30.0 mm), mobile phase: acetonitrile/water.
The Thin Layer Chromatography (TLC) uses Qingdao ocean chemical GF254 silica gel plate, the specification of the silica gel plate used for reaction monitoring is 0.20 mm-0.25 mm, and the specification of the silica gel plate used for separation and purification is 0.5mm.
The silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai Shuya, shanghai Enoki, an Naiji chemistry, shanghai Picide, nanjing medical stone, and the like.
The examples are not particularly described, and the reactions can all be carried out under nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The reaction solvent, the organic solvent or the inert solvent are each expressed as a solvent which does not participate in the reaction under the reaction conditions described, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. The examples are not specifically described, and the solution refers to an aqueous solution.
The chemical reactions described in the present invention are generally carried out at atmospheric pressure. The reaction time and conditions are, for example, between-78 ℃ and 200 ℃ at one atmosphere, completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is typically 16 hours. The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: a: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.
The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying the compound include: a: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can be added for regulation.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.
Preparation example 1: synthesis of 4-bromo-3-fluoro-5-nitropyridine (intermediate A1)
Step 1: preparation of 3-fluoro-5-nitropyridin-4-amine (A1-2)
3-Fluoropyridin-4-amine (A1-1) (30 g,268mmol,1.0 eq.) was dissolved in cold concentrated sulfuric acid (180 mL), concentrated HNO 3 (42.2 g,402mmol,1.5 eq.) was added dropwise under ice-bath and stirred for 3 hours at 60 ℃. The reaction mixture was cooled to room temperature, added to 1000mL of ice water, then 400mL of aqueous KOH (10 mol/L) was added to ph=12, then 500mL of ethyl acetate was added, extracted three times with ethyl acetate, the organic phases were combined, washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate=1:2) to give compound A1-2 as a yellow solid, 15.0g, yield 33.8%.
Step 2: preparation of 4-bromo-3-fluoro-5-nitropyridine (A1)
Compound A1-2 (15 g,98.5mmol,1.0 eq.) was dissolved in anhydrous ACN (150 mL), cuBr (21.5 g,150mmol,1.5 eq.) was added, tert-butyl nitrite (16 g,150mmol,1.5 eq.) was added dropwise with stirring at 70℃and stirring at 70℃for 4 hours. The reaction mixture was added with 300mL of water, followed by addition of 300mL of ethyl acetate, extraction with ethyl acetate 3 times, and washing of the combined organic phases with 300mL of saturated brine, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the residue by flash column chromatography (eluent: petroleum ether/ethyl acetate=5:2) gave compound A1,7.0g as a yellow solid in 85.7% yield.
Preparation example 2: synthesis of 3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxylic acid (intermediate A2)
Step 1: preparation of methyl 3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxylate (A2-3)
Methyl 3-amino-6-bromopyrazine-2-carboxylate (A2-1) (10.0 g,43.3mmol,1.0 eq.), (4- (isopropylsulfonyl) phenyl) boronic acid (A2-2) (11.9 g,52mmol,1.2 eq.), cs2CO3 (42.4 g,130mmol,3.0 eq.), pd (dppf) Cl 2 (800 mg, 8%) were dissolved in dioxane (90 mL), and 10mL of water was added. Stirring was carried out at 80℃for 8 hours under nitrogen atmosphere. The reaction mixture was washed with 300mL of water, further 300mL of ethyl acetate, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound A2-3 as a yellow solid, 11.0g, yield 75.8%.
Step 2: preparation of 3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxylic acid (A2)
Compound A2-3 (11 g,32.8mmol,1.0 eq.) was dissolved in MeOH/THF/H 2 O (3:2:1, 100 mL) and LiOH.H 2 O (4.2 g,98.4mmol,3.0 eq.) was added and stirred at 25℃for 8 hours. 1moL/L HCl was added dropwise to the reaction mixture until the solid in the reaction mixture was no longer precipitated, and the resulting solid was filtered to give compound A2 as a yellow solid, 7.4g, yield 74.0%.
Preparation example 3: synthesis of 1- (3- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxamide) -5-fluoropyridin-4-yl) piperidine-4-carboxylic acid (intermediate A3)
Step 1: preparation of methyl 1- (3-fluoro-5-nitropyridin-4-yl) piperidine-4-carboxylate (A3-2)
Compound A1 (3.1 g,14.1mmol,1.0 eq.) piperidine-4-carboxylic acid methyl ester (A3-1) (2.44 g,17mmol,1.2 eq.) TEA (2.9 g,28.2mmol,2.0 eq.) was dissolved in DMF (20 mL) and stirred at 25℃for 3 hours. The reaction mixture was added with 100mL of water, extracted with 100mL of ethyl acetate again, extracted with ethyl acetate 3 times, the organic phases were combined, washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to give compound A3-2,3.4g as a yellow solid in 82.5% yield.
Step 2: preparation of 1- (3-fluoro-5-nitropyridin-4-yl) piperidine-4-carboxylic acid methyl ester (A3-3)
Compound A3-2 (3.4 g,12mmol,1.0 eq.) was dissolved in anhydrous methanol (40 mL) and Pd/C (680 mg, 20%) was added and stirred under a hydrogen atmosphere at 25℃for 16 hours. After the reaction mixture was filtered through celite, the cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give compound A3-3,3.0g as a yellow solid in 96.5% yield.
