CN111777593A

CN111777593A - Novel compounds as inhibitors of rearrangement kinase during transfection

Info

Publication number: CN111777593A
Application number: CN201910265375.3A
Authority: CN
Inventors: 孔祥龙; 周超; 郑之祥
Original assignee: Nanjing Innocare Pharma Tech Co ltd
Current assignee: Nanjing Innocare Pharma Tech Co ltd
Priority date: 2019-04-03
Filing date: 2019-04-03
Publication date: 2020-10-16

Abstract

The present invention relates to compounds, pharmaceutical compositions containing them, as well as processes for their preparation and their use as inhibitors of rearrangement-during-transfection (RET) kinase. The compound is a compound shown as a formula (I), or pharmaceutically acceptable salt, prodrug, solvate, polymorph, isomer and stable isotope derivative thereof. The invention also relates to the use of said compounds for the treatment or prevention of related diseases mediated by RET kinases, such as tumours, and to methods of using them for the treatment of said diseases.

Description

Novel compounds as inhibitors of rearrangement kinase during transfection

Technical Field

The present invention relates to compounds, pharmaceutical compositions containing them and their use as inhibitors of rearrangement-during-transfection (RET) kinase. More particularly, the present invention provides novel compounds that are inhibitors of RET kinase, pharmaceutical compositions containing such compounds and methods of using such compounds to treat or prevent related diseases mediated by RET kinase, such as tumors. The invention also relates to a process for the preparation of the compounds described below.

Background

The RET (secreted protein) gene encodes the membrane receptor tyrosine kinase RET protein, belongs to the cadherin superfamily, is expressed in cells of neural crest origin and urogenital system, and plays a vital role in the neural crest development process. RET kinases activate Ras/MAPK, PI3K/Akt, JNK, p38, and PLCg pathway signaling cascades by binding to one of the four glial cell-derived neurotrophic factor (GDNF) family receptor a (gfra) proteins to form a complex that homodimerizes, phosphorylates, and activates its tyrosine kinase activity (Mulligan, l.m. Nature Reviews Cancer, 2014, 14, 173-186).

Oncogenic, activating mutations (mainly rearrangements or fusions at the cytogenetic level) of the RET gene can amplify signaling cascades independent of ligand binding, while also activating other signaling cascades (such as STAT3 and STAT 1) reactions, promoting tumorigenesis. RET is a cancer driver gene and mutations can lead to overactivity of the RET signaling pathway, leading to uncontrolled cell growth and thus to tumor formation.

The RET protein mutation types mainly comprise fusion mutation with genes such as KIF5B, TRIM33, CCDC6 and NCOA4, and point mutation at a M918T locus, common RET mutation mainly occurs in various cancer types such as thyroid cancer, non-small cell lung cancer and the like, although the incidence rate of the RET mutation in the non-small cell lung cancer is only 2%, the base number of patients in China is very large, the patients are not rare in clinical treatment, RET fusion is more common in young patients, particularly young patients with non-smoking lung adenocarcinoma, and the incidence rate is as high as 7% -17%.

In the treatment of the prior RET positive patients, the targeted drug is usually cabozantinib or vandetanib, and the two drugs are used as multi-target tyrosine kinase inhibitors and have poor selectivity on RET. Cabozantinib was studied on 26 small samples of RET therapy with a primary endpoint ORR of 28% and a median time for PFS of 5.5 months, whereas 19 patients on treatment were dose adjusted for adverse effects and the toxic response was very significant. Development of selective RET kinase inhibitors may reduce adverse reactions caused by off-target and improve therapeutic efficacy. Currently, there are mainly developed selective RET kinase inhibitors Blu-667(US20170121312a1, subcbian, v.; Gainor, j.f.;et al. CancerDiscovery.2018,8(7),836-849.) and Loxo-292 (WO 2018071454A1, WO2018071447A1, WO2017011776A1, Subbiah, V.; Busaidy, N.L.;et al. Annal Oncolology, 2018,29 (8),1869-1876.). There remains a need for new selective RET kinase inhibitors that reduce adverse effects caused by off-target and improve therapeutic efficacy.

Disclosure of Invention

The invention aims to provide a compound which can be used as a selective RET kinase inhibitor and is shown as a formula (I), an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof:

，

wherein

X is selected from CR¹Or N; preferably selected from CH or N;

Y¹selected from the group consisting of CR²Or N; preferably selected from CH or N;

Y²selected from the group consisting of CR³Or N; preferably selected from CH or N; most preferably CH;

Y³selected from the group consisting of CR⁴Or N; preferably selected from CH or N;

Y⁴selected from the group consisting of CR⁵Or N; preferably selected from CH or N; most preferably CH;

provided that Y is¹、Y²、Y³And Y⁴Up to 2N;

one of the following conditions is preferred: y is¹Is CR²，Y²Is CR³，Y³Is CR⁴And Y⁴Is CR⁵(ii) a Y alone¹Or Y²Is N; y is¹And Y²Are both N; or Y¹And Y³Are both N;

further preferred is one of the following conditions: y is¹、Y²、Y³And Y⁴Are all CH; y is¹Is N, Y²、Y³And Y⁴Are all CH; or Y¹And Y³Is N, Y²And Y⁴Is CH;

R¹、R²、R³、R⁴、R⁵each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O OR S, aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR⁶、-NR⁷R⁸、-OC(O)NR⁷R⁸、-C(O)OR⁶、-C(O)NR⁷R⁸、-NR⁹C(O)R⁶、-NR⁹C(O)NR⁷R⁸、-S(O)mR⁶、-NR⁹S(O)mR⁶、-SR⁶、-S(O)mNR⁷R⁸、-NR⁹S(O)mNR⁷R⁸Wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl, alkenyl, alkynyl is optionally substituted by one OR more substituents selected from the group consisting of halogen, cyano, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O OR S, -OR¹⁰、-NR¹¹R¹², -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²、-S(O)mR¹⁰、-NR¹³S(O)mR¹⁰、-SR¹⁰、-S(O)mNR¹¹R¹²、-NR¹³S(O)mNR¹¹R¹²Substituted with the substituent(s); preferably selected from hydrogen, halogen, cyano, C1-C6 alkyl; further preferably selected from hydrogen, halogen, C1-C4 alkyl; most preferably selected from hydrogen;

a is selected from hydrogen, halogen, cyano, C1-C8 alkyl, -OR¹⁴、-NR¹⁵R¹⁶(ii) a Preferably selected from hydrogen, halogen, C1-C6 alkyl, -OR¹⁴、-NR¹⁵R¹⁶(ii) a Further preferably selected from hydrogen, halogen, C1-C6 alkyl; even further preferably selected from hydrogen, halogen, C1-C4 alkyl; most preferably selected from hydrogen;

wherein R is¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, aryl, heteroaryl; preferably selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S; further preferably selected from hydrogen, C1-C4 alkyl;

b is selected from hydrogen, halogen, cyano, C1-C4 alkyl, -OR¹⁷Optionally substituted Ar¹(ii) a Preferably selected from hydrogen, C1-C4 alkyl, -OR¹⁷Optionally substituted Ar¹(ii) a Most preferably selected from the group consisting of-OR¹⁷Optionally substituted Ar¹；

Wherein R is¹⁷Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S; preferably selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or a 3-6 membered heterocyclyl containing 1-2 heteroatoms each independently selected from N or O; most preferably selected from C1-C4 alkyl;

Ar¹selected from 5 or 6 membered heteroaryl containing 1 to 3 ring heteroatoms, wherein each of said heteroatoms is independently selected from N, O, S; preferably 5 or 6 membered heteroaryl containing two ring N atoms; further preferred is a 5-membered heteroaryl group containing two ring N atoms; even further preferred from

Or

；Ar¹Optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O OR S, aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR⁶、-NR⁷R⁸、-OC(O)NR⁷R⁸、-C(O)OR⁶、-C(O)R⁶、-C(O)NR⁷R⁸、-NR⁹C(O)R⁶、-NR⁹C(O)NR⁷R⁸、-S(O)mR⁶、-NR⁹S(O)mR⁶、-SR⁶、-S(O)mNR⁷R⁸、-NR⁹S(O)mNR⁷R⁸Wherein said alkyl, cyclyl, heterocyclyl, aryl OR heteroaryl, alkenyl, alkynyl is optionally substituted with one OR more substituents selected from halogen, cyano, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O OR S, -OR¹⁰、-NR¹¹R¹², -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²、-S(O)mR¹⁰、-NR¹³S(O)mR¹⁰、-SR¹⁰、-S(O)mNR¹¹R¹²、-NR¹³S(O)mNR¹¹R¹²Substituted with the substituent(s);

R¹⁸selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, aryl, heteroaryl; preferably selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; further preferably selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms each independently selected from N, O or S;

d is a compound containing4-8 membered heterocyclylene, 6-8 membered bridged heterocyclyl or 7-11 membered spiroheterocyclylene of 1-3 heteroatoms selected from N or O; preferably 4-6-membered heterocyclylene containing two N, 6-7-membered bridged heterocyclylene containing two N, or 7-11-membered spiroheterocyclylene containing two N; most preferably

、

、

；

Wherein the ring is optionally substituted with one or two substituents each independently selected from halogen, cyano, C1-C8 alkyl, hydroxy, wherein the alkyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy;

e is selected from the group consisting of hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S,

、

Aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OR⁶、-NR⁷R⁸、-OC(O)NR⁷R⁸、-C(O)OR⁶、-C(O)R^x、-C(O)NR⁷R⁸、-NR⁹C(O)R⁶、-NR⁹C(O)NR⁷R⁸、-S(O)mR⁶、-NR⁹S(O)mR⁶、-SR⁶、-S(O)mNR⁷R⁸、-NR⁹S(O)mNR⁷R⁸(ii) a Preferably selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x(ii) a Most preferably selected from hydrogen,

、

、-C(O)R^x；

Said alkyl, cyclyl, heterocyclyl, aryl OR heteroaryl, alkenyl, alkynyl being optionally substituted by one OR more groups selected from hydroxy, halogen, cyano, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O OR S, -OR¹⁰、-NR¹¹R¹²、-OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²、-S(O)mR¹⁰、-NR¹³S(O)mR¹⁰、-SR¹⁰、-S(O)mNR¹¹R¹²、-NR¹³S(O)mNR¹¹R¹²Substituted with the substituent(s);

R²¹and R²²Each independently selected from aryl or heteroaryl; said aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²、-S(O)_mR¹⁰、-NR¹³S(O)_mR¹⁰、-SR¹⁰、-S(O)_mNR¹¹R¹²、-NR¹³S(O)_mNR¹¹R¹²Substituted with the substituent(s); preferably R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl, wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -O (CH)₂)_pR^y、-NR^vR^wSubstituted with the substituent(s);

R^xselected from hydrogen, C1-C8 alkoxy, C1-C8 alkyl optionally substituted with a 3-8 membered heterocyclyl or hydroxy group containing a heteroatom selected from N, O or S, amino optionally mono-or di-substituted with C1-C8 alkyl, C3-C8 cycloalkyl; preferably selected from hydrogen, C1-C6 alkoxy, C1-C6 alkyl optionally substituted with a 3-8 membered heterocyclyl or hydroxy group containing 1-2 heteroatoms selected from N, O or S, amino optionally mono-or di-substituted with C1-C6 alkyl, C3-C6 cycloalkyl; most preferably selected from hydrogen, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with a 3-6 membered heterocyclyl or hydroxy group containing 1-2 heteroatoms selected from N, O or S, amino optionally mono-or di-substituted with C1-C6 alkyl, C3-C6 cycloalkyl;

ry is selected from hydrogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, and amino optionally mono-or di-substituted with C1-C8 alkyl; preferably selected from hydrogen, hydroxy, and amino optionally mono-or di-substituted with C1-C6 alkyl;

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl; preferably selected from hydrogen, C1-C6 alkyl; most preferably selected from hydrogen, C1-C4 alkyl;

R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl optionally substituted with halogen or hydroxy, C1-C8 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, heteroaryl or aryl, C2-C8 alkenyl, C2-C8 alkynyl; or

R¹⁹And R²⁰To carbon to which they are attached, or R²³And R²⁴Together with the carbon to which they are attached may form a C3-C8 cycloalkyl group; preferably C3-C6 cycloalkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

In a preferred embodiment of the present invention, there is provided a compound represented by formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof,

wherein

X is selected from CR¹Or N;

Y¹selected from the group consisting of CR²Or N;

Y²selected from the group consisting of CR³Or N;

Y³selected from the group consisting of CR⁴Or N;

Y⁴selected from the group consisting of CR⁵Or N;

provided that Y is¹、 Y²、Y³And Y⁴Up to 2N;

R¹、R²、R³、R⁴、R⁵each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl;

a is selected from hydrogen, halogen, cyano, C1-C8 alkyl, -OR¹⁴、-NR¹⁵R¹⁶；

Wherein R is¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, aryl, heteroaryl;

b is selected from hydrogen, halogen, cyano, C1-C4 alkyl, -OR¹⁷Optionally substituted Ar¹；

Wherein R is¹⁷Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S;

Ar¹selected from 5 or 6 membered heteroaryl containing 1 to 3 ring heteroatoms, wherein each ring heteroatom is independently selected from N, O or S; the 5-or 6-membered heteroaryl group may be optionally substituted with one or more substituents each independently selected from halogen, cyano, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OC (O) NR (O)⁷R⁸、-C(O)OR⁶、-C(O)NR⁷R⁸、-NR⁹C(O)R⁶、-NR⁹C(O)NR⁷R⁸、-S(O)mR⁶、-NR⁹S(O)mR⁶、-SR⁶、-S(O)mNR⁷R⁸、-NR⁹S(O)mNR⁷R⁸Wherein said alkyl, cyclyl, heterocyclyl, aryl or heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -OC (O) NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

d is selected from 4-8 membered heterocyclylene, 6-8 membered bridged heterocyclylene or 7-11 membered spiroheterocyclylene containing 1-3 heteroatoms selected from N or O, wherein the ring is optionally substituted with one or two substituents each independently selected from halogen, cyano, C1-C8 alkyl, hydroxy;

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^xselected from hydrogen, C1-C8 alkoxy, C1-C8 alkyl optionally substituted with a 3-8 membered heterocyclyl or hydroxy group containing a heteroatom selected from N, O or S, amino optionally mono-or di-substituted with C1-C8 alkyl, C3-C8 cycloalkyl;

ry is selected from hydrogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, and amino optionally mono-or di-substituted with C1-C8 alkyl;

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

R¹⁹And R²⁰To carbon to which they are attached, or R²³And R²⁴Together with the carbon to which they are attached may form a C3-C8 cycloalkyl group;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

In a further preferred embodiment of the present invention, there is provided a compound represented by the formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof,

wherein

X is selected from CR¹Or N;

Y¹selected from the group consisting of CR²Or N;

Y²selected from the group consisting of CR³Or N;

Y³selected from the group consisting of CR⁴Or N;

Y⁴selected from the group consisting of CR⁵Or N;

with the proviso that one of the following: y is¹Is CR²，Y²Is CR³，Y³Is CR⁴And Y⁴Is CR⁵(ii) a Y alone¹Or Y²Is N; y is¹And Y²Are both N; or Y¹And Y³Are both N;

R¹、R²、R³、R⁴、R⁵each independently selected from hydrogen, halogen, C1-C4 alkyl;

R¹⁷Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S;

d is selected from two N4-6-membered heterocyclylene groups, two N6-7-membered bridged heterocyclylene groups or two N7-11-membered spiroheterocyclylene groups, and is optionally substituted on the ring by one or two substituents independently selected from hydrogen, halogen, cyano, C1-C8 alkyl and hydroxyl; wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy;

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkane optionally substituted with halogen or hydroxyC1-C8 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, heteroaryl or aryl, C2-C8 alkenyl, C2-C8 alkynyl; or

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

wherein

X is selected from CR¹Or N;

Y¹selected from the group consisting of CR²Or N;

Y²selected from the group consisting of CR³Or N;

Y³selected from the group consisting of CR⁴Or N;

Y⁴selected from the group consisting of CR⁵Or N;

R¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, aryl, heteroaryl;

b is selected from hydrogen, C1-C4 alkyl, -OR¹⁷And optionally substituted Ar¹；

Ar¹selected from 5-or 6-membered heteroaryl containing 2 ring N atoms, which 5-or 6-membered heteroaryl is optionally substituted by one or more substituents, each independently selected from halogen, cyano, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OC (O) NR⁷R⁸、-C(O)OR⁶、-C(O)NR⁷R⁸、-NR⁹C(O)R⁶、-NR⁹C(O)NR⁷R⁸、-S(O)mR⁶、-NR⁹S(O)mR⁶、-SR⁶、-S(O)mNR⁷R⁸、-NR⁹S(O)mNR⁷R⁸Wherein said alkyl, cyclyl, heterocyclyl, aryl or heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -OC (O) NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

d is selected from

、

、

And the ring is optionally substituted by one or two substituents independently selected from halogen, cyano, C1-C8 alkyl and hydroxyl; wherein the C1-C8 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy;

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

In another preferred embodiment of the present invention, there is provided a compound represented by formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

with the proviso that one of the following: y is¹、Y²、Y³And Y⁴Are all CH; y is¹Is N, Y²、Y³And Y⁴Are all CH; or Y¹And Y³Is N, Y²And Y⁴Is CH;

a is selected from hydrogen, halogen, C1-C6 alkyl, -OR¹⁴、-NR¹⁵R¹⁶；

R¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S;

Ar¹selected from the group consisting of 5-membered heteroaryl having 2 ring N atoms, said 5-membered heteroaryl being optionally substituted by one or more substituents, each independently selected from the group consisting of halogen, cyano, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl having a heteroatom selected from N, O or S, aryl, heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl, -OC (O) NR⁷R⁸、-C(O)OR⁶、-C(O)NR⁷R⁸、-NR⁹C(O)R⁶、-NR⁹C(O)NR⁷R⁸、-S(O)mR⁶、-NR⁹S(O)mR⁶、-SR⁶、-S(O)mNR⁷R⁸、-NR⁹S(O)mNR⁷R⁸Wherein said alkyl, cyclyl, heterocyclyl, aryl or heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -OC (O) NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

d is selected from

、

、

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

In still another preferred embodiment of the present invention, there is provided a compound represented by formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C6 alkyl, -OR¹⁴、-NR¹⁵R¹⁶；

R¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, C1-C4 alkyl;

b is selected from hydrogen, C1-C4 alkyl, -OR¹⁷And optionally substituted on the ring by one or two substituents of halogen, cyano, C1-C8 alkyl, hydroxy C1-C8 alkyl and C3-C8 cycloalkyl

Or

；

R¹⁸selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, aryl, heteroaryl;

d is selected from

、

、

And the ring is optionally substituted by one or two substituents independently selected from F, C1-C8 alkyl and hydroxyl; wherein the C1-C8 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy;

e is selected from hydrogen, halogen, C1-C6 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl; wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^v、R^weach independently selected from hydrogen, C1-C6 alkyl;

R¹⁰、R¹¹、R¹²、R¹³、R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl optionally substituted with halogen or hydroxy, C1-C8 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, heteroaryl or aryl, C2-C8 alkenyl, C2-C8 alkynyl; or

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

In still another preferred embodiment of the present invention, there is provided a compound represented by the formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C6 alkyl;

b is selected from hydrogen, C1-C4 alkyl, -OR¹⁷And optionally C1-C6 alkyl or halogen substituted on the ring

Or

；

d is selected from the following three heterocyclic rings

、

、

；

E is selected from hydrogen, halogen, C1-C4 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl, wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted with one or more substituents selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^v、R^weach independently selected from hydrogen, C1-C6 alkyl;

R¹⁰、R¹¹、R¹²、R¹³、R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl optionally substituted with halogen or hydroxy, C1-C8 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, heteroaryl or arylC2-C8 alkenyl, C2-C8 alkynyl; or

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

In a further preferred embodiment of the present invention, there is provided a compound represented by formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C4 alkyl;

Or

；

R¹⁷Selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or a 3-6 membered heterocyclyl containing 1-2 heteroatoms each independently selected from N and O;

R¹⁸selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms each independently selected from N or O;

d is selected from the following three heterocyclic rings

、

、

；

E is selected from hydrogen,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl, wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, 3-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^wSubstituted with the substituent(s);

R^xselected from hydrogen, C1-C6 alkoxy, C1-C6 alkyl optionally substituted with a 3-8 membered heterocyclyl or hydroxy group containing 1-2 heteroatoms selected from N, O or S, amino optionally mono-or di-substituted with C1-C6 alkyl, C3-C6 cycloalkyl;

R^yselected from hydrogen, hydroxy, and amino optionally mono-or di-substituted with C1-C6 alkyl;

R^v、R^weach independently selected from hydrogen, C1-C6 alkyl;

R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, C1-C6 alkyl optionally substituted with halogen or hydroxy, hydroxy; or

R¹⁹And R²⁰To carbon or R attached thereto²³And R²⁴Together with the carbon to which they are attached may form a C3-C8 cycloalkyl group;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is hydrogen;

b is selected from C1-C4 alkoxy, optionally substituted on the ring by C1-C4 alkyl

Or

，

R¹⁸Selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N or O;

d is selected from the following three heterocyclic rings

、

、

；

E is selected from hydrogen,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl, wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted with one or more substituents selected from halogen, C1-C4 alkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^wSubstituted with the substituent(s);

R^xselected from hydrogen, C1-C4 alkoxy, C1-C4 alkyl optionally substituted with a 3-6 membered heterocyclyl or hydroxy group containing 1-2 heteroatoms selected from N, O or S, amino optionally mono-or di-substituted with C1-C6 alkyl, C3-C6 cycloalkyl;

R^v、R^weach independently selected from hydrogen, C1-C4 alkyl;

R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, C1-C4 alkyl optionally substituted with halogen or hydroxy, hydroxy; or

R¹⁹And R²⁰To carbon or R attached thereto²³And R²⁴Together with the carbon to which they are attached may form a C3-C6 cycloalkyl group;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

In a still further preferred embodiment of the present invention, there is provided a compound represented by the general formula (I), an isomer, a prodrug, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof, wherein the compound is:

the present invention further relates to a pharmaceutical composition comprising a compound of formula (I) as described in any one of the embodiments of the present invention or an isomer, prodrug, stable isotopic derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

The invention also relates to the use of a compound of formula (I) as described in any one of the embodiments or an isomer, prodrug, stable isotopic derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by RET kinase, such as cancer, in particular hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

The invention also relates to the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of a disease mediated by RET kinase, such as cancer, in particular hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

The present invention also relates to a method for treating or preventing a RET kinase-mediated disease (e.g. a tumor, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to the invention.

Another aspect of the present invention relates to a compound according to any one of the embodiments of the present invention, or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a RET kinase-mediated disease, such as a tumor, in particular, hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as described in any one of the embodiments of the present invention or an isomer, prodrug, stable isotope derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, excipient for use in the treatment or prevention of RET kinase mediated diseases, such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

Another aspect of the present invention relates to a compound represented by formula (I) as described in any one of the embodiments of the present invention for treating and/or preventing diseases such as tumor, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Said tumor is especially hematological malignancy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

Typical compounds of the invention include, but are not limited to:

and isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof.

According to the present invention, the drug may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized formulations, injections.

The pharmaceutical preparations of the present invention may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1g, preferably from 1 mg to 700 mg, particularly preferably from 5mg to 300 mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparations may be administered in dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods well known in the pharmaceutical art.

The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants using all methods known in the pharmaceutical art.

Preparation process

The invention also provides a method for preparing the compound.

Scheme 1

R²⁶Selected from C1-C4 alkyl;

X¹and X²Each independently selected from halogen, such as chlorine, bromine, iodine, and the like;

the first step is as follows:

adding a base (e.g., sodium bicarbonate) to a solvent selected from 1, 4-dioxane, tetrahydrofuran, water, etc., and reacting at room temperature or under oil bath heating (20 to 50 ℃), thereby obtaining a compound (II);

the second step is that:

adding the compound (II) and R in an anhydrous solvent (such as anhydrous toluene) under an inert gas (such as nitrogen or argon) atmosphere²⁶OH alcohol, azido diphenyl phosphate and alkali (such as anhydrous triethylamine) are heated in an oil bath, and Curtius rearrangement reaction is carried out at the temperature of 70-90 ℃ to obtain a compound (III);

the third step:

adding the compound (II) and R in an anhydrous solvent (such as anhydrous toluene) under an inert gas (such as nitrogen or argon) atmosphere²⁶OH alcohol, azido diphenyl phosphate and alkali (such as anhydrous triethylamine) are heated in an oil bath, and Curtius rearrangement reaction is carried out at the temperature of 60-80 ℃ to obtain a compound (IV);

the fourth step:

adding a compound (III) and an alkali (such as hexamethylenetetramine) into a solvent (such as trifluoroacetic acid) and the like), heating in an oil bath, and keeping the temperature at 80-100 ℃ for carrying out a ring-closing reaction to obtain a compound (V);

the fifth step:

dissolving the compound (V) in a solvent (such as ethanol and water), adding an alkali (such as potassium hydroxide), heating in an oil bath, stirring at 70-90 ℃ for 1-3 hours, adding an oxidant (such as potassium ferricyanide) and continuously stirring at the same temperature for 2-6 hours to perform hydrolysis and oxidation reaction to obtain a compound (VI);

and a sixth step:

dissolving a compound (VI) in 5-15% dilute hydrochloric acid, slowly adding a sodium nitrite aqueous solution under an ice bath cooling condition, heating in an oil bath, keeping the temperature at 40-50 ℃, stirring for 1-3 hours, then dropwise adding an aqueous solution of a halogenated salt (such as potassium iodide) and continuously stirring for 1-3 hours at 40-50 ℃, and carrying out amino diazotization and halogenation reaction to obtain a compound (IX);

the seventh step:

a compound of (A), (B), (CVII) lithium diisopropylamide withN,NAdding dimethylformamide into a solvent (such as tetrahydrofuran and the like), and performing formylation reaction at-78 ℃ to obtain a compound (VIII);

eighth step:

adding the compound (VIII), potassium carbonate and formamidine acetate into a solvent (such as anhydrous acetonitrile and the like), heating in an oil bath, and performing substitution ring closure reaction at 100-120 ℃ to obtain a compound (IX).

