CN114163454A - Pyridine-containing polycyclic derivative inhibitor, and preparation method and application thereof - Google Patents

Pyridine-containing polycyclic derivative inhibitor, and preparation method and application thereof Download PDF

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CN114163454A
CN114163454A CN202111031086.0A CN202111031086A CN114163454A CN 114163454 A CN114163454 A CN 114163454A CN 202111031086 A CN202111031086 A CN 202111031086A CN 114163454 A CN114163454 A CN 114163454A
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高鹏
孙广俊
王少宝
修文华
谭松良
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Shanghai Hansoh Biomedical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention relates to a composition containingPyridine polycyclic derivative inhibitors, and preparation methods and applications thereof. In particular, the invention relates to a compound shown in a general formula (V), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as an EGFR inhibitor in treating cancer-related diseases, wherein each substituent in the general formula (V) is defined as the specification.

Description

Pyridine-containing polycyclic derivative inhibitor, and preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a pyridine-containing polycyclic derivative inhibitor, and a preparation method and application thereof.
Background
Egfr (epidemal Growth Factor receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases and is activated by binding to its ligand Epidermal Growth Factor (EGF) or transforming Growth Factor alpha (TGF α). Activated EGFR forms homodimers on cell membranes or heterodimers with other receptors in the family (e.g., ErbB-2, ErbB-3, or ErbB-4), causing phosphorylation of key tyrosine residues in EGFR cells, thereby activating intracellular downstream signaling pathways that play important roles in cell proliferation, survival, and anti-apoptosis. Activating mutation, overexpression, gene amplification and the like of the EGFR can cause over-activation of the EGFR, promote transformation of cells into tumor cells, play an important role in proliferation, invasion, metastasis and angiogenesis of the tumor cells, and are important targets for development of anti-cancer drugs, particularly lung cancer treatment drugs.
First generation EGFR small molecule inhibitors including gefitinib (iressa) and erlotinib (tarceva) showed good efficacy in lung cancer treatment, and have been used as first line drugs for the treatment of non-small cell lung cancer (NSCLC) with EGFR activating mutations including L858R and del e746_ a 750. However, after 10-12 months of treatment with the first-generation small molecule EGFR inhibitor, almost all NSCLC patients develop drug resistance to the first-generation small molecule inhibitor, and more than half of the drug resistance mechanism is caused by secondary mutation of the EGFR gatekeeper gene residue T790M.
Oxititinib (Osimetinib or AZD9291) is a third-generation EGFR TKI inhibitor, has high response rate and good treatment effect on drug resistance caused by EGFR T790M mutation, is obtained in 11 months of 2015 and is sold in the market under the accelerated FDA approval in the United states, and can be used for effectively treating patients with advanced non-small cell lung cancer with EGFR T790M drug resistance mutation clinically. Although the axitinib achieves great success in clinically treating the EGFR T790M mutant non-small cell lung cancer, the drug resistance of a patient after 9-14 months of treatment still cannot be avoided. Research shows that the drug resistance of 20-40% of drug resistant patients is caused by EGFR C797S mutation. The EGFR C797S mutation converts the cysteine at position 797 to serine, resulting in the failure of axitinib to form a covalent bond with the EGFR protein, thereby causing drug resistance. Currently, no effective inhibitor aiming at EGFR C797S drug-resistant mutation exists in clinic. Therefore, there is an urgent need to develop new highly active EGFR inhibitors to solve the problem of drug resistance caused by EGFR C797S mutation.
Nowa company reports that a compound EAI0450 aiming at EGFR C797S drug resistance belongs to an EGFR allosteric inhibitor, and after the compound is combined with an EGFR monoclonal antibody drug such as cetuximab, the compound shows a good anti-tumor effect in a mouse in-vivo efficacy model of L858R/T790M/C797S mutation, but the compound is ineffective in single drug and cannot inhibit the C797S drug resistance mutation containing deeE 746_ A750, and cannot enter clinical research. Ken Uchibori and the like report in 2017 that Brigatinib (AP26113) and EGFR monoclonal antibody (such as cetuximab) are combined, the third-generation EGFR inhibitor drug resistance caused by the mutation of C797S can be overcome, and a PC9(EGFR-C797S/T790M/de119) mouse drug effect model shows good anti-tumor effect, but Brigatinib also faces low in vitro activity and no remarkable in vivo anti-tumor activity of a single drug, and further clinical research is not carried out.
Lung cancer is a serious disease threatening human health, and the death rate of lung cancer accounts for the first place of all malignant tumors. In China, the incidence rate of lung cancer is rising year by year, and about 70 ten thousand new cases occur every year. The lung cancer of China is accompanied by EGFR activating mutation cases which account for about 35 percent of all NSCLC, and the use of the first generation or the third generation EGFR inhibitor can achieve good treatment effect, but new drug-resistant mutation can be generated in the later period, so the development of a new generation of high-activity drug-resistant EGFR inhibitor has huge clinical and market values.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure BDA0003245287820000021
wherein:
R1selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nRaa、-(CH2)nORaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nOC(O)Raa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nNRaaC(O)Rbb、-(CH2)nNRaaC(O)ORbb、-(CH2)nC(O)NRaaRbbOr- (CH)2)nNRaaS(O)mRbbSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaromatic radicalsOptionally may be further substituted;
R2selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
Raindependently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1RA1、-(CH2)n1ORA1、-(CH2)n1C(O)RA1、-(CH2)n1C(O)ORA1、-(CH2)n1OC(O)RA1、-(CH2)n1S(O)m1RA1、-(CH2)n1NRA1RA2、-(CH2)n1NRA1C(O)RA2、-(CH2)n1NRA1C(O)ORA2、-(CH2)n1C(O)NRA1RA2、-(CH2)n1NRA1S(O)m1RA2、-(CH2)n1O(CH2)n2RA1Or- (CH)2)n1NRA1(CH2)n2NRA1RA2Said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
Rbindependently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
or, R1、R2And RbAny two of which are linked to form a heterocyclyl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally being further substituted;
Raa、Rbb、RA1and RA2Each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
x is 1,2, 3 or 4;
y is 1,2, 3 or 4;
z is 1,2, 3 or 4;
m is 0, 1 or 2;
m1 is 0, 1 or 2;
n is 0, 1,2, 3 or 4;
n1 is 0, 1,2, 3 or 4; and is
n2 is 0, 1,2, 3 or 4.
In a further preferred embodiment of the present invention, the compound has the structure according to formula (II):
Figure BDA0003245287820000041
ring D is selected from 7-20 membered heterocyclyl;
r is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfydryl, cyano, amino and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; preferably hydrogen or C1-6An alkyl group; more preferably hydrogen or C1-3An alkyl group; further preferably hydrogen or methyl;
or, any two R are linked to the atom to which they are attached to form C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted; preferably C3-8A cycloalkyl group; more preferably C3-6A cycloalkyl group; further preferred is cyclopropyl;
s is an integer of 0 to 12.
In a further preferred embodiment of the present invention, the compound has the structure according to formula (III):
Figure BDA0003245287820000042
wherein:
M1is selected from-CR1-、-CR1R2-、N、-NR1-, -S-or-O-;
M2is selected from-CR3R4-、-NR3-、-NR3-c (O) -, -S-or-O-;
R1、R2、R3and R4Each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; preferably C1-6An alkyl group; more preferably C1-3An alkyl group; further preferably methyl;
optionally, R or R3Can be reacted with R1Are connected to form a ring;
and t is 0, 1,2, 3 or 4.
In a further preferred embodiment of the present invention, the compound has the structure according to formula (IV):
Figure BDA0003245287820000051
wherein:
ring C is selected from C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably a 3-12 membered heterocyclyl containing 1-3N, O or S atoms; further preferred are the following groups:
Figure BDA0003245287820000052
Rcselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n5RA5、-(CH2)n5ORA5、-(CH2)n5C(O)RA5、-(CH2)n5C(O)ORA5、-(CH2)n5OC(O)RA5、-(CH2)n5S(O)m3RA5、-(CH2)n5NRA5RA6、-(CH2)n5NRA5C(O)RA6、-(CH2)n5NRA5C(O)ORA6、-(CH2)n5C(O)NRA5RA6、-(CH2)n5NRA5S(O)m3RA6、-(CH2)n5O(CH2)n6RA5Or- (CH)2)n5O(CH2)n6ORA5(ii) a The amino group and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
deuterium, halogen, amino, hydroxy, cyano, oxo, C are preferred1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n5RA5、-(CH2)n5ORA5、-(CH2)n5C(O)RA5、-(CH2)n5S(O)m3RA5、-(CH2)n5NRA5RA6、-(CH2)n5NRA5C(O)RA6、-(CH2)n5C(O)NRA5RA6Or- (CH)2)n5O(CH2)n6RA5(ii) a The amino group and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
further preferred are deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, oxetanyl, -CH2F、-CH2CH2F、-CH2OH、-CH2CH2OH、-C(CH3)2OH、-CH2CN、-CH2OCH3、-CH2CH2OCH3、-OCH3、-OCH2CH3、-C(O)CH3、-N(CH3)2、-N(CH2CH3)2、-N(CH2CH3)CH3、-N(CH3)C(O)CH3、-S(O)2CH3Or
Figure BDA0003245287820000061
RA5And RA6Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
u is 0, 1,2, 3,4 or 5;
m3 is 0, 1 or 2;
n5 is 0, 1,2, 3 or 4; and is
n6 is 0, 1,2, 3 or 4.