Step 3: preparation of methyl 1- (3- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxamide) -5-fluoropyridin-4-yl) piperidine-4-carboxylate (A3-4)
Compound A2 (4.3 g,13.4mmol,1.0 eq.) compound A3-3 (4.1 g,16.1mmol,1.2 eq.) DIEA (4.2 g,32.2mmol,2.5 eq.) and HATU (6.6 g,17.4mmol,1.3 eq.) were dissolved in DMF (30 mL) and stirred at 25℃for 3 hours. The reaction mixture was stirred for 8 minutes with 30mL of water and then stirred for an additional 5 minutes with 10mL of water. The solid precipitated, the reaction mixture was filtered, and the filter cake was washed with 8mL of methanol and then with 8mL of ethyl acetate. The cake was dried to give compound A3-4,4.9g as a yellow solid in 66.2% yield.
Step 4: preparation of 1- (3- (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxamide) -5-fluoropyridin-4-yl) piperidine-4-carboxylic acid (A3)
Compound A3-4 (4.9 g,8.8mmol,1.0 eq.) was dissolved in MeOH/DCM/H 2 O (3:2:1, 50 mL) and LiOH.H 2 O (11.1 g,26.4mmol,3.0 eq.) was added and stirred at 40℃for 6 hours. The reaction mixture was added dropwise with 1moL/L HCl until the solid of the reaction liquid was no longer precipitated, and filtered to give compound A3,4.1g as a yellow solid in a yield of 84.3%.
Example 1: preparation of 3-amino-6- (4- (methylsulfonyl) phenyl) -N- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazole-2-carboxamide (1)
Step 1: preparation of methyl 3-amino-6- (4- (methylsulfonyl) phenyl) pyrazine-2-carboxylate (1-3)
Methyl 3-amino-6-bromopyrazine-2-carboxylate (1-1) (500 mg,2.16mmol,1.00 eq), (4- (methylsulfonyl) phenyl) boronic acid (1-2) (356 mg,2.38mmol,1.1 eq), 1' -bis-diphenylphosphino ferrocene palladium dichloride (354 mg,0.43mmol,0.2 eq), sodium carbonate (459 mg,4.3mmol,2.00 eq) were dissolved in dioxane (10 mL) and water (1 mL) and reacted at 100℃for 1.5 hours under nitrogen atmosphere. Then, the reaction solution was concentrated in vacuo to give a crude product, which was purified by column chromatography (eluent: 100% ethyl acetate/petroleum ether) to give compound 1-3 (544 mg, yield 84%, purity 93%) as a black solid.
LCMS(ESI)m/z 308,(M+H)+。
Step 2: preparation of 3-amino-6- (4- (methylsulfonyl) phenyl) pyrazine-2-carboxylic acid (1-4)
Compounds 1-3 (544 mg,1.77mmol,1.0 eq.) and lithium hydroxide (212 mg,8.85mmol,5.0 eq.) were dissolved in methanol (5 mL) and water (5 mL) and reacted for 2 hours at 90 ℃. The reaction mixture was cooled, 1N diluted hydrochloric acid was added, and solids were precipitated, filtered to give a cake, which was concentrated in vacuo to give crude compound 1-4 as a black solid (375 mg, yield 72%, purity 95%).
LCMS(ESI)m/z 294,(M+H)+。
Step 3: preparation of 3-amino-6- (4- (methylsulfonyl) phenyl) -N- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazole-2-carboxamide (1)
Compound 1-4 (100 mg,0.34mmol,1.00 eq), 1H-pyrrolo [2,3-b ] pyridin-4-amine (1-5) (45 mg,0.34mmol,1.0 eq), HATU (156 mg,0.42mmol,1.2 eq), DIPEA (132 mg,1.02mmol,3.00 eq) were dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. The reaction solution was purified by reverse phase preparative high performance liquid chromatography (mobile phase water/acetonitrile=100% -70%/30%, gradient elution, 0.1% formic acid was added in the mobile phase by volume percentage, flow rate was 20.0 mL/min) to give compound 1 as a yellow solid (30.5 mg, yield 22%, purity 98%).
LCMS(ESI)m/z 409,(M+H)+。
1H NMR(400MHz,DMSO-d6)δ11.2(s,1H),10.55(s,1H),9.03(s,1H),8.51(d,J＝8.5Hz,2H),8.33(s,1H),7.97–7.82(m,4H),7.63(d,J＝8.4Hz,1H),6.95(d,J＝8.7Hz,1H),3.23(s,3H).
Example 2: preparation of 3-amino-6- (4- (isopropylsulfonyl) phenyl) -N- (4- ((methylamino) methyl) benzyl) pyrazole-2-carboxamide (2)
Step 1: preparation of tert-butyl (4- ((3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazine-2-carboxamide) methyl) benzyl) (methyl) carbamate (2-2)
To a solution of compound A2 (500 mg,1.5mmol,1.0 eq.), HATU (709.9 mg,1.87mmol,1.2 eq.) and DIPEA (401 mg,3.1mmol,2.0 eq.) in DMF (6 ml) was added tert-butyl (4- (aminomethyl) benzyl) (methyl) carbamate (2-1) (467 mg,1.87mmol,1.2 eq.) and stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO 3, washed with saturated brine, and concentrated under reduced pressure to give compound 2-2 (800 mg, yield 92%, purity 95%) as a colorless transparent liquid.
LCMS(ESI)m/z 554.69,(M+H)+。
Step 2: preparation of 3-amino-6- (4- (isopropylsulfonyl) phenyl) -N- (4- ((methylamino) methyl) benzyl) pyrazole-2-carboxamide (2)
To a solution of compound 2-2 (800 mg,1.44mmol,1.0 eq.) in DCM (10 ml) was added TFA (2 ml) and stirred at room temperature for 0.5 h. The reaction mixture was adjusted to PH 10-11 with 1mol/L NaOH/H 2 O solution, extracted with DCM, washed with saturated brine, concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel (eluent: meOH/dcm=0% -10%), affording compound 2 as a yellow solid (390 mg, 59% yield, 96% purity).