Scheme 2

X¹、X²、X³Each independently selected from halogen, such as chlorine, bromine, iodine, and the like;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

PG¹selected from tert-butyloxycarbonyl;

R⁷、R⁸each independently selected from hydrogen, C1-C4 alkyl;

Ar¹selected from optionally C1-C6 alkyl or halogen substituted

Or

；

Wherein R is¹⁸Selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N or O;

d is selected from the following three heterocyclic rings

、

、

；

R^v、R^weach independently selected from hydrogen, C1-C4 alkyl;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

The first step is as follows:

suzuki coupling reaction when X¹Is chlorine, X²In the case of bromine or iodine, the starting material (IX), an N-substituted pyrazole boronic acid ester (or boronic acid) is dissolved in a solvent (dioxane and water)Using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using sodium carbonate or potassium carbonate as a base, heating in an oil bath under the protection of nitrogen or argon, and stirring at the temperature of 70-100 ℃ for 2-12 hours to obtain a compound (X);

the second step is that:

suzuki coupling reaction, the starting material (X), boric acid ester (or boric acid) (XI) are dissolved in solvent (dioxane or boric acid)N,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium carbonate or potassium phosphate as a base, heating in an oil bath or microwave under the protection of nitrogen or argon, and stirring at 90-140 ℃ for 1-12 hours to obtain a compound (XIV);

the third step:

preparation of pinacol borate ester: dissolving a starting material (X) and pinacol ester with boric acid in a solvent (such as dioxane), using a palladium complex such as 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride as a catalyst or tris (dibenzylideneacetone) dipalladium as a catalyst, adding a phosphine ligand such as tricyclohexylphosphine, using potassium acetate as an alkali, heating in an oil bath under the protection of nitrogen or argon, and stirring at the temperature of 60-100 ℃ for 2-12 hours to obtain a compound (XII);

the fourth step:

suzuki coupling reaction by dissolving the starting material (XII), heterocyclic aryl halide (XIII) in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium carbonate or potassium phosphate as a base, heating in an oil bath or microwave under the protection of nitrogen or argon, and stirring at 90-140 ℃ for 1-12 hours to obtain a compound (XIV);

the fifth step:

PG¹deprotection of, for example, t-butyloxycarbonyl using trifluoroacetic acid or hydrochloric acid as the acid; in a solvent such as dichloromethane or dioxane, the reaction is carried out at the temperature of 0-25 ℃; reacting to obtain a compound (XV);

and a sixth step:

reduction and ammoniation reaction: dissolving an initial raw material (XV) and a corresponding aldehyde or ketone in a solvent (methanol, ethanol, tetrahydrofuran or the like), stirring at room temperature for 5-30 minutes for condensation, adding a reducing agent such as sodium triacetoxyborohydride or the like, and continuously stirring at room temperature for 6-24 hours to obtain a compound (XVI);

the seventh step:

amide synthesis reaction: dissolving the starting material (XV) and corresponding acyl chloride in a solvent (such as tetrahydrofuran, dichloromethane and the like), adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; or by dissolving the starting material (XV) with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.), a condensing agent such as 2- (7-benzotriazole oxide) -is addedN,N,N',N' -tetramethylurea hexafluorophosphate and the like, adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; compound (XVII) is obtained;

eighth step:

synthesis reaction of urea: the starting materials (XV) are dissolved with the corresponding isocyanates in a solvent (tetrahydrofuran, dichloromethane orN,N-dimethylformamide, etc.), stirring at room temperature for 20 minutes to 18 hours; or by reacting the starting materials (XV) withN,N' -carbonyldiimidazole orN,N' -carbonylbis (1,2, 4-triazole) and the like in a solvent (tetrahydrofuran, dichloromethane orN,N-dimethylformamide and the like), heating at room temperature or oil bath (20-70 ℃) and stirring for 20 minutes, adding corresponding amine, heating at room temperature or oil bath (20-70 ℃) and stirring for 20 minutes-18 hours for condensation; compound (XVIII) is obtained;

the ninth step:

amide synthesis reaction: the starting material (XV) is dissolved with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.), a condensing agent such as 2- (7-benzotriazole oxide) -is addedN,N,N',N' -tetramethylurea hexafluorophosphate and the like, adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; to obtain compound (XIX);

the tenth step:

suzuki coupling reaction when X¹Is bromineOr iodine, X²When the compound is chlorine, dissolving a starting material (IX), boric acid ester (or boric acid) (XI) in a solvent (dioxane and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using sodium carbonate or potassium carbonate as an alkali, heating in an oil bath under the protection of nitrogen or argon, and stirring at 50-100 ℃ for 2-12 hours to obtain a compound (XX);

the eleventh step:

suzuki coupling reaction, dissolving the starting material (X), N-substituted pyrazole boric acid ester (or boric acid) in a solvent (dioxane or boric acid)N,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium carbonate or potassium phosphate as a base, heating in an oil bath or microwave under the protection of nitrogen or argon, and stirring at 90-140 ℃ for 1-12 hours to obtain a compound (XIV).

And (3) a flow path:

first step of

Dissolving 8-aminoquinoline (XXI) in dichloromethane, sequentially adding triethylamine and benzoyl chloride, and reacting at 25 ℃ for 1 hour to obtain the compoundN- (quinolin-8-yl) benzamide XXII;

second step of

Will be provided withN- (Quinolin-8-Yl) benzamide XXII is added to the water in portionsNBromosuccinimide, and reacting at 25 ℃ for 15 hours. To obtainN- (5-bromoquinolin-8-yl) benzamide XXIII;

the third step

Will be provided withN- (5-bromoquinolin-8-yl) benzamide XXIII is dissolved in ethanol, 1M ethanol solution of sodium hydroxide is added with stirring at 25 ℃ and stirred for 15 hours at 85 ℃ to obtain 5-bromo-8-aminoquinoline XXIV;

the fourth step

Dissolving 5-bromo-8-aminoquinoline XXIV in acetonitrile, addingN-chlorosuccinimide, stirred at 80 ℃ for 6 hours, giving 5-bromo-7-chloro-8-aminoquinoline XXV;

the fifth step

5-bromo-7-chloro-8-aminoquinoline XXV is added to water, concentrated sulfuric acid is added dropwise at 0 ℃ until most of the solid disappears, 4M aqueous sodium nitrite solution is added dropwise when the solution turns orange red, the mixture is stirred at 0 ℃ for 0.5 hour, finally the mixture is added dropwise to hypophosphorous acid, the mixture is stirred at 65 ℃ for 4 hours, and the mixture is poured into saturated aqueous sodium hydroxide solution (3L) to obtain 5-bromo-7-chloroquinoline XXVI.

Scheme 4

X³Selected from halogens such as chlorine, bromine, iodine, and the like;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

PG¹selected from tert-butyloxycarbonyl;

R⁷、R⁸each independently selected from hydrogen, C1-C4 alkyl;

d is selected from the following three heterocyclic rings

、

、

；

R^v、R^weach independently selected from hydrogen, C1-C4 alkyl;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

The first step is as follows:

suzuki coupling reaction, namely dissolving a starting material (XXVI), boric acid ester (or boric acid) (XI) in a solvent (dioxane and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using sodium carbonate or potassium carbonate as alkali, heating in an oil bath under the protection of nitrogen or argon, and stirring at 50-100 ℃ for 2-12 hours to obtain a compound (XXVII);

the second step is that:

suzuki coupling reaction, starting material (XXVII), N-substituted pyrazole boric acid ester (or boric acid) are dissolved in solvent (dioxane or boric acid)N,NDimethylformamide with water), using palladium complexes such as tetrakis (triphenylphosphine)) Palladium is used as a catalyst, potassium carbonate or potassium phosphate is used as alkali, under the protection of nitrogen or argon, oil bath or microwave heating is carried out, and the mixture is stirred for 1 to 12 hours at the temperature of 90 to 140 ℃ to obtain a compound (XXVIII);

the third step:

PG¹deprotection of, for example, t-butyloxycarbonyl using trifluoroacetic acid or hydrochloric acid as the acid; in a solvent such as dichloromethane or dioxane, the reaction is carried out at the temperature of 0-25 ℃; the reaction gives compound (XXIX);

the fourth step:

reduction and ammoniation reaction: dissolving an initial raw material (XXIX) and a corresponding aldehyde or ketone in a solvent (methanol, ethanol, tetrahydrofuran or the like), stirring at room temperature for 5-30 minutes for condensation, adding a reducing agent such as sodium triacetoxyborohydride or the like, and continuously stirring at room temperature for 6-24 hours to obtain a compound (XXX);

the fifth step:

amide synthesis reaction: dissolving the starting material (XXIX) and corresponding acyl chloride in a solvent (such as tetrahydrofuran, dichloromethane and the like), adding a base such as triethylamine and the like, and stirring at room temperature for 20 minutes to 18 hours for condensation; or by dissolving the starting material (XXIX) with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.), a condensing agent such as 2- (7-benzotriazole oxide) -is addedN,N,N',N' -tetramethylurea hexafluorophosphate and the like, adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; to obtain compound (XXXI);

and a sixth step:

synthesis reaction of urea: the starting materials (XXIX) are dissolved with the corresponding isocyanates in a solvent (tetrahydrofuran, dichloromethane orN,N-dimethylformamide, etc.), stirring at room temperature for 20 minutes to 18 hours; or reacting the starting material (XXIX) withN,N' -carbonyldiimidazole orN,N' -carbonylbis (1,2, 4-triazole) and the like in a solvent (tetrahydrofuran, dichloromethane orN,N-dimethylformamide and the like), heating at room temperature or oil bath (20-70 ℃) and stirring for 20 minutes, adding corresponding amine, heating at room temperature or oil bath (20-70 ℃) and stirringStirring for 20 minutes to 18 hours for condensation; to obtain compound (XXXII);

the seventh step:

amide synthesis reaction: the starting material (XXIX) is dissolved with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.), a condensing agent such as 2- (7-benzotriazole oxide) -is addedN,N,N',N' -tetramethylurea hexafluorophosphate and the like, adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; to obtain compound (XXXIII);

eighth step:

dissolving XXVI and pinacolorthoborate in tetrahydrofuran, adding potassium acetate and 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride, bubbling the system with nitrogen for 10 minutes, stirring for 2 hours at the temperature of 60 ℃ under the protection of nitrogen, and directly performing rotary evaporation to obtain 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (XXXIV), wherein a crude product is used for the next step without purification;

the ninth step:

suzuki coupling reaction, starting material 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (XXXIV), heterocyclic aryl halide (XIII) are dissolved in solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium carbonate or potassium phosphate as a base, heating in an oil bath or microwave under the protection of nitrogen or argon, and stirring at 90-140 ℃ for 1-12 hours to obtain the compound (XXVIII).

Scheme 5

X³Selected from halogens such as chlorine, bromine, iodine, and the like;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

PG¹selected from tert-butyloxycarbonyl;

R⁷、R⁸each independently selected from hydrogen, C1-C4 alkyl;

d is selected from the following three heterocyclic rings

、

、

；

R^v、R^weach independently selected from hydrogen, C1-C4 alkyl;

R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, C1-C4 alkyl optionally substituted with halogen or hydroxy, hydroxy; or R¹⁹And R²⁰To carbon or R attached thereto²³And R²⁴Together with the carbon to which they are attached mayTo form a C3-C6 cycloalkyl group;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

The first step is as follows:

dissolving the compound 2-chloro-6-fluoro-4-hydroxybenzaldehyde (XXXV) in acetonitrile, adding potassium carbonate and iodoethane under stirring, and stirring at 50 deg.C for 2 hr to obtain 2-chloro-4-ethoxy-6-fluorobenzaldehyde (XXXVI)

The second step is that:

dissolving 2-chloro-4-ethoxy-6-fluorobenzaldehyde (XXXVI) in dimethyl sulfoxide, adding potassium carbonate and formamidine acetate under stirring, and stirring at 110 deg.C for 6 hr to obtain 5-chloro-7-ethoxyquinazoline (XXXVII)

The third step:

suzuki coupling reaction by dissolving the starting material 5-chloro-7-ethoxyquinazoline (XXXVII), boronic acid ester (or boronic acid) (XI) in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium carbonate or potassium phosphate as a base, heating in an oil bath or microwave under the protection of nitrogen or argon, and stirring at 90-140 ℃ for 1-12 hours to obtain a compound (XXXVIII);

the fourth step:

preparation of pinacol borate ester: dissolving 5-chloro-7-ethoxyquinazoline (XXXVII) as a starting material and pinacol ester of boronic acid in a solvent (such as dioxane), adding a phosphine ligand such as tricyclohexylphosphine by using a palladium complex such as 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride as a catalyst or tris (dibenzylideneacetone) dipalladium as a catalyst, adding potassium acetate as a base, heating in an oil bath under the protection of nitrogen or argon, and stirring at 60-100 ℃ for 2-12 hours to obtain a compound (XXXIX);

the fifth step:

suzuki coupling reaction starting material (XXXIX), heterocyclic aryl halide (XIII) are dissolved in solvent (dioxane orN,NDimethylformamide with water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as catalyst, potassium carbonate or phosphate as base, under nitrogenOr heating in oil bath or microwave under the protection of argon, and stirring at 90-140 ℃ for 1-12 hours to obtain a compound (XXXVIII);

and a sixth step:

PG¹deprotection of, for example, t-butyloxycarbonyl using trifluoroacetic acid or hydrochloric acid as the acid; in a solvent such as dichloromethane or dioxane, the reaction is carried out at the temperature of 0-25 ℃; reaction to give compound (XXXX);

the seventh step:

reduction and ammoniation reaction: dissolving a starting material (XXXX) and a corresponding aldehyde or ketone in a solvent (methanol, ethanol, tetrahydrofuran or the like), stirring at room temperature for 5-30 minutes for condensation, adding a reducing agent such as sodium triacetoxyborohydride or the like, and continuously stirring at room temperature for 6-24 hours to obtain a compound (XXXXI);

eighth step:

amide synthesis reaction: dissolving a starting material (XXXX) and corresponding acyl chloride in a solvent (such as tetrahydrofuran, dichloromethane and the like), adding a base such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; or by dissolving the starting material (XXXX) with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.), a condensing agent such as 2- (7-benzotriazole oxide) -is addedN,N,N',N' -tetramethylurea hexafluorophosphate and the like, adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; to obtain compound (XXXXII);

the ninth step:

synthesis reaction of urea: the starting materials (XXXX) are dissolved with the corresponding isocyanates in a solvent (tetrahydrofuran, dichloromethane orN,N-dimethylformamide, etc.), stirring at room temperature for 20 minutes to 18 hours; or by reacting the starting materials (XV) withN,N' -carbonyldiimidazole orN,N' -carbonylbis (1,2, 4-triazole) and the like in a solvent (tetrahydrofuran, dichloromethane orN,N-dimethylformamide and the like), heating at room temperature or oil bath (20-70 ℃) and stirring for 20 minutes, adding corresponding amine, heating at room temperature or oil bath (20-70 ℃) and stirring for 20 minutes-18 hours for condensation; to obtain compound (XXXIII);

the tenth step:

amide synthesis reaction: the starting material (XXXX) is dissolved with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.), a condensing agent such as 2- (7-benzotriazole oxide) -is addedN,N,N',N' -tetramethylurea hexafluorophosphate and the like, adding alkali such as triethylamine and the like, stirring at room temperature for 20 minutes to 18 hours, and condensing; compound (XXXXIV) can be obtained.

Detailed Description

Definition of

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

The expression "Cx-Cy" as used in the present invention denotes the range of the number of carbon atoms, wherein x and y are both integers, e.g. C3-C8 cycloalkyl denotes cycloalkyl having 3-8 carbon atoms, -C0-C2 alkyl denotes alkyl having 0-2 carbon atoms, wherein-C0 alkyl denotes a single chemical bond.

In the present invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 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, and the various branched chain isomers thereof, and the like. Alkyl groups may be optionally substituted or unsubstituted.

In the present invention, the term "alkenyl" refers to straight-chain, branched-chain hydrocarbon groups containing at least 1 carbon-carbon double bond, which may include 2 to 20 carbon atoms, for example, straight-chain and branched-chain groups of 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Wherein 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, may be present. The term "C2-C4 alkenyl" refers to alkenyl groups having 2-4 carbon atoms. Including ethenyl, propenyl, butenyl, buten-2-yl, 2-methylbutenyl. The alkenyl group may be optionally substituted or unsubstituted.

In the present invention, the term "alkynyl" refers to a straight, branched hydrocarbon group containing at least 1 carbon-carbon triple bond, which may include 2 to 20 carbon atoms, for example, straight and branched groups of 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Wherein 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond, may be present. The term "C2-C4 alkynyl" refers to alkynyl groups having 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, butynyl, and butyn-2-yl, 3-methylbutynyl. The alkynyl group may be optionally substituted or unsubstituted.

In the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, or may be a 3, 4,5, 6-membered ring. Non-limiting examples of monocyclic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.

In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S (O) m (wherein m is an integer from 0 to 2), but not including 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 a heterocyclyl ring comprising 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably a 5-or 6-membered ring of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. The heterocyclic group may be optionally substituted or unsubstituted.

In the present invention, the term "heterocyclylene" refers to a substituted or unsubstituted heterocyclic group having a core of two terminal monovalent groups resulting from the removal of one hydrogen atom from each of the two terminal atoms; the heterocyclyl group has the meaning as described hereinbefore. Non-limiting examples of "heterocyclylene" include pyrrolidinylene, piperidinyl, piperazinyl, morpholinylene, and the like.

In the present invention, the term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group which shares one atom (referred to as the spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of s (o) m (wherein m is an integer of 0 to 2), the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably, the single spiro cyclic group and the double spiro cyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclic group. Non-limiting examples of spiro ring groups include

. The spiro ring group may be optionally substituted or unsubstituted.

In the present invention, the term "spiroheterocyclylene" refers to a substituted or unsubstituted spiroheterocyclyl having a core of two terminal monovalent groups resulting from the removal of one hydrogen atom from each of the two terminal atoms; the spiroheterocyclyl group has the meaning described hereinbefore. Non-limiting examples of "spiroheterocyclylene" include

。

In the present invention, the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or a heteroatom of s (o) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include

。

The 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:

and the like. The fused heterocyclic group may be optionally substituted or unsubstituted.

In the present invention, the term "fused heterocyclic group" means a substituted or unsubstituted fused heterocyclic group having a core of two terminal monovalent groups, which is produced by removing one hydrogen atom from each of two terminal atoms; the fused heterocyclic group has the meaning as described hereinbefore. Non-limiting examples of "fused heterocyclic" radicals include

。

In the present invention, 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, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cyclyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

，

the aryl group may be substituted or unsubstituted.

In the present invention, the term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably 5 to 10 membered. More preferably heteroaryl is 5-or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, and the like, which heteroaryl ring may be fused to an aryl, heterocyclyl, or cyclic ring wherein the ring linked together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

。

heteroaryl groups may be optionally substituted or unsubstituted.

In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

In the present invention, the term "cyano" refers to — CN.

In the context of the present invention, the term "heteroalkyl" refers to a stable straight or branched chain hydrocarbon radical consisting of the indicated number of carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, wherein the nitrogen and sulfur atoms may optionally be oxidized, the nitrogen atom may optionally be quaternized, the heteroatom oxygen, nitrogen and sulfur may be located at any internal position of the heteroalkyl radical, and may also be located at a position where the alkyl radical is attached to the remainder of the molecule, and two or more heteroatoms may be independent or continuous.

In the present invention, the term "alkoxy" refers to an alkyl group attached through an oxygen bridge, including alkyloxy, cycloalkyloxy, and heterocycloalkyloxy. The alkyl, heterocycloalkyl and cycloalkyl radicals have the meanings indicated above.

In the present invention, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, including hydroxyalkyl, hydroxycycloalkyl, and hydroxyheterocycloalkyl groups. The alkyl, heterocycloalkyl and cycloalkyl radicals have the meanings indicated above.

In the present invention, the term "haloalkyl" refers to an alkyl substituent wherein at least one hydrogen is replaced by a halogen group. Typical halogen groups include chlorine, fluorine, bromine and iodine. Examples of the haloalkyl group include a fluoromethyl group, a fluoroethyl group, a chloromethyl group, a chloroethyl group, a 1-bromoethyl group, a difluoromethyl group, a trifluoromethyl group and a1, 1, 1-trifluoroethyl group. It will be appreciated that if a substituent is substituted with more than one halo group, those halo groups may be the same or different (unless otherwise specified).

In the present invention, the term "amino" refers to "-NH₂”。

In the present invention, "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.

In the present invention, "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that 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.

Such substituents include, but are not limited to, the various groups described previously.

The compounds claimed in the present invention include not only the compounds themselves, but also isomers, prodrugs, stable isotopic derivatives of the compounds or pharmaceutically acceptable salts thereof.

The term "pharmaceutical composition" as used herein means a mixture containing one or more of the isomers, prodrugs, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, of the compounds of the present invention and other chemical components. Other components such as pharmaceutically acceptable carriers, diluents 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.

The term "comprising" as used in the specification includes "consisting of ….

The "room temperature" of the invention means 15-30 ℃.

The "stable isotope derivative" of the present invention includes: an isotopically substituted derivative in which any hydrogen atom in formula I is substituted with 1 to 5 deuterium atoms, an isotopically substituted derivative in which any carbon atom in formula I is substituted with 1 to 3 carbon 14 atoms, or an isotopically substituted derivative in which any oxygen atom in formula I is substituted with 1 to 3 oxygen 18 atoms.

The "pharmaceutically acceptable salts" of the present invention are described in Berge, et al, "pharmaceutical acceptable salts",J. Pharm. Sci.,66, 1-19(1977), which is discussed and is apparent to the pharmaceutical chemist, is substantially non-toxic and provides desirable pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.

The pharmaceutically acceptable salts of the present invention can be synthesized by a general chemical method.

In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric amount or an excess of the acid (inorganic or organic) or base in a suitable solvent or solvent composition.

By "prodrug" as used herein is meant a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.

The "isomer" of the present invention means a tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, etc. of the compound of the formula (I) of the present invention. All such isomers, including stereoisomers, geometric isomers, are included in the present invention. The geometric isomers include cis-trans isomers.

The present invention includes any polymorph as well as any hydrate or other solvate of the compound or salt thereof.

In the present invention, the term "patient" generally refers to a mammal, especially a human.

In the present invention, the term "tumor" includes benign tumors and malignant tumors, such as cancers.

In the present invention, the term "cancer" includes various tumors mediated by RET kinase, including but not limited to hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

In the present invention, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention effective to treat or prevent the associated disease mediated by RET kinase.

Examples

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The structures of all compounds of the invention can be determined by nuclear magnetic resonance¹H NMR) and/or mass spectrometric detection (MS).

¹H NMR chemical shifts () are recorded in PPM (parts per million). NMR was performed by a Bruker AVANCE III-400MHz spectrometer. Suitable solvents are selected from deuterated chloroform（CDCl₃) Deuterated methanol (CD)₃OD), deuterated dimethyl sulfoxide (DMSO-d ₆) Etc., tetramethylsilane as an internal standard (TMS).

Low resolution Mass Spectrometry (MS) was determined by an Agilent 1260 HPLC/6120 mass spectrometer using an Agilent ZORBAXXDB-C18, 4.6X 50 mm, 3.5 μm.

Gradient elution conditions one: 0: 95% solvent A1 and 5% solvent B1,1-2:5% solvent A1 and 95% solvent B1; 2.01-2.50, 95% solvent A1 and 5% solvent B1. The percentages are volume percentages of a solvent based on the total solvent volume. Solvent a 1: 0.01% aqueous formic acid; solvent B1: 0.01% formic acid in acetonitrile; the percentages are the volume percent of solute in solution.

The thin-layer silica gel plate is a tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. The column chromatography generally uses 100-200 or 200-300 mesh silica gel of the yellow sea of the tobacco pipe as a carrier.

Preparative liquid chromatography (prep-HPLC) using Waters SQD2 mass spectrometry directed to a high pressure liquid chromatography separator, XBridge-C18; 30X 150 mm preparation column, 5 μm;

the method comprises the following steps: acetonitrile-water (0.2% formic acid), flow rate 25 mL/min; the second method comprises the following steps: acetonitrile-water (0.8% ammonium bicarbonate) flow rate 25 mL/min;

known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Shanghai Bidi medicine, Shanghai Aladdin chemistry, Shanghai Michelle chemistry, Bailingwei chemistry, Annai and chemistry.

In the examples, unless otherwise specified, all solvents used in the reaction were anhydrous solvents, wherein the anhydrous tetrahydrofuran was commercially available tetrahydrofuran, sodium block was used as a water scavenger, benzophenone was used as an indicator, the solution was refluxed to bluish purple under argon protection, collected by distillation, stored at room temperature under argon protection, and other anhydrous solvents were purchased from ann nai and chemistry and carbofuran chemistry, and all the transfer and use of the anhydrous solvents were performed under argon protection unless otherwise specified.

In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, unless otherwise specified, the reaction temperature was room temperature and the temperature range was 15 deg.C℃ -30 ℃。

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.

Example 1

4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

First step of

4-bromo-2-chloro-6-fluorobenzaldehyde

Anhydrous tetrahydrofuran (400 mL) was added to a 500 mL three-necked flask, lithium diisopropylamide (0.26 mol, 130 mL, 2M in THF) was added at-78 deg.C, and a solution of compound 1-bromo-3-chloro-5-fluorobenzene 1a (25.00 g, 0.12 mol) in anhydrous tetrahydrofuran (100 mL) was slowly added dropwise. Stirring at-78 ℃ for 1 hourDropwise addition ofN,N-dimethylformamide (17.50 g, 0.24 mol), -78 ℃ stirring for 2 hours, quenching with saturated ammonium chloride solution at low temperature, desolventizing under reduced pressure to remove part of the solvent, extracting with dichloromethane (200 mL × 3), washing the organic phase with saturated brine (500 mL), water (500 mL), drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and desolventizing under reduced pressure to obtain the crude product the residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 100:0-19: 1) to give the desired product 4-bromo-2-chloro-6-fluorobenzene (meth) aldehyde 1b (14.50 g, red solid) with a yield of 51%.