In a further preferred embodiment of the present invention, the compound has the structure of formula (V):
Figure BDA0003245287820000071
wherein:
R3selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; preferably C1-6An alkyl group; more preferablyC1-3An alkyl group; further preferred is methyl, ethyl or propyl.
In a further preferred embodiment of the present invention, the compound has the structure according to formula (VI):
Figure BDA0003245287820000072
the invention also provides a preferable scheme and also relates to a pharmaceutical composition which comprises a therapeutically effective dose of the compound shown in the general formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to any compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in preparation of MEK inhibitors, EGFR monoclonal antibodies and related medicines for combination.
The invention also provides a preferable scheme, and also relates to the application of the compound shown in each general formula and the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicaments for treating cancer related diseases; wherein the cancer disease is selected from lung cancer.
The invention further relates to a method for preparing a compound shown in each general formula, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating cancer-related diseases.
The present invention also relates to a method of treating a cancer-related disease comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In some embodiments, the methods relate to the treatment of disorders such as cancer-related disorders.
The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention provides a method of treating a condition comprising a cancer-related disorder in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 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-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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably 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 8 carbon atoms. Monocyclic cycloalkyl contains 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms; non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably 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, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1-3N, O or S atoms, optionally substituted with 1-2 oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group, or a nitrogen-containing fused heterocyclic group.
Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1, 4-diazepanyl, 1, 4-oxazolepanyl, pyranyl, oxazolinyl, tetrahydrooxazolinyl, dihydropyrazinyl, dihydropyrazinonyl, oxazinyl, and dihydrooxazinyl and the like, preferably oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrooxazolyl, piperazinyl, morpholinyl, or 1, 4-oxazolepanyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0003245287820000101
Figure BDA0003245287820000102
and the like.
The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They can be divided into bicyclic, tricyclic and tetracyclic rings according to the number of constituent ringsOr a polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0003245287820000103
Figure BDA0003245287820000104
and the like.
The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0003245287820000111
Figure BDA0003245287820000112
and the like.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0003245287820000113
Figure BDA0003245287820000114
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably 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, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share 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 can be fused on a heteroaryl, heterocyclic or cycloalkyl ring and comprises benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10-membered, more preferably 5-or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably oxazolyl, thiazolyl, pyridyl, pyrazolyl, pyrazinyl, triazolyl, thienyl, imidazolyl or pyrimidinyl; more preferably oxazolyl, thiazolyl, pyridyl, pyrazolyl or pyrazinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0003245287820000121
Figure BDA0003245287820000122
and the like.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably 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, carboxy or carboxylate groups.
The term "alkylthio" refers to-S- (alkyl) and-S- (unsubstituted cycloalkyl) groups, wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably 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, carboxy or carboxylate.
"alkylaminocarbonyl" refers to (alkyl) -N-C (O) -, wherein alkyl is as defined above.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"haloalkylthio" refers to an alkylthio group substituted with one or more halogens wherein the alkylthio group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"cyanoalkyl" refers to an alkyl group substituted with a cyano group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
The term "alkenylcarbonyl" refers to-C (O) - (alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl groups include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group. "halogen" means fluorine, chlorine, bromine or iodine. "amino" means-NH2. "cyano" means-CN. "nitro" means-NO2. "carbonyl" means-C (O) -. "carboxy" refers to-C (O) OH. "THF" refers to tetrahydrofuran. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "DMF" refers to N, N-dimethylformamide. "DIPEA" refers to diisopropylethylamine. "TFA" refers to trifluoroacetic acid. "MeCN" refers to acetonitrile. "DMA" refers to N, N-dimethylacetamide. "Et2O "means diethyl ether. "DCE" refers to 1,2 dichloroethane. "DIPEA" refers to N, N-diisopropylethylamine. "NBS" refers to N-bromosuccinimide. "NIS" refers to N-iodosuccinimide. "Cbz-Cl" refers to benzyl chloroformate。“Pd2(dba)3"refers to tris (dibenzylideneacetone) dipalladium. "Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene. "HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate. "KHMDS" refers to potassium hexamethyldisilazide. "LiHMDS" refers to lithium bistrimethylsilyl amide. "MeLi" refers to methyllithium. "n-BuLi" refers to n-butyllithium. "NaBH (OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably 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 the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was measured using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C)18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
(R,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000141
The first step is as follows: preparation of methyl 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid ester
Figure BDA0003245287820000151
Methyl 2-chloro-6-methylisonicotinate (5.0g, 27mmol), 1-methyl-1H-pyrazol-5-ol (5.3g, 54mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (661mg, 0.81mmol) and sodium carbonate (7.2g, 67.5mmol) were dissolved in anisole (60mL) at room temperature, warmed to 130 ℃ and stirred for 16H. Cooled to room temperature, filtered through celite, 4M dioxane hydrochloride solution (10mL) was added to the filtrate, the solid was filtered off, and the solid was washed with toluene and n-hexane to give the title compound methyl 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid ester (6.7g, yield: 100%).
MS m/z(ESI):248.2[M+H]+.
The second step is that: preparation of tert-amyl (R) - (2, 6-dimethylhept-5-en-1-yl) carbamate
Figure BDA0003245287820000152
To a solution of (R) -3, 7-dimethyloct-6-enoic acid (2.9g, 20mmol) in t-amyl alcohol (20mL) was added diphenyl phosphorazidate (5g, 20mmol) and triethylamine (5g, 20mmol) in this order, the mixture was heated to 110 ℃ to react for 8 hours, cooled to room temperature, added water, extracted with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound t-amyl (R) - (2, 6-dimethylhept-5-en-1-yl) carbamate (4.9g, yield: 91%).
MS m/z(ESI):256.2[M+H]+.
The third step: preparation of (R) -2, 6-dimethylhept-5-en-1-amine
Figure BDA0003245287820000153
Tert-amyl (R) - (2, 6-dimethylhept-5-en-1-yl) carbamate (2.55g, 10mmol) was dissolved in tetrahydrofuran (40mL), potassium tert-butoxide (40mL, 1mol/L) was added and stirred at 90 ℃ for 3 h. Concentrated under reduced pressure, saturated ammonium chloride was added, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to give the title compound (R) -2, 6-dimethylhept-5-en-1-amine as a crude product to be used in the next reaction.
MS m/z(ESI):142.2[M+H]+.
The fourth step: preparation of (R) -5-bromo-N- (2, 6-dimethylhept-5-en-1-yl) -2-nitroaniline
Figure BDA0003245287820000161
Add potassium carbonate (2.7g, 20mmol) to a solution of 4-bromo-2-fluoro-1-nitrobenzene (2.2g, 10mmol) and (R) -2, 6-dimethylhept-5-en-1-ylamine (1.9g, 10mmol) in DMF (10mL) and stir at room temperature for 16 h. Water was added thereto, and extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, and then the separated organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound (R) -5-bromo-N- (2, 6-dimethylhept-5-en-1-yl) -2-nitroaniline (3.1g, yield: 91%).
MS m/z(ESI):341.1[M+H]+.
The fifth step: preparation of 5-bromo-N- ((2R) -4- (3, 3-dimethyloxapropan-2-yl) -2-methylbutyl) -2-nitroaniline
Figure BDA0003245287820000162
To a solution of (R) -5-bromo-N- (2, 6-dimethylhept-5-en-1-yl) -2-nitroaniline (3.1g, 9.1mmol) in dichloromethane (25mL) under ice-bath conditions was added m-chloroperoxybenzoic acid (1.7g, 10.0mmol) in portions and stirred for 1 h. Saturated sodium carbonate solution was added, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, then the separated organic phase was dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to give the title compound, 5-bromo-N- ((2R) -4- (3, 3-dimethyloxaprop-2-yl) -2-methylbutyl) -2-nitroaniline, as a crude product, which was used directly in the next reaction.