LCMS(ESI)m/z 454,(M+H)+。
1H NMR(400MHz,DMSO)δ9.49(s,1H),8.99(s,1H),8.48(d,J＝8.4Hz,2H),7.89(d,J＝8.4Hz,4H),7.28(q,J＝8.4Hz,4H),4.53(d,J＝6.4Hz,2H),3.61(s,2H),3.46(dt,J＝13.2,6.6Hz,2H),2.24(s,3H),1.18(d,J＝6.8Hz,6H).).
The following compounds were prepared with reference to the synthetic method of example 2:
Example 3: preparation of (3-amino-6- (4- (isopropylsulfonyl) phenyl) pyrazin-2-yl) (3, 4-dihydroisoquinolin-2 (1H) -yl) methanone (3)
Compound A2 (50 mg,155.6mmol,1.0 eq.) 1,2,3, 4-tetrahydroisoquinoline (3-1) (27 mg,203mmol,1.3 eq.) HATU (77 mg,203mmol,1.0 eq.) and DIPEA (41 mg,318mmol,2.0 eq.) were dissolved in DMF (2 mL) and stirred at 25℃for 14 h. The reaction mixture was stirred for 10 minutes with 2mL of water and then with 6mL of water for further stirring for 10 minutes, the mixture was filtered, the filter cake was rinsed with 2mL of methanol and then with 2mL of ethyl acetate, the filter cake was collected and dried to give compound 3 as a yellow solid, 63mg (yield 92.6%, purity 96.2%).
LCMS(ESI)m/z 437,(M+H)+。
1H NMR(400MHz,DMSO)δ8.85(s,1H),8.22(d,J＝8.4Hz,2H),7.90(d,J＝8.8Hz,2H),7.25(d,J＝28.6Hz,3H),6.98(s,2H),4.84(s,1H),4.75(s,1H),3.91(s,1H),3.71(s,1H),3.44(s,1H),2.91(d,J＝12.0Hz,2H),2.08–1.93(m,1H),1.18(d,J＝6.8Hz,6H).
The following compounds were prepared with reference to the synthetic method of example 3:
example 5: preparation of 3-amino-6- (4- (isopropylsulfonyl) phenyl) -N- (4- ((methylamino) methyl) benzoyl) pyrazole-2-carboxamide (5)
To a solution of H 5IO6 (602.9 mg,2.64mmol,6.0 eq.) and CrO3 (2.2 mg,0.02mmol,5 mol%) in ACN (6 ml) was added Ac 2 O (270 mg,2.64mmol,6.0 eq.) and stirred at 0deg.C for 0.5 hours. Compound 2 (200 mg,0.44mmol,1.0 eq.) was then added to the reaction mixture. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO 3, washed with saturated brine, concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluent: meOH/dcm=0% -10%) to give compound 5 (3 mg, yield 1.5%, purity 96%) as a yellow solid.
LCMS(ESI)m/z 468,(M+H)+。
1H NMR(400MHz,DMSO)δ9.13(s,1H),8.41(d,J＝8.4Hz,2H),7.98(d,J＝8.0Hz 1H),7.92(d,J＝7.8Hz 1H),7.63(d,J＝8.0Hz,2H),4.36(s,1H),3.93(s,2H),3.53–3.45(m,1H),3.42(s,1H),2.40(s,3H),1.20(d,J＝6.8Hz,6H).
Example 6: preparation of 3-amino-N- (5-fluoro-4- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (6)
Step 1: preparation of 1- (3-fluoro-5-nitropyridin-4-yl) -4- (oxetan-3-yl) piperazine (6-2)
Compound A1 (200 mg,0.91mmol,1.0 eq.) 1- (oxetan-3-yl) piperazine (6-1) (129 mg,0.91mmol,1.0 eq.) and TEA (235 mg,1.82mmol,2.0 eq.) were dissolved in DMF (5 mL) and stirred at 25℃for 4 hours. The reaction mixture was stirred for 10min with 20mL of water, followed by additional stirring for 5min with 20mL of ethyl acetate, extraction three times with ethyl acetate, combining the organic phases, and washing the organic phases with 30mL of saturated brine, drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification of the residue by column chromatography on silica gel (eluent: meOH/dcm=0% -5%) afforded compound 6-2 as a yellow powder, 220mg (yield: 89.5%).
Step 2: preparation of 5-fluoro-4- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-amine (6-3)
To a 50mL single flask was added compound 6-2 (220 mg,0.79mmol,1.0 eq.) and then Pd/C44 mg (20%), 35mL methanol was added and the mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The reaction solution was filtered through celite, and the filter cake was washed with 4mL of methanol, and the filtrate was concentrated under reduced pressure to give compound 6-3 (170 mg, yield: 86.7%).
Step 3: preparation of 3-amino-N- (5-fluoro-4- (4- (oxetan-3-yl) piperazin-1-yl) pyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (6)
Compound A2 (50 mg,0.16mmol,1.0 eq.) compound 6-3 (53 mg,0.21mmol,1.3 eq.) HATU (80 mg,0.21mmol,1.3 eq.) and DIPEA (42 mg,0.32mmol,2.0 eq.) were dissolved in DMF (2.5 mL) and stirred at 25℃for 14 h. The reaction mixture was stirred for 10 min with 2mL of water and then with 6mL of water for further 10 min, the mixture was filtered, the filter cake was rinsed with 2mL of methanol and then with 2mL of ethyl acetate, the filter cake was collected and dried to give compound 6 as a yellow solid, 37mg (43% yield, 96% purity).