Second step of

7-bromo-5-chloroquinazoline

Compound 4-bromo-2-chloro-6-fluorobenzaldehyde 1b (10.00 g, 0.04 mol), cimetidine acetate (10.90 g, 0.11 mol), potassium carbonate (29.00 g, 0.21 mol) and anhydrous acetonitrile (400 mL) were mixed, and stirred at 110 ℃ for 16 hours. Cooling to room temperature, suction filtration, vacuum desolventizing the filtrate to give a crude product, and purifying the residue by flash column chromatography (petroleum ether: ethyl acetate = 100: 0-12: 1) to give the desired product 7-bromo-5-chloroquinazoline 1c (3.20 g, yellow solid) in yield: 31 percent.

MS m/z (ESI): 243&245 [M + 1]；

The third step

5-chloro-7- (1-methyl-1)H-pyrazol-4-yl) quinazolines

The compound 7-bromo-5-chloroquinazoline 1c (3.20 g, 0.013 mol), methylpyrazole borate (4.20 g, 0.02 mol), potassium carbonate (5.50 g, 0.04 mol), tetrakis (triphenylphosphine) palladium (1.50 g, 1.30 mmol), 1, 4-dioxane (40 mL) and water (10 mL) were mixed, replaced three times with argon and stirred at 90 ℃ for 5 hours. Cooling to room temperature, desolventizing under reduced pressure to obtain crude product, and purifying the residue by flash column chromatography (dichloromethane: methanol = 100:0-30: 1) to obtain the target product 5-chloro-7- (1-methyl-1)H-pyrazol-4-yl) quinazoline 1d (1.20 g, yellow solid), yield: 37 percent.

MS m/z (ESI): 245&247 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.68 (s, 1H), 9.33 (s, 1H), 8.00 (s, 1H), 7.94(s, 1H), 7.87-7.76 (m, 2H), 4.01 (s, 3H)。

The fourth step

The compound 5-chloro-7- (1-methyl-1)H-pyrazol-4-yl) quinazoline 1d (0.53 g, 2.20 mmol), 1-methyl-1HPyrazole-4-boronic acid pinacol ester (0.94 g, 2.40 mmol), potassium carbonate (0.91 g, 6.60 mmol), tetrakis (triphenylphosphine) palladium (0.25 g, 0.22 mmol), 1, 4-dioxane (10 mL) and water (2 mL) were mixed and 120 mL of a sealed tube was added, replaced with argon three times, and stirred at 140 ℃ for 2 hours. Cooling to room temperature, desolventizing under reduced pressure to give crude product, and purifying the residue by flash column chromatography (dichloromethane: methanol = 100:0-30: 1) to give 4- (5- (7- (1-methyl-1) as the target productH-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 1 (0.80 g, yellow solid), yield: 78 percent.

MS m/z(ESI): 472 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.37 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.74-7.54 (m, 2H), 6.90-6.74 (m, 1H),4.01 (s, 3H), 3.74-3.53 (m, 8H), 1.51 (s, 9H)。

Example 2

7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline

Compound 4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 1 (0.50 g, 1.06 mmol) was dissolved in methanol (5 mL), methanol hydrochloride (80 mmol, 4M, 20 mL) was added, stirring was performed at room temperature for 3 hours, desolventization under reduced pressure was performed to obtain a crude product, and the residue was dissolved in water (20 mL)Adding saturated aqueous sodium bicarbonate solution to pH = 8-9, extracting with dichloromethane (20 mL × 5), drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and desolventizing under reduced pressure to obtain the target compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (0.37 g, yellow solid), yield: 94 percent.

MS m/z(ESI): 372 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.75-7.62 (m, 2H), 6.91-6.68 (m, 1H),4.01 (s, 3H), 3.87-3.71 (m, 2H), 3.71-3.59 (m, 4H), 3.16-3.00 (m, 2H) 。

Example 3

5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (10 mg, 0.02 mmol), m-fluorobenzaldehyde (5 mg, 0.04 mmol) and methanol (1 mL) were mixed, and stirred at room temperature for 5 minutes. Then, sodium triacetoxyborohydride (11 mg, 0.04 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated ammonium chloride (2 mL), extracted with ethyl acetate (5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give a crude product, which was purified with preparative silica gel plate (dichloromethane: methanol = 12: 1) to give the desired product 5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline 3 (7 mg, yellow solid), yield: 56 percent.

MS m/z (ESI): 480 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.29 (s, 1H), 8.36 (s, 1H), 8.20(s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.36-7.30(m, 1H), 7.18-713 (m, 2H), 7.03-7.01 (m, 1H), 6.81 (d,J= 8.8 Hz, 1H), 4.01(s, 3H), 3.75-3.70 (m, 6H), 2.73 (t,J= 4.4 Hz, 4H)。

Synthetic procedures for examples 4 to 20 reference was made to example 3 wherein m-fluorobenzaldehyde was replaced by a different aldehyde.

Example 4

5- (6- (4-Benzylpiperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 462 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.28 (s, 1H), 8.35 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.70-7.59 (m, 2H), 7.48-7.35 (m, 5H),6.88-6.76 (m, 1H), 4.01 (s, 3H), 3.86-3.73 (m, 6H), 2.83-2.73 (m, 4H)。

Example 5

5- (6- (4- (2-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 2.0Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.64 (d,J=2.0 Hz, 1H), 7.48 (d,J= 7.2 Hz, 1H), 7.30 (d,J= 7.2 Hz, 1H), 7.09 (d,J=7.2 Hz, 1H), 6.92 (d,J= 8.4 Hz, 1H), 6.79 (d,J= 8.8 Hz, 1H), 4.01 (s,3H), 3.86 (s, 3H), 3.81-3.79 (m, 6H), 2.81-2.79 (m, 4H)。

Example 6

5- (6- (4- (3-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-Methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.0Hz, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.64 (d,J=2.4 Hz, 1H), 7.29 (s, 1H), 6.98-6.96 (m, 2H), 6.85-6.79 (m, 2H), 4.01 (s,3H), 3.84 (s, 3H), 3.73-3.71 (m, 4H), 3.49 (s, 2H), 2.65-2.63 (m, 4H)。

Example 7

5- (6- (4- (4-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 480 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.65 (d,J= 8.8 Hz,1H),7.38-7.35 (m, 2H), 7.07-7.03 (m, 2H), 6.81 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H),3.74-3.72 (m, 4H), 3.49 (s, 2H), 2.67-2.65 (m, 4H)。

Example 8

5- (6- (4- (2-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 480 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.35 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 7.45 (t,J=7.6 Hz, 1H), 7.30-7.28 (m, 1H), 7.15 (t,J= 7.2 Hz, 1H), 7.07 (t,J= 8.8Hz, 1H), 6.80 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H), 3.73-3.71 (m, 6H), 2.70-2.68(m, 4H)。

Example 9

5- (6- (4- (4-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.05(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67-7.64 (m, 2H),7.31 (d,J= 8.4 Hz,2H), 6.90 (d,J= 8.4 Hz, 2H), 6.79 (d,J= 8.8 Hz, 1H), 4.00 (s, 3H), 3.82(s, 3H), 3.72-3.70 (m, 4H), 3.58 (s, 2H), 2.65-2.63 (m, 4H)。

Example 10

5- (6- (4- ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z(ESI): 493 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.31(s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.76-7.61 (m, 2H), 7.54-7.41 (m, 1H), 7.25-7.20 (m, 1H), 6.88-6.75 (m, 1H), 4.01 (s, 3H), 3.89 (s,3H), 3.85 (s, 2H), 3.80 –3.70 (m, 4H), 2.89-2.74 (m, 4H)。

Example 11

5- (6- (4- ((5-fluoropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-Pyrazol-4-yl) quinazolines

MS m/z (ESI): 481 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 8.36(s, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.72-7.62 (m, 2H), 7.61-7.48 (m, 1H), 7.47-7.34 (m, 1H), 6.89-6.77(m, 1H), 4.01 (s, 3H), 3.87-3.68(m, 6H), 2.81-2.64 (m, 4H)。

Example 12

5- (6- (4- (2, 6-difluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 498 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.28 (s, 1H), 8.34 (s, 1H), 8.05(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.75-7.60 (m, 2H), 7.37-7.28 (m, 1H),7.00-6.89 (m, 2H), 6.84-6.70 (m, 1H), 4.00 (s, 3H), 3.88 (s, 2H), 3.79-3.62(m, 4H), 2.85-2.66 (s, 4H)。

Example 13

N,N-dimethyl-4- ((4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) methyl) aniline

MS m/z (ESI): 505 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.41-9.22 (m, 2H), 8.48-8.27 (m, 2H), 8.08 (s,1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.77-7.61 (m, 2H), 7.25-7.15 (m, 1H), 6.90-6.70 (m, 1H), 6.76-6.63 (m, 2H), 4.01 (s, 3H), 3.97-3.74 (m, 6H), 3.08-2.86(m, 10H)。

Example 14

7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) quinazoline

MS m/z (ESI): 463 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.70-8.57 (m, 1H),8.36 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.83-7.75 (m, 1H),7.72-7.65 (m, 2H), 7.65-7.58 (m, 1H), 7.41-7.29 (m, 1H), 6.88-6.77(m, 1H),4.04-3.92 (m, 5H), 3.90-3.78 (m, 4H), 3.04-2.86 (m, 4H)。

Example 15

5- (6- (4- (3, 5-difluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 498 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.69-7.64 (m, 2H), 6.95-6.93 (m, 2H), 6.81 (d,J= 8.8 Hz, 1H), 6.75-6.70 (m, 1H), 4.01 (s, 3H),3.81-3.75 (m, 3H), 3.67-3.62 (m, 3H), 2.63-2.60 (m, 4H)。

Example 16

5- (6- (4- (2-chlorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 496&498 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.72-7.63 (m, 2H), 7.60-7.57 (m, 1H), 7.40-7.38 (m, 1H), 7.31-7.20 (m, 2H), 6.81 (d,J= 8.8 Hz, 1H),4.01 (s, 3H), 3.81-3.70 (m, 6H), 2.75-2.71 (m, 4H)。

Example 17

5- (6- (4- (2-fluoro-4-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 510 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 2.4Hz, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67-7.63 (m, 2H), 7.10-7.04 (m, 1H), 6.79 (d,J= 9.2 Hz, 1H), 6.65 (d,J= 2.4 Hz, 1H), 6.63 (d,J= 2.4 Hz, 1H), 4.00 (s, 3H), 3.75-3.69 (m, 6H), 2.73-2.70 (m, 4H), 3.22 (s,3H)。

Example 18

5- (6- (4- (3-fluoro-4-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 510 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.68-7.64 (m, 2H), 7.16-7.13 (m, 1H), 7.10-7.05 (m, 1H), 6.96-6.91 (m, 1H), 6.81 (d,J= 8.8 Hz, 1H),4.01 (s, 3H), 3.75-3.69 (m, 6H), 2.73-2.70 (m, 4H), 3.22 (s, 3H)。

Example 19

5- (6- (4- (4-chloro) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 496&498 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.68-7.65 (m, 2H), 7.39-7.34 (m, 4H), 6.81 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H), 3.79-3.76 (m, 4H), 3.71(s, 2H), 2.74-2.65 (m, 4H) 。

Example 20

5- (6- (4- (3-chloro) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 496&498 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.67-7.64 (m, 2H), 7.40(s, 1H), 7.31-7.28 (m, 3H), 6.81 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H), 3.70-3.67(m, 4H), 3.57 (s, 2H), 2.68-2.59 (m, 4H) 。

Example 21

(4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) (phenyl) methanone

First step of

3-bromo-5- ((n-propoxycarbonyl) amino) benzoic acid

Compound 3-amino-5-bromobenzoic acid 21a (100.00 g, 0.46 mol), sodium bicarbonate (78.00 g, 0.93 mol), water (400 mL) and 1, 4-dioxane (400 mL) were added to a 2L single-neck flask, followed by cooling in an ice-water bath to 0 ℃ and the addition of n-propyl chloroformate (63.00 g, 0.51 mol) dropwise. After 1 hour at 0 ℃ and then to room temperature for 2 hours, the reaction was completed as detected by HPLC, neutralized to pH = 5 with dilute hydrochloric acid (2M), the aqueous phase was extracted with ethyl acetate (500 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was directly used in the next step, whereby the target product, 3-bromo-5- ((n-propoxycarbonyl) amino) benzoic acid 21b (128.00 g, brown solid), was obtained in yield: 91 percent.

MS m/z (ESI):302&304 [M + 1]；

Second step of

Di-n-propyl (5-bromo-1, 3-phenylene) dicarbamate

The compound 3-bromo-5- ((n-propoxycarbonyl) amino) benzoic acid 21b (42.00 g, 0.14 mol), diphenylphosphorylazide (45 mL, 0.21 mol), triethylamine (29 mL, 0.21 mol) and toluene (700 mL) were added to a 1L three-necked flask, followed by heating to 80 ℃ for 4 hours. Cooled to room temperature, added with n-propanol (15.6 mL, 0.21 mol) and reheated to 80 ℃ for overnight reaction, checked by HPLC for completion of the reaction, directly spun off, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1), thereby obtaining the target product group of di-n-propyl (5-bromo-1, 3-phenylene) dicarbamate 21c (45.00 g, yellow solid), yield: 89 percent.

MS m/z (ESI): 359&361 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 7.46 (s, 1H), 7.30 (d,J= 1.8 Hz, 1H), 6.68(s, 1H), 4.12 (t,J= 6.8 Hz, 4H), 1.72-1.67 (m, 4H), 0.97 (t,J= 7.4 Hz,6H)。

The third step

5-bromo-7- ((n-propoxycarbonyl) amino) quinazoline-1 (2)H) -carboxylic acid n-propyl ester

Adding the compound (5-bromo-1, 3-phenylene) dicarbamic acid di-n-propyl ester 21c (135.00 g, 0.38 mol), hexamethylenetetramine (158.00 g, 1.13 mol) and trifluoroacetic acid (1L) into a 2L three-necked flask, heating to 90 ℃ for 2 hours, LCMS detecting that the reaction is finished, cooling to room temperature, directly spinning, quenching the residue with sodium bicarbonate aqueous solution until the pH of the aqueous phase is about 7, extracting with ethyl acetate (500 mL × 3), concentrating the organic phase by drying, and directly using the residue in the next step to obtain the target product 5-bromo-7- ((n-propyl-n-propyl)Oxycarbonyl) amino) quinazoline-1 (2)H) N-propyl carboxylate 21d (173.00 g, yellow oil), crude.

MS m/z (ESI)：398&400 [M + 1]；

The fourth step

5-bromoquinazolin-7-amines

Reacting the compound 5-bromo-7- ((propoxycarbonyl) amino) quinazoline-1 (2)H) Propyl carboxylate 21d (crude, 10.00 g, yellow oil) and potassium hydroxide (16.80 g, 0.30 mol) were dissolved in ethanol (60 mL) and water (50 mL) and reacted at 80 ℃ for 2 hours, and then potassium ferricyanide (25.00 g, 75 mmol) was added thereto and reacted at 80 ℃ for 4 hours. The reaction was filtered and the filter cake was washed with dichloromethane: methanol (10: 1, 150 mL) wash, combine filtrates, separate layers, and add the aqueous phase to dichloromethane: methanol (10: 1, 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the desired product 5-bromoquinazolin-7-amine 21e (3.30 g, brown solid), crude product.

MS m/z(ESI): 224&226 [M + 1]；

¹H NMR (400 MHz, DMSO-d ₆) 9.09 (s, 1H), 8.92 (s, 1H), 7.41 (d,J= 1.8Hz, 1H), 6.80 (d,J= 1.8 Hz, 1H), 6.69 (s, 2H)。

The fifth step

5-bromo-7-iodoquinazolines

The compound 5-bromoquinazolin-7-amine 21e (3.30 g, 14.73 mmol) was dissolved in 10% aqueous hydrochloric acid (60 mL), an aqueous solution (10 mL) of sodium nitrite (3.05 g, 44.20 mmol) was added dropwise in an ice bath, and after the mixture was stirred at low temperature for 30 minutes, an aqueous solution (20 mL) of potassium iodide (12.22 g, 73.65 mmol) was added dropwise thereto, followed by reaction at 40 ℃ for 2 hours. The reaction was quenched with saturated aqueous sodium sulfite (20 mL) and neutralized with aqueous sodium bicarbonate (20 mL) to pH 8. The mixture was extracted with ethyl acetate (150 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the desired product 5-bromo-7-iodoquinazoline 21f (3.70 g, yellow solid) in 75% yield.

MS m/z (ESI): 335&337 [M + 1]；

The sixth step

5-bromo-7- (1-methyl-1)H-pyrazol-4-yl) quinazolines

Dissolving the compound 5-bromo-7-iodoquinazoline 21f (3.70 g, 11.04 mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (2.30 g, 11.04 mmol) and potassium carbonate (3.05 g, 22.08 mmol) in dioxane (60 mL) and water (10 mL), adding tetrakis (triphenylphosphine) palladium (0.64 g, 0.55 mmol) under nitrogen protection, reacting the mixture at 65 ℃ for 12 hours, diluting the reaction solution with ethyl acetate (300 mL), washing with water (50 mL × 3), drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, desolventizing under reduced pressure, and purifying the residue with silica gel column chromatography (petroleum ether: ethyl acetate 3:2) to obtain the target product 5-bromo-7- (1-methyl-1H-pyrazol-4-yl) quinazoline 21g (2.30 g, yellow solid). Yield: 72 percent.

MS m/z (ESI): 289&291 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.61 (s, 1H), 9.31 (s, 1H), 8.04-8.03 (m, 1H),8.02-8.01 (m, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 4.01(s, 3H)。

Seventh step

The synthesis was carried out in the fourth operating step according to example 1, using 5-bromo-7- (1-methyl-1)H-pyrazol-4-yl) quinazoline 21g substituted 5-chloro-7- (1-methyl-1HThe (E) -pyrazol-4-yl) quinazoline 1d obtains a target product 4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 1.

Eighth step

Synthesized according to the procedure of example 2 to obtain the desired product 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2.

The ninth step

(4-(5-(7-(1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) (phenyl) methanone

Reacting the compound 7- (1-methyl-1)HPyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (8 mg, 0.02 mmol), benzoic acid (5 mg, 0.04 mmol), triethylamine (4 mg, 0.04 mmol), 2- (7-oxybenzotriazole) -N,N,N',N'Tetramethyluronium hexafluorophosphate (16 mg, 0.04 mmol) was dissolved inN,NDimethylformamide (0.5 mL), stirring for 30 min, the mixture was quenched with saturated sodium carbonate solution (10 mL), extracted with dichloromethane (10 mL × 3), the organic phase was desolventized under reduced pressure, and the residue was purified by preparative liquid phase (Xbridge-C18; 30X 150 mm preparative column, 5 μm; CH-18; 30X 150 mm preparative column; 5 μm; CH)₃CN/H₂O20% -40%) to obtain the target product (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) (phenyl) methanone 21 (3.3 mg, white solid), yield: 32 percent.

MS m/z (ESI): 476 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.29 (s, 1H), 8.38 (s, 1H), 8.08(s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.74-7.63 (m, 2H), 7.51-7.42 (m, 5H),6.90-6.80 (m, 1H), 4.01 (s, 3H), 3.98-3.86 (m, 2H), 3.81-3.57 (m, 6H)。

The synthetic procedures of examples 22 to 42 refer to the procedure of example 21, wherein benzoic acid is replaced by a different acid.

Example 22

(2, 6-difluorophenyl) (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) methanone

MS m/z (ESI): 512 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.29 (s, 1H), 8.37 (s, 1H), 8.07(s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.76-7.62 (m, 2H), 7.46-7.34 (m, 1H),7.08-6.94 (m, 2H), 6.94-6.77 (m, 1H), 4.14-3.87 (m, 5H), 3.86-3.66 (m, 4H),3.58-3.42 (m, 2H)。

Example 23

(4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) (1-phenylcyclopropyl) methanone

MS m/z (ESI): 516 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.32 (s, 1H), 9.28 (s, 1H), 8.33 (s, 1H), 8.06(s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.67-7.63 (m, 2H), 7.35-7.31 (m, 2H),7.24-7.22 (m, 3H), 6.76 (d,J= 8.8 Hz, 1H), 4.07 (s, 3H), 3.83-3.39 (m, 8H),1.80-1.78 (m, 4H)。

Example 24

2- (5-Fluoropyridin-2-yl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 509 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.29 (s, 1H), 8.40 (s, 1H), 8.36(s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.70-7.67 (m, 2H), 7.42-7.40 (m, 2H), 6.81 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H), 4.00 (s, 2H), 3.83-3.81(m, 4H), 3.67-3.65 (m, 4H)。

Example 25

2- (5-Chloropyridin-2-yl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 525&527 [M+1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.29 (s, 1H), 8.51 (d,J= 2.4Hz, 1H), 8.37 (d,J= 2.4 Hz, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H),7.70-7.65 (m, 3H), 7.36 (d,J= 8.4 Hz, 1H), 6.81 (d,J= 8.8 Hz, 1H), 4.01(s, 3H), 3.98 (s, 2H), 3.68-3.63 (m, 8H)。

Example 26

2- (2-fluorophenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 508 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.29 (s, 1H), 8.36 (d,J= 2.0Hz, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.69 (d,J= 2.4 Hz, 1H),7.68-7.67 (m, 1H), 7.35 (d,J= 7.6 Hz, 1H), 7.30-7.25 (m, 1H), 7.15-7.06 (m,2H), 6.80 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H), 3.86-3.83 (m, 2H), 3.82 (s, 2H),3.68-3.64 (m, 6H)。

Example 27

2- (3-fluorophenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 508 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 2.0Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.70-7.67 (m, 1H), 7.67(d,J= 1.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.08-6.96 (m, 3H), 6.80 (d,J= 8.8Hz, 1H), 4.01 (s, 3H), 3.86-3.83 (m, 2H), 3.81 (s, 2H), 3.66-3.62 (m, 6H)。

Example 28

(4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) (pyridin-2-yl) methanones

MS m/z (ESI): 477 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.29 (s, 1H), 8.64 (d,J= 4.0Hz, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.88-7.84 (m, 2H), 7.77-7.66 (m, 3H), 7.43-7.37 (m, 1H), 6.85 (d,J= 8.6 Hz, 1H), 4.02-3.99 (m, 5H),3.85-3.82 (m, 4H), 3.78-3.84 (s, 2H)。

Example 29

3-methyl-1- (4- (5- (7- (1-methylpyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) butan-1-one

MS m/z (ESI): 456 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.29 (s, 1H), 8.38 (d,J= 2.0Hz, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.71-7.67 (m, 2H), 6.83(d,J= 8.6 Hz, 1H), 4.01 (s, 3H), 3.84-3.81 (m, 2H), 3.77-3.74 (m, 2H),3.68-3.63 (m, 4H), 2.30-2.28 (m, 3H), 1.02 (d,J= 6.6 Hz, 6H)。

Example 30

3-hydroxy-1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylpropan-1-one

MS m/z (ESI): 520 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.31 (s, 1H), 9.27 (s, 1H), 8.32 (s, 1H), 8.06(s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.68-7.64 (m, 2H), 7.34-7.26 (m, 5H),6.73 (d,J= 8.8 Hz, 1H), 4.10-4.01 (m, 3H), 4.00 (s, 3H), 3.81-3.77 (m, 2H),3.65-3.63 (m, 4H), 3.49-3.46 (m, 2H) , 2.98-2.95 (m, 1H)。

Example 31

(R) -2-hydroxy-3-methyl-1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) butan-1-one

MS m/z (ESI): 472 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.29 (s, 1H), 8.38 (s, 1H), 8.08(s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.73-7.68 (m, 2H), 6.84 (d,J= 8.8 Hz,1H), 4.34-4.32 (m, 1H), 4.01 (s, 3H), 3.78-3.77 (m, 4H), 3.65-3.61 (m, 5H),1.93-1.91 (m, 1H) , 1.12 (d,J= 6.8 Hz, 3H), 0.87 (d,J= 6.8 Hz, 3H)。

Example 32

2- (3-chlorophenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 524&526 [M + 1]；

¹H NMR (400 MHz, CDCl3) 9.33 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 4.0Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.72-7.64 (m, 2H), 7.32(d,J= 8.0 Hz, 2H), 7.23 (d,J= 8.0 Hz, 2H), 6.80 (d,J= 8.0 Hz, 1H), 4.00(s, 3H), 3.86-3.80 (m, 2H), 3.78 (s, 2H), 3.67-3.63 (m, 4H), 3.59-3.53 (m,2H)。

Example 33

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenyleth-1-one

MS m/z (ESI): 490 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.34 (s, 1H), 8.06(s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.68 (d,J= 2.4 Hz, 1H), 7.67 (s, 1H),7.35 (t,J= 8.0 Hz, 2H), 7.30-7.27 (m, 3H), 6.78 (d,J= 8.8 Hz, 1H), 4.00(s, 3H), 3.85-3.53 (m, 4H), 3.65-3.62 (m, 4H), 3.56-3.54 (m, 2H)。

Example 34

MS m/z (ESI): 524&526 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 4.0Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.71-7.65 (m, 2H), 7.29(d,J= 8.0 Hz, 2H), 7.27 (s, 1H), 7.18 (d,J= 8.0 Hz, 1H), 6.80 (d,J= 8.0Hz, 1H), 4.00 (s, 3H), 3.88-3.82 (m, 2H), 3.79 (s, 2H), 3.67-3.63 (m, 4H),3.59-3.53 (m, 2H)。