MS m/z(ESI):357.2[M+H]+.
And a sixth step: preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentanal
Figure BDA0003245287820000163
Periodic acid (2.1g, 10.0mmol) was added in portions to a solution of 5-bromo-N- ((2R) -4- (3, 3-dimethyloxapropan-2-yl) -2-methylbutyl) -2-nitroaniline (3.3g, 9.1mmol) in tetrahydrofuran/diethyl ether (25mL/13mL) under ice-bath conditions and stirred for 1 h. After extraction with ice water and ether, the organic phase was washed successively with a saturated sodium bicarbonate solution and a saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentanal (1.7g, yield: 61%).
MS m/z(ESI):315.2[M+H]+.
The seventh step: preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentane-1-ol
Figure BDA0003245287820000171
To a solution of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentanal (1.7g, 5.4mmol) in methanol (20mL) under ice-bath conditions was added sodium borohydride (0.2g, 5.4mmol) in portions and stirred for 1 h. Methanol was concentrated under reduced pressure, water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentane-1-ol (1.45g, yield: 85%).
MS m/z(ESI):317.2[M+H]+.
Eighth step: preparation of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl methanesulfonate
Figure BDA0003245287820000172
Methanesulfonyl chloride (632mg, 5.5mmol) was slowly added dropwise to a solution of (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentane-1-ol (1.45g, 4.6mmol) and triethylamine (697mg, 6.9mmol) in dichloromethane (20mL) under ice-bath conditions, and stirred for 1 h. After extraction with saturated sodium bicarbonate solution and dichloromethane, and washing of the organic phase with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound (R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl methanesulfonate (1.68g, yield: 93%).
MS m/z(ESI):395.2[M+H]+.
The ninth step: preparation of methyl (R) -2- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate
Figure BDA0003245287820000173
(R) -5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl methanesulfonate (1.68g, 4.3mmol) and methyl 2- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (1.06g, 4.3mmol) were dissolved in a solution of N.N.dimethylformamide (20mL) at room temperature, potassium carbonate (1.48g, 10.8mmol) was added, and the mixture was heated to 60 ℃ and stirred for 16H. Water and ethyl acetate were added for extraction, the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound methyl (R) -2- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (2.1g, yield: 90%).
MS m/z(ESI):546.2[M+H]+.
The tenth step: preparation of methyl (R) -2- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid ester
Figure BDA0003245287820000181
Methyl (R) -2- (5- ((5- ((5-bromo-2-nitrophenyl) amino) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (2.1g, 3.9mmol) was dissolved in ethanol/water solution (20mL/7mL) at room temperature, reduced iron powder (1.76g, 31.2mmol) and ammonium chloride (835mg, 15.6mmol) were added in this order, and the temperature was raised to 90 ℃ to react for 5H. The organic solvent was concentrated under reduced pressure and the crude product was purified by column chromatography to give the title compound methyl (R) -2- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid ester (1.6g, yield: 81%).
MS m/z(ESI):516.2[M+H]+.
The eleventh step: methyl (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d)]Preparation of imidazol-1-yl) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid ester
Figure BDA0003245287820000182
Methyl (R) -2- (5- ((5- ((2-amino-5-bromophenyl) amino) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid ester (1.6g, 3.1mmol) was dissolved in dichloromethane/tert-butanol solution (20mL/4mL) at room temperature, cyanogen bromide (394mg, 3.7mmol) was added, and the mixture was stirred at room temperature overnight. Extraction with saturated sodium bicarbonate solution and dichloromethane was added, the separated organic phase was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give the title compound methyl (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (1.47g, yield: 88%).
MS m/z(ESI):541.2[M+H]+.
The twelfth step: preparation of (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid
Figure BDA0003245287820000191
Methyl (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinate (1.47g, 2.7mmol) was dissolved in tetrahydrofuran/water solution (10mL/10mL) at room temperature, sodium hydroxide (540mg, 13.5mmol) was added, and the mixture was stirred at room temperature for 2H. Concentration, pH to 5 with 6N hydrochloric acid, concentration of the organic solvent under reduced pressure, washing of the solid with water and drying under vacuum gave the title compound (R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid (1.35g, yield: 95%).
MS m/z(ESI):527.2[M+H]+.
The thirteenth step: (R, E) -56-bromo-11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000192
(R) -2- (5- ((5- (2-amino-6-bromo-1H-benzo [ d) at room temperature]Imidazol-1-yl) -4-methylpentyl) oxo) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid (1.35g, 2.6mmol) was dissolved in dichloromethane (15mL), and triethylamine (1.05g, 10.4mmol) and 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (1.25g,3.9mmol), stirred at room temperature for 2 h. Adding water, extracting with dichloromethane, concentrating the organic solvent under reduced pressure, and purifying by column chromatography to obtain the title compound (R, E) -56-bromo-11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one (858mg, yield: 65%).
MS m/z(ESI):509.2[M+H]+.
The fourteenth step is that: (R, E) -11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of formaldehyde
Figure BDA0003245287820000201
Reacting (R, E) -5 at room temperature6-bromo-11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one (858mg, 1.7mmol), palladium acetate (38mg, 0.17mmol), bis (1-adamantyl) n-butylphosphine (183mg, 0.51mmol) and tetramethylethylenediamine (394mg, 3.4mmol) were dissolved in dioxane (15mL), carbon monoxide was substituted three times, the temperature was raised to 110 ℃ and the mixture was stirred under 80psi pressure for 16 h. Cooling to room temperature, concentrating the organic solvent under reduced pressure, and purifying by column chromatography to obtain the title compound (R, E) -11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Formaldehyde (701mg, yield: 90%).
MS m/z(ESI):459.2[M+H]+.
The fifteenth step: (R, E) -56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]ImidazoPreparation of oxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000202
Reacting (R, E) -1 at room temperature1,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56-Formaldehyde (701mg, 1.5mmol) and 3- (methoxymethyl) azetidinium trifluoroacetate (297mg, 1.5mmol) were dissolved in dichloroethane (15mL), two drops of acetic acid were added dropwise, after stirring for 1h, sodium borohydride acetate (636mg, 3.0mmol) was added in portions, and stirring was carried out overnight. Adding saturated sodium bicarbonate solution and dichloromethane for extraction, washing the organic phase with saturated sodium chloride solution, separating the organic phase, drying with anhydrous sodium sulfate, concentrating the organic solvent under reduced pressure, and purifying the crude product by column chromatography to obtain the title compound (R, E) -56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one (537mg, yield: 66%).
1H NMR(400MHz,CDCl3)δ0.94(d,J＝6.0Hz,3H),1.95-1.96(m,2H),2.13-2.26(m,2H),2.64(s,3H),2.77-2.99(m,2H),3.28-3.52(m,7H),3.66-4.10(m,9H),4.35-4.45(m,2H),7.18-7.19(m,1H),7.27-7.35(m,2H),7.65(s,1H),8.16(s,1H),8.48(s,1H),12.01(s,1H)；
MS m/z(ESI):544.2[M+H]+.
Example 2
(R,E)-56- ((3-methoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000211
(R,E)-56- ((3-methoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):530.2[M+H]+.
Example 3
(R,E)-56- ((3-ethoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000212
(R,E)-56- ((3-ethoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
Example 4
(R,E)-1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (Yl) methyl) azetidine-3-carbonitrile
Figure BDA0003245287820000221
(R,E)-1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of-yl) methyl) azetidine-3-carbonitrile reference is made to example 1.
MS m/z(ESI):525.2[M+H]+.
Example 5
(R,E)-2-(1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000222
(R,E)-2-(1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):539.2[M+H]+.
Example 6
(R, E) -2- (3-methyl-1- ((1)1,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ b ], [2d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000223
(R, E) -2- (3-methyl-1- ((1)1,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ b ], [2d]Imidazolazoles-2(2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):553.2[M+H]+.
Example 7
(R,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000231
(R,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):543.2[M+H]+.
Example 8
(R,E)-56- ((3- (diethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000232
(R,E)-56- ((3- (diethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):571.2[M+H]+.
Example 9
(R,E)-56- ((3- (Ethyl (methyl) amino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000241
(R,E)-56- ((3- (Ethyl (methyl) amino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 10
(R, E) -N-methyl-N- (1- ((1)1,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (YL) METHYL) AZUTIDIN-3-YL) ACETAMIDES
Figure BDA0003245287820000242
(R, E) -N-methyl-N- (1- ((1)1,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of-yl) methyl) azetidin-3-yl) acetamide reference is made to example 1.
MS m/z(ESI):571.2[M+H]+.