LCMS(ESI)m/z 556,(M+H)+。
1H NMR(400MHz,DMSO)δ10.56(s,1H),9.24(s,1H),9.14(s,1H),8.72(s,1H),8.47(d,4H),8.14–7.82(m,5H),7.83(d,2H),4.40(m,1H),4.11(m,1H),3.66(m,5H),3.47(m,2H),3.27(m,3H),3.14(m,3H),2.65(m,5H),2.40(m,5H),2.05(s,1H),1.93(s,6H),1.61(d,2H),1.22(s,6H).
The following compounds were prepared according to the synthetic method of example 6:
example 8: preparation of 3-amino-N- (4- (4- (ethylcarbamoyl) piperidin-1-yl) -5-fluoropyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (8)
Compound A3 (100 mg,0.18 mmol) and ethylamine hydrochloride (18 mg,0.22 mmol) were dissolved in DMF (2 ml), HATU (84 mg,0.22 mmol) and DIPEA (46 mg,0.36 mmol) were added and reacted at room temperature under nitrogen for 3 hours. To the reaction solution was added dropwise water (6 ml), and solids were precipitated, filtered, and the cake was rinsed with a small amount of water and dried to give compound 8 (68 mg, yellow solid, yield 65%).
LCMS(ESI)m/z 570.3,(M+H)+。
1H NMR(400MHz,DMSO)δ10.51(s,1H),9.28(s,1H),9.10(s,1H),8.37(dd,J＝18.7,5.8Hz,3H),8.09–7.88(m,4H),7.78(t,J＝5.4Hz,1H),3.59(dt,J＝13.5,6.7Hz,1H),3.26–3.18(m,2H),3.05(dd,J＝7.1,5.6Hz,4H),2.31–2.22(m,1H),1.87–1.77(m,4H),1.20(d,J＝6.8Hz,6H),0.99(t,J＝7.2Hz,3H).
The following compounds were prepared according to the synthetic method of example 8
Example 54: preparation of 3-amino-6- (4- (isopropylsulfonyl) phenyl) -N- (4- (4- (methylcarbamoyl) piperidin-1-yl) -6-oxo-1, 6-dihydropyridin-3-yl) pyrazole-2-carboxamide (54)
Step 1: preparation of 1- (2-hydroxy-5-nitropyridin-4-yl) -N-methylpiperidine-4-carboxamide (54-3)
4-Chloro-5-nitropyridin-2-ol (54-1) (200 mg,1.15mmol,1.0 eq.) N-methylpiperidine-4-carboxamide hydrochloride (54-2) (246 mg,1.37mmol,1.2 eq.) and triethylamine (0.48 mL,3.45mmol,3 eq.) were added sequentially to DMF (5 mL) at room temperature. The reaction mixture was stirred at 40℃for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0 to 29%) to give compound 54-3 (330 mg, yield 100%).
Step 2: preparation of 1- (5-amino-2-hydroxypyridin-4-yl) -N-methylpiperidine-4-carboxamide (54-4)
Compound 54-3 (330 mg,1.2mmol,1.0 eq.) palladium on carbon (10 wt.%, palladium loading) (100 mg) was added sequentially to THF/DMF/H 2 O (10 mL/5mL/1 mL) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at 20 ℃ for 16 hours. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=4:1)/dichloromethane=0 to 78%) to give compound 54-4 (130 mg, yield 43.8%).
Step 3: preparation of 3-amino-6- (4- (isopropylsulfonyl) phenyl) -N- (4- (4- (methylcarbamoyl) piperidin-1-yl) -6-oxo-1, 6-dihydropyridin-3-yl) pyrazole-2-carboxamide (54)
HATU (100 mg,0.26mmol,1.2 eq.) was slowly added to a solution of compound 54-4 (66 mg,0.26mmol,1.2 eq.), compound A2 (73 mg,0.22mmol,1.0 eq.) and DIPEA (0.12 mL,0.66mmol,3.0 eq.) in DMF (2.0 mL) at room temperature and the reaction stirred at 30 ℃ for 6 hours. The reaction solution was cooled to room temperature, water (2 mL) was added and stirred for 10 minutes, filtration was performed, the cake was rinsed with methanol (2 mL), and then with EA (2 mL), and the cake was collected and dried under reduced pressure to give compound 54 (45 mg, yield 36%, purity 96.7%).
LCMS(ESI)m/z 554.2,(M+H)+。
1H NMR(400MHz,DMSO)δ11.20(s,1H),9.88(s,1H),9.08(s,1H),8.41(d,J＝8.3Hz,2H),8.03-7.84(m,4H),7.72(d,J＝4.6Hz,1H),5.94(s,1H),3.59(dt,J＝13.9,7.0Hz,1H),3.31-3.28(m,4H),2.62(dd,J＝25.1,16.6Hz,3H),2.20(d,J＝26.6Hz,1H),1.77(s,4H),1.23(d,J＝6.8Hz,6H).
Example 85: preparation of 3-amino-N- (5-carbamoyl-4- (4- (methylcarbamoyl) piperidin-1-yl) pyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (85)
Compound 56 (60 mg,0.1mmol,1.0 eq) is added to 1ml concentrated sulfuric acid and stirred at ambient temperature for 12h. The reaction solution was poured into ice water, sodium carbonate was added to make the solution alkaline, DCM and water were added to extract and then purified to give compound 85 (18.7 mg, purity 100%).