Example 35

2- (4-methoxyphenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 520 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.32 (s, 1H), 9.29 (s, 1H), 8.36 (d,J= 4.0Hz, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.74-7.63 (m, 2H), 7.21(d,J= 8.0 Hz, 2H), 6.88 (d,J= 8.0 Hz, 2H), 6.81 (d,J= 8.0 Hz, 1H), 4.01(s, 3H), 3.88-3.82 (m, 2H), 3.80 (s, 3H), 3.75 (s, 2H), 3.67-3.63 (m, 4H),3.59-3.53 (m, 2H)。

Example 36

2- (3-methoxyphenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 520 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 4.0Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.69-7.66 (m, 2H), 7.27(s, 1H), 6.87 (d,J= 8.0 Hz, 2H), 6.82-6.78 (m, 2H), 4.00 (s, 3H), 3.87-3.82(m, 2H), 3.81 (s, 3H), 3.80 (s, 2H), 3.67-3.63 (m, 4H), 3.59-3.53 (m, 2H)。

Example 37

2- (2-methoxyphenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 520 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 4.0Hz, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.69-7.66 (m, 2H), 7.29(d,J= 4.0 Hz, 1H), 7.23 (d,J= 8.0 Hz, 1H), 6.98-6.88 (m, 2H), 6.79 (d,J= 8.0 Hz, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 3.87-3.82 (m, 2H), 3.79 (s, 2H),3.67-3.63 (m, 4H), 3.59-3.53 (m, 2H)。

Example 38

2- (4-fluorophenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z(ESI): 508 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.26 (s, 1H), 9.21 (s, 1H), 8.28 (s, 1H), 7.99(s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.67-7.57(m, 2H), 7.19-7.14 (m, 2H),7.05-6.87 (m, 2H), 6.76-6.68 (m, 1H), 3.93 (s, 3H), 3.81-3.74 (m, 2H), 3.71(s, 2H), 3.63-3.44 (m, 6H)。

Example 39

2- (2-chlorophenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z(ESI): 524&526 [M+1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.07(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.74-7.62 (m, 2H), 7.45-7.35 (m, 2H),7.26-7.20 (m, 2H), 6.87-6.76 (m, 1H), 4.01 (s, 3H), 3.91 (s, 2H), 3.89-3.81(m, 2H), 3.72-3.60 (m, 6H)。

Example 40

(R) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylpropan-1-one

MS m/z(ESI): 504 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.31 (s, 1H), 9.27 (s, 1H), 8.31 (s, 1H), 8.06(s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.68-7.62 (m, 2H), 7.35-7.23 (m, 5H),6.73 (d,J= 8.8 Hz, 1H), 4.00 (s, 3H), 3.94 (q,J= 8.4 Hz, 1H), 3.83-3.49(m, 6H), 3.47-3.37 (m, 1H), 3.08-2.95 (m, 1H), 1.50 (d,J= 8.4 Hz, 3H)。

EXAMPLE 41

(3-Fluoropyridin-2-yl) (4- (5- (7- (1-methyl-1))H-pyrazoles-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) methanone

MS m/z (ESI): 495 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.28 (s, 1H), 8.62 (d,J= 4.8Hz, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.72-7.69(m, 2H), 7.58-7.54 (m, 1H), 7.46-7.42 (m, 1H), 6.85 (d,J= 8.8 Hz, 1H),4.04-4.01 (m, 5H), 3.83-3.81 (m, 2H), 3.77-3.74 (m, 2H), 3.55-3.52 (m, 2H)。

Example 42

(4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) (pyridin-2-yl) methanone

MS m/z (ESI): 477 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.28 (s, 1H), 8.62 (d,J= 4.8Hz, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.86-7.82 (m, 2H), 7.75-7.60 (m, 3H), 7.40-7.37 (m, 1H), 6.83 (d,J= 8.8 Hz, 1H), 4.09-3.99 (m, 5H),3.85-3.82 (m, 4H), 3.77-3.74 (m, 2H)。

Example 43

2- (3- (2- (dimethylamino) ethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

The first step is as follows:

2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid methyl ester

The compound methyl 2- (3-hydroxyphenyl) acetate 43a (0.10 g, 0.60 mmol), 2-chloro-N,NDimethylethylamine hydrochloride (95 mg, 0.66 mmol), potassium carbonate (0.25 g, 1.81 mmol) and potassium iodide (0.1 g, 0.60 mmol) were dissolved inN,N-dimethylformamide (5 mL), oil bath 80 ℃ stirring overnight, reaction washed with water (5 mL × 3), ethyl acetate (20 mL), organic phase dried over anhydrous sodium sulfate, desolventization under reduced pressure, preparative plate purification (dichloromethane: methanol = 6: 1) gave the desired product methyl 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetate 43b (14 mg, yellow solid) in 10% yield.

MS m/z (ESI): 238 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 7.28-7.22 (m, 1H), 6.90-6.82 (m, 3H), 4.29-4.26(m, 2H), 3.69 (s, 3H), 3.59 (s, 2H), 3.11-3.09 (m, 2H), 2.63 (s, 6H)；

Second step of

2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid

The compound methyl 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetate 43b (14 mg, 0.06 mmol), lithium hydroxide (8 mg, 0.3 mmol), tetrahydrofuran (0.5 mL), methanol (0.5 mL) and water (0.5 mL) were mixed and stirred at room temperature for 30 minutes. The reaction was concentrated, diluted hydrochloric acid (4 mL, 1M) was added, and concentration was again performed to obtain the objective 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid 43c (10 mg, yellow solid), yield: 90% and the product was used in the next reaction without purification.

MS m/z (ESI): 224 [M + 1]；

The third step

The compound (43 c, 3 mg, 0.03 mmol) of 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid and 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (5 m)g, 0.02 mmol), 2- (7-benzotriazole oxide)N,N,N',N' -tetramethyluronium hexafluorophosphate (8 mg, 0.02 mmol) and triethylamine (0.2 mL) were dissolved inN,N-dimethylformamide (0.5 mL), stirring at room temperature for 30 minutes the reaction mixture was extracted with ethyl acetate (5 mL), washed with water (2 mL × 3), the organic phase was desolventized under reduced pressure, and preparative plate purification (dichloromethane: methanol = 12: 1) gave the objective product 2- (3- (2- (dimethylamino) ethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1) phenyl) -1- (4- (2- (dimethylamino) ethoxy) ethyl esterH-pyrazol-4-yl) quinazolin-5-yl) 43 (4 mg, yellow solid), yield: 53 percent.

MS m/z (ESI): 577 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.34 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.69-7.66 (m, 2H), 7.28-7.24 (m, 1H), 6.91-6.89 (m, 2H), 6.83-6.78 (m, 2H), 4.27 (t,J= 5.2 Hz, 2H),4.01 (s, 3H), 3.86-3.82 (m, 2H), 3.70 (s, 2H), 3.66-3.62 (m, 4H), 3.60-3.58(m, 2H), 3.09 (t,J= 4.8 Hz, 2H), 2.62 (s, 6H)。

Example 44

2- (3- (2- (ethylamino) ethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) eth-1-one hydrochloride

First step of

2- (3- (2- ((tert-Butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid methyl ester

The compound methyl 2- (3-hydroxyphenyl) acetate 44a (0.15 g, 0.90 mmol), tert-butyl (2-hydroxyethyl) carbamate (0.25 g, 1.35 mmol) and triphenylphosphine (0.35 g, 1.35 mmol) were dissolved in dichloromethane (6 mL), and diisopropyl azodicarboxylate (0.27 g, 1.35 mmol) was slowly added dropwise under nitrogen atmosphere under ice salt bath conditions, and after completion of dropwise addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with dilute hydrochloric acid (5 mL, 1M), saturated aqueous sodium bicarbonate (5 mL), water (5 mL × 2), and organic phase was desolventized under reduced pressure to obtain methyl 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetate 44b (0.35 g, yellow liquid) as a target product, in yield: 95 percent.

MS m/z (ESI): 360 [M + 23]；

Second step of

2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid

Compound 44b (0.35 g, 0.90 mmol) of methyl 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetate, tetrahydrofuran (2 mL), lithium hydroxide (90 mg, 4.5 mmol), methanol (2 mL) and water (2 mL) were mixed and stirred at room temperature for 30 minutes. The reaction solution was desolventized under reduced pressure, extracted with water (5 mL), washed with ethyl acetate (5 mL × 2), the aqueous phase was added with dilute aqueous hydrochloric acid (10 mL, 2N), extracted with ethyl acetate (20 mL), and desolventized with organic phase under reduced pressure to give the desired product, 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid 44c (0.2 g, yellow liquid), yield: and 69 percent.

MS m/z (ESI): 346 [M + 23]；

The third step

(2- (3- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1 yl) -2-oxoethyl) phenoxy) ethyl) carbamic acid tert-butyl ester

Reference was made to the third procedure of example 43, which was conducted in such a manner that 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid 43c was substituted with 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid 44c to give the objective product (2- (3- (2- (4- (5- (7- (1-methyl-1-yl-1-ethoxy)) acetic acidH-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1 yl) -2-oxoethyl) phenoxy) ethyl) carbamic acid tert-butyl ester 44d (3 mg, yellow solid), yield: 40 percent.

MS m/z (ESI): 677 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.34 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.69-7.66 (m, 2H), 7.25-7.23 (m, 2H), 6.88-6.7 (m, 3H), 4.35-4.33 (m, 2H), 4.00 (s, 3H), 3.81-3.77(m, 4H), 3.70-3.64 (m, 6H), 3.32-3.30 (m, 2H), 3.13-3.09 (m, 2H), 1.40 (t,J= 7.2 Hz, 3H), 1.46 (s, 9H)；

The fourth step

Compound (2- (3- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1 yl) -2-oxoethyl) phenoxy) ethyl) carbamic acid tert-butyl ester 44d (3 mg, 0.01 mmol) was dissolved in dioxane (1 mL) solution of hydrochloric acid and stirred for 30 minutes. Decompressing and desolventizing the reaction liquid to obtain the target product 2- (3- (2- (ethylamino) ethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one hydrochloride 44 (2 mg, yellow solid), yield: 80 percent.

MS m/z (ESI): 577 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.32 (s, 1H), 9.27 (s, 1H), 8.33 (d,J= 2.0Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.66 (s, 1H), 7.24 (s,1H), 6.94 (s, 1H), 6.88 (d,J= 7.2 Hz, 1H), 6.83-6.79 (m, 3H), 4.35-4.33 (m,2H), 4.00 (s, 3H), 3.81-3.77 (m, 4H), 3.70-3.64 (m, 6H), 3.32-3.30 (m, 2H),3.13-3.09 (m, 2H), 1.40 (t,J= 7.2 Hz, 3H)。

Example 45

2- (3- (2-hydroxyethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

First step of

3- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenylacetic acid methyl ester

Methyl 3-hydroxyphenylacetate 45a (0.17 g, 1.00 mol) was dissolved inN,N-dimethylacetamide (5 mL), potassium carbonate (0.42 g, 3.00 mol), potassium iodide (0.17 g, 1.00 mol) and (2-bromoethoxy) (tert-butyl) dimethylsilane (0.24 g, 1.00 mol) were added in this order, and after the addition was completed, reaction was carried out at 80 ℃ for 15 hours, the mixture was quenched with 50mL of water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (25 mL × 2), the combined organic phases were washed with saturated brine (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and desolventization under reduced pressure was carried out to obtain the objective product ethyl 3- (2- ((tert-butyldimethylsilyl) oxyethoxy) benzoate 45b (0.10 g, 0.3 mmol, yellow solid) in a yield of 30%.

¹H NMR (400 MHz, CDCl₃) 7.14 (t,J= 7.6 Hz, 1H), 6.77-6.70 (m, 3H),3.93-3.91 (m, 2H), 3.87-3.85 (m, 2H), 3.59 (s, 3H), 3.49 (s, 2H), 0.81 (s,9H), 0.02 (s, 6H)；

Second step of

3- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenylacetic acid

Ethyl 3- (2- ((tert-butyldimethylsilyl) oxyethoxy) benzoate 45b (0.10 g, 0.30 mmol) was added to tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), lithium hydroxide (36 mg, 1.50 mol) was added, and after the addition was completed, reaction was carried out at 25 ℃ for 1 hour.

MS m/z (ESI): 311 [M + 1]；

The third step

The compound 37- (1-methylpyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (5 mg, 0.01 mmol), 3- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenylacetic acid 45c (10 mg, 0.03 mmol) and triethylamine (20 mg, 0.2 mmol) were dissolved in tetrahydrofuran (1 mL), and 2- (7-oxybenzotriazole) was added at room temperatureN,N,N',N' -tetramethylurea hexafluorophosphate (19 mg, 0.05 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 2- (3- (2-hydroxyethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one 45 (0.8 mg, yellow solid). Yield: 11 percent.

MS m/z (ESI): 550 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.32 (s, 2H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.35-7.30 (m, 2H), 7.15-7.10 (m, 2H),6.88-6.81 (m, 2H), 4.10-4.06 (m, 2H), 4.01 (s, 3H), 3.98-3.95 (m, 4H), 3.66-6.62 (m, 4H), 3.14-3.10 (m, 4H)；

Example 46

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (piperidin-4-yl) ethan-1-one

First step of

4- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-carbonylethyl) piperidine-1-carboxylic acid tert-butyl ester

Reference example 43 was conducted to the third procedure in which 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid 43c was substituted with 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) acetic acid to obtain the objective compoundProduct 4- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-carbonylethyl) piperidine-1-carboxylic acid tert-butyl ester 46a (4 mg, yellow solid), yield: 52 percent.

MS m/z (ESI): 597 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.29 (s, 1H), 8.37 (d,J= 2.4Hz, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.72-7.68 (m, 2H), 6.83(d,J= 8.8 Hz, 1H), 4.10-4.07 (m, 4H), 4.01 (s, 3H), 3.83-3.65 (m, 10H),1.45 (s, 9H), 1.29-1.14 (m, 5H)；

Second step of

Reference example 44 was made to the second procedure for the synthesis of 4- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-carbonylethyl) piperidine-1-carboxylic acid tert-butyl ester 46a substitution (2- (3- (2- (4- (5- (7- (1-methyl-))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-oxoethyl) phenoxy) ethyl) carbamic acid tert-butyl ester 44d gave the target product 1- (4- (5- (7- (1-methyl-1-H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (piperidin-4-yl) ethan-1-one 46 (2 mg, yellow solid), yield: 90 percent.

MS m/z (ESI): 497 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.29 (s, 1H), 8.37 (d,J= 2.4Hz, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.72-7.68 (m, 2H), 6.83(d,J= 8.8 Hz, 1H), 4.10-4.07 (m, 4H), 4.01 (s, 3H), 3.83-3.65 (m, 10H),1.29-1.14 (m, 5H)。

Example 47

4- {3- [2- (4- {5- [7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl]Pyridin-2-yl } piperazin-1-yl) -2-carbonylethyl]Phenyl piperazine

First step of

4- [3- (2-methoxy-2-carbonylethyl) phenyl ] piperazine-1-carboxylic acid tert-butyl ester

The compound methyl 2- (3-bromophenyl) acetate 47a (0.23 g, 1.00 mmol), 1-Boc-piperazine (0.28 g,1.50 mmol), cesium carbonate (0.98 g, 3.00 mmol) and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.12 g, 0.20 mmol) were dissolved in waterN,N-dimethylformamide (10 mL), tris (dibenzylideneacetone) dipalladium (92 mg, 0.10 mmol) was added under nitrogen blanket, heated to 100 ℃ and stirred for 3 hours, cooled to room temperature, extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, spun-dried and purified by silica gel plate preparation (petroleum ether: ethyl acetate = 5: 1) to give the desired product 4- [3- (2-methoxy-2-carbonylethyl) phenyl ] ethyl]Piperazine-1-carboxylic acid tert-butyl ester 47b (50 mg, 0.15mmol, yellow oil), yield: 15 percent.

MS m/z (ESI): 335 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 7.24-7.19 (m, 1H), 6.84-6.78 (m, 3H), 3.68 (s,3H), 3.58-3.55 (m, 6H), 3.14-3.12 (m, 4H), 1.48 (s, 9H)。

Second step of

{3- [4- (tert-Butoxycarbonyl) piperazin-1-yl ] phenyl } acetic acid

The compound tert-butyl-4- [3- (2-methoxy-2-carbonylethyl) phenyl ] piperazine-1-carboxylate 47b (50 mg, 0.15 mmol) was dissolved in methanol (5 mL), a 2N aqueous lithium hydroxide solution (1 mL) was added with stirring, stirred at room temperature for 16 hours, spun dry, diluted with water (10 mL), acidified to pH (3 to 5) with 0.5N hydrochloric acid, extracted with dichloromethane (20 mL), the organic phase was washed with a saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give {3- [4- (tert-butoxycarbonyl) piperazin-1-yl ] phenyl } acetic acid 47c (48.00 mg, yellow solid) with a yield of 100%.

MS m/z (ESI): 321 [M + 1]；

The third step

4- {3- [2- (4- {5- [7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl]Pyridin-2-yl } piperazin-1-yl) -2-carbonylethyl]Phenyl } piperazine-1-carboxylic acid tert-butyl ester

Reference example 43 was made to the third procedure which was used to synthesize {3- [4- (tert-butoxycarbonyl) piperazin-1-yl]Phenyl } acetic acid 47c replaces 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid 43c to obtain a target product 4- {3- [2- (4- {5- [7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl]Pyridin-2-yl } piperazin-1-yl) -2-carbonylethyl]Phenyl } piperazine-1-carboxylic acid tert-butyl ester 47d (10 mg, 0.015 mmol, yellow solid), yield: 75 percent.

MS m/z (ESI): 674 [M + 1]；

The fourth step

The compound tert-butyl-4- {3- [2- (4- {5- [7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl]Pyridin-2-yl } piperazin-1-yl) -2-carbonylethyl]Phenyl } piperazine-1-carboxylate 47d (10.00 mg, 0.015 mmol) was dissolved in methanolic hydrogen chloride solution (4M, 5 mL) and stirred at room temperature for 2 hours. Spin-drying, diluting with water (10 mL), adjusting the pH to 8-10 with 0.5N aqueous sodium hydroxide solution, extracting with dichloromethane (20 mL), washing the organic phase with saturated brine (20 mL), drying over anhydrous sodium sulfate, filtering, spin-drying, purifying with silica gel plate (dichloromethane: methanol = 10: 1) to obtain the target compound 4- {3- [2- (4- {5- [7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl]Pyridin-2-yl } piperazin-1-yl) -2-carbonylethyl]Phenyl } piperazine 47 (7 mg, 0.012 mmol, yellow solid), yield: 80 percent.

MS m/z (ESI): 574 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.27 (s, 1H), 8.34 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.68-7.66 (m, 2H), 7.24-7.21 (m, 1H),6.87 (s, 1H), 6.84-6.75 (m, 3H), 4.06 (s, 3H), 3.89-3.82 (m, 4H), 3.78 (s,2H), 3.65-3.62 (m, 4H), 3.54-3.51 (m, 2H), 3.17-3.14 (m, 3H), 3.05-3.02 (m,3H)。

Example 48

2- (2- (2-hydroxyethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

First step of

2-Hydroxyphenylacetic acid methyl ester

2-Hydroxyphenylacetic acid 48a (5.00 g, 33.00 mmol) was dissolved in methanol (50 mL), and 98% concentrated sulfuric acid (1.5 mL) was slowly added dropwise thereto, after which the mixture was heated to 60 ℃ for reflux reaction for 5 hours. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), washed with saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, and concentrated to give methyl 2-hydroxyphenylacetate 48b (5.30 g, pale yellow oil) in 96.7% yield.

¹H NMR (400 MHz, CDCl₃) 7.32 (s, 1H), 7.22-7.18 (m, 1H), 7.11-7.09(m, 1H), 6.95-6.86 (m, 2H), 3.75 (s, 3H), 3.67 (s, 2H)。

Second step of

2- (2- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenyl) acetic acid methyl ester

Methyl 2-hydroxyphenylacetate 48b (0.50 g, 3.0 mmol) was dissolved inN,N-dimethylacetamide (5 mL), potassium iodide (0.50 g, 3.0 mmol), potassium carbonate (1.00 g, 7.5 mmol), and (2-bromoethoxy) (tert-butyl) dimethylsilane (0.72 g, 3.0 mmol) were added in this order, after completion of addition, the temperature was raised to 70 ℃ to react for 18 hours, the reaction mixture was concentrated and then diluted with ethyl acetate (25 mL) and 30mL of water, separated, extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL × 4), dried over anhydrous sodium sulfate,concentration and purification by column chromatography (petroleum ether: ethyl acetate = 20:1) gave crude methyl 2- (2- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenyl) acetate 48c (0.60 g, pale yellow oil) in 61.7% yield.

¹H NMR (400 MHz, CDCl₃) 7.16-7.08 (m, 2H), 6.84-6.79 (m, 2H), 3.97-3.96 (m, 2H), 3.86-3.83 (m, 2H), 3.58 (s, 3H), 3.57 (s, 2H), 0.82 (s, 9H),0.00 (s, 6H)；

The third step

2- (2- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenyl) acetic acid lithium salt

Methyl 2- (2- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenyl) acetate 48c (44 mg, 0.14 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (2 mL) and water (1 mL) were added, lithium hydroxide (6.5 mg, 0.27 mmol) was added after stirring for 5 minutes, the temperature was raised to 45 ℃ and reaction was carried out for 18 hours the reaction was concentrated to give crude lithium 2- (2- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenyl) acetate 48d (60 mg, white solid) which was directly charged to the next step;

the fourth step

Lithium 2- (2- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenyl) acetate 48d (8.7 mg, 0.028 mmol) was dissolved in methanol (5 mL), adjusted to pH = 2-3 with 4M methanolic hydrochloric acid solution, concentrated and added to dichloromethane (3 mL) for further use.

Reacting 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (5 mg, 0.01 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (5 mg, 0.04 mmol) and 2- (7-oxybenzotriazole) were added in this orderN,N,N',N'Tetramethyluronium hexafluorophosphate (11 mg, 0.03 mmol) was stirred for 5 minutes, and then the methylene chloride solution prepared above was added and stirred for 20 minutes. The reaction mixture was concentrated to prepare a silica gel plate (dichloromethane: methanol = 20:1), and the silica gel plate was purified to obtain the objective compound 2- (2- (2-hydroxyethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one 48 (5 mg, white solid) yield 64.9%.

MS m/z (ESI): 550 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.33 (s, 1H), 9.28 (s, 1H), 8.34 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.70-7.62 (m, 2H), 7.25-7.20 (m, 2H),6.98-6.94 (m, 1H), 6.89 (d,J= 8.0 Hz, 1H), 6.78 (d,J= 8.8 Hz, 1H), 4.12(s, 2H), 4.01(s, 3H), 3.93-3.89 (m, 2H), 3.83-3.77 (m, 4H), 3.75-3.69 (m,4H), 3.65-3.57 (m, 2H), 3.33-3.28 (m, 1H)。

Example 49

4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -N-propylpiperazine-1-carboxamide

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (10 mg, 0.03 mmol) and triethylamine (11 mg, 0.11 mmol) were dissolved in tetrahydrofuran (2 mL), propyl isocyanate (7 mg, 0.08 mmol) was added at room temperature, and the reaction was stirred at room temperature for 1 hour. The reaction solution was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -N-propylpiperazine-1-carboxamide 49 (10 mg, 0.022 mmol, yellow solid). Yield: 81 percent.

MS m/z (ESI): 457 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.35 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.76-7.59 (m, 2H), 6.81(d,J= 8.8 Hz, 1H), 4.56 (br s, 1H), 4.01 (s, 3H), 3.80-3.71 (m, 4H), 3.63-3.56 (m, 4H), 3.28-3.23 (m, 2H), 1.62-1.52 (m, 2H), 1.05-0.90 (m, 3H)。

Example 50

N-isobutyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide

The compound 7- (1-methylpyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline 2 (10 mg, 0.03 mmol) and triethylamine (10 mg, 0.10 mmol) were dissolved in tetrahydrofuran (1.0 mL) and added at room temperatureN,N' -carbonylbis (1,2, 4-triazole) (10 mg, 0.06 mmol) was stirred at room temperature for reaction for 0.5 hour, isobutylamine (15 mg, 0.20 mmol) was added at room temperature, and stirred at 50 ℃ for reaction for 15 hours. The reaction solution is decompressed and desolventized, and the residue is purified by a silica gel plate (dichloromethane/methanol 20:1) to obtain the target productN-isobutyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide 50 (7 mg, 0.015 mmol, yellow solid). Yield: 50 percent.

MS m/z (ESI): 471 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.34 (s, 1H), 9.28 (s, 1H), 8.36 (s, 2H), 8.07(s, 1H), 7.96 (s, 1H), 7.85 (m, 1H), 7.70-7.68 (m, 2H), 6.81 (d,J= 8.8 Hz,1H), 4.62-4.58 (m, 1H)，4.01 (s, 3H), 3.79-3.73 (m, 4H), 3.65-3.59 (m, 4H),3.12 (t,J= 6.4 Hz, 2H) , 0.94 (d,J= 6.4 Hz, 6H)。

Example 51

N-ethyl-N-methyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide

Synthesis 51 by the procedure of reference example 50, usingNSubstituting isobutylamine with methylethylamine to obtain target productN-ethyl-N-methyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide 51.

MS m/z (ESI): 457 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.37 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.71-7.65 (m, 2H), 6.83 (d,J= 8.8 Hz,1H), 4.01 (s, 3H), 3.75-3.62 (m, 6H), 3.42-3.33 (m, 4H), 2.87 (s, 3H), 1.18(t,J= 7.2 Hz, 3H)。

Example 52

N,N-diethyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide

Synthesis 52 according to the procedure of example 50, in which isobutylamine was replaced with diethylamine to obtain the objective productN,N-diethyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide 52.