Example 11
(R,E)-11,267-trimethyl-56- ((3- (methyl (oxetan-3-yl) amino) azetidin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000251
(R,E)-11,267-trimethyl-56- ((3- (methyl (oxetan-3-yl) amino) azetidin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):585.2[M+H]+.
Example 12
(R,E)-56- ((3-Aminoazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000252
(R,E)-56- ((3-Aminoazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):515.2[M+H]+.
Example 13
(R,E)-56- ((3-hydroxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000253
(R,E)-56- ((3-hydroxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):516.2[M+H]+.
Example 14
(R,E)-56- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000261
(R,E)-56- ((3-hydroxy-3-methylazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):530.2[M+H]+.
Example 15
(R,E)-56- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000262
(R,E)-56- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):530.2[M+H]+.
Example 16
(R,E)-56- ((3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000271
(R,E)-56- ((3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):558.2[M+H]+.
Example 17
(R,E)-56- ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000272
(R,E)-56- ((3- (hydroxymethyl) -3-methylazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
Example 18
(R,E)-56- ((3- (methoxymethyl) -3-methylazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000273
(R,E)-56- ((3- (methoxymethyl) -3-methylazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):558.2[M+H]+.
Example 19
(R,E)-56- ((3-fluoro-3- (hydroxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000281
(R,E)-56- ((3-fluoro-3- (hydroxymethyl) azetidin-1-yl) methyl) -11,267-trimethylRadical-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):548.2[M+H]+.
Example 20
(R,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000282
(R,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):576.2[M+H]+.
Example 21
(R,E)-56- ((3-fluoro-3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000291
(R,E)-56- ((3-fluoro-3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]ImidazolazolesPreparation of (E) -2(2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):562.2[M+H]+.
Example 22
(R,E)-56- ((3- (fluoromethyl) -3-hydroxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000292
(R,E)-56- ((3- (fluoromethyl) -3-hydroxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):548.2[M+H]+.
Example 23
(R,E)-56- ((4-acetylpiperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000301
(R,E)-56- ((4-acetylpiperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):571.2[M+H]+.
Example 24
(R,E)-11,267-trimethyl-56- ((4-methyl-2-carbonylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000302
(R,E)-11,267-trimethyl-56- ((4-methyl-2-carbonylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 25
(R,E)-11,267-trimethyl-56- ((4-methyl-3-carbonylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000303
(R,E)-11,267-trimethyl-56- ((4-methyl-3-carbonylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 26
(R,E)-11,267-trimethyl-56- (morpholinomethyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000311
(R,E)-11,267-trimethyl-56- (morpholinomethyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):530.2[M+H]+.
Example 27
(R,E)-56- ((1, 4-oxazepin-4-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000312
(R,E)-56- ((1, 4-oxazepin-4-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
Example 28
(R,E)-56- ((4-Cyclopropylpiperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000321
(R,E)-56- ((4-Cyclopropylpiperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):569.2[M+H]+.
Example 29
(R,E)-11,267-trimethyl-56- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000322
(R,E)-11,267-trimethyl-56- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):585.2[M+H]+.
Example 30
(R,E)-56- ((4- (2-fluoroethyl) piperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000331
(R,E)-56- ((4- (2-fluoroethyl) piperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):575.2[M+H]+.
Example 31
(R,E)-56- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000332
(R,E)-56- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):573.2[M+H]+.
Example 32
(R,E)-56- ((4- (2-methoxyethyl) piperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000341
(R,E)-56- ((4- (2-methoxyethyl) piperazin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-Aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):586.2[M+H]+.
Example 33
(R,E)-11,267-trimethyl-56- (pyrrolidin-1-ylmethyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000342
(R,E)-11,267-trimethyl-56- (pyrrolidin-1-ylmethyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):514.2[M+H]+.
Example 34
(R,E)-56- ((diethylamino) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000343
(R,E)-56- ((diethylamino) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):516.2[M+H]+.
Example 35
(R,E)-56-((R) -3-Methoxypyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000351
(R,E)-56-((R) -3-Methoxypyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
Example 36
(R,E)-56- (((S) -3-Methoxypyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000352
(R,E)-56- (((S) -3-Methoxypyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
Example 37
(R,E)-56- (((R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000361
(R,E)-56- (((R) -3- (dimethylamino) pyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 38
(R,E)-56- (((S) -3- (dimethylamino) pyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000362
(R,E)-56- (((S) -3- (dimethylamino) pyrrolidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 39
(R,E)-11,267-trimethyl-56- ((2-carbonyloxazolidin-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000363
(R,E)-11,267-trimethyl-56- ((2-carbonyloxazolidin-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):530.2[M+H]+.
Example 40
(R,E)-11,267-trimethyl-56- ((2-carbonyl-1, 3-oxacyclohex-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000371
(R,E)-11,267-trimethyl-56- ((2-carbonyl-1, 3-oxacyclohex-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
EXAMPLE 41
(R,E)-11,267-trimethyl-56- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one
Figure BDA0003245287820000372
(R,E)-11,267-trimethyl-56- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 42
(R,E)-11,267-trimethyl-56- (((1R,4R) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000381
(R,E)-11,267-trimethyl-56- (((1R,4R) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 43
(7R,E)-11,267-trimethyl-56- ((6-methyl-3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000382
(7R,E)-11,267-trimethyl-56- ((6-methyl-3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 44
(7R,E)-11,267-trimethyl-56- ((3-methyl-3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000383
(7R,E)-11,267-trimethyl-56- ((3-methyl-3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 45
(R,E)-56- (((1R,5S) -8-oxa-3-azabicyclo [ 3.2.1)]Octane-3-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000391
(R,E)-56- (((1R,5S) -8-oxa-3-azabicyclo [ 3.2.1)]Octane-3-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):556.2[M+H]+.
Example 46
(R,E)-56- (((1R,5S) -3-oxa-8-azabicyclo [ 3.2.1)]Octane-8-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000392
(R,E)-56- (((1R,5S) -3-oxa-8-azabicyclo [ 3.2.1)]Octane-8-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):556.2[M+H]+.
Example 47
(R,E)-56- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000401
(R,E)-56- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-nitrogenHetero-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):545.2[M+H]+.
Example 48
(R,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000402
(R,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):597.2[M+H]+.
Example 49
(R,E)-11,267-trimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000411
(R,E)-11,267-trimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridinesPreparation of (E) -1(4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):633.2[M+H]+.
Example 50
(R,E)-11,267-trimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000412
(R,E)-11,267-trimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
1H NMR(400MHz,CDCl3)δ0.94(d,J＝5.8Hz,3H),1.83-2.16(m,3H),2.21-2.55(m,3H),2.65(s,3H),2.76-3.13(m,4H),3.58-3.93(m,12H),4.26-4.61(m,2H),7.20-7.22(m,2H),7.29-7.30(m,1H),7.66(s,1H),8.16(s,1H),8.48(s,1H),11.99(s,1H)；
MS m/z(ESI):556.2[M+H]+.
Example 51
(R,E)-56- ((2-oxa-7-azaspiro [ 3.5)]Nonan-7-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000421
(R,E)-56- ((2-oxa-7-azaspiro [ 3.5)]Nonan-7-yl) methanesRadical) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):570.2[M+H]+.
Example 52
(R,E)-56- ((6-oxa-2-azaspiro [ 3.4)]Octane-2-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000422
(R,E)-56- ((6-oxa-2-azaspiro [ 3.4)]Octane-2-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):556.2[M+H]+.
Example 53
(E)-11,267, 7-tetramethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000423
(E)-11,267, 7-tetramethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazoxazole-2 (2,4) -pyridine-Preparation of 1(4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 54
(E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000431
(E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):557.2[M+H]+.
Example 55
(E)-2-(1-((11,267, 7-tetramethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000432
(E)-2-(1-((11,267, 7-tetramethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):553.2[M+H]+.
Example 56
(E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000441
(E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):558.2[M+H]+.
Example 57
(E)-56- ((3-methoxyazetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000442
(E)-56- ((3-methoxyazetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):544.2[M+H]+.
Example 58
(E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000451
(E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):611.2[M+H]+.
Example 59
(E)-11,267, 7-tetramethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000452
(E)-11,267, 7-tetramethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):647.2[M+H]+.
Example 60
(E)-11,267, 7-tetramethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000461
(E)-11,267, 7-tetramethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):570.2[M+H]+.
Example 61
(E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000462
(E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267, 7-tetramethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):590.2[M+H]+.