LCMS(ESI)m/z 582.2,(M+H)+。
1H NMR(400MHz,DMSO)δ10.30(s,1H),9.21(s,1H),9.13(s,1H),8.44(d,J＝8.4Hz,2H),8.28(s,1H),8.17(s,1H),8.02(d,J＝8.5Hz,3H),7.74(s,1H),7.67(d,J＝4.6Hz,1H),3.56(dt,J＝13.7,6.8Hz,1H),3.16(d,J＝13.0Hz,5H),2.26–2.13(m,1H),1.81(d,J＝3.8Hz,4H),1.26(d,J＝6.8Hz,7H).
Example 100: preparation of 3-amino-N- (5-fluoro-4- (4- (3- (piperidin-1-yl) azetidine-1-carbonyl) phenyl) pyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (100)
Step 1: preparation of (3- (piperidin-1-yl) azetidin-1-yl) (4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) methanone (100-3)
HATU (5531 mg,1.45mmol,1.2 eq.) was slowly added to a solution of 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoic acid (100-1) (300 mg,1.21mmol,1.0 eq.) 1- (azetidin-3-yl) piperidine (100-2) (309 mg,1.45mmol,1.2 eq.) and DIPEA (0.9 mL,4.84mmol,4.0 eq.) in DMF (6.0 mL) at room temperature. The reaction solution was stirred at 30℃for 3 hours. Saturated aqueous sodium bicarbonate (20.0 mL) was added, extracted with ethyl acetate (10.0 mL x 2), and the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0-16%) to give compound 100-3 (482 mg, yield 100%).
Step 2: preparation of (4- (3-amino-5-fluoropyridin-4-yl) phenyl) (3- (piperidin-1-yl) azetidin-1-yl) methanone (100-4)
Compound 100-3 (30 mg,0.158mmol,1.0 eq.) compound A1 (59 mg,0.158mmol,1.0 eq.) compound Pd (dppf) Cl2 (13 mg,0.016mmol,0.1 eq.) and potassium acetate (46.5 mg,0.474mmol,3 eq.) were added sequentially to dioxane/H 2 O (1.2 mL/0.3 mL) at room temperature. The reaction mixture was stirred at 80℃for 16 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0 to 32%) to give compound 100-4 (63 mg, yield 100%).
Step 3: preparation of 3-amino-N- (5-fluoro-4- (4- (3- (piperidin-1-yl) azetidine-1-carbonyl) phenyl) pyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (100)
HATU (81 mg,0.213mmol,1.2 eq.) was slowly added to a solution of compound 100-4 (63 mg,0.178mmol,1.0 eq.) compound A2 (68.5 mg,0.213mmol,1.2 eq.) and DIPEA (0.1 mL, 0.284 mmol,3.0 eq.) in DMF (2 mL) at room temperature and the reaction stirred at 25 ℃ for 16 hours. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate (10.0 mL), extracted with ethyl acetate (10.0 mL. Times.2), and the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0-32%) to give compound 100 (35 mg, yield 29.9%, purity 98.2%).
LCMS(ESI)m/z 658.2(M+H)+。
1H NMR(400MHz,DMSO)δ10.05(s,1H),9.39(s,1H),9.02(s,1H),8.61(s,1H),7.94–7.85(m,8H),7.71(d,J＝7.9Hz,2H),4.31-4.05(m,2H),3.58–3.49(m,1H),3.28-2.99(m,3H),2.52–1.95(m,4H),1.61-1.37(m,6H),1.23(d,J＝6.8Hz,6H).
The following compounds were prepared according to the synthetic method of example 100:
Example 101: preparation of 3-amino-N- (3, 5-difluoro-2- (4- (methylcarbamoyl) piperidin-1-yl) phenyl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (101)
Step 1: preparation of 1- (2, 4-difluoro-6-nitrophenyl) -N-methylpiperidine-4-carboxamide (101-3)
2-Bromo-1, 5-difluoro-3-nitrobenzene (101-1) (160 mg,0.67mmol,1.2 eq.) compound 54-2 (100 mg,0.56mmol,1.0 eq.) Pd2 (dba) 3 (77 mg,0.08mmol,0.15 eq.) xantphos (65 mg,0.112mmol,0.2 eq.) and cesium carbonate (547 mg,1.68mmol,3 eq.) were added sequentially to dioxane (6 mL) at room temperature. The reaction mixture was stirred at 100℃for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0 to 11%) to give compound 101-3 (99 mg, yield 28.5%, purity 48.3%).
Step 2: preparation of 1- (2-amino-4, 6-difluorophenyl) -N-methylpiperidine-4-carboxamide (101-4)
Compound 101-3 (99 mg,0.33mmol,1.0 eq.) iron powder (93 mg,1.65mmol,5 eq.) ammonium chloride (176 mg,3.3mmol,10 eq.) was added sequentially to methanol/water (6 mL/1.5 mL) at room temperature. The reaction mixture was stirred at 65℃for 9 hours. Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0 to 12%) to give compound 101-4 (20 mg, yield 46.5%).
Step 3: preparation of 3-amino-N- (3, 5-difluoro-2- (4- (methylcarbamoyl) piperidin-1-yl) phenyl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (101)
HATU (34 mg,0.089mmol,1.2 eq.) was slowly added to a solution of compound 101-4 (20 mg,0.074mmol,1.0 eq.) compound A2 (28.6 mg,0.089mmol,1.2 eq.) and DIPEA (28 mg,0.22mmol,3.0 eq.) in DMF (1 mL) at room temperature and the reaction stirred at 25 ℃ for 7 hours. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogencarbonate (5.0 mL) was then added thereto, extraction was performed with ethyl acetate (10.0 ml×2), and the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent (dichloromethane: methanol=4:1)/dichloromethane=0-5.5%) to give compound 101 (12 mg, yield 28.2%, purity 98.98%).