MS m/z (ESI): 471 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.29 (s, 1H), 8.37 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.71-7.65 (m, 2H), 6.83 (d,J= 8.4 Hz,1H), 4.01 (s, 3H), 3.74-3.64 (m, 4H), 3.42-3.32 (m, 4H), 3.28 (q,J= 7.2 Hz,4H), 1.18 (t,J= 7.2 Hz, 6H)。

Example 53

6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester

First step of

(6- (6- (tert-Butoxycarbonyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) boronic acid

2-Fluoropyridine-3-boronic acid pinacol ester 53a (780 mg, 3.5 mmol) was dissolved inN,N-dimethylformamide (10 mL), cesium carbonate (4.40 g, 14 mol) and 2, 6-diazaspiro [3.3] were added sequentially]Tert-butyl ester oxalate heptane-2-carboxylate (1.00 g, 3.5 mol), after the addition was completed, reacted at 120 ℃ for 15 hours, the mixture was quenched with 50mL of water, diluted with 50mL of ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with saturated brine (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure to give a crude product, which was purified by silica gel chromatography (dichloromethane/methanol = 100:1 to 97: 3) to give the desired product (6- (6- (tert-butoxycarbonyl) -2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) boronic acid 53b (0.30 g, 0.94 mmol, yellow liquid). Yield: 27 percent.

MS m/z (ESI)：320 [M + 1]；

Second step of

Reacting (6- (6- (tert-butoxycarbonyl) -2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) boronic acid 53b (0.30 g, 0.94 mmol) was dissolved in 1, 4-dioxane (4 mL) and potassium carbonate (280 mg, 2.0 mol), tetrakistriphenylphosphine palladium (23 mg, 0.02 mmol), 5-chloro-7- (1-methyl-1) were added in that order under nitrogen protectionH-pyrazol-4-yl) quinazoline 1-4 (108 mg, 0.45 mmol) and water (1 mL) were added and the mixture was subjected to a jar reaction at 140 ℃ for 2 hours, the mixture was quenched with 25mL of water, diluted with 25mL of ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (25 mL × 2), the combined organic phases were washed with saturated brine (25 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was reducedPerforming pressure exsolution to obtain crude product, and preparing silica gel plate (dichloromethane/methanol = 15: 1) to obtain target product 6- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester 53 (90 mg, 0.19 mmol, yellow solid). Yield: 41 percent.

MS m/z (ESI)：484 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.32 (s, 1H), 9.28 (s, 1H), 8.32 (s, 1H), 8.06(s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.69-7.65 (m, 2H), 6.46 (d,J= 8.4 Hz,1H), 4.25-4.15 (m, 8H), 4.01 (s, 3H), 1.46 (s, 9H)。

Example 54

5- (6- (2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline hydrochloride

Mixing 6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Tert-butyl heptane-2-carboxylate 53 (90 mg, 0.19 mmol) was dissolved in methanol (5.0 mL), a solution of hydrogen chloride in 1, 4-dioxane (2.5 mL, 10 mmol, 4M solution in 1, 4-dioxane) was added with stirring at 25 deg.C, the solvent was evaporated with stirring at 25 deg.C for 3 hours, the residue was dissolved in water (25 mL), dichloromethane (25 mL × 2) was extracted, the aqueous phase was adjusted to pH about 8 with 40% aqueous sodium bicarbonate, extracted with dichloromethane (25 × 3), the combined organic phases were washed with saturated brine (25 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the desired product 5- (6- (2, 6-diazaspiro [ 3.3.3.3 ] diazaspiro [3.3] 5]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1HPyrazol-4-yl) quinazoline hydrochloride 54 (60 mg, 0.16 mmol, yellow solid). Yield: 74 percent.

MS m/z (ESI): 384 [M + 1]；

¹H NMR (400 MHz, CD₃OD) 8.75 (s, 1H), 8.25 (s, 1H), 8.06-8.03 (m, 3H),7.66 (s, 1H), 7.57 (s, 1H), 7.07 (m, 1H), 5.91-5.89 (m, 1H), 4.67-4.65 (m,4H), 4.43-4.42 (m, 4H), 4.01 (s, 3H)。

Example 55

5- (6- (6- (3-fluorobenzyl) -2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

The compound 5- (6- (2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline 54 (5 mg, 0.01 mmol), m-fluorobenzaldehyde (5 mg, 0.04 mmol) and sodium triacetoxyborohydride (9 mg, 0.05 mmol) were dissolved in methanol (1 mL) and stirred at room temperature overnight. Quenching the reaction solution with saturated ammonium chloride (2 mL), extracting with dichloromethane (5 mL), desolventizing the organic phase under reduced pressure, and purifying by high performance liquid chromatography (acetonitrile: water = 20-50) to obtain the target product 5- (6- (6- (3-fluorobenzyl) -2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline 55 (2 mg, yellow solid), yield: 60 percent.

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.31 (s, 1H), 9.28 (s, 1H), 8.30 (s, 1H), 8.20(s, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.71-7.62 (m, 2H), 7.34-7.32 (m, 1H), 7.12-7.01 (m, 2H), 6.46 (d,J= 8.4 Hz, 1H), 4.24 (s, 2H), 4.01(s, 3H), 3.77-3.73 (m, 8H)。

Example 56

2- (3-methoxyphenyl) -1- (6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Heptane-2-yl) ethan-1-one

The compound 5- (6- (2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline 54 (5 mg, 0.01 mmol), 3-methoxyphenylacetic acid (16 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol) were dissolved in tetrahydrofuran (1.0 mL), and 2- (7-oxybenzotriazole) was added at room temperatureN,N,N',N' -tetramethylurea hexafluorophosphate (38 mg, 0.1 mmol), was reacted with stirring at room temperature for 1 hour. The reaction solution was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 2- (3-methoxyphenyl) -1- (6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Heptan-2-yl) ethan-1-one 56 (4 mg, yellow solid). Yield: 58 percent.

MS m/z (ESI): 532 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.30 (s, 1H), 9.28 (s, 1H), 8.31 (s, 1H), 8.06(s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.65-7.62 (m, 2H), 6.87-6.83 (m, 4H),6.47 (d,J= 8.4 Hz, 1H), 4.33-4.31 (m, 2H), 4.07 (s, 3H), 3.82 (s, 3H),3.79-3.77 (s, 2H), 3.65-3.63 (m, 2H), 3.17-3.15 (m, 4H)。

Example 57

1- (6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Hept-2-yl) -2-phenyl methanones

Synthesis of 57 by reference to the procedure of example 56, wherein 3-methoxyphenylacetic acid was substituted with benzoic acid to give the desired product 1- (6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro[3.3]Hept-2-yl) -2-phenyl methanone 57.

MS m/z (ESI): 488 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.31 (s, 1H), 9.28 (s, 1H), 8.33 (d,J= 2.0Hz, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.71-7.66 (m, 3H), 7.52-7.43 (m, 4H), 6.48 (d,J= 8.8 Hz, 1H), 4.54-4.45 (m, 4H), 4.30-4.28 (m, 4H),4.01 (s, 3H)。

Example 58

1- (6- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Hept-2-yl) -2-phenyleth-1-ones

Reference example 56 was conducted to Synthesis 58, in which phenylacetic acid was substituted with benzoic acid to give the desired product 1- (6- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Hept-2-yl) -2-phenyleth-1-one 58.

MS m/z (ESI): 502 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.32-9.28 (m, 2H), 8.31 (d,J= 2.0 Hz, 1H),8.07 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.70-7.63 (m, 2H), 7.37-7.29 (m,5H),6.46 (d,J= 8.4 Hz, 1H), 4.32-4.21 (m, 8H), 4.01 (s, 3H), 3.52 (s, 2H)。

Example 59

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester

First step of

(6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid

2-Fluoropyridine-3-boronic acid pinacol ester 59a (1.00 g, 4.5 mmol) was dissolved inN,NTo dimethylacetamide (10 mL), potassium carbonate (1.40 g, 10 mol) and 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1]Heptane (900 mg, 4.5 mol), after addition at 120 ℃ for 15 h, the mixture was quenched with 50mL water, diluted with 50mL ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with saturated brine (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the crude product was desolventized under reduced pressure to obtain the desired product (6- (6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [ 3.1.1: 3) by silica gel chromatography (dichloromethane/methanol = 100: 1-dichloromethane/methanol = 97: 3)]Heptane-3-yl) pyridin-3-yl) boronic acid 59b (170 mg, 0.53 mmol, yellow liquid). Yield: 12 percent.

MS m/z(ESI)：320 [M + 1]；

Second step of

Reacting 6- (6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) boronic acid 59b (0.17 g, 0.53 mmol) was dissolved in 1, 4-dioxane (4 mL) and potassium carbonate (280 mg, 2.0 mol), tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mmol), 5-chloro-7- (1-methyl-1) were added in that order under nitrogen protectionH-pyrazol-4-yl) quinazoline (0.13 g, 0.53 mmol) and water (1 mL), after addition, the tube was sealed at 140 ℃ for 2 hours, the mixture was quenched with 25mL of water, diluted with 25mL of ethyl acetate, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (25 mL × 2), the combined organic phases were washed with saturated brine (25 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure to give the crude product, which was purified by preparative silica gel plate (dichloromethane/methanol = 15: 1) to give the desired product 3- (5- (7- (1-methyl-1: 1) 3- (5-methyl-7-ethyl-1) quinazolineH-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl esterEster 59 (0.10 g, 0.21 mmol, yellow solid). Yield: 39 percent.

MS m/z (ESI)：484 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.29 (s, 1H), 8.39 (s, 1H), 8.06(s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.71-7.69 (m, 2H), 6.71 (d,J= 8.8 Hz,1H), 4.36-4.35 (m, 2H), 4.21-4.19 (m, 2H), 4.01 (s, 3H), 3.65-3.63 (m, 2H),2.75-2.69 (m, 1H), 2.01-1.97 (m, 1H), 1.41 (s, 9H)。

Example 60

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Synthesis of 60 according to the procedure of example 54, wherein 6- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester 53 used as 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Tert-butyl heptane-6-carboxylate 59. The target product 3- (5- (7- (1-methyl-1) is obtainedH-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 60 (60 mg, 0.16 mmol, yellow solid). Yield: 74 percent.

MS m/z (ESI): 384 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.39 (s, 1H), 9.29 (s, 1H), 8.41 (s, 1H), 8.06(s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.72-7.69 (m, 2H), 6.71 (d,J= 8.4 Hz,1H), 4.01 (s, 3H), 3.98-3.96 (m, 2H), 3.84-3.82 (m, 4H), 2.86-2.80 (m, 1H),2.01-1.99 (m, 1H)。

Example 61

6- (3-fluorophenylmethyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Synthesis of 61 by reference to the procedure of example 55, wherein 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 60 substituted 5- (6- (2, 6-diazaspiro [3.3]]Heptane-2-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline 54 to obtain a target product 6- (3-fluorobenzyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 61 (2.5 mg, 0.005 mmol, yellow solid). Yield: 39 percent.

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.41 (s, 1H), 9.28 (s, 1H), 8.41 (s, 1H), 8.06(s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.76-7.71 (m, 2H), 7.35-7.21 (m, 3H),7.00-6.97 (m, 1H), 6.74 (d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.93-3.90 (m, 4H),3.77-3.70 (m, 4H), 2.95-2.89 (m, 1H), 1.95-1.92 (m, 1H)。

Example 62

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -6- (pyridin-2-ylmethyl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Synthesis of 62 by reference to the procedure of example 61, wherein m-fluorobenzaldehyde was substituted with picolinic aldehyde to give the objective product 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -6- (pyridin-2-ylmethyl) -3, 6-diazabicyclo [3.1.1]Heptane 62.

MS m/z (ESI): 475 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.31 (s, 1H), 8.70 (d,J= 4.0Hz, 1H), 8.45 (d,J= 4.0 Hz, 1H), 8.10 (s, 1H), 8.03-7.94 (m, 2H), 7.87 (s,1H), 7.81-7.78 (m, 1H), 7.71 (s, 1H), 7.61-7.59 (m, 1H), 7.46 (d,J= 8.0 Hz,1H), 6.80 (d,J= 8.0 Hz, 1H), 4.44-4.42 (m, 2H), 4.09 (s, 2H), 4.02 (s, 3H),3.96-3.90 (m, 2H), 3.76-3.71 (m, 2H) , 3.36-3.30 (m, 1H), 2.25-2.17 (m, 1H)。

Example 63

2- (5-Fluoropyridin-2-yl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 60 (5 mg, 0.013 mmol), 2- (5-fluoropyridin-2-yl) acetic acid (3.0 mg, 0.02 mmol) and triethylamine (20 mg, 0.2 mmol) were dissolved in tetrahydrofuran (1.0 mL), and 2- (7-oxybenzotriazole) was added at room temperatureN, N,N',N'Tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol), reacted with stirring at room temperature for 3 hours. The reaction solution was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 2- (5-fluoropyridin-2-yl) -1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptan-6-yl) ethan-1-one 63 (4 mg, yellow solid). Yield: 59 percent.

MS m/z (ESI): 521 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.32 (s, 1H), 9.29 (s, 1H), 8.34 (s, 2H), 8.07(s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.71-7.69 (m, 2H), 7.52-7.41 (m, 2H),6.67 (d,J= 8.8 Hz, 1H), 4.79-4.76 (m, 1H), 4.68-4.65 (m, 1H), 4.18-4.15 (m,1H), 3.99 (s, 3H), 3.78-3.76 (m, 1H), 3.74-3.70 (m, 2H), 3.69-3.65 (m, 2H),3.23-3.21 (m, 1H), 2.01-1.97 (m, 1H)。

Example 64

2- (3- (2- (dimethylamino) ethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

Reference example 63 was conducted to synthesize 64 a reaction mixture in which 2- (5-fluoropyridin-2-yl) acetic acid was substituted with 43c 2- (3- (2- (dimethylamino) ethoxy) phenyl) acetic acid to obtain the objective 2- (3- (2- (dimethylamino) ethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1-yl) acetic acidH-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptan-6-yl) ethan-1-one 64.

MS m/z (ESI): 589 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.41-8.32 (m, 1H),8.07 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.74-7.65 (m, 2H), 7.24-7.15 (m,1H), 6.95-6.88 (m, 2H), 6.83-6.76 (m, 1H), 6.69-6.63 (m, 1H), 4.71-4.57 (m,2H), 4.39-4.32 (m, 2H), 4.21 -4.12 (m, 1H), 4.01 (s, 3H), 3.91-3.83 (m, 2H),3.80-3.74 (m, 2H), 3.66-3.60 (m, 2H), 3.36-3.27 (m, 2H), 2.81 (s, 6H), 1.74-1.71 (m, 1H)。

Example 65

2- (3- (2-hydroxyethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

Reference example 63 procedure Synthesis 65 in which 2- (5-fluoropyridin-2-yl) acetic acid was substituted with 3- (2- ((tert-butyldimethylsilyl) oxyethoxy) phenylacetic acid 45c to give the desired product 2- (3- (2-hydroxyethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1-yl) ethoxy)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptan-6-yl) ethan-1-one 65.

MS m/z(ESI): 562 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.29 (s, 1H), 8.36-8.32(m, 1H),8.07 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.71-7.64 (m, 2H), 7.23-7.17 (m,1H), 6.89-6.84 (m, 2H), 6.80-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.70-4.66 (m,1H), 4.59-4.53 (m, 1H), 4.21-4.17 (m, 1H), 4.04-3.97 (m, 5H), 3.92-3.88 (m,2H), 3.79-3.75 (m, 2H), 3.68-3.61 (m, 2H), 3.55-3.47 (m, 2H), 2.85-2.76 (m,1H), 2.26-2.19 (m, 1H)。

Example 66

2- (3- (2- (ethylamino) ethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

First step of

(2- (3- (2- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -2-carbonylethyl) phenoxy) ethyl) carbamic acid tert-butyl ester

Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 60 (6 mg, 0.016 mmol), 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid 44c (8 mg, 0.024 mmol), 2- (7-oxybenzotriazole) -N,N,N,NTetramethyluronium hexafluorophosphate (12 mg, 0.03 mmol), triethylamine (3 mg, 0.03 mmol) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 1 hour. Desolventizing under reduced pressure to obtain crude product, purifying the crude product with preparative liquid phase (Xbridge-C18; 30X 150 mm preparative column, MeCN/H)₂O20% -50%) to obtain the target product (2- (3- (2- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl)-3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -2-carbonylethyl) phenoxy) ethyl) carbamic acid tert-butyl ester 66a (2.0 mg, white solid), yield: 19 percent.

MS m/z(ESI): 689 [M + 1]；

Second step of

Compound (2- (3- (2- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -2-carbonylethyl) phenoxy) ethyl) carbamic acid tert-butyl ester 66a (2 mg, 0.003 mmol) and hydrogen chloride in methanol (6 mL, 24 mmol, 4M in methanol) were mixed and stirred at room temperature for half an hour. Desolventizing under reduced pressure, adding saturated aqueous sodium bicarbonate (0.5 mL) to the residue andN,Ndimethylformamide (2 mL), purification from the preparative liquid phase (Xbridge-C18; 30X 150 mm preparative column, MeCN/H₂O20% -50%) to obtain the target product 2- (3- (2- (ethylamino) ethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one 66 (0.9 mg, white solid), yield: 53 percent.

MS m/z (ESI): 589 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.29 (s, 1H), 8.32 (s, 1H), 8.07(s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.76-7.64 (m, 2H), 7.15-7.07 (m, 1H),6.92-6.86 (m, 2H), 6.80-6.73 (m, 1H), 6.67-6.59 (m, 1H), 4.75-4.63 (m, 1H),4.62-4.53 (m, 1H), 4.23-4.12 (m, 2H), 4.01 (s, 3H), 3.83-3.73 (m, 4H), 3.71-3.59 (m, 4H), 3.52-3.43 (m, 2H), 3.21-3.11 (m, 1H), 2.98-2.87 (m, 1H), 2.86-2.74 (m, 1H), 1.24-1.18 (m, 3H)。

Example 67

1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -2- (3- (piperazin-1-yl) phenyl) ethan-1-one

Example 67 was synthesized according to the procedure for example 66, except that in the first step {3- [4- (tert-butoxycarbonyl) piperazin-1-yl]Phenyl } acetic acid 47c substituted 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid 44 c. Obtaining the target product 1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -2- (3- (piperazin-1-yl) phenyl) ethan-1-one 67 (1.5 mg, white solid), yield: 44 percent.

MS m/z (ESI): 586 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.29 (s, 1H), 8.36 (s, 1H), 8.07(s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.76-7.64 (m, 2H), 7.22-7.16 (m, 1H),6.86 (s, 1H), 6.85-6.72 (m, 2H), 6.63 (d,J= 8.0 Hz, 1H), 4.71-4.64 (m, 1H),4.59-4.50 (m, 1H), 4.22-4.14 (m, 1H), 4.01 (s, 3H), 3.91-3.80 (m, 2H), 3.81-3.74 (m, 2H), 3.69-3.61 (m, 2H), 3.29-3.15 (m, 4H), 3.15-3.03 (m, 4H), 2.84-2.75 (m, 1H), 1.74-1.67 (m, 1H)。

Example 68

2- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -1- (piperidin-4-yl) ethan-1-one

Example 68 was synthesized by reference to the procedure of example 66, except that in the first step 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid 44c was substituted with 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid. Obtaining the target product 2- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -1- (piperidin-4-yl) ethan-1-one 68.

MS m/z(ESI): 509 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.31 (s, 1H), 9.19 (s, 1H), 8.34-8.32 (m, 2H),8.17 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.85 (d,J= 8.4 Hz, 1H), 6.88 (d,J= 8.4 Hz, 1H), 5.34-5.32 (m, 1H), 4.65-4.56 (m, 2H), 3.98 (s, 3H), 3.88-3.86 (m, 1H), 3.78-3.73 (m, 2H), 2.98-2.95 (m, 2H), 2.85-2.80 (m, 1H), 2.35-2.32 (m, 1H), 2.19-2.14 (m, 2H), 1.91-1.88 (m, 2H), 1.75-1.73 (m, 1H), 1.58-1.52 (m, 2H), 1.40-1.38 (m, 2H)。

Example 69

N-isobutyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxamide

Mixing 3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 60 (5 mg, 0.01 mmol), 2-methylpropan-1-amine (1 mg, 0.01 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (4 mg, 0.04 mmol) andN，Ncarbonyl diimidazole (2 mg, 0.01 mmol), stirring at 80 ℃ for 4 hours, adding 2mL of a saturated saline solution, stirring for 10 minutes, extracting with methylene chloride (5 mL × 2), drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying the filtrate, and purifying with a silica gel column (methylene chloride: methanol = 15: 1) to obtain the objective productN-isobutyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxamide 69 (3.5 mg, white solid), yield 51%.

MS m/z (ESI): 483 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 4.0Hz, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.73-7.63 (m, 2H), 6.70(d,J= 8.0 Hz, 1H), 4.38-4.37 (m, 2H), 4.24-4.21 (m, 2H), 4.01 (s, 3H),3.64-3.60 (m, 2H), 3.05-3.01 (m, 2H), 2.79-2.73(m, 1H), 2.25-2.19 (m, 1H),2.02-2.00 (m, 2H), 0.85 (d,J= 8.0 Hz, 6H)。

Example 70

5- (5- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyrazin-2-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinazolines

First step of

4- (5-Bromopyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

The compound 2, 5-dibromopyrazine 70b-1 (5.00 g, 21.00 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.90 g, 21.00 mmol) and potassium carbonate (4.40 g, 31.50 mmol) were dissolved in waterN-methylpyrrolidone (21 mL), stirred at 100 ℃ for 12 hours reaction liquid diluted with ethyl acetate (300 mL), washed with water (80 mL × 4), organic phase dried over anhydrous sodium sulfate, filtered to remove drying agent, desolventized under reduced pressure, and column silica gel purified residue (petroleum ether: ethyl acetate = 100: 0-1: 1) to obtain the target product tert-butyl 4- (5-bromopyrazin-2-yl) piperazine-1-carboxylate 70b (5.60 g, yellow solid): yield: 78%.

¹H NMR (400 MHz, CDCl₃) 8.12 (s, 1H), 7.87 (s, 1H), 3.54-3.51 (m,4H), 2.99-2.97 (m, 4H), 1.46 (s, 9H)。

Second step of

7- (1-methyl-1)H-pyrazol-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline

The compound 5-chloro-7- (1-methyl-1)H-pyrazol-4-yl) quinazoline 1d (0.1 g, 0.41 mmol), pinacol ester of boronic acid (0.21 g, 0.82 mmol) and dioxane (10 mL) were combined and potassium acetate (0.12 g, 1.23 mmol), tricyclohexylphosphine (23 mg, 0.08 mmol) and tris (dii) were added under argon protectionBenzylacetone) dipalladium (38 mg, 0.041 mmol), replaced with argon three times and stirred at 90 ℃ for 2 hours. Cooled to room temperature and the mixture was used in the next reaction without purification.

MS m/z (ESI): 337 [M + 1]；

The third step

4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline 70a (mixture of the previous step), tert-butyl 4- (5-bromopyrazin-2-yl) piperazine-1-carboxylate 70b (0.21 g, 0.62 mmol) and water (2 mL) were mixed, potassium carbonate (0.17 g, 1.23 mmol) and tetrakis (triphenylphosphine) palladium (0.047 g, 0.041 mmol) were added under argon shielding, argon substitution was carried out three times, stirring was carried out at 80 ℃ for 2 hours, cooling was carried out to room temperature, desolvation was carried out under reduced pressure, water (20 mL) was added to the residue, extraction was carried out with ethyl acetate (15 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the drying agent was removed by filtration, the crude product was obtained by desolvation under reduced pressure, and purification by preparation of a silica gel plate (dichloromethane/methanol = 12: 1) gave 4- (5- (1-methyl-1) as the target productH-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 70c (80.0 mg, yellow solid), yield: 42% (two-step yield).

MS m/z (ESI): 473 [M + 1]；

The fourth step

7- (1-methyl-1)H-pyrazol-4-yl) -5- (5- (piperazin-1-yl) pyrazin-2-yl) quinazoline

Compound 4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 70c (80.0 mg, 0.17 mmol) and hydrogen chloride (12 mL, 48 mmol, 4M in methanol) were mixed, stirred at room temperature for 1 hour, desolventized under reduced pressure, a saturated aqueous sodium bicarbonate solution (20 mL) was added to the residue, extracted with dichloromethane (15 mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the desired product 7- (1-methyl-1-carboxylic acidH-pyrazol-4-yl) -5- (5- (piperazin-1-yl) pyrazin-2-yl) quinazoline 70d (50.0 mg, yellow solid), yield: 79 percent.The product was used in the next reaction without purification.

MS m/z (ESI): 373 [M +1]；

¹H NMR (400 MHz, CDCl₃) 9.74 (s, 1H), 9.29 (s, 1H), 8.45 (s, 1H), 8.32(s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.86 (d,J= 4.0 Hz, 2H), 5.35 (s, 1H),4.01 (s, 3H), 3.79-3.76 (m, 4H), 3.66-3.62 (m, 4H)。

The fifth step

Dissolving 7- (1-methyl-1H-pyrazol-4-yl) -5- (5- (piperazin-1-yl) pyrazin-2-yl) quinazoline 70d (5 mg, 0.01 mmol), 3-fluorobenzaldehyde (2 mg, 0.01 mmol) in methanol (2 mL), adding sodium borohydride acetate (8.5 mg, 0.04 mmol) with stirring, stirring overnight at room temperature, adding 2mL of a saturated ammonium chloride solution, stirring for 10 minutes, extracting with dichloromethane (5 mL × 2), drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying the filtrate, and purifying with a silica gel column (dichloromethane: methanol = 15: 1) to obtain 5- (5- (4- (3-fluorobenzyl) piperazin-1-yl) pyrazin-2-yl) -7- (1-methyl-1-yl) quinazoline 70d (5 mg, 0.01 mmol), 3-fluorobenzaldehyde (2 mg, 0.01 mmol)HPyrazol-4-yl) quinazoline 70 (1.0 mg, white solid), yield 16%.