Example 62
(E) Preparation of (4-methylpiperazin-1-yl) methyl-1 ',6' -dimethyl-6 ' - ((4-methylpiperazin-1-yl) methyl) spiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000463
(E) Preparation of (e) -1',6' -dimethyl-6 ' - ((4-methylpiperazin-1-yl) methyl) spiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 63
(E) Preparation of (3- (dimethylamino) azetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7 '-11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000471
(E) Preparation of (E) -6' - ((3- (dimethylamino) azetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 64
(E) Preparation of (E) -2- (1- ((1',6' -dimethyl-3 ' -carbonylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazolycloundecane ] -6' -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000472
(E) Preparation of (E) -2- (1- ((1',6' -dimethyl-3 ' -carbonylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazolycloundecane ] -6' -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):551.2[M+H]+.
Example 65
(E) Preparation of (3- (methoxymethyl) azetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7 '-11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000481
(E) Preparation of (E) -6' - ((3- (methoxymethyl) azetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):556.2[M+H]+.
Example 66
(E) Preparation of (6 ' - ((3-methoxyazetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000482
(E) Preparation of (E) -6' - ((3-methoxyazetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):542.2[M+H]+.
Example 67
(E) Preparation of (E) -6' - ((3aR,6aS) -5-acetylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000491
(E) Preparation of (E) -6' - (((3aR,6aS) -5-acetylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):609.2[M+H]+.
Example 68
(E) Preparation of (E) -1',6' -dimethyl-6 ' - (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) spiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000492
(E) Preparation of (E) -1',6' -dimethyl-6 ' - (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) spiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):645.2[M+H]+.
Example 69
(E) Preparation of (E) -1',6' -dimethyl-6 ' - (((3aR,6aS) -tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) spiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one
Figure BDA0003245287820000501
(E) Preparation of (E) -1',6' -dimethyl-6 ' - (((3aR,6aS) -tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) spiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):568.2[M+H]+.
Example 70
(E) Preparation of (3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7 '-11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecane ] -3' -one
Figure BDA0003245287820000502
(E) Preparation of (E) -6' - ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -1',6' -dimethylspiro [ cyclopropane-1, 7' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecane ] -3' -one reference is made to example 1.
MS m/z(ESI):588.2[M+H]+.
Example 71
(S,E)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000503
(S,E)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):545.2[M+H]+.
Example 72
(S,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000511
(S,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):545.2[M+H]+.
Example 73
(S,E)-2-(1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000512
(S,E)-2-(1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):541.2[M+H]+.
Example 74
(S,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000521
(S,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):546.2[M+H]+.
Example 75
(S,E)-56- ((3-methoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000522
(S,E)-56- ((3-methoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):532.2[M+H]+.
Example 76
(S,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000531
(S,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) methyl)-11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):599.2[M+H]+.
Example 77
(S,E)-11,267-trimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000532
(S,E)-11,267-trimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):635.2[M+H]+.
Example 78
(S,E)-11,267-trimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000541
(S,E)-11,267-trimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrole-5 (3H) -yl) methyl)-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):558.2[M+H]+.
Example 79
(S,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000542
(S,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-8, 11-dioxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):578.2[M+H]+.
Example 80
(R,E)-11,267-trimethyl-55- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000543
(R,E)-11,267-trimethyl-55- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Imidazolazole-2 (2,4) -pyridinesPreparation of (E) -1(4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):549.2[M+H]+.
Example 81
(R,E)-55- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000551
(R,E)-55- ((3- (dimethylamino) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):549.2[M+H]+.
Example 82
(R,E)-2-(1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-55-yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000552
(R,E)-2-(1-((11,267-trimethyl-3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-55-yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):545.2[M+H]+.
Example 83
(R,E)-55- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000561
(R,E)-55- ((3- (methoxymethyl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):550.2[M+H]+.
Example 84
(R,E)-55- ((3-methoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000562
(R,E)-55- ((3-methoxyazetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):536.2[M+H]+.
Example 85
(R,E)-55- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000571
(R,E)-55- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):603.2[M+H]+.
Example 86
(R,E)-11,267-trimethyl-55- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000572
(R,E)-11,267-trimethyl-55- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):639.2[M+H]+.
Example 87
(R,E)-11,267-trimethyl-55- (((3aR,6aS) -tetrahydro-1H-)Furo [3,4-c ]]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000581
(R,E)-11,267-trimethyl-55- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):562.2[M+H]+.
Example 88
(R,E)-55- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000582
(R,E)-55- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -11,267-trimethyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -thieno [2,3-d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):582.2[M+H]+.
Example 89
(52E,7Z)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecan-7-en-3-one
Figure BDA0003245287820000583
(52E,7Z)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecen-7-en-3-one reference is made to example 1.
MS m/z(ESI):541.2[M+H]+.
Example 90
(52E,7E)-11,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazolycloundecan-7-en-3-one
Figure BDA0003245287820000591
(52E,7E)-11,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecen-7-en-3-one reference is made to example 1.
MS m/z(ESI):527.2[M+H]+.
Example 91
(E) Preparation of (E) -2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -11- ((4-methylpiperazin-1-yl) methyl) -7, 8-dihydro-6H-benzo [4,5] imidazo [2,1-f ] pyrido [3,4-b ] [1,5,7] oxadiazodecazin-16 (14H) -one
Figure BDA0003245287820000592
(E) Preparation of (e) -2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -11- ((4-methylpiperazin-1-yl) methyl) -7, 8-dihydro-6H-benzo [4,5] imidazo [2,1-f ] pyrido [3,4-b ] [1,5,7] oxadiazodecazin-16 (14H) -one reference example 1.
MS m/z(ESI):501.2[M+H]+.
Example 92
(E) Preparation of (E) -2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -12- ((4-methylpiperazin-1-yl) methyl) -6,7,8, 9-tetrahydrobenzo [4,5] imidazo [2,1-f ] pyrido [3,4-b ] [1] oxa [5,7] diazacycloundecen-17 (15H) -one
Figure BDA0003245287820000601
(E) Preparation of (E) -2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -12- ((4-methylpiperazin-1-yl) methyl) -6,7,8, 9-tetrahydrobenzo [4,5] imidazo [2,1-f ] pyrido [3,4-b ] [1] oxa [5,7] diazacycloundecen-17 (15H) -one reference example 1.
MS m/z(ESI):515.2[M+H]+.
Example 93
(E) Preparation of (E) -2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -13- ((4-methylpiperazin-1-yl) methyl) -7,8,9, 10-tetrahydro-6H-benzo [4,5] imidazo [2,1-f ] pyrido [3,4-b ] [1] oxa [5,7] diazacyclododecan-18 (16H) -one
Figure BDA0003245287820000602
(E) Preparation of (E) -2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -13- ((4-methylpiperazin-1-yl) methyl) -7,8,9, 10-tetrahydro-6H-benzo [4,5] imidazo [2,1-f ] pyrido [3,4-b ] [1] oxa [5,7] diazacyclododecan-18 (16H) -one refers to example 1.
MS m/z(ESI):529.2[M+H]+.
Example 94
(E) Preparation of (E) -1, 23-dimethyl-12- ((4-methylpiperazin-1-yl) methyl) -1,15,16,17,18, 20-hexahydro-4, 6- (azepin-ethylenebridge) -5, 19-methylenebenzo [4,5] imidazo [2,1-b ] pyrazolo [3,4-j ] [1,3,8] triaza cyclopentadecan-7 (9H) -one
Figure BDA0003245287820000603
(E) Preparation of (E) -1, 23-dimethyl-12- ((4-methylpiperazin-1-yl) methyl) -1,15,16,17,18, 20-hexahydro-4, 6- (azepin-ethylenebridge) -5, 19-methylenebenzo [4,5] imidazo [2,1-b ] pyrazolo [3,4-j ] [1,3,8] triaza cyclopentadecanon-7 (9H) -one reference is made to example 1.
MS m/z(ESI):540.2[M+H]+.
Example 95
(13Z,52E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000611
(13Z,52E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):540.2[M+H]+.
Example 96
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -15,16,52,53-tetrahydro-14H,51H-10-oxa-4-aza-5 (2,1) -benzo [ d]ImidazoleAnd azol-1 (3,4) -pyrrolo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000612
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -15,16,52,53-tetrahydro-14H,51H-10-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-1 (3,4) -pyrrolo [1,2-b ] compounds]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):541.2[M+H]+.
Example 97
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-1 (2,1) -indol-2 (2,4) -pyridincycloundecan-3-ones
Figure BDA0003245287820000621
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-1 (2,1) -indol-2 (2,4) -pyridylcycloundecan-3-one reference is made to example 1.
MS m/z(ESI):562.2[M+H]+.