LCMS(ESI)m/z 573.2,(M+H)+。
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.09(s,1H),8.36(d,J＝8.4Hz,2H),8.27(d,J＝11.0Hz,1H),8.07(d,J＝8.2Hz,3H),7.79(t,J＝9.0Hz,1H),7.13–6.97(m,1H),3.56–3.37(m,1H),3.19-2.99(m,4H),2.65(d,J＝4.5Hz,3H),2.35-2.24(m,1H),1.93-1.78(m,4H),1.23(d,J＝6.8Hz,6H).
Example 111: preparation of 3-amino-N- (5- (aminomethyl) -4- (4- (methylcarbamoyl) piperidin-1-yl) pyridin-3-yl) -6- (4- (isopropylsulfonyl) phenyl) pyrazole-2-carboxamide (111)
Raney nickel (188 mg,1.89mmol,20.0 eq.) was added to an aqueous ammonia-methanol (6 ml) solution of compound 56 (90 mg,0.16mmol,1.0 eq.) and reacted at room temperature for 48h. The reaction solution was purified by preparative high performance liquid chromatography (mobile phase water/acetonitrile=100% -70%/30%, gradient elution, 0.1% formic acid was added in volume percentage to mobile phase at a flow rate of 20.0 mL/min) to give compound 111 (19.2 mg, yield 22%).
LCMS(ESI)m/z 567,(M+H)+。
1H NMR(400MHz,DMSO)δ10.39(s,1H),9.08(d,J＝5.1Hz,1H),8.87(s,1H),8.49–8.38(m,3H),8.34(s,1H),7.96(d,J＝8.5Hz,4H),7.71–7.59(m,1H),4.29(d,J＝5.5Hz,1H),3.87(s,2H),3.60–3.45(m,2H),3.17(s,5H),2.19(s,2H),1.76(s,5H),1.22(d,J＝6.8Hz,6H).
Biological testing
Test example 1: ATR in vitro enzymatic Activity inhibition assay
The inhibition of ATR kinase (Eurofins-14-953M) by the compounds was evaluated using HTRF detection techniques, and GST-tagged P53 protein (Eurofins-14-952M) was used as a substrate. The compound (0-10000 nM) and ATR kinase were diluted with 1 Xkinase assay buffer (cisbio) containing 1.25mM MnCl 2, 50nM SEB and 1mM DTT. The compound was incubated with 30ng of ATR kinase per well for 15 minutes at room temperature. The reaction was started by adding 500nM P53 and 3.91uM ATP, the total reaction system being 10uL. The reaction was continued at room temperature for 90 minutes, and then 10uL of a detection solution containing Mab Anti-phospho P53-Eu cryptate (cisbio-61P 08 KAZ) and Mab Anti GST-d2 (cisbio-61 GSTDLB) was added and reacted at room temperature for 1 hour. HTRF signals the signal values at 620nm and 665nm wavelength were collected using a TECAN SPARK multifunctional microplate reader for calculation of IC 50 values for the compounds for ATR kinase inhibition. Table 1 reports the results of inhibition of ATR enzymatic activity for each compound.
TABLE 1 IC 50 values for ATR kinase inhibition by the compounds of the invention
Examples IC50(nM) Examples IC50(nM) Examples IC50(nM) Examples IC50(nM)
1 6301.82 33 9.20 65 232.31 97 53.81
2 5505.51 34 24.00 66 65.24 98 167.77
3 2675.13 35 4.50 67 71.59 99 102.54
4 1512.82 36 23.00 68 361.97 100 604.97
5 256.67 37 24.00 69 1725.02 101 17.08
6 >10000 38 14.00 70 183.04 102 15.59
7 >10000 39 4.30 71 38.57 103 165.33
8 19.41 40 33.00 72 34.24 104 46.09
9 24.23 41 15.00 73 109.06 105 5.43
10 37.35 42 49.00 74 250.22 106 158.75
11 238.25 43 56.00 75 61.49 107 49.76
12 >10000 44 24.00 76 42.78 108 179.84
13 51.11 45 22.00 77 160.02 109 118.97
14 218.92 46 >10000 78 302 110 12.11
15 159.62 47 212.00 79 618.17 111 70.25
16 2.50 48 70.00 80 122.48 112 170.44
17 10.79 49 98.00 81 169.83 113 2547.95
18 62.93 50 19.00 82 35.74 114 4.50
19 19.13 51 28.00 83 31.08 115 13.32
20 77.50 52 35.00 84 6.40 116 7.55
21 908.33 53 30.00 85 21.34 117 12.92
22 13.97 54 67.00 86 122.78 118 71.01
23 25.82 55 58.00 87 11.31 119 14.13
24 8.55 56 475.00 88 20.15 120 117.07
25 224.49 57 34.00 89 20.44 121 104.12
26 9.98 58 166.00 90 409.34 122 47.77
27 27.82 59 27.00 91 15.25 123 28.97
28 16.99 60 127.00 92 17.00 124 383.50
29 27.90 61 114.00 93 12.26 125 127.64
30 57.02 62 2772.00 94 7.83 126 232.86
31 3.70 63 83.00 95 868.70 127 278.29
32 20.00 64 1137.92 96 13.42 128 26.9
M6620 5.15
Conclusion: in an ATR enzyme activity inhibition experiment, the compound provided by the invention shows stronger inhibition activity.