MS m/z (ESI): 481 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.74 (s, 1H), 9.29 (s, 1H), 8.45 (s, 1H), 8.32(s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.77-7.75 (m, 2H), 7.46-7.40 (m, 1H), 7.36-7.30 (m, 1H), 7.16-7.13 (m, 1H), 4.01 (s, 3H), 3.70 (s,2H), 3.65-3.63 (m, 4H), 2.69-2.62 (m, 4H)。

Example 71

2- (3-methoxyphenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) ethan-1-one

Reacting the compound 7- (1-methyl-1)HPyrazol-4-yl) -5- (5- (piperazin-1-yl) pyrazin-2-yl) quinazoline 70d (5.0 mg, 0.013 mmol), 3-methoxyphenylacetic acid (3.3 mg, 0.02 mmol), 2- (7-oxybenzotriazole-N,N,N', N'Tetramethylurea hexafluorophosphate (9.9 mg, 0.026 mmol), triethylamine (one drop) andN,Ndimethylformamide (2 mL) and stirred at room temperature for 1 hour. The mixture was purified from the preparative liquid phase (Xbridge-C18; 30X 150 mm preparative column, MeCN/H₂O25% -50%) to obtain the target product 2- (3-methoxyphenyl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) ethan-1-one 71(3.8 mg, white solid), yield: 54 percent.

MS m/z(ESI): 521 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.71 (s, 1H), 9.29 (s, 1H), 8.45 (s, 1H), 8.29(s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.94-7.78 (m, 2H), 7.34-7.27 (m, 1H),6.93-6.79 (m, 3H), 4.01 (s, 3H), 3.90-3.83 (m, 2H), 3.83-3.78 (m, 5H), 3.76-3.70 (m, 2H), 3.67-3.62 (m, 2H), 3.61-3.54 (m, 2H)。

Example 72

(2, 6-difluorophenyl) (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) methanone

Example 72 was synthesized according to the procedure of example 71, wherein 3-methoxyphenylacetic acid was substituted with 2, 6-difluorobenzoic acid to give the desired product (2, 6-difluorophenyl) (4- (5- (7- (1-methyl-1-yl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) methanone 72.

MS m/z (ESI): 513 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.72 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 8.36(s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.91-7.82 (m, 2H), 7.50-7.36 (m, 1H),7.06-6.96 (m, 2H), 4.10-4.02 (m, 2H), 4.01 (s, 3H), 3.95-3.83 (m, 2H), 3.82-3.73 (m, 2H), 3.59-3.51 (m, 2H)。

Example 73

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) -2-phenylethane-1-one

Synthesis example 73 by referring to the procedure of example 71, wherein 3-methoxyphenylacetic acid was substituted with phenylacetic acid to give the objective product 1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) -2-phenylethane-1-one 73.

MS m/z (ESI): 491 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.68 (s, 1H), 9.25 (s, 1H), 8.44 (s, 1H), 8.28(s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.85 (s, 2H), 7.38-7.30 (m, 5H), 4.00(s, 3H), 3.88-3.85 (m, 4H), 3.83 (s, 2H), 3.76-3.73 (m, 4H)。

Example 74

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) -2- (piperidin-4-yl) ethan-1-one

Example 74 was synthesized by reference to the procedure of example 46, except that 7- (1-methyl-1) was used in the first stepH-pyrazol-4-yl) -5- (5- (piperazin-1-yl) pyrazin-2-yl) quinazoline 70d substituted 7- (1-methyl-1HThe (E) -pyrazol-4-yl) -5- (6- (piperazine-1-yl) pyridine-3-yl) quinazoline 2 is used for obtaining the target product 1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) -2- (piperidin-4-yl) ethan-1-one 74.

MS m/z (ESI): 498 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.73 (s, 1H), 9.29 (s, 1H), 8.49 (s, 1H), 8.35(s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.92-7.83 (m, 2H), 4.01 (s, 3H), 3.87-3.77 (m, 4H), 3.78-3.65 (m, 4H), 3.46-3.37 (m, 2H), 2.96-2.83 (m, 4H), 2.45-2.35 (m, 2H), 2.28-2.19 (m, 1H), 1.71-1.57 (m, 2H), 1.35-1.30 (m, 1H)。

Example 75

6- (3-Fluorobenzyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

First step of

3- (5-Bromopyrazin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester

The compound 2, 5-dibromopyrazine 70b-1 (0.61 g, 2.65 mmol), 3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester (0.50 g, 2.53 mmol) and potassium carbonate (0.53 g, 3.78 mmol) are dissolved inN-methylpyrrolidone (21 mL), stirred at 100 ℃ for 2 hours the reaction solution was diluted with ethyl acetate (300 mL), washed with water (80 mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure, and the residue was purified on silica gel (petroleum ether: ethyl acetate = 100:0 to 89: 11) to give the desired product 3- (5-bromopyrazin-2-yl) -3, 6-diazabicyclo [ 3.1.1:1 ]]Tert-butyl heptane-6-carboxylate 75a (0.80 g, yellow solid). Yield: 89 percent.

MS m/z (ESI): 355 [M + 1]；

Second step of

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline 70a (0.10 g, 0.3 mmol), 3- (5-bromopyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Tert-butyl heptane-6-carboxylate 75a, tetrakis (triphenylphosphine) palladium (30 mg, 0.03 mmol), and potassium carbonate (82 mg, 0.6 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL), and stirred in an oil bath at 80 ℃ for 2.5 hours under nitrogen atmosphere. Cooling to room temperature, filtering the reaction solution, desolventizing the filtrate under reduced pressure, and purifying with silica gel plates (dichloromethane: methanol = 10: 1) to obtain the target product 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester 75b (0.12 g, yellow solid), yield: 79 percent.

MS m/z (ESI): 485 [M + 1]；

The third step

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester 75b (20 mg, 0.04 mmol) was dissolved in hydrogen chloride (4 mL, 8mmol, 2M in methanol), stirred for 1 hour, the reaction was neutralized with saturated aqueous sodium bicarbonate (3 mL), extracted with dichloromethane (10 mL), washed with organic phase water (5 mL × 3) and desolventized under reduced pressure to give the desired product 3- (5- (7- (1-methyl-1-yl-5-methyl-1-carboxylate)H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 75c (15 mg, yellow solid), yield: 95 percent.

MS m/z (ESI): 385 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.75 (s, 1H), 9.29 (s, 1H), 8.50 (s, 1H), 8.24(s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 4.04-4.02(m, 1H), 4.01 (s, 3H), 3.88-3.70 (m, 6H), 2.31-2.30 (m, 2H)。

The fourth step

Compound 3- (5- (7- (1-methyl-1)H-Pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 75c (7 mg, 0.02 mmo)l), m-fluorobenzaldehyde (7 mg, 0.06 mmol), and sodium triacetoxyborohydride (19 mg, 0.09 mmol) were dissolved in methanol (1.5 mL), and stirred in an oil bath at 40 ℃ overnight. The reaction mixture was washed with saturated ammonium chloride (2 mL) and extracted with dichloromethane (10 mL). The organic phase was desolventized under reduced pressure and purified on preparative plates (dichloromethane: methanol = 10: 1) to give the desired product 6- (3-fluorobenzyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinazolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 75 (1.4 mg, yellow solid), yield: 15 percent.

MS m/z (ESI): 493 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.77 (s, 1H), 9.30 (s, 1H), 8.54 (s, 1H), 8.29(s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.90 (d,J= 1.6 Hz, 1H), 7.88 (s, 1H),7.54-7.52 (m, 1H), 7.36-7.34 (m, 1H), 7.14-7.07 (m, 1H), 7.01-6.99 (m, 1H),4.02 (s, 3H), 3.95-3.71 (m, 6H), 3.67 (s, 2H), 2.36-2.22 (m, 2H)。

Example 76

7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline

First step of

N- (quinolin-8-yl) benzamides

Dissolving 8-aminoquinoline 76a (100 g, 0.7 mol) in dichloromethane (1.0L), adding triethylamine (140 g, 1.4 mol) and benzoyl chloride (100 g, 0.7 mol) in sequence, reacting at 25 ℃ for 1 hour after the addition, quenching the mixture with 1L of water, separating out an organic phase, extracting an aqueous phase with dichloromethane (1L × 2), combining the organic phases, washing the organic phases with saturated saline (1L × 2), drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, desolventizing under reduced pressure to obtain a crude product, washing with ethyl acetate to obtain the target productN- (quinolin-8-yl) benzenesFormamide 76b (145 g, 585 mmol, yellow solid). Yield: 84 percent.

MS m/z(ESI)：249 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 10.75 (s, 1H), 8.94 (d,J= 7.2 Hz, 1H), 8.86(d,J= 4.0 Hz, 1H), 8.08 (d,J= 7.2 Hz, 1H), 8.10-8.09 (m, 2H), 7.62-7.47(m, 6H)。

Second step of

N- (5-bromoquinolin-8-yl) benzamides

Will be provided withN- (Quinolin-8-yl) benzamide 76b (10 g, 40 mmol) was added to water (150 mL) in portionsNBromosuccinimide (9 g, 50 mol), after addition, is reacted for 15 hours at 25 ℃, the mixture is quenched with 100 mL of saturated aqueous sodium sulfite solution, diluted with 100 mL of dichloromethane, the organic phase is separated, the aqueous phase is extracted with dichloromethane (100 mL × 2), the combined organic phases are washed with saturated brine (100 mL × 2), the organic phase is dried over anhydrous sodium sulfate, the drying agent is removed by filtration, and desolventization under reduced pressure is carried out to obtain the desired productN- (5-bromoquinolin-8-yl) benzamide 76c (13 g, 40 mmol, yellow solid), crude.

MS m/z(ESI)：327&329 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 10.71 (s, 1H), 8.87-8.85 (m, 2H), 8.55 (d,J=8.4 Hz, 1H), 8.08-8.06 (m, 2H), 7.85 (d,J= 8.4 Hz, 1H), 7.62-7.54 (m, 4H)。

The third step

5-bromo-8-aminoquinolines

Will be provided withN- (5-bromoquinolin-8-yl) benzamide 76c (13 g, 40 mmol) is dissolved in ethanol (100 mL), 1M sodium hydroxide in ethanol (100 mL) is added with stirring at 25 ℃, stirred at 85 ℃ for 15 hours, the solvent is evaporated to dryness, the residue is dissolved in water (300 mL), dichloromethane (100 mL × 2) is extracted, the combined organic phases are washed with saturated brine (100 mL × 2), the organic phase is dried over anhydrous sodium sulfate, the drying agent is removed by filtration, the crude product is obtained by desolventizing under reduced pressure, and the crude product is purified by chromatography on a silica gel column (petroleum ether/ethyl acetate = 100: 1-petroleum ether/ethyl acetate = 10)1) the desired product 5-bromo-8-aminoquinoline 76d (7.9 g, 35.4 mmol, yellow solid) is obtained. Yield: 88 percent.

MS m/z (ESI): 223&225 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.77-8.76 (m, 1H), 8.43 (d,J= 8.4 Hz, 1H),7.57 (d,J= 8.0 Hz, 1H), 7.58-7.47 (m, 1H), 7.80 (d,J= 8.0 Hz, 1H), 5.04(brs, 2H)。

The fourth step

5-bromo-7-chloro-8-aminoquinoline

5-bromo-8-aminoquinoline 76d (7.9 g, 35.4 mmol) was dissolved in acetonitrile (100 mL) and addedNChlorosuccinimide (4.7 g, 35 mol), stirring at 80 ℃ for 6 hours, quenching the mixture with 100 mL of saturated aqueous sodium sulfite solution, diluting with 100 mL of dichloromethane, separating the organic phase, extracting the aqueous phase with dichloromethane (100 mL × 2), washing the combined organic phases with saturated brine (100 mL × 2), drying the organic phase over anhydrous sodium sulfate, filtering off the drying agent, desolventizing under reduced pressure to give the crude product, which is purified by chromatography on a silica gel column (petroleum ether/ethyl acetate = 100: 1-petroleum ether/ethyl acetate = 10: 1) to give the desired product 5-bromo-7-chloro-8-aminoquinoline 76e (4.7 g, 18.3 mmol, yellow solid) in 52% yield.

MS m/z (ESI): 257&259 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.79-8.78 (m, 1H), 8.40 (d,J= 8.4 Hz, 1H),7.68 (s, 1H), 7.50-7.47 (m, 1H), 5.39 (brs, 2H)。

The fifth step

5-bromo-7-chloroquinolines

5-bromo-7-chloro-8-aminoquinoline 76e (4.7 g, 18.3 mmol) was added to water (100 mL), concentrated sulfuric acid (30 mL) was added dropwise at 0 deg.C, most of the solids disappeared, 4M aqueous sodium nitrite solution (10 mL) was added dropwise when the solution became orange-red, the mixture was stirred at 0 deg.C for 0.5 hour, finally the mixture was added dropwise to hypophosphorous acid (400 mL), stirred at 65 deg.C for 4 hours, the mixture was poured into saturated aqueous sodium hydroxide solution (3L), diluted with 1L of dichloromethane, the organic phase was separated, the aqueous phase was extracted with dichloromethane (1L. times.2), and the combined organic phases were washed with saturated brine (1L. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the desired product 5-bromo-7-chloroquinoline 76f (2.8 g, 11.6 mmol, tan solid). Yield: and 63 percent.

MS m/z (ESI): 242&244 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.94-8.93 (m, 1H), 8.50 (d,J= 8.8 Hz, 1H),8.10 (s, 1H), 7.83 (s, 1H), 7.52-7.49 (m, 1H)。

The sixth step

4- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

5-bromo-7-chloroquinoline 76f (1.8 g, 7.4 mmol) was dissolved in 1, 4-dioxane (20 mL), and sodium carbonate (2.3 g, 22 mol), tetrakis (triphenylphosphine) palladium (0.80 g, 0.7 mmol), tert-butyl 4- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) piperidin-2-yl ] diethyldiamine-1-carboxylate (2.9 g, 7.5 mmol) and water (4 mL) were added in this order under nitrogen, followed by reaction at 80 ℃ for 15 hours. The mixture was quenched with 100 mL of water, diluted with 100 mL of dichloromethane, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL. times.2), and the combined organic phases were washed with saturated brine (100 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100: 1-petroleum ether/ethyl acetate = 3: 1) to give 76g (2.8 g, 6.6 mmol, yellow solid) of the target product tert-butyl 4- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylate. Yield: 89 percent.

MS m/z(ESI)：425&427 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.93-8.92 (m, 1H), 8.29 (s, 1H), 8.21 (d,J=8.8 Hz, 1H), 8.11 (s, 1H), 7.61-7.59 (m, 1H), 7.45 (s, 1H), 7.38-7.35 (m,1H), 6.78 (d,J= 8.8 Hz, 1H), 3.65-3.60 (m, 8H), 1.51 (s, 9H)。

Seventh step

4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-Carboxylic acid tert-butyl ester

76g (2.8 g, 6.6 mmol) of tert-butyl 4- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylate was dissolved in 1, 4-dioxane (20 mL), potassium carbonate (2.8 g, 20 mol), tetrakis (triphenylphosphine) palladium (700 mg, 0.6 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (1.6 g, 8 mmol) and water (4 mL) were added in this order under nitrogen protection, after completion of the addition, the tube was sealed at 140 ℃ for 15 hours, the mixture was quenched with 100 mL of water, diluted with 100 mL of dichloromethane, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL × 2), the combined organic phases were washed with saturated brine (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol = 100: 1-dichloromethane = 97: 3) to give the target product 4- (5- (1-methyl-1-7-1-methyl-1-ethyl acetate = 97: 3)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 76h (2.3 g, 4.9 mmol, yellow solid). Yield: 74 percent.

MS m/z (ESI)：471 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90-8.89 (m, 1H), 8.34 (s, 1H), 8.19-8.18 (m,2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.65 (d,J= 8.4 Hz, 1H), 7.60 (s, 1H),7.32-7.30 (m, 1H), 6.80 (d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.64-3.62 (m, 8H),1.51 (s, 9H)。

Eighth step

7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline

Mixing 4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 76h (2.3 g, 4.9 mmol) was dissolved in methanol (20 mL), hydrochloric acid (10 mL, 40 mmol, 4M1, 4-dioxane solution) was added with stirring at 25 ℃, hydrochloric acid (10 mL, 40 mmol, 4M1, 4-dioxane solution) was stirred at 25 ℃ for 3 hours, the solvent was evaporated, the residue was dissolved in water (300 mL), extracted with dichloromethane (100 mL × 2), the aqueous phase was adjusted to pH about 8 with 40% aqueous sodium bicarbonate, extracted with dichloromethane (100 × 3), the combined organic phases were washed with saturated brine (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the pressure was reducedDesolventizing to obtain the target product 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (1.7 g, 4.6 mmol, yellow solid). Yield: 94 percent.

MS m/z (ESI): 371 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90-8.89 (m, 1H), 8.33 (s, 1H), 8.19-8.17 (m,2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.64 (d,J= 8.8 Hz, 1H), 7.61 (s, 1H),7.32-7.31 (m, 1H), 6.79 (d,J= 7.2 Hz, 1H), 3.99 (s, 3H), 3.64-3.6 (m, 4H),3.06-3.03 (m, 4H)。

Example 77

7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) quinoline

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (17.5 mg, 0.05 mmol) and pyridine-2-carbaldehyde (11 mg, 0.1 mmol) were dissolved in tetrahydrofuran (1.0 mL), and sodium borohydride acetate (42 mg, 0.2 mmol) was added at room temperature, and the reaction was stirred at 40 ℃ for 12 hours. The reaction solution is decompressed and desolventized, and the residue is purified by a silica gel plate (dichloromethane/methanol 20:1) to obtain the target product 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) quinoline 77 (7 mg, 0.015 mmol, yellow solid). Yield: 30 percent.

MS m/z (ESI): 462 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90-8.89 (m, 1H), 8.62 (s, 1H), 8.33 (s, 1H),8.20-8.19 (m, 2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.78-7.61 (m, 5H), 7.32-7.31(m, 1H), 6.80 (d,J= 8.8 Hz, 1H), 4.01 (s, 3H), 3.96-3.72 (m, 6H), 2.87-2.78(m, 4H)。

Example 78

5- (6- (4-Benzylpiperazin-1-yl) pyridin-3-yl) -7- (1H-pyrazol-4-yl) quinolines

First step of

4-(5-(7-(1H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

Reference example 76 Synthesis of 78a according to the seventh operating procedure in which 1-methylpyrazole-4-boronic acid pinacol ester was substituted with 4-pyrazoleboronic acid pinacol ester to give the desired product 4- (5- (7- (1-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 78 a. Yield: 40 percent.

MS m/z (ESI): 457 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.20(d,J= 8.0 Hz, 1H), 8.06-8.04 (m, 2H), 7.67-7.64 (m, 2H), 7.34-7.31 (m, 1H),6.81 (d,J= 8.0 Hz, 1H), 3.64-3.57 (m, 8H), 1.51 (s, 9H)。

Second step of

5- (6- (piperazin-1-yl) pyridin-3-yl) -7- (1)H-pyrazol-4-yl) quinolines

Reference is made to the eighth operating step of example 76 for the synthesis of 78b, using 4- (5- (7- (1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 78a substituted 4- (5- (7- (1-methyl-1)HThe (E) -pyrazol-4-yl) quinoline-5-yl) pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester is subjected to 76h to obtain a target product, namely 5- (6- (piperazine-1-yl) pyridine-3-yl) -7- (1H-pyrazol-4-yl) quinoline 78 b. Yield: 85 percent.

MS m/z (ESI): 357 [M + 1]；

The third step

5- (6- (4-Benzylpiperazin-1-yl) pyridin-3-yl) -7- (1H-pyrazol-4-yl) quinolines

Synthesis 78 by reference to procedure of example 77Wherein 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 with 5- (6- (piperazin-1-yl) pyridin-3-yl) -7- (1HSubstituting the (E) -pyrazol-4-yl) quinoline 78b to obtain a target product 5- (6- (4-benzylpiperazine-1-yl) pyridine-3-yl) -7- (1)H-pyrazol-4-yl) quinoline 78. Yield: 32 percent.

MS m/z (ESI): 447 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.21(d,J= 8.0 Hz, 1H), 8.05-8.04 (m, 2H), 7.64-7.63 (m, 2H), 7.34-7.31 (m, 7H),6.79 (d,J= 8.0 Hz, 1H), 3.75-3.72 (m, 6H), 2.74-2.72 (m, 4H)。

Synthesis steps of examples 79 to 91 were performed as in the procedure of example 77: wherein pyridine-2-carbaldehyde is replaced by different aldehydes.

Example 79

5- (6- (4- ((5-fluoropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 480 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.86-8.85 (m, 1H), 8.44 (s, 1H), 8.33 (s, 1H),8.25-8.21 (m, 2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.64-7.41 (m, 4H), 7.33-7.29(m, 1H), 6.80 (d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.76-3.71 (m, 6H), 2.73-2.70(m, 4H)。

Example 80

5- (6- (4- ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinoline carboxylic acid salt

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.92-8.91 (m, 1H), 8.37-8.25 (m, 3H), 8.17 (s,1H), 7.96 (s, 1H), 7.91-7.88 (m, 2H), 7.69-7.65 (m, 2H), 7.42-7.39 (m, 1H),6.85-6.82 (m, 2H), 4.03-4.01 (m, 5H), 3.96-3.85 (m, 7H), 3.01-2.95 (m, 4H)。

Example 81

5- (6- (4-Benzylpiperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinoline carboxylic acid salt

MS m/z (ESI): 461 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.90 (m, 1H), 8.32 (s, 1H), 8.20-8.19 (m,2H), 8.13 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.64-7.61 (m, 2H), 7.42-7.31(m, 6H), 6.79 (d,J= 8.4 Hz, 1H), 4.01 (s, 3H), 3.76-3.74 (m, 6H), 2.78-2.75(m, 4H)。

Example 82

5- (6- (4- (4-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 491 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90-8.89 (m, 1H), 8.32 (s, 1H), 8.20-8.18 (m,2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.63-7.60 (m, 2H), 7.32-7.29 (m, 3H), 6.91-6.89 (m, 2H), 6.78 (d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.82 (s, 3H), 3.67-3.58(m, 6H), 2.67-2.62 (m, 4H)。

Example 83

5- (6- (4- (2-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 479 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.81 (d,J= 3.2 Hz, 1H), 8.24 (d,J= 2.0 Hz,1H), 8.14-8.10 (m, 2H), 7.86 (s, 1H), 7.73 (s, 1H), 7.56 (d,J= 2.0 Hz, 1H),7.58-7.50 (m, 1H), 7.39-7.35 (m, 1H), 7.25-7.20 (m, 2H), 7.10-7.06 (m, 1H),7.02-6.98 (m, 1H), 6.71 (d,J= 8.4 Hz, 1H), 3.92 (s, 3H), 3.62(s, 2H), 3.61-3.57 (m, 4H), 2.61-2.58 (m, 4H)。

Example 84

5- (6- (4- (2, 6-difluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 497 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.81 (d,J= 3.2 Hz, 1H), 8.24 (d,J= 2.0 Hz,1H), 8.14-8.10 (m, 2H), 7.86 (s, 1H), 7.73 (s, 1H), 7.56 (d,J= 2.0 Hz, 1H),7.58-7.50 (m, 1H), 7.25-7.20 (m, 2H), 6.87-6.83 (m, 2H), 6.69 (d,J= 8.8 Hz,1H), 3.92 (s, 3H), 3.74 (s, 2H), 3.61-3.58 (m, 4H), 2.63-2.61 (m, 4H)。

Example 85

5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 479 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 3.2 Hz, 1H), 8.32 (d,J= 2.4 Hz,1H), 8.24-8.22 (m, 2H), 7.94 (s, 1H), 7.82 (s, 1H), 7.65-7.62 (m, 2H), 7.36-7.32 (m, 2H), 7.17-7.13 (m, 2H), 7.03-7.00 (m, 1H), 6.80 (d,J= 8.8 Hz, 1H),4.00 (s, 3H), 3.75-3.69 (m, 6H), 2.73-2.70 (m, 4H)。

Example 86

N,N-dimethyl-4- ((4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) methyl) aniline

MS m/z (ESI): 504 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.31 (s, 1H), 8.23(s, 1H), 8.19 (d,J= 8.4 Hz, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.65 (d,J=8.4 Hz, 1H), 7.61 (s, 1H), 7.36-7.33 (m, 1H), 7.24 (d,J= 8.0 Hz, 2H), 6.79(d,J= 8.8 Hz, 1H), 6.71 (d,J= 8.0 Hz, 2H), 3.98 (s, 3H), 3.67(s, 2H),3.64-3.62 (m, 4H), 2.95, (s, 6H), 2.61-2.58 (m, 4H)。

Example 87

5- (6- (4- (2-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 491 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (s, 1H), 8.31 (s, 1H), 8.19-8.17 (m, 2H),7.93 (s, 1H), 7.80 (s, 1H), 7.65-7.60 (m, 2H), 7.54-7.52 (m, 1H), 7.45-7.41(m, 2H), 7.03-6.99 (m, 1H), 6.93 (d,J= 8.4 Hz, 1H), 6.78 (d,J= 8.4 Hz,1H), 3.99 (s, 3H), 3.92 (s, 2H), 3.87-3.84 (m, 4H), 3.49 (s, 3H), 2.90-2.88(m, 4H)。

Example 88

5- (6- (4- (4-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 479 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.29 (s, 1H), 8.23-8.21 (m, 2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.65-7.62 (m, 2H), 7.42-7.32 (m,3H), 7.09-7.05 (m, 2H), 6.80 (d,J= 8.0 Hz, 1H), 4.00 (s, 3H), 3.78 (s, 2H),3.72-3.68 (m, 4H), 2.85-2.80 (m, 4H)。

Example 89

MS m/z (ESI): 480 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.47 (s, 1H), 8.33(s, 1H), 8.23-8.21 (m, 2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.71-7.58 (m, 3H),7.47 (s,1H), 7.36-7.33 (m, 1H), 6.81 (d,J= 8.0 Hz, 1H), 4.00 (s, 3H), 3.90(s, 2H), 3.82-3.76 (m, 4H), 2.88-2.82 (m, 4H)。

Example 90

5- (6- (4- ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.35-8.30 (m, 2H),8.27-8.16 (m, 2H), 7.94 (s, 1H), 7.82 (s, 1H), 7.65 (d,J= 8.0 Hz, 1H), 7.61(s, 1H), 7.40 (s, 1H), 7.38-7.28 (m, 2H), 6.81 (d,J= 8.0 Hz, 1H), 4.00 (s,3H), 3.90 (s, 2H), 3.82-3.76 (s, 4H) , 3.49 (s, 3H), 2.93-2.88 (s, 4H)。

Example 91

5- (6- (4- (3-methoxybenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

MS m/z (ESI): 491 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 4.0 Hz, 1H), 8.32 (s, 1H), 8.21-8.19 (m, 2H), 7.94 (s, 1H), 7.81 (s, 1H), 7.65 (d,J= 4.0 Hz, 1H), 7.63-7.61(m, 2H), 7.35-7.30 (m, 1H), 7.06 (s, 1H), 6.99 (d,J= 8.0 Hz, 1H), 6.88 (d,J= 8.0 Hz, 1H), 6.79 (d,J= 8.0 Hz, 1H), 4.00 (s, 3H), 3.85 (s, 2H), 3.82-3.75 (m, 4H), 3.49 (s, 3H), 2.83-2.76 (m, 4H)。

Example 92

(4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) (1-phenylcyclopropyl) methanone

Reacting the compound 7- (1-methyl-1)H(E) -pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (10 mg, 0.03 mmol), 1-phenylcyclopropane-1-carboxylic acid (8 mg, 0.05 mmol) and triethylamine (20 mg, 0.2 mmol) were dissolved in tetrahydrofuran (1.0 mL), and 2- (7-benzotriazole oxide) -one was added at room temperatureN,N,N',N' -tetramethylurea hexafluorophosphate (38 mg, 0.1 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction mixture was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective product (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) (1-phenylcyclopropyl) methanone 92 (3.0 mg, 0.006 mmol, yellow solid). Yield: 30 percent.