Example 98
(E)-11,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51Preparation of H-11-oxa-4-aza-1 (5,4),5(2,1) -diindioxazol-2 (2,4) -pyridinylundecan-3-one
Figure BDA0003245287820000622
(E)-11,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51Preparation of H-11-oxa-4-aza-1 (5,4),5(2,1) -diindioxazol-2 (2,4) -pyridylcycloundecan-3-one reference is made to example 1.
MS m/z(ESI):579.2[M+H]+.
Example 99
(E)-12,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-12H,51Preparation of H-11-oxa-4-aza-1 (5,4),5(2,1) -diindioxazol-2 (2,4) -pyridinylundecan-3-one
Figure BDA0003245287820000623
(E)-12,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-12H,51Preparation of H-11-oxa-4-aza-1 (5,4),5(2,1) -diindioxazol-2 (2,4) -pyridylcycloundecan-3-one reference is made to example 1.
MS m/z(ESI):579.2[M+H]+.
Example 100
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (6,5) -benzo [ b ]][1,4]Preparation of dioxin cyclododecan-3-one
Figure BDA0003245287820000631
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazoxazole-2 (2,4) -pirPyridine-1 (6,5) -benzo [ b][1,4]Preparation of dioxin cyclododecan-3-one reference is made to example 1.
MS m/z(ESI):583.2[M+H]+.
Example 101
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (5,4) -benzo [ d][1,3]Preparation of dioxacyclododecan-3-one
Figure BDA0003245287820000632
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (5,4) -benzo [ d][1,3]Dioxocyclododecan-3-one was prepared as described in example 1.
MS m/z(ESI):569.2[M+H]+.
Example 102
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-51H-11-oxa-4-aza-1 (6,5) -quinoxaline-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridylcycloundecan-3-ones
Figure BDA0003245287820000633
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-51H-11-oxa-4-aza-1 (6,5) -quinoxaline-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridylcycloundecan-3-one reference is made to example 1.
MS m/z(ESI):577.2[M+H]+.
Example 103
(13Z,14E,52E)-26-methyl radical-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-51H-10-oxa-4-aza-1 (3,5),5(2,1) -dipyrazolo [1,5-a]Preparation of pyridin-2 (2,4) -pyridylcycloundecan-3-ones
Figure BDA0003245287820000641
(13Z,14E,52E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-51H-10-oxa-4-aza-1 (3,5),5(2,1) -dipyrazolo [1,5-a]Preparation of pyridin-2 (2,4) -pyridylcycloundecan-3-one reference is made to example 1.
MS m/z(ESI):551.2[M+H]+.
Example 104
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -13,14,52,53-tetrahydro-12H,51H-4-aza-1 (6,4) -benzo [ b][1,4]Oxazin-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridylcycloundecan-3-ones
Figure BDA0003245287820000642
(E)-26-methyl-56- ((4-methylpiperazin-1-yl) methyl) -13,14,52,53-tetrahydro-12H,51H-4-aza-1 (6,4) -benzo [ b][1,4]Oxazin-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridylcycloundecan-3-one reference is made to example 1.
MS m/z(ESI):566.2[M+H]+.
Example 105
(E)-14,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -11,12,13,14,52,53-hexahydro-51H-4-aza-1 (7,1) -quinoxaline-5 (2,1) -benzo [ d]ImidazolePreparation of benzoxazol-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000651
(E)-14,26-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -11,12,13,14,52,53-hexahydro-51H-4-aza-1 (7,1) -quinoxaline-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):579.2[M+H]+.
Example 106
(R,E)-26-cyclopropyl-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000652
(R,E)-26-cyclopropyl-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
1H NMR(400MHz,CD3Cl)δ0.91(d,J＝6.6Hz,3H),0.97-1.02(m,2H),1.10-1.16(m,2H),1.45-1.57(m,3H),1.91-2.01(m,2H),2.10-2.20(m,2H),2.23-2.31(m,1H),2.41-2.49(m,3H),2.59-2.74(m,5H),2.81-2.89(m,1H),3.64-3.76(m,3H),3.78(s,3H),3.84-3.92(m,1H),4.31-4.40(m,1H),4.42-4.51(m,1H),7.19-7.23(m,1H),7.27-7.34(m,2H),7.63(s,1H),8.10(s,1H),8.41(s,1H),11.89-12.06(m,1H)；
MS m/z(ESI):569.2[M+H]+.
Example 107
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-26Preparation of (E) -carbonitrile
Figure BDA0003245287820000661
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -3-carbonyl-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-26Preparation of carbonitrile referring to example 1.
MS m/z(ESI):554.2[M+H]+.
Example 108
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -26- (trifluoromethyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000662
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -26- (trifluoromethyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):597.2[M+H]+.
Example 109
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -26-phenoxy-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000663
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -26-phenoxy-52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):621.2[M+H]+.
Example 110
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -26- (phenylamino) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000671
(R,E)-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -26- (phenylamino) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
MS m/z(ESI):620.2[M+H]+.
Example 111
(13Z,52E,7R)-267-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzols[d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000672
(13Z,52E,7R)-267-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):554.2[M+H]+.
Example 112
(13Z,52E,7R)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000681
(13Z,52E,7R)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):554.2[M+H]+.
Example 113
2-(1-(((13Z,52E,7R)-267-dimethyl-3-carbonyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Imidazolazol-2 (2,4) -pyridinylcyclononane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000682
2-(1-(((13Z,52E,7R)-267-dimethyl-3-carbonyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Imidazolazol-2 (2,4) -pyridinylcyclononane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):550.2[M+H]+.
Example 114
(13Z,52E,7R)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000691
(13Z,52E,7R)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 115
(13Z,52E,7R)-56- ((3-methoxyazetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000692
(13Z,52E,7R)-56- ((3-methoxyazetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):541.2[M+H]+.
Example 116
(13Z,52E,7R)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000693
(13Z,52E,7R)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):608.2[M+H]+.
Example 117
(13Z,52E,7R)-267-dimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000701
(13Z,52E,7R)-267-dimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):644.2[M+H]+.
Example 118
(13Z,52E,7R)-267-dimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000702
(13Z,52E,7R)-267-dimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-onesThe process is referred to example 1.
MS m/z(ESI):567.2[M+H]+.
Example 119
(13Z,52E,7R)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000711
(13Z,52E,7R)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):587.2[M+H]+.
Example 120
(R,E)-267-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000712
(R,E)-267-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Pyrano-azazole-2 (2,4) -pyridine ringPreparation of decan-3-one reference was made to example 1.
MS m/z(ESI):554.2[M+H]+.
Example 121
(R,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000721
(R,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):554.2[M+H]+.
Example 122
(R,E)-2-(1-((267-dimethyl-3-carbonyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Pyrano-azazole-2 (2,4) -pyridine cyclodecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000722
(R,E)-2-(1-((267-dimethyl-3-carbonyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Pyrano-azazole-2 (2,4) -pyridine cyclodecane-56Preparation of (E) -Yl) methyl) azetidin-3-yl) acetonitrileExample 1.
MS m/z(ESI):550.2[M+H]+.
Example 123
(R,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000723
(R,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 124
(R,E)-56- ((3-methoxyazetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000731
(R,E)-56- ((3-methoxyazetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):541.2[M+H]+.
Example 125
(R,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000732
(R,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):608.2[M+H]+.
Example 126
(R,E)-267-dimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000741
(R,E)-267-dimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Pyrano-azazole-2 (2,4) -pyridine cyclodecan-3-onesReference is made to example 1 for the preparation thereof.
MS m/z(ESI):644.2[M+H]+.
Example 127
(R,E)-267-dimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000742
(R,E)-267-dimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):567.2[M+H]+.
Example 128
(R,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000751
(R,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -267-dimethyl-12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Pyrano-azazole-2 (Preparation of 2,4) -pyridylcyclodecan-3-one reference was made to example 1.
MS m/z(ESI):587.2[M+H]+.
Example 129
(R,E)-267-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000752
(R,E)-267-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):568.2[M+H]+.
Example 130
(R,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000753
(R,E)-56- ((3- (dimethylamino) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of Imidazolol-2 (2,4) -pyridylcyclodecan-3-one reference exampleExample 1.
MS m/z(ESI):568.2[M+H]+.
Example 131
(R,E)-2-(1-((267-dimethyl-3-carbonyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridylcyclodecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile
Figure BDA0003245287820000761
(R,E)-2-(1-((267-dimethyl-3-carbonyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridylcyclodecane-56Preparation of (E) -yl) methyl) azetidin-3-yl) acetonitrile reference is made to example 1.
MS m/z(ESI):564.2[M+H]+.
Example 132
(R,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000762
(R,E)-56- ((3- (methoxymethyl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):569.2[M+H]+.