Test example 2: experiments of inhibiting proliferation Activity of the Compounds of the present invention on 22RV1 (human prostate cancer cell) and MDA-MB-436 (breast cancer cell)
22RV1 cells (from Nanjac Bai Biotechnology Co., ltd.) and MDA-MB-436 cells (from Nanjac Bai Biotechnology Co., ltd.) were seeded into the 96-well plate at a density of 5000 per well. The following day, compounds were diluted 4-fold from 10000nM for 8 gradients, added to 96-well plate corresponding wells and incubated in 37℃incubator for 72h. Cell plates were equilibrated to room temperature, then 50uL of CellTiter-Glo solution was added to each well, after 10 minutes of room temperature reaction, chemiluminescent signals were read on a biotek H1 multifunctional microplate reader, and the results were analyzed using xlfit software to calculate the inhibition efficiency of the compounds on 22RV1 and MDA-MB-436 cell viability. Table 2 reports the results of inhibition of cell proliferation by the compounds on 22RV1 and MDA-MB-436 cells.
TABLE 2 cell proliferation inhibition IC 50 values of the inventive compounds on 22RV1 and MDA-MB-436 cells
Conclusion: the compound has better cell proliferation inhibition activity on 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells).

Claims (22)

1. A compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, said alkyl, alkenyl, alkynyl optionally substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkoxy, halohydroxyalkyl, alkenyl, alkynyl;
or R 1 is
Wherein:
L is selected from the group consisting of bond, alkylene, alkenylene, alkynylene, -C (O) -, -S (O) 2-、-C(O)NH-、-S(O)NH-、-S(O)2 NH-, -C (O) O-;
Ring a is selected from aryl, heteroaryl, cycloalkyl, or heterocyclyl, optionally substituted with one or more Q groups;
q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc), said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc;
r 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, said alkyl, alkenyl, alkynyl optionally substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl;
Or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl group, which is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH 2)qNRaRb);
R 3 is selected from alkyl, haloalkyl or cycloalkyl;
Each R 4 is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkoxy, halohydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
m is 0,1, 2 or 3;
p is 0, 1 or 2;
q is an integer from 0 to 6.
2. The compound represented by the general formula (I) according to claim 1, or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
R 1 is
Wherein:
L is selected from the group consisting of bond, alkylene, alkenylene, alkynylene, -C (O) -, -S (O) 2-、-C(O)NH-、-S(O)NH-、-S(O)2 NH-, -C (O) O-; preferably selected from the group consisting of bond, alkylene, -C (O) -;
Ring a is selected from aryl, heteroaryl, preferably C 6-10 aryl or 5-10 membered heteroaryl; the aryl, heteroaryl groups are optionally substituted with one or more Q groups;
Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc), said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is 0, 1 or 2;
q is an integer from 0 to 6.
3. The compound of the formula (I) according to claim 1 or 2, which is a compound of the formula (II) or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
L is selected from the group consisting of a bond, an alkylene, -C (O) -; preferably a bond;
Each X 1、X2、X3、X4 is independently selected from CH or N;
Q 1 is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc), said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc, or- (CH 2)qNRaS(O)pRc;
Each Q 2 is independently selected from hydrogen, halogen, alkyl, haloalkyl, - (CH 2)qC(O)NRaRb), said alkyl optionally further substituted with NR aRb;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is 0, 1 or 2;
R 2、R3、R4, m, p, q are as defined in claim 1.
4. A compound of the general formula (I) according to claim 3, wherein,
Q 1 is-NR aRb;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRd(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf, or- (CH 2)qNRdS(O)pRf);
Or R a and R b together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl, preferably a 4-6 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf or- (CH 2)qNRdS(O)pRf), the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, C 6-10 aryl, and 5-to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3-to 6-membered heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is 1 or 2;
q is an integer of 0 to 6, preferably an integer of 1 to 6, more preferably an integer of 1 to 4.
5. A compound of the general formula (I) according to claim 1 to 4, or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (III), or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2、X3、X4 is independently selected from CH or N; preferably, X 1 is N and X 2、X3、X4 is CH, or X 2 is N and X 1、X3、X4 is CH, or X 1、X2、X3、X4 is CH;
Y is selected from NR 5、CR5R6 or SO 2;
R 5 is selected from hydrogen, halogen, amino, oxo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、C(O)Rf、C(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-S(O)pRf、-S(O)pNRdRe、-NRdC(O)Rf; said C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R 6 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
Or R 5 and R 6 together with the carbon atom to which they are attached form a 3-to 12-membered heterocyclyl, preferably a 3-to 6-membered heterocyclyl; the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R d and R e are each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl, and heteroaryl;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, the cycloalkyl and heterocyclyl being optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
R f is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is 1 or 2;
q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;
n is 0, 1 or 2;
s is 1 or 2; preferably 1;
t is 1 or 2; preferably 1;
R 2、R3、R4, m are as defined in claim 1; q 2 is as defined in claim 3.
6. The compound represented by the general formula (I) or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (IIIA) or (IIIB) or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2 is independently selected from CH or N;
Y 1 is selected from N or CR 6;
R 6 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, - (CH 2)qNRdRe) wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 6 membered heterocyclyl;
R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;
Or R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, preferably a 6 membered heterocyclyl, wherein the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, di C 1-6 alkylamino, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, wherein the C 3-6 cycloalkyl, 3-8 membered heterocyclyl is optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl are optionally further substituted with one or more substituents selected from halogen;
Or R d and R e together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl;
q is an integer from 1 to 4, preferably 1 or 2;
n is 0, 1 or 2;
R 2、R3、R4, m are as defined in claim 1; q 2 is as defined in claim 3.