MS m/z (ESI): 515 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.90 (m, 1H), 8.29 (s, 1H), 8.16-8.14 (m,2H), 7.92 (s, 1H), 7.86 (s, 1H), 7.62 (d,J= 8.8 Hz, 1H), 7.58 (s, 1H),7.35-7.28 (m, 3H), 7.24-7.21 (m, 3H), 6.75 (d,J= 8.8 Hz, 1H), 3.99 (s, 3H),3.82-3.63 (m, 8H), 1.25-1.21 (m, 4H)。

Synthetic procedures examples 93 to 103 were carried out referring to the synthetic procedure of example 92: wherein 1-phenylcyclopropane-1-carboxylic acid is substituted with different acids.

Example 93

(1- (4-fluorophenyl) cyclopropyl) (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) methanone formate salt

MS m/z (ESI): 533 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.92-8.91 (m, 1H), 8.30 (s, 1H), 8.24-8.20 (m,2H), 8.16 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.65-7.62 (m, 2H), 7.37-7.34(m, 1H), 7.23-7.20 (m, 2H), 7.05-7.00 (m, 2H), 6.76 (d,J= 8.4 Hz, 1H), 3.99(s, 3H), 3.82-3.63 (m, 8H), 1.48-1.45 (m, 2H) , 1.23-1.21 (m, 2H)。

Example 94

2- (5-Fluoropyridin-2-yl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 508 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.87 (m, 1H), 8.40 (s, 1H), 8.33 (s, 1H),8.18-8.15 (m, 2H), 7.93 (s, 1H), 7.82 (s, 1H), 7.65 (d,J= 8.4 Hz, 1H), 7.60(s, 1H), 7.42-7.38 (m, 2H), 7.30-7.27 (m, 1H), 6.79 (d,J= 8.4 Hz, 1H),4.02-3.98 (m, 5H), 3.82-3.78 (m, 4H), 3.63-3.60 (m, 4H)。

Example 95

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylethane-1-one

MS m/z (ESI): 489 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.89 (m, 1H), 8.31 (s, 1H), 8.18-8.16 (m,2H), 7.92 (s, 1H), 7.80 (s, 1H), 7.65-7.60 (m, 2H), 7.37-7.29 (m, 6H), 6.76(d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.85-3.81 (m, 4H), 3.63-3.59 (m, 4H) ,3.53-3.49 (m, 2H)。

Example 96

(2, 6-difluorophenyl) (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) methanone

MS m/z (ESI): 511 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.87 (m, 1H), 8.33 (s, 1H), 8.18-8.15 (m,2H), 7.93 (s, 1H), 7.81 (s, 1H), 7.68-7.58 (m, 1H), 7.61 (s, 1H), 7.44-7.30(m, 2H), 7.02-6.98 (m, 2H), 6.83 (d,J= 8.8 Hz, 1H), 4.03-4.00 (m, 5H),3.78-3.70 (m, 4H), 3.55-3.51 (m, 2H)。

Example 97

(4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) (phenyl) methanone

MS m/z (ESI): 475 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.89 (m, 1H), 8.35 (s, 1H), 8.21-8.14 (m,2H), 7.94 (s, 1H), 7.81 (s, 1H), 7.67 (d,J= 8.8 Hz, 1H), 7.61 (s, 1H),7.49-7.40 (m, 5H), 7.34-7.30 (m, 1H), 6.81 (d,J= 8.8 Hz, 1H), 4.00 (s, 3H),3.71-3.54 (m, 8H)。

Example 98

(R) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylpropan-1-one

MS m/z (ESI): 503 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.88 (m, 1H), 8.29 (s, 1H), 8.18-8.13 (m,2H), 7.92 (s, 1H), 7.80 (s, 1H), 7.62-7.58 (m, 2H), 7.36-7.27 (m, 6H), 6.71(d,J= 8.8 Hz, 1H), 4.08-3.94 (m, 5H), 3.78-3.71 (m, 1H), 3.65-3.58 (m, 4H),3.54-3.47 (m, 1H), 3.07-3.02 (m, 1H), 1.51 (d,J= 8.0 Hz, 3H)。

Example 99

3-hydroxy-1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylpropan-1-one

MS m/z (ESI): 519 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.88 (m, 1H), 8.28 (s, 1H), 8.17-8.12 (m,2H), 7.92 (s, 1H), 7.78 (s, 1H), 7.63-7.57 (m, 2H), 7.37-7.30 (m, 2H), 7.29-7.25 (m, 4H), 6.71 (d,J= 8.8 Hz, 1H), 4.10-4.01 (m, 3H), 3.98 (s, 3H),3.81-3.77 (m, 2H), 3.65-3.63 (m, 4H), 3.49-3.46 (m, 2H) , 3.07-3.02 (m, 1H)。

Example 100

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (tetrahydro-2H-pyran-4-yl) ethan-1-one

MS m/z (ESI): 497 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.89 (m, 1H), 8.35 (s, 1H), 8.20-8.17 (m,2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.66-7.61 (m, 2H), 7.33-7.30 (m, 1H), 6.82(d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.98-3.95 (m, 2H), 3.83-3.62 (m, 8H),3.49-3.42 (m, 2H), 2.41-2.36 (m, 2H), 2.25-2.21 (m, 1H), 1.74-1.70 (m, 2H),1.45-1.38 (m, 2H)。

Example 101

(R) -2-hydroxy-3-methyl-1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) butan-1-one

MS m/z (ESI): 471 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.84-8.83 (m, 1H), 8.28 (d,J= 2.0 Hz, 1H),8.12 (s, 1H), 8.10 (d,J= 8.0 Hz, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.60-7.54(m, 1H), 7.53 (s, 1H), 7.26-7.24 (m, 1H), 6.75 (d,J= 8.0 Hz, 1H), 4.25 (d,J= 2.8 Hz, 1H), 3.92 (s, 3H), 3.71-3.69 (m, 1H), 3.67-3.65 (m, 4H), 3.59-3.54 (m, 4H), 1.18-1.17 (m, 1H), 1.04 (d,J= 6.8 Hz, 3H), 0.78 (d,J= 6.8Hz, 3H)。

Example 102

2- (3- (2- (dimethylamino) ethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethane-1-one hydrochloride

MS m/z (ESI): 576 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89 (d,J= 4.0 Hz, 1H), 8.30 (d,J= 4.0 Hz,1H), 8.21-8.13 (m, 2H), 7.92 (s, 1H), 7.80 (s, 1H), 7.66-7.62 (m, 1H), 7.59(d,J= 4.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.25-7.23 (m, 1H), 6.92-6.86 (m, 2H),6.84-6.74 (m, 2H), 4.24-7.21 (m, 2H), 3.99 (s, 3H), 3.82-3.79 (m, 2H), 3.78(s, 2H), 3.68-7.61 (m, 4H), 3.58-7.56 (m, 2H), 3.12-3.08 (m, 2H), 2.62 (s,6H)。

Example 103

2- (3- (2-hydroxyethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one

MS m/z (ESI): 549 [M + 1]；

¹H NMR (400 MHz, CD₃OD) 9.20 (d,J= 4.0 Hz, 1H), 9.02 (s, 1H), 8.49(s, 1H), 8.38 (s, 1H), 8.28-8.23 (m, 3H), 8.23 (s, 1H), 8.02 (s, 1H), 7.61(s, 1H), 7.28-7.25 (m, 1H), 6.92-6.86 (m, 3H), 4.08-4.03 (m, 2H), 4.02 (s,3H), 3.97-3.89 (m, 6H), 3.87 (s, 2H), 3.85-3.78 (m, 2H), 3.31-3.29 (m, 2H)。

Example 104

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (piperidin-4-yl) ethan-1-one hydrochloride

First step of

4- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-carbonylethyl) piperidine-1-carboxylic acid tert-butyl ester

Reacting the compound 7- (1-methyl-1)HPyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (20 mg, 0.054 mmol), 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (20 mg, 0.082 mmol), 2- (7-oxybenzotriazole) -N,N,N',N' -tetramethyluronium hexafluorophosphate (31 mg, 0.082 mmol), triethylamine (12 mg, 0.108 mmol) andN,N-dimethylformamide (1 mL)Then, the mixture was stirred at room temperature for 1 hour. The reaction mixture was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 4- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-carbonylethyl) piperidine-1-carboxylic acid tert-butyl ester 104a (30 mg, yellow solid), yield: 93 percent.

MS m/z (ESI): 596 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.88 (m, 1H), 8.35 (s, 1H), 8.16-8.15 (m,2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.68-7.66 (m, 1H), 7.61 (s, 1H), 7.33-7.30(m, 1H), 6.81 (d,J= 8.4 Hz, 1H), 4.12-4.10 (m, 2H), 3.99 (s, 3H), 3.84-3.81(m, 2H), 3.75-3.73 (m, 2H), 3.67-3.61 (m, 4H), 2.76-2.74 (m, 2H), 2.34-2.32(m, 2H), 2.08-2.05 (m, 1H), 1.79-1.75 (m, 2H), 1.46 (s, 9H), 1.24-1.22 (m,2H)。

Second step of

Compound 4- (2- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-carbonylethyl) piperidine-1-carboxylic acid tert-butyl ester 104a (27 mg, 0.045 mmol) and hydrogen chloride (1mL, 4mmol, 4M dioxane solution) were mixed with methanol (2 mL) and stirred at room temperature for half an hour. Decompression desolventizing to obtain the target product 1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (piperidin-4-yl) ethan-1-one hydrochloride 104 (25 mg, yellow solid).

MS m/z (ESI): 496 [M + 1]；

¹H NMR (400 MHz, CD₃OD) 9.22 (s, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 8.43(s, 1H), 8.32-8.29 (m, 4H), 8.05-8.03 (m, 1H), 7.67-7.65 (m, 1H), 4.04 (s,3H), 3.96-3.94 (m, 4H), 3.69-3.66 (m, 4H), 3.47-3.42 (m, 2H), 3.07-3.04 (m,2H), 2.55-2.53 (m, 2H), 2.22-2.20 (m, 1H), 2.07-2.03 (m, 2H), 1.56-1.54 (m,2H)。

Example 105

2- (3- (2- (ethylamino) ethoxy group)) Phenyl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethane-1-one hydrochloride

Example 105 was synthesized according to the procedure of example 104, except that 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid was substituted with 2- (3- (2- ((tert-butoxycarbonyl) (ethyl) amino) ethoxy) phenyl) acetic acid 44c in the first step to give the objective product 2- (3- (2- (ethylamino) ethoxy) phenyl) -1- (4- (5- (7- (1-methyl-1-yl) ethoxy) phenyl) -1- (4-hydroxy-ethyl-2-oxo-1-methyl-1-hydroxy-ethyl-4-carboxylic acidH-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) ethane-1-one hydrochloride 105 (3 mg, white solid) in 74% yield.

MS m/z (ESI): 576 [M + 1]；

¹H NMR (400 MHz, CD₃OD) 8.84 (d,J= 4.0 Hz, 1H), 8.38 (s, 2H), 8.27-8.21 (m, 2H), 8.21 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.77-7.74 (m, 1H),7.47-7.44 (m, 1H), 7.33-7.29 (m, 1H), 7.03-6.96 (m, 2H), 6.94 (d,J= 8.0 Hz,1H), 4.30-4.25 (m, 2H), 3.97 (s, 3H), 3.87 (s, 2H), 3.82-3.71 (m, 4H), 3.65-3.63 (m, 2H), 3.59-3.54 (m, 2H), 3.47-3.42 (m, 2H), 3.19-3.14 (m, 2H), 1.35(t,J= 8.0 Hz, 3H)。

Example 106

1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (3- (piperazin-1-yl) phenyl) ethan-1-one

Example 106 was synthesized according to the procedure for example 104, except that {3- [4- (tert-butoxycarbonyl) piperazin-1-yl ] was used in the first step]Phenyl } acetic acid 47c replaces 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid to obtain a target product 1- (4- (5- (7- (1-methyl-1)H-pyridineOxazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (3- (piperazin-1-yl) phenyl) ethan-1-one 106.

MS m/z (ESI): 573 [M + 1]；

¹H NMR (400 MHz, CD₃OD) 9.21 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H), 8.41(s, 1H), 8.36-8.22 (m, 4H), 8.03 (s, 1H), 7.64 (s, 1H), 7.36-7.32 (m, 1H),7.15 (s, 1H), 7.09 (d,J= 8.0 Hz, 1H), 7.01 (d,J= 8.0 Hz, 1H), 4.02 (s,3H), 3.95-3.91 (m, 9H), 3.60-3.50 (m, 5H), 3.50-3.40 (m, 4H)。

Example 107

4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -N-propylpiperazine-1-carboxamide

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (10 mg, 0.03 mmol) and triethylamine (10 mg, 0.1 mmol) were dissolved in tetrahydrofuran (1 mL), and propyl isocyanate (8 mg, 0.1 mmol) was added at room temperature, followed by stirring at room temperature for reaction for 1 hour. The reaction solution was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -N-propylpiperazine-1-carboxamide 107 (10 mg, 0.022 mmol, yellow solid). Yield: 73 percent.

MS m/z (ESI): 456 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90-8.89 (m, 1H), 8.33 (s, 1H), 8.17-8.15 (m,2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.65 (d,J= 8.4 Hz, 1H), 7.61 (s, 1H),7.33-7.31 (m, 1H), 6.79 (d,J= 8.4 Hz, 1H), 4.59-4.56 (m, 1H), 3.99 (s, 3H),3.73-3.71 (m, 4H), 3.60-3.58 (m, 4H), 3.28-3.23 (m, 2H) , 1.60-1.54 (m, 2H) ,0.95 (t,J= 7.2 Hz, 3H)。

Example 108

N-isobutyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide formate salt

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (10 mg, 0.03 mmol) and triethylamine (10 mg, 0.1 mmol) were dissolved in tetrahydrofuran (1.0 mL) and added at room temperatureN,NCarbonyl bis (1,2, 4-triazole) (5 mg, 0.03 mmol) was stirred at room temperature for reaction for 0.5 hour, isobutylamine (15 mg, 0.2 mmol) was added at room temperature, and stirred at 50 ℃ for reaction for 15 hours. The reaction solution was desolventized under reduced pressure, and the residue was purified by preparative HPLC (Xbridge-C18; 30X 150 mm preparative column, 0.5% formic acid, acetonitrile/water 20: 80-acetonitrile/water 40: 60) to give the desired productN-isobutyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide formate 108 (5 mg, 0.011 mmol, yellow solid). Yield: 35 percent.

MS m/z (ESI): 470 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.93-8.92 (m, 1H), 8.33 (s, 1H), 8.25-8.22 (m,2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.67-7.64 (m, 2H), 7.33-7.31 (m, 1H), 6.80(d,J= 8.4 Hz, 1H), 4.61-4.59 (m, 1H), 4.00 (s, 3H), 3.74-3.72 (m, 4H),3.60-3.58 (m, 4H), 3.14-3.10 (m, 2H) , 1.84-1.78 (m, 1H), 0.94 (d,J= 6.8Hz, 6H)。

Example 109

4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -N-neopentyl piperazine-1-carboxamide

Synthesis example 109 was synthesized by referring to the procedure of example 108, wherein isobutylamine was substituted with 2, 2-dimethylpropane-1-amine to give 4- (5- (7- (1-methyl-1) as the objective productH-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -N-neopentyl piperazine-1-carboxamide 109.

MS m/z (ESI): 484 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.90 (m, 1H), 8.34 (s, 1H), 8.19-8.15 (m,2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.65 (d,J= 8.8 Hz, 1H), 7.61 (s, 1H),7.34-7.28 (m, 2H), 6.80 (d,J= 8.8 Hz, 1H), 4.00 (s, 3H), 3.65-3.58 (m, 8H),3.12 (d,J= 6.0 Hz, 2H), 0.94 (s, 9H)。

Example 110

N-cyclopropyl-N-methyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide

Example 110 was synthesized according to the procedure of example 108, usingN-methyl cyclopropylamine is substituted for isobutylamine to obtain the target productN-cyclopropyl-N-methyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide 110.

MS m/z (ESI): 468 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.90 (m, 1H), 8.34 (s, 1H), 8.19-8.16 (m,2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.64 (d,J= 8.8 Hz, 1H), 7.61 (s, 1H),7.34-7.28 (m, 1H), 6.81 (d,J= 8.8 Hz, 1H), 4.00 (s, 3H), 3.65-3.58 (m, 8H),2.91 (s, 3H), 2.56-2.51 (m, 1H), 0.85 (d,J= 6.0 Hz, 4H)。

Example 111

N-ethyl-N-methyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinoline 76 (11 mg, 0.03 mmol), and triethylamine (20 mg, 0.2 mmol) were dissolved in tetrahydrofuran (1.0 mL), and added at room temperatureN-ethyl-NMethylchloroformamide (12 mg, 0.1 mmol), stirring the reaction at room temperature for 15 minutes. The reaction solution is decompressed and desolventized, and the residue is purified by a silica gel plate (dichloromethane/methanol 20:1) to obtain the target productN-ethyl-N-methyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide 111 (10 mg, 0.022 mmol, yellow solid). Yield: 73 percent.

MS m/z (ESI): 456 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.88 (m, 1H), 8.33 (s, 1H), 8.19-8.17 (m,2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.67-7.64 (m, 2H), 7.30-7.27 (m, 1H), 6.81(d,J= 8.4 Hz, 1H), 3.99 (s, 3H), 3.79-3.67 (m, 4H), 3.42-3.93 (m, 4H), 2.86(s, 3H), 3.31-3.26 (m, 2H), 1.17 (t,J= 7.2 Hz, 3H)。

Example 112

N,N-diethyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide

Example 112 was synthesized according to the procedure of example 111, usingN,N-diethylchlorocarboxamide substitutionN-ethyl-NObtaining the target product from methyl chloroformamideN,N-diethyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperazine-1-carboxamide 112.

MS m/z (ESI): 470 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.89-8.88 (m, 1H), 8.34 (s, 1H), 8.20-8.18 (m,2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.66-7.64 (m, 2H), 7.33-7.30 (m, 1H), 6.81(d,J= 8.8 Hz, 1H), 3.99 (s, 3H), 3.78-3.68 (m, 4H), 3.41-3.88 (m, 4H),3.31-3.26 (m, 4H), 1.17 (t,J= 6.8 Hz, 6H)。

Example 113

7- (1-methyl-1)H-pyrazol-4-yl) -5- (4- (piperazin-1-yl) phenyl) quinoline

First step of

4- (4- (7-chloroquinolin-5-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

5-bromo-7-chloroquinoline 76f (0.10 g, 0.40 mmol) was dissolved in 1, 4-dioxane (5 mL), and potassium phosphate (0.25 g, 1.20 mol), tetrakis (triphenylphosphine) palladium (70 mg, 0.06 mmol), tert-butyl 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (0.31 g, 0.80 mmol, from Bi) and water (1 mL) were added in that order under nitrogen protection. After the addition, the reaction was carried out at 80 ℃ for 15 hours. The mixture was quenched with 100 mL of water, diluted with 100 mL of dichloromethane, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL. times.2), and the combined organic phases were washed with saturated brine (100 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100: 1-5: 1) to give the target product, tert-butyl 4- (4- (7-chloroquinolin-5-yl) phenyl) piperazine-1-carboxylate 113a (0.12 g, yellow oil). Yield: 71 percent.

MS m/z(ESI)：424&426 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91-8.90 (m, 1H), 8.25 (d,J= 8.8 Hz, 1H),8.08 (s, 1H), 7.46 (s, 1H), 7.37-7.32 (m, 3H), 7.04 (d,J= 8.8 Hz, 2H),3.65-3.62 (m, 4H), 3.26-3.23 (m, 4H), 1.24 (s, 9H)。

Second step of

4- (4- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (4- (7-chloroquinolin-5-yl) phenyl) piperazine-1-carboxylate 113a (60 mg, 0.15 mmol) was dissolved inN,N-dimethylacetamide (5 mL), potassium phosphate (0.11 g, 0.50 mmol), tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (63 mg, 0.30 mmol) and water (1 mL) were added in this order under nitrogen protection, after addition, the mixture was subjected to a closed-pot reaction at 120 ℃ for 6 hours, the mixture was quenched with 100 mL of water, 100 mL of dichloromethane was diluted, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL × 2), the combined organic phases were washed with saturated brine (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give a crude product, and the target product 4- (4- (7- (1-methyl-1: 1) was obtained by preparative plate (dichloromethane/methanol = 15: 1)H-pyrazol-4-yl) quinolin-5-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester 113b (40 mg, yellow solid). Yield: 60 percent.

MS m/z (ESI)：470 [M + 1]；

The third step

7- (1-methyl-1)H-pyrazol-4-yl) -5- (4- (piperazin-1-yl) phenyl) quinoline

4- (4- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester 113b (30 mg, 0.07 mmol) was dissolved in methanol (2 mL), hydrochloric acid (1mL, 4mmol, 4M methanol solution) was added with stirring at 25 ℃,3 hours with stirring at 25 ℃, the solvent was evaporated, the residue was dissolved in water (100 mL), dichloromethane (100 mL × 2) was extracted, the aqueous phase was adjusted to pH about 8 with 40% aqueous sodium bicarbonate solution, dichloromethane (100 mL × 3) was extracted, the combined organic phases were washed with saturated brine (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the objective product 7- (1-methyl-1H-pyrazol-4-yl) -5- (4- (piperazin-1-yl) phenyl) quinoline 113 (3)0mg, yellow oil). And (5) crude product.

MS m/z (ESI): 370 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.88-8.86 (m, 1H), 8.23 (d,J= 8.8 Hz, 1H),8.15 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.40 (d,J= 8.8 Hz,2H),7.29-7.28 (m, 1H), 7.06 (d,J= 8.4 Hz, 2H), 3.98 (s, 3H), 3.27-3.25 (m,4H), 3.10-3.08 (m, 4H)。

Example 114

5- (4- (4-Benzylpiperazin-1-yl) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) quinolines

Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (4- (piperazin-1-yl) phenyl) quinoline 113 (10 mg, 0.03 mmol) and benzaldehyde (10 mg, 0.10 mmol) were dissolved in tetrahydrofuran (1.0 mL), and sodium cyanoborohydride (6 mg, 0.10 mmol) was added at room temperature, and the reaction was stirred at room temperature for 12 hours. The reaction solution was desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 20:1) to give the objective 5- (4- (4-benzylpiperazin-1-yl) phenyl) -7- (1-methyl-1)H-pyrazol-4-yl) quinoline 114 (12 mg, yellow solid). Yield: 84 percent.

MS m/z (ESI): 460 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.88-8.86 (m, 1H), 8.23 (d,J= 8.8 Hz, 1H),8.16 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.62 (s, 1H), 7.42-7.35 (m, 6H),7.32-7.28 (m, 2H), 7.05 (d,J= 8.4 Hz, 2H), 3.98 (s, 3H), 3.67 (s, 2H),3.37-3.35 (m, 4H), 2.74-2.72 (m, 4H)。

Example 115

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester

First step of

3- (5- (7-Chloroquinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester

The compound (6- (6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid 59b (0.26 g, 0.83 mmol), 5-bromo-7-chloroquinoline 76f (0.18 g, 0.75 mmol), potassium carbonate (0.31 g, 2.25 mmol), tetrakis (triphenylphosphine) palladium (87 mg, 0.075 mmol) were mixed, replaced with argon three times, and stirred at 90 ℃ for 2 hours. Cooled to room temperature, desolventized under reduced pressure, water (20 mL) was added to the residue, extracted with ethyl acetate (15 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and desolventized under reduced pressure to give a crude product, which was purified by flash column chromatography on silica gel (dichloromethane/methanol 100:0-19: 1) to give the target product tert-butyl 3- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate 115a (0.23 g, yellow solid), yield: 71 percent.