Example 133
(R,E)-56- ((3-methoxyazetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000771
(R,E)-56- ((3-methoxyazetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):555.2[M+H]+.
Example 134
(R,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000772
(R,E)-56- (((3aR,6aS) -5-acetylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):622.2[M+H]+.
Example 135
(R,E)-267-dimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000781
(R,E)-267-dimethyl-56- (((3aR,6aS) -5- (methylsulfonyl) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):658.2[M+H]+.
Example 136
(R,E)-267-dimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000782
(R,E)-267-dimethyl-56- (((3aR,6aS) -tetrahydro-1H-furo [3, 4-c)]Pyrrol-5 (3H) -yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Imidazolazole-2 (2,4) -pyridinesCyclodecan-3-one preparation method reference was made to example 1.
MS m/z(ESI):581.2[M+H]+.
Example 137
(R,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000791
(R,E)-56- ((3-fluoro-3- (2-hydroxypropan-2-yl) azetidin-1-yl) methyl) -267-dimethyl-14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):601.2[M+H]+.
Example 138
(13Z,17S,52E,7R)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000792
(13Z,17S,52E,7R)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):568.2[M+H]+.
Example 139
(13Z,17R,52E,7R)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazole-2 (2,4) -pyridylcyclononan-3-ones
Figure BDA0003245287820000793
(13Z,17R,52E,7R)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,5) -pyrazolo [1,5-a]Pyrazine-5 (2,1) -benzo [ d ] s]Preparation of imidazoxazol-2 (2,4) -pyridylcyclononan-3-one reference is made to example 1.
MS m/z(ESI):568.2[M+H]+.
Example 140
(13S,7R,E)-13,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000801
(13S,7R,E)-13,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):568.2[M+H]+.
Example 141
(13R,7R,E)-13,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of pyranoazazol-2 (2,4) -pyridylcyclodecan-3-ones
Figure BDA0003245287820000802
(13R,7R,E)-13,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -12,13,52,53-tetrahydro-11H,51H-4-aza-5 (2,1) -benzo [ d]Imidazo-1 (7,1) -imidazo [1,2-b]Preparation of Pyrano-azazol-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):568.2[M+H]+.
Example 142
(17S,7R,E)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000811
(17S,7R,E)-17,267-trimethyl-56- ((4-methylpiper)Oxazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):582.2[M+H]+.
Example 143
(17R,7R,E)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one
Figure BDA0003245287820000812
(17R,7R,E)-17,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -14,15,16,17,52,53-hexahydro-51H-4-aza-1 (3,4) -pyrazolo [1,5-a]Pyrimidine-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridylcyclodecan-3-one reference is made to example 1.
MS m/z(ESI):582.2[M+H]+.
Example 144
(R,E)-26-methoxy-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000821
(R,E)-26-methoxy-117-dimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-one reference is made to example 1.
1H NMR(400MHz,CD3Cl)δ0.91(d,J＝6.5Hz,3H),1.47-1.58(m,1H),1.92-2.01(m,3H),2.11-2.18(m,1H),2.23-2.31(m,1H),2.38(s,3H),2.52-2.65(m,6H),2.80-2.92(m,1H),3.59-3.69(m,2H),3.69-3.75(m,1H),3.79(s,3H),3.85-3.92(m,1H),4.03(s,3H),4.31-4.39(m,1H),4.46-4.54(m,1H),7.18-7.23(m,1H),7.27-7.33(m,3H),8.11(s,1H),8.26(s,1H),11.91-12.10(m,1H)；
MS m/z(ESI):559.2[M+H]+.
Example 145
(R,E)-11,267, 10-tetramethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-4, 10-diaza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-3, 11-dione
Figure BDA0003245287820000822
(R,E)-11,267, 10-tetramethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-4, 10-diaza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-3, 11-dione reference is made to example 1.
MS m/z(ESI):570.2[M+H]+.
Example 146
(R,E)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-3-thia-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-3, 3-dioxide
Figure BDA0003245287820000831
(R,E)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-3-thia-4-aza-5 (2,1) -benzo [ d]Preparation of imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane-3, 3-dioxide reference is made to example 1.
MS m/z(ESI):579.2[M+H]+.
Example 147
Preparation of (R, E) -1',6',7' -trimethyl-6 ' - ((4-methylpiperazin-1-yl) methyl) spiro [ oxetanyl-3, 3' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ]
Figure BDA0003245287820000832
Preparation of (R, E) -1',6',7' -trimethyl-6 ' - ((4-methylpiperazin-1-yl) methyl) spiro [ oxetanyl-3, 3' -11-oxa-4-aza-5 (2,1) -benzo [ d ] imidazoxazole-2 (2,4) -pyridine-1 (4,5) -pyrazoloundecane ] reference is made to example 1.
MS m/z(ESI):571.2[M+H]+.
Example 148
(R,E)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-5 (2,1) -benzo [ d ]]Preparation of imidazoxazole-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-ones
Figure BDA0003245287820000833
(R,E)-11,267-trimethyl-56- ((4-methylpiperazin-1-yl) methyl) -52,53-dihydro-11H,51H-11-oxa-5 (2,1) -benzo [ d ]]Imidazolazol-2 (2,4) -pyridin-1 (4,5) -pyrazoloundecan-3-onesReference is made to example 1 for the preparation thereof.
MS m/z(ESI):542.2[M+H]+.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 determination of the inhibitory Effect of the Compounds of the present invention on the kinase Activity of EGFR wild type, EGFR del19/T790M/C797S, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutations
Purpose of the experiment: the purpose of this test example was to test the activity of compounds against the inhibition of the kinase activity of EGFR wild type, EGFR del19/T790M/C797S, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutations.
An experimental instrument: the centrifuge (5810R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: the experiment adopts an HTRF kinase determination method (Cisbio #62TK0PEB) of Cisbio company, substrate polypeptides TK and ATP carry out catalytic reaction under the condition that tyrosine kinase EGFR wild type, EGFR del19/T790M/C797S, EGFR del746-750/T790M/C797S or EGFR L858R/T790M/C797S mutation exists, the substrates are phosphorylated, the kinase activity is characterized by determining the content of the phosphorylated substrate generated in the reaction, and the half inhibition concentration IC of the compound on the EGFR wild type, EGFR del-746-750/T790M/C797S, EGFR del-19/T790M/C797S or EGFR L858R/T790M/C797S mutation kinase activity inhibition is obtained50。
The specific experimental operations were as follows:
the kinase reaction was performed in white 384-well plates (Perkin Elmer #6008280) with 1-5. mu.L of ddH containing 1% DMSO per well2O diluted compounds of different concentrations, 1-5 μ L ddH containing 1% DMSO was added to positive control wells2O, then adding 1-5 μ L of Dilution buffer (5 Xkinase buffer, MgCl) into each well2 6.65Mm，MnCl21.33mM, DTT 1.33mM) of 4 × EGFR wild type, EGFR del19/T790M/C797S, EGFR del746-750/T790M/C797S or EGFR L858R/T790M/C797S mutant kinase solution, 1-5 muL Dilution buffer is added into a negative control hole, 1-5 muL 4 Xsubstrate TK solution prepared by 10 Xdilution buffer is added into all the holes, 1-5 muL 24 muM 4 XATP solution diluted by Dilution buffer is added to start reaction, 10 muL detection solution (TK antibody 16nM, XL 6650.5 muM) is added into each hole after 120 minutes of room temperature reaction, and chemiluminescence value is detected by a BioTek Synergy H1 enzyme labeling instrument after 20 minutes of room temperature dark reaction.
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by counting the percent inhibition data for wells treated with compound over positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate]V (positive control value-negative control value) × 100 }. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the above protocol shows that the compounds of the present invention show about 1nM to 1000nM or more (IC) in the EGFR wild-type kinase activity assay50) The biological activity of (1).
In some embodiments, the IC of the activity of a compound of the invention against EGFR L858R/T790M/C797S-resistant mutant kinase50Less than about 100nM, preferably less than about 10nM, more preferably less than about 1nM, and even more preferably less than about 0.1 nM.
In some embodiments, the IC of the activity of a compound of the invention for the del746-750/T790M/C797S drug-resistant mutant kinase50Less than about 100nM, preferably less than about 10nM, more preferably less than about 1nM, and even more preferably less than about 0.1 nM.
Inhibition of kinase activity by some of the example compounds against EGFR wild type, EGFR del746-750/T790M/C797S, and EGFR L858R/T790M/C797S mutations is shown in Table 1.