7. The compound represented by the general formula (I) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (IIIC) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
Each X 1、X2 is independently selected from CH or N;
Y 2 is selected from NR 11、CR11R12、SO2;
R 12 is selected from hydrogen, halogen, amino, and C 1-6 alkyl;
R 11 is substituted with one or more substituents selected from hydrogen, halogen, oxo, thioxo, cyano, hydroxy, mercapto, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl 、-(CH2)qNRdRe、-C(O)NRdRe、-S(O)pNRdRe, and-NR dC(O)Rf; the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
Or R 11 and R 12 together with the carbon atom to which they are attached form a 3-to 12-membered heterocyclyl, preferably a 3-to 6-membered heterocyclyl; the heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl;
r f is selected from C 1-6 alkyl;
p is 1 or 2;
q is an integer from 0 to 4, preferably an integer from 0 to 2;
R 2、R3、R4, m are as defined in claim 1; q 2, n are as defined in claim 3.
8. A compound of the general formula (I) according to claim 1 to 3, or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Q 1 is selected from NR aRb;
R a is selected from hydrogen and C 1-6 alkyl;
R b is selected from C 1-6 alkyl, said C 1-6 alkyl optionally further substituted with a substituent selected from-NR dRe、-NRdC(O)Rf、-C(O)NRdRe;
R d and R e are each independently selected from hydrogen and C 1-6 alkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl being optionally further substituted with a substituent selected from halogen, amino, oxo, C 1-6 alkyl;
r f is selected from C 1-6 alkyl.
9. A compound of the formula (I) according to claim 1 to 3, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,
Wherein:
Each X 1、X2 is independently selected from CH or N;
y 3、Y4、Y5、Y6 are each independently selected from CH or N, preferably both CH, or one of them is N, the others are CH, or two of them are N, the others are CH;
Each R 13a is independently selected from hydrogen, halogen, C 1-6 alkyl; s is 0,1, 2, 3 or 4, preferably 0,1 or 2;
R 13b is selected from hydrogen, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C (O) NR dRe、-C(O)NRf(CH2)qNRdRe;
R d and R e are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl;
Or R d and R e together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl being optionally further substituted with a substituent selected from halogen, amino, oxo, C 1-6 alkyl, 5-6 membered heterocyclyl;
r f is selected from hydrogen and C 1-6 alkyl;
q is an integer from 1 to 4, preferably 1 or 2;
R 2、R3、R4, m are as defined in claim 1; q 2, n are as defined in claim 3.
10. A compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from 8-10 membered fused heterocyclyl, preferablyWhich is optionally further substituted with a substituent selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl.
11. A compound of the general formula (I) according to claim 1, or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
R 1 is
L is selected from a bond, alkylene or-C (O) -;
Ring a is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, preferably phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyridopyrrolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl; optionally substituted with one or more Q groups;
Q is selected from halogen, hydroxy, mercapto, cyano, C 1-6 alkyl, C 1-6 haloalkyl, - (CH 2)qNRaRb);
R a and R b are each independently selected from hydrogen and C 1-6 alkyl;
q is an integer from 0 to 4, preferably an integer from 0 to 2.
12. A compound of the general formula (I) according to claim 1 to 11, or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein R 2 is selected from hydrogen and C 1-6 alkyl.
13. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, preferably an 8-10 membered heterocyclyl, more preferablyWhich is optionally further substituted with one or more substituents selected from halogen, amino, cyano, hydroxy, mercapto, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, - (CH 2)qNRaRb);
q is an integer from 1 to 4, preferably 1 or 2;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl.
14. A compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl or C 1-6 haloalkyl.
15. A compound of formula (I) according to any one of claims 1 to 14, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl; m is 0 or 1.
16. A compound of formula (I) according to any one of claims 3 to 10, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each Q 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, cyano, (CH 2)qC(O)NRaRb、C1-6 haloalkyl, said C 1-6 alkyl optionally being further substituted with NR aRb;
R a and R b are each independently selected from hydrogen or C 1-6 alkyl;
q is an integer from 0 to 6;
n is an integer from 0 to 4, preferably an integer from 0 to 2.
17. A compound of formula (I) according to any one of claims 1 to 16, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:
18. A process for preparing a compound of formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Under alkaline condition, in the presence of condensing agent, the compound of general formula (IA) and the compound of general formula (IB) undergo condensation reaction to obtain the compound of general formula (I);
the alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP, triethylamine and DIPEA;
the condensing agent is preferably EDCI, DCC, CDI, HOBt, HOAT, HATU, TBTU, HBTU, pyBOP;
Wherein: r 1、R2、R3、R4, m are as defined in claim 1.
19. A process for preparing a compound of formula (IIIA) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Under alkaline conditions, in the presence of a condensing agent, carrying out condensation reaction on a compound of a general formula (IIIAa) and a compound of a general formula (IIIAb) to obtain a compound of a general formula (IIIA);
the alkali is preferably organic alkali or inorganic alkali, the inorganic alkali is preferably potassium carbonate, cesium carbonate and sodium carbonate, and the organic alkali is preferably DMAP, triethylamine and DIPEA;
the condensing agent is preferably EDCI, DCC, CDI, HOBt, HOAT, HATU, TBTU, HBTU, pyBOP;
wherein ：R2、R3、R4、R7、R8、X1、X2、Y1、Q2、m、n is as defined in claim 6.
20. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 17 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
21. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a stereoisomer, a tautomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the preparation of an ATR kinase inhibitor.
22. Use of a compound of general formula (I) according to any one of claims 1-17 or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for the treatment of ATR kinase mediated diseases, preferably melanoma, brain tumor, oesophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer), kidney cancer, bladder cancer, gall bladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemias (including Acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML)), multiple myeloma and lymphomatosis.
CN202211714390.XA 2022-12-27 2022-12-27 A pyrimidine compound and its preparation method and medical use Pending CN118255760A (en)

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