Table 1 inhibitory Activity of some of the example compounds
Figure BDA0003245287820000851
Test example 2 cell proliferation inhibition experiment
Purpose of the experiment: the purpose of this test example was to test the activity of the compounds on inhibition of cell proliferation.
An experimental instrument: pipettes were purchased from Eppendorf Co, CO2The incubator is purchased from Thermo corporation of America, and the enzyme-labeling instrument is purchased from BioTek corporation of America, and the model is SynergyH1 full-function enzyme-labeling instrument.
The experimental method comprises the following steps: the CTG (CELL TITER-GLO) luminescence method is adopted in the experiment to detect the A431 cell and Ba/F of the compound3(EGFR del19/T790M/C797S) cell proliferation inhibitory activity, and the median inhibitory concentration IC of the compound on the cell proliferation activity was obtained50。
The specific experimental operations were as follows:
for a431 cells: on the first day, a suspension of 90. mu. L A431 cells was plated in a 96-well assay plate at 3000 cells per well, with no negative control added, and the plate was placed in a chamber containing 5% CO2Was cultured overnight in a 37 ℃ incubator. The next day, 10 μ L of the compound solution diluted in a gradient was added to each well, 10 μ L of the culture medium containing DMSO was added to the positive and negative control wells, and the plates were placed in a carbon dioxide incubator and incubated for 72 hours. After culturing for 72h, adding 50 μ L Cell Titer Glo into each well of the Cell plate, shaking for 2min in the dark, and standing for 10 min; then detecting a luminescence value in a BioTek Synergy H1 enzyme-labeling instrument, calculating an inhibition rate through a chemiluminescence signal value, and obtaining the IC of the compound through curve fitting according to the inhibition rates of different concentrations50。
For Ba/F3(EGFR del19/T790M/C797S) suspension cells:
in 96 hole assay plate spread 90 u L Ba/F3Cell suspension, the number of cells per well is 3000, wherein the negative control is not added with cells; after standing for 2h, 10. mu.L of the compound solution diluted in a gradient was added to each well, 10. mu.L of the culture medium containing DMSO was added to the positive and negative control wells, and the wells were placed in a carbon dioxide incubator and cultured for 72 hours, followed by CTG detection in the same manner as described above for A431 cells.
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated from positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate]V (positive control value-negative control value) × 100 }. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the above protocol shows that the compounds of the present invention exhibit about 1nM to 1000nM (IC) in the A431 cell proliferation inhibitory activity assay50) The biological activity of (1).
The compound pair Ba/F shown by the invention is obtained through the scheme3(EGFR del19/T790M/C797S) cells showed about 0.01nM to 100nM (IC)50) The biological activity of (1).
In some embodiments, the compounds of the invention are directed to Ba/F3(EGFR del19/T790M/C797S) cell proliferation inhibitory Activity IC50Less than about 100nM, preferably less than about 10nM, more preferably less than about 5nM, and even more preferably less than about 1nM, and most preferably less than 0.1nM or even less than about 0.01nM of the compounds listed in the present invention.

Claims (10)

1. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (V):
Figure FDA0003245287810000011
wherein:
M1is selected from-CR1-、-CR1R2-、N、-NR1-, -S-or-O-;
M2is selected from-CR3R4-、-NR3-, -S-or-O-;
R1、R2and R4Each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
R3selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
r is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, sulfydryl, cyano, amino and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
ring C is selected from C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
Rcselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n5RA5、-(CH2)n5ORA5、-(CH2)n5C(O)RA5、-(CH2)n5C(O)ORA5、-(CH2)n5OC(O)RA5、-(CH2)n5S(O)m3RA5、-(CH2)n5NRA5RA6、-(CH2)n5NRA5C(O)RA6、-(CH2)n5NRA5C(O)ORA6、-(CH2)n5C(O)NRA5RA6、-(CH2)n5NRA5S(O)m3RA6、-(CH2)n5O(CH2)n6RA5Or- (CH)2)n5O(CH2)n6ORA5(ii) a The amino group and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
RA5and RA6Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
t is 0, 1,2, 3 or 4;
s is an integer of 0 to 12;
y is 1,2, 3 or 4;
u is 0, 1,2, 3,4 or 5;
m3 is 0, 1 or 2;
n5 is 0, 1,2, 3 or 4; and is
n6 is 0, 1,2, 3 or 4.
2. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1,
R1、R2and R4Each independently is C1-3An alkyl group;
R3is C1-3An alkyl group;
r is hydrogen or C1-3An alkyl group.
3. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 2,
R1、R2and R4Is methyl;
R3is methyl, ethyl or propyl;
r is hydrogen or methyl.
4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein formula (V) is further represented by formula (VI):
Figure FDA0003245287810000031
5. the compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 4,
ring C is a 3-12 membered heterocyclyl containing 1-3N, O or S atoms;
Rcselected from deuterium, halogen, amino, hydroxy, cyano, oxo, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n5RA5、-(CH2)n5ORA5、-(CH2)n5C(O)RA5、-(CH2)n5S(O)m3RA5、-(CH2)n5NRA5RA6、-(CH2)n5NRA5C(O)RA6、-(CH2)n5C(O)NRA5RA6Or- (CH)2)n5O(CH2)n6RA5(ii) a The amino group and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyanoOxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 5, characterized in that ring C is selected from
Figure FDA0003245287810000041
Figure FDA0003245287810000042
RcSelected from deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, oxetanyl, -CH2F、-CH2CH2F、-CH2OH、-CH2CH2OH、-C(CH3)2OH、-CH2CN、-CH2OCH3、-CH2CH2OCH3、-OCH3、-OCH2CH3、-C(O)CH3、-N(CH3)2、-N(CH2CH3)2、-N(CH2CH3)CH3、-N(CH3)C(O)CH3、-S(O)2CH3Or
Figure FDA0003245287810000043
7. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003245287810000044
Figure FDA0003245287810000051
Figure FDA0003245287810000061
Figure FDA0003245287810000071
Figure FDA0003245287810000081
Figure FDA0003245287810000091
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (la), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.
9. Use of a compound of general formula (la), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for the preparation of a MEK inhibitor, an EGFR inhibitor and EGFR mab, or a combination thereof.
10. Use of a compound of general formula (la), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of a cancer-related disease; wherein the cancer is lung cancer.
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CN114057771A (en) * 2020-12-03 2022-02-18 北京鞍石生物科技有限责任公司 Macrocyclic compound and preparation method and application thereof
WO2022204544A1 (en) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Macrocyclic egfr inhibitors for the treatment of cancer
WO2022242712A1 (en) * 2021-05-21 2022-11-24 深圳市塔吉瑞生物医药有限公司 Substituted macrocyclic compound, composition comprising compound, and use thereof
WO2023001069A1 (en) * 2021-07-23 2023-01-26 南京明德新药研发有限公司 Macrocyclic amide compounds and application thereof
WO2023098730A1 (en) * 2021-11-30 2023-06-08 正大天晴药业集团股份有限公司 Compound containing cycloalkyl or haloalkyl
WO2023216871A1 (en) * 2022-05-09 2023-11-16 元启(苏州)生物制药有限公司 Egfr inhibitor and application thereof
WO2024016986A1 (en) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Macrocyclic compound and pharmaceutical composition and use thereof
WO2024017358A1 (en) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Macrocyclic compound, pharmaceutical composition thereof, and use thereof
WO2024046221A1 (en) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Egfr inhibitors and uses thereof

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114057771A (en) * 2020-12-03 2022-02-18 北京鞍石生物科技有限责任公司 Macrocyclic compound and preparation method and application thereof
CN114057771B (en) * 2020-12-03 2023-10-03 北京鞍石生物科技有限责任公司 Macrocyclic compounds, their preparation and use
WO2022204544A1 (en) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Macrocyclic egfr inhibitors for the treatment of cancer
WO2022242712A1 (en) * 2021-05-21 2022-11-24 深圳市塔吉瑞生物医药有限公司 Substituted macrocyclic compound, composition comprising compound, and use thereof
WO2023001069A1 (en) * 2021-07-23 2023-01-26 南京明德新药研发有限公司 Macrocyclic amide compounds and application thereof
WO2023098730A1 (en) * 2021-11-30 2023-06-08 正大天晴药业集团股份有限公司 Compound containing cycloalkyl or haloalkyl
WO2023216871A1 (en) * 2022-05-09 2023-11-16 元启(苏州)生物制药有限公司 Egfr inhibitor and application thereof
WO2024016986A1 (en) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Macrocyclic compound and pharmaceutical composition and use thereof
WO2024017358A1 (en) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Macrocyclic compound, pharmaceutical composition thereof, and use thereof
WO2024046221A1 (en) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Egfr inhibitors and uses thereof

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