MS m/z (ESI): 437&439 [M + 1]；

Second step of

The compound 3- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Tert-butyl heptane-6-carboxylate 115a (0.23 g, 0.53 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (available from Bigde pharmaceutical science Co., Ltd.) (0.17 g, 0.80 mmol), potassium carbonate (0.22 g, 1.59 mmol), tetrakis (triphenylphosphine) palladium (61.2 mg, 0.053 mmol), water (1 mL) and dioxane (6 mL) were mixed, and 35 mL of a tube was sealed, replaced with argon gas three times, and stirred at 140 ℃ for 2 hours. Cooling to room temperature, desolventizing under reduced pressure, and collecting the residueAdding water (20 mL), extracting with ethyl acetate (15 mL × 3), drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, desolventizing under reduced pressure to give the crude product, and purifying by preparative silica gel plate (dichloromethane/methanol = 15: 1) to give the desired product 3- (5- (7- (1-methyl-1: 1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Tert-butyl heptane-6-carboxylate 115 (50 mg, yellow solid), yield: 22 percent.

MS m/z(ESI): 483 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (s, 1H), 8.35 (s, 1H), 8.26-8.13 (m, 2H),7.94 (s, 1H), 7.80 (s, 1H), 7.69-7.58 (m, 2H), 7.37-7.28 (m, 1H), 6.73-6.60(m, 1H), 4.44-4.26 (m, 2H), 4.25-4.11 (m, 2H), 3.99 (s, 3H), 3.70-3.44 (m,2H), 2.79-2.62 (m, 1H), 1.60-1.51 (m, 1H), 1.41 (s, 9H)。

Example 116

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Mixing tert-butyl heptane-6-carboxylate 115 (50 mg, 0.1 mmol) and hydrogen chloride (6 mL, 24 mmol, 4M in methanol), stirring at room temperature for 1 hr, desolventizing under reduced pressure, adding saturated aqueous sodium bicarbonate (10 mL) to the residue, extracting with dichloromethane (10 mL × 4), drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and desolventizing under reduced pressure to obtain the target product 3- (5- (7- (1-methyl-1) 3- (5-methyl-1-hydroxy-ethyl-5-methyl-ethyl-1-hydroxy-ethylH-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 116 (35 mg, yellow solid), the product was used in the next reaction without purification.

MS m/z(ESI): 383 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.98-8.85 (m, 1H), 8.37 (s, 1H), 8.29-8.14 (m,2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.73-7.65 (m, 1H), 7.62 (s, 1H), 7.36-7.29(m, 1H), 6.77-6.65 (m, 1H), 3.99 (s, 3H), 3.97-3.89 (m, 2H), 3.89-3.67 (m,4H), 2.89-2.74 (m, 1H), 1.67-1.62 (m, 1H)。

Example 117

6-benzyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 116 (10 mg, 0.026 mmol), benzaldehyde (6 mg, 0.05 mmol), sodium borohydride acetate (11 mg, 0.052 mmol) and tetrahydrofuran (5 mL) were mixed and stirred at room temperature for 16 hours. Vacuum desolventizing to obtain crude product, purifying with preparative liquid phase (Xbridge-C18; 30X 150 mm preparative column, 5 μm; MeCN/H)₂O20% -50%) to obtain the target product 6-benzyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 117 (2.5 mg, white solid), yield: 20 percent.

MS m/z (ESI): 473 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.96-8.88 (m, 1H), 8.41 (s, 1H), 8.30-8.23 (m,1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.74-7.68 (m, 1H), 7.65 (s,1H), 7.46-7.39 (m, 2H), 7.39-7.28 (m, 4H), 6.79-6.69 (m, 1H), 4.08-4.03 (m,2H), 4.02-3.94 (m, 5H), 3.88-3.80 (m, 2H), 3.77-3.70 (m, 2H), 2.91-2.89 (m,1H), 1.80-1.73 (m, 1H)。

Synthetic procedures for carrying out examples 118 to 120 reference was made to the procedure of example 117: wherein benzaldehyde is substituted with a different aldehyde.

Example 118

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -6- (pyridin-2-ylmethyl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

MS m/z (ESI): 474 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.98-8.84 (m, 1H), 8.66-8.50 (m, 1H), 8.39 (s,1H), 8.33 (s, 1H), 8.28-8.18 (m, 2H), 7.95 (s, 1H), 7.82 (s, 1H), 7.78-7.67(m, 2H), 7.64 (s, 1H), 7.58-7.46 (m, 1H), 7.40-7.31 (m,1H), 6.83-6.66 (m,1H), 4.33-4.20 (m, 2H), 4.17-4.07 (m, 4H), 4.00 (s, 3H), 3.86-3.78 (m, 2H),3.04-2.88 (m, 1H), 1.89-1.74 (m, 1H)。

Example 119

6- (3-fluorophenylmethyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

MS m/z (ESI): 491 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.40 (s, 1H), 8.24(d,J= 8.8 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.70 (d,J=8.8 Hz, 1H), 7.64 (s, 1H), 7.32-7.28 (m, 2H), 7.20-7.17 (m, 2H), 6.99-6.94(m, 1H), 6.71 (d,J= 8.8 Hz, 1H), 4.00 (s, 3H), 3.95-3.82 (m, 4H), 3.75-3.62(m, 4H), 2.93-2.81 (m, 1H), 1.67-1.60 (m, 1H)。

Example 120

6- (3-chlorobenzyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

MS m/z (ESI): 507&509 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 2.8 Hz, 1H), 8.40 (d,J= 2.4 Hz,1H), 8.25 (d,J= 4.4 Hz, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H),7.72-7.69 (m, 1H), 7.64 (d,J= 1.6 Hz, 1H), 7.53 (d,J= 8.8 Hz, 1H), 7.42(s, 1H), 7.36-7.31 (m, 2H), 7.25 (s, 1H), 6.73 (d,J= 8.4 Hz, 1H), 4.00 (s,3H), 3.90-3.87 (m, 4H), 3.54-3.51 (m, 2H), 3.49 (s, 2H), 2.36-2.20 (m, 2H)。

Example 121

1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) -2-phenylethane-1-one

Mixing 3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 116 (5 mg, 0.01 mmol), phenylacetic acid (14 mg, 0.1 mmol), triethylamine (11 mg, 0.1 mmol), 2- (7-oxybenzotriazole) -N,N,N',N'-tetramethyluronium hexafluorophosphate (38 mg, 0.1 mmol) was dissolved inN,N-dimethylformamide (2 mL), stirring at room temperature for 1 hour, adding 2mL of saturated aqueous lithium hydroxide solution, stirring for 10 minutes, extracting with dichloromethane (5 mL × 2), drying the organic phase over anhydrous sodium sulfate, filtering, spin-drying the filtrate, and purifying by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain the objective product 1- (3- (5- (7- (1-methyl-1: 1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptan-6-yl) -2-phenylethane-1-one 121 (3 mg, white solid) in 46% yield.

MS m/z (ESI): 501 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.33 (d,J= 4.0 Hz,1H), 8.22-8.19 (m, 2H), 7.94 (s, 1H), 7.81 (s, 1H), 7.70-7.60 (m, 2H), 7.34(d,J= 8.0 Hz, 1H), 7.32-7.27 (m, 5H), 6.63 (d,J= 8.0 Hz, 1H), 4.67-4.52(m, 2H), 4.00 (s, 3H), 3.88-3.78 (m, 2H), 3.69-3.62 (m, 2H), 3.49 (s, 2H),2.80-2.75 (m, 1H), 2.24-2.19 (m, 1H)。

Synthesis procedure for carrying out examples 122 to 127 reference is made to the procedure of example 121: wherein different acids are substituted.

Example 122

2- (5-Fluoropyridin-2-yl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

MS m/z (ESI): 520 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.34-8.33 (m, 2H),8.22 (d,J= 8.0 Hz, 2H), 7.95 (s, 1H), 7.83 (s, 1H), 7.70-7.61 (m, 2H),7.42-7.37 (m, 1H), 7.36-7.32 (m, 2H), 6.66 (d,J= 8.0 Hz, 1H), 4.79-7.67 (m,2H), 4.00 (s, 3H), 3.81-3.62 (m, 4H), 3.49 (s, 2H), 2.86-2.81 (m, 1H), 2.27-2.18 (m, 1H)。

Example 123

2- (3-chlorophenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

MS m/z (ESI): 535&537 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 3.6 Hz, 1H), 8.33 (d,J= 2.0 Hz,1H), 8.22-8.20 (m, 2H), 7.94 (s, 1H), 7.81 (s, 1H), 7.68-7.65 (dd,J _1,2= 8.8,2.4 Hz, 1H), 7.62 (d,J= 1.6 Hz, 1H), 7.34-7.32 (m, 1H), 7.28-7.26 (m, 1H),7.23-7.21 (m, 2H), 7.18-7.13 (m, 1H), 6.64 (d,J= 8.8 Hz, 1H), 4.68-4.66 (m,1H), 4.59-4.57 (m, 1H), 4.21-4.18 (m, 1H), 4.00 (s, 3H), 3.93-3.84 (m, 2H),3.66-3.63 (m, 1H), 358-3.46 (m, 2H), 1.72 (d,J= 8.8 Hz, 2H)。

Example 124

2- (3-fluorophenyl) -1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

MS m/z (ESI): 519 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 3.6 Hz, 1H), 8.32 (d,J= 2.4 Hz,1H), 8.20 (d,J= 8.0 Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H),7.67-7.65 (m, 1H), 7.61 (d,J= 1.2 Hz, 1H), 7.34-7.31 (m, 1H), 7.28-7.23 (m,1H), 7.06-6.99 (m, 2H), 6.96-6.92 (m, 1H), 6.64 (d,J= 8.4 Hz, 1H), 4.00 (s,3H), 3.92-3.83 (m, 2H), 3.66-3.52 (m, 4H), 3.49 (s, 2H), 2.84-2.78 (m, 2H)。

Example 125

(3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) (phenyl) methanones

MS m/z (ESI): 487 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 4.0 Hz, 1H), 8.31 (d,J= 4.0 Hz,1H), 8.22-8.19 (m, 2H), 7.93 (s, 1H), 7.80 (s, 1H), 7.67-7.64 (m, 3H), 7.61(d,J= 4.0 Hz, 1H), 7.48 (d,J= 8.0 Hz, 1H), 7.44-7.40 (m, 2H), 7.33-7.30(m, 1H), 6.66 (d,J= 8.0 Hz, 1H), 4.80-4.74 (m, 2H), 3.99 (s, 3H), 3.84-3.64(m, 4H), 2.98-2.93 (m, 1H), 2.03-1.98 (m, 1H)。

Example 126

2- (3- (2- (dimethylamino) ethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

MS m/z (ESI): 588 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 3.2 Hz, 1H), 8.33 (d,J= 2.4 Hz,1H), 8.22-8.19 (m, 2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.68-7.65 (dd,J _1,2= 8.8,2.4 Hz, 1H), 7.62 (d,J= 1.6, 1H), 7.36-7.32 (m, 1H), 7.23-7.19 (m, 1H),6.90-6.85 (m, 2H), 6.81-6.79 (m, 1H), 6.64 (d,J= 8.8 Hz, 1H), 4.67-4.65 (m,1H), 4.59-4.57 (m, 1H), 4.29-4.26 (m, 2H), 4.00 (s, 3H), 3.90-3.82 (m, 2H),3.70-3.64 (m, 2H), 358-3.46 (m, 2H), 3.14-3.11 (m, 2H), 2.66 (s, 6H), 1.72(d,J= 8.8 Hz, 2H)。

Example 127

2- (3- (2-hydroxyethoxy) phenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

MS m/z (ESI): 561 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 3.6 Hz, 1H), 8.32 (d,J= 2.0 Hz,1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.67-7.65 (m,2H), 7.36-7.33 (m, 1H), 7.21 (t,J= 8.4 Hz, 1H), 6.88-6.84 (m, 2H), 6.82-6.79 (m, 1H), 6.63 (d,J= 8.8 Hz, 1H), 4.68-4.66 (m, 1H), 4.56-4.54 (m, 1H),4.19-4.17 (m, 1H), 4.06-4.02 (m, 2H), 4.00 (s, 3H), 3.90 (t,J= 4.4 Hz, 1H),3.85-3.83 (m, 2H), 3.66-3.63 (m, 1H), 3.58-3.50 (m, 1H), 3.49 (s, 2H), 2.36-2.20 (m, 2H)。

Example 128

N-isobutyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxamide

Mixing 3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 116 (5 mg, 0.01 mmol), 2-methylpropan-1-amine (1 mg, 0.01 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (4 mg, 0.04 mmol) andN,Ncarbonyl diimidazole (2.1 mg, 0.01 mmol), stirring at 80 ℃ for 4 hours, adding 2mL of a saturated saline solution, stirring for 10 minutes, extracting with dichloromethane (5 mL × 2), drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying the filtrate, and purifying by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtainN-isobutyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxamide 128 (1.5 mg, white solid), yield 24%.

MS m/z (ESI): 482 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.90 (d,J= 4.0 Hz, 1H), 8.32 (d,J= 4.0 Hz,1H), 8.22-8.19 (m, 2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.68-7.59 (m, 2H), 7.34-7.31 (m, 2H), 6.68 (d,J= 8.0 Hz, 1H), 4.39-4.37 (m, 2H), 4.24-4.21 (m, 2H),4.00 (s, 3H), 3.61-3.58 (m, 2H), 3.05-3.01 (m, 2H), 2.78-2.73 (m, 1H), 2.24-2.17 (m, 2H) , 0.87 (d,J= 8.0 Hz, 6H)。

Example 129

6-benzyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

First step of

7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline

5-bromo-7-chloroquinoline 76f (0.10 g, 0.47 mmol), 4,4,4',4',5,5' -hexamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (0.13 g, 0.49 mmol) were dissolved in tetrahydrofuran (10 mL), potassium acetate (0.13 g, 1.34 mmol) and 1,1 ' -bis (diphenylphosphino) ferrocene dichloropalladium (0.04 g, 0.04 mmol) were added, the system was bubbled with nitrogen for 10 minutes, stirred at 60 ℃ for 2 hours under nitrogen protection, and rotary evaporated directly to give crude 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-diboronol-2-yl) quinoline 129a (0.14 g), which was used in the next step without purification.

MS m/z (ESI): 290 [M + 1]；

Second step of

3- (5- (7-Chloroquinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester

Tert-butyl 3- (5-bromopyrazin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate 75a (85 mg, 0.36 mmol), 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline 129a (0.14 g, 0.47 mmol) were dissolved in 1, 4-dioxane (25 mL) and water (1 mL), potassium carbonate (0.70 g, 0.54 mmol) and tetrakis (triphenylphosphine) palladium (4 mg, 0.004 mmol) were added, the system was bubbled with nitrogen for 10 minutes, stirred at 80 ℃ for 2 hours, extracted with dichloromethane (5 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was rotary dried, and purified with silica gel column (petroleum ether: ethyl acetate = 2: 1) to give 3- (5- (7-chloroquinoline: -5-chloroquinoline) -5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester 129b (100 mg, light yellow solid) in 99.1% yield.

MS m/z (ESI): 438 [M + 1]；

The third step

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester

Will give 3- (5- (7-chloroquinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Tert-butyl heptane-6-carboxylate 129b (0.12 g, 0.27 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (purchased from Bigde pharmaceutical science Co., Ltd.) (0.08 g, 0.40 mmol) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL), potassium phosphate (0.17 g, 0.60 mmol) and tetrakis (triphenylphosphine) palladium (0.02 g, 0.02 mmol) were added with stirring, the reaction solution was bubbled with nitrogen for 10 minutes to remove oxygen, then stirred at 120 ℃ overnight, concentrated and purified by silica gel column (dichloromethane: methanol = 20:1) to obtain 3- (5- (7- (1-methyl-1) 3- (5-methyl-1-boronic acid)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Tert-butyl heptane-6-carboxylate 129c (80 mg, white solid) in 61% yield.

MS m/z (ESI): 484 [M + 1]；

The fourth step

3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Mixing 3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carboxylic acid tert-butyl ester 129c (0.08 g, 0.16 mmol) is dissolved in 1, 4-dioxane (1 mL), hydrogen chloride (5 mL, 20mmol, 4M1, 4-dioxane solution) is added at room temperature, stirring is carried out at room temperature for 1 hour, concentration and spin-drying are carried out to obtain crude hydrochloride, 5mL of dichloromethane and 1mL of triethylamine are added, stirring is carried out for 10 minutes, concentration and spin-drying are carried out to obtain crude 3- (5- (7- (1-methyl-1-yl-5-methyl-1-ethyl-methyl-5-carboxylateH-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 129d (30 mg, yellow solid), crude.

MS m/z (ESI): 384 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.92-8.90 (m, 1H), 8.51 (d,J= 8.0 Hz, 1H),8.45 (s, 1H), 8.26-8.20 (m, 2H), 7.96 (s, 1H), 7.83-7.79 (m, 2H), 7.37-7.33(m, 1H), 4.05-4.01 (m, 2H), 4.00 (s, 3H), 3.93-3.86(m, 4H), 2.30-2.19 (m,1H), 2.06-1.96 (m, 1H)。

The fifth step

Mixing 3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 129d (5 mg, 0.01 mmol), benzaldehyde (2.0 mg, 0.01 mmol), dissolved in methanol (2 mL), added sodium borohydride acetate (8.5 mg, 0.04 mmol) with stirring, stirred at room temperature overnight, added 2mL saturated ammonium chloride solution, stirred for 10 min, extracted with dichloromethane (5 mL × 2), the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried and purified on silica gel column (dichloromethane: methanol = 15: 1) to give 6-benzyl-3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (4.5 mg, white solid), yield 77%.

MS m/z (ESI): 474 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.92 (d,J= 4.0 Hz, 1H), 8.54 (d,J= 8.0 Hz,1H), 8.47 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.84-7.82 (m,2H), 7.43-7.32 (m, 5H), 7.29 (s, 1H), 4.00 (s, 3H), 3.96-3.90 (m, 4H), 3.74(s, 2H), 3.69-3.66 (m, 2H), 2.86-2.81 (m, 1H), 2.26-2.15 (m, 1H)。

Example 130

6- (3-fluorophenylmethyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)

Synthesis example 130 according to the fifth operating step of example 129, in which benzaldehyde is substituted with m-fluorobenzaldehyde to give the desired product 6- (3-fluorobenzyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]And heptane 130.

MS m/z (ESI): 492 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.93 (d,J= 4.0 Hz, 1H), 8.56 (d,J= 8.0 Hz,1H), 8.48 (s, 1H), 8.30-8.24 (m, 2H), 7.97 (s, 1H), 7.85-7.80 (m, 2H), 7.39-7.36 (m, 1H), 7.33-7.28 (m, 1H), 7.22-7.15 (m, 2H), 6.70-6.96 (m, 1H), 4.00(s, 3H), 3.98-3.93 (m, 4H), 3.78 (s, 2H), 3.74-3.71 (m, 2H), 2.95-2.88 (m,1H), 2.25-2.19 (m, 1H)。

Example 131

2- (3-methoxyphenyl) -1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

Mixing 3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane 129d (5 mg, 0.01 mmol), 2- (3-methoxyphenyl) acetic acid (2.3 mg, 0.01 mmol) were dissolved in dichloromethane (2 mL), and triethylamine (4 mg, 0.04 mmol) and 2- (7-oxybenzotriazole) -N,N,N',N'Tetramethyluronium hexafluorophosphate (5 mg, 0.01 mmol) was stirred at room temperature for half an hour, 2mL of a saturated lithium hydroxide solution was added, stirred for 10 minutes, extracted with dichloromethane (5 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spinning and purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain 2- (3-methoxyphenyl) -1- (3- (5- (7- (1-methyl-1): 1)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptan-6-yl) ethan-1-one 131 (3 mg, white solid), yield 41%.

MS m/z (ESI): 532 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0 Hz, 1H), 8.50 (d,J= 8.0 Hz,1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H),7.80 (s, 1H), 7.38-7.35 (m, 1H), 7.23-7.19 (m, 1H), 6.88-6.75 (m, 3H), 4.71-4.65 (m, 1H), 4.58-4.53 (m, 1H), 4.00 (s, 3H), 3.73 (s, 2H), 3.71 (s, 3H),3.60-3.50 (m, 4H), 2.85-2.78 (m, 1H), 2.27-2.16 (m, 1H)。

Example 132

2- (3-fluorophenyl) -1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) ethan-1-one

Synthesis example 132 according to the procedure of example 131, wherein m-methoxyphenylacetic acid was substituted with m-fluorophenylacetic acid to give the objective 2- (3-fluorophenyl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptan-6-yl) ethan-1-one 132.

MS m/z (ESI): 520 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.92 (d,J= 4.0 Hz, 1H), 8.50 (d,J= 8.0 Hz,1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.84-7.77 (m,2H), 7.39-7.36 (m, 1H), 7.06-6.92 (m, 4H), 4.72-4.67 (m, 1H), 4.63-4.57 (m,1H), 4.00 (s, 3H), 3.82 (s, 2H), 3.74-3.47 (m, 4H), 2.88-2.80 (m, 1H), 2.27-2.16 (m, 1H)。

Example 133

(2, 6-difluorophenyl) (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) methanones

Synthesis example 133 was synthesized by reference to the procedure of example 131, wherein m-methoxyphenylacetic acid was substituted with 2, 6-difluorobenzoic acid to give the desired product (2, 6-difluorophenyl) (3- (5- (7- (1-methyl-1-yl-1))H-pyrazol-4-yl) quinolin-5-yl) pyrazin-2-yl) -3, 6-diazaBicyclo [3.1.1]Heptane-6-yl) methanone 133.

MS m/z (ESI): 524 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.91 (d,J= 4.0, 1H), 8.51 (d,J= 8.0 Hz,1H), 8.43 (s, 1H), 8.23 (d,J= 4.0 Hz, 2H), 7.95 (d,J= 8.0 Hz, 1H), 7.85-7.79 (m, 2H), 7.41-7.34 (m, 2H), 7.00-6.96 (m, 2H), 4.45-4.35 (m, 2H), 4.00(s, 3H), 3.93-3.76 (m, 4H), 3.02-2.97 (m, 1H), 2.24-2.20 (m, 1H)。

Example 134

7- (1-cyclopropyl-1)H-pyrazol-4-yl) -5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) quinazoline

First step of

(5-bromo-1, 3-phenylene) dicarbamic acid diethyl ester

The compound 134a (2.45 g, 10.00 mmol) of 5-bromo-1, 3-benzenedicarboxylic acid was dissolved in toluene (20 mL) and absolute ethanol (20 mL) in a 120 mL sealed tube, and diphenyl phosphorazidate (5.50 g, 20.00 mmol) and triethylamine (2.02 g, 20.0 mmol) were added under nitrogen protection at room temperature with stirring, and the sealed tube was heated to 70 ℃ for 16 hours. Cooling to room temperature, quenching with saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate (50 mL × 3), drying over anhydrous sodium sulfate, filtering off the drying agent, spin-drying, and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1-4/1), thereby obtaining the target product diethyl (5-bromo-1, 3-phenylene) dicarbamate 134b (1.15 g, gray solid). Yield: 35 percent.

MS m/z (ESI): 331&333 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 7.45 (s, 1H), 7.30 (d,J= 1.6 Hz, 2H), 6.57(bs, 2H), 4.22 (t,J= 7.2 Hz, 4H), 1.31 (t,J= 7.2 Hz, 6H)。

Second step of

5-bromo-7- ((ethoxycarbonyl) amino) quinazoline-1 (2)H) -Carboxylic acid ethyl ester

The compound diethyl 5-bromo-1, 3-phenylene dicarbamate 134b (0.66 g, 2.0 mmol), hexamethylenetetramine (0.84 g, 1.13 mol) were dissolved in trifluoroacetic acid (4 mL), then heated to 85 ℃ for 4 hours, cooled to room temperature, directly dried, the residue quenched with aqueous sodium bicarbonate solution to an aqueous pH of about 8, extracted with ethyl acetate (25 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was used directly in the next step, whereby the desired product 5-bromo-7- ((ethoxycarbonyl) amino) quinazoline-1 (2)H) Ethyl carboxylate 134c (0.61 g, yellow solid), crude.

MS m/z (ESI)：370&372 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.48 (s, 1H), 7.70 (d,J= 1.6 Hz, 1H), 6.79(s, 1H), 6.69 (s, 2H), 5.28 (d,J= 2.0 Hz, 1H), 4.26 (d,J= 7.2 Hz, 4H),1.37-1.29 (m, 6H)。

The third step

5- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -7- ((acetoxycarbonyl) amino) quinazoline-1 (2)H) -carboxylic acid ethyl ester 134d

Reacting the compound 5-bromo-7- ((ethoxycarbonyl) amino) quinazoline-1 (2)H) -carboxylic acid ethyl ester 134c (0.55 g, 1.6 mmol), 4- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) piperidin-2-yl]Tert-butyl diethyldiamine-1-carboxylate (0.67 g, 1.7 mmol), sodium carbonate (0.53 g, 5.0 mmol), tetrakis (triphenylphosphine) palladium (0.12 g, 0.1 mmol), 1, 4-dioxane (5 mL) and water (3 mL) were mixed and 120 mL of a stoppered tube was added, replaced with argon three times, and stirred at 80 ℃ for 3 hours. Cooling to room temperature, desolventizing under reduced pressure to obtain a crude product, and purifying the residue by flash column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain the target product 5- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -7- ((acetoxycarbonyl) amino) quinazoline-1 (2)H) Ethyl carboxylate 134d (0.67 g, yellow solid), yield: 55% (two steps)Yield).

MS m/z (ESI): 553 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.17 (d,J= 2.4 Hz, 1H), 8.10 (s, 1H), 7.79(d,J= 2.4 Hz, 1H), 7.58-7.43 (m, 1H), 7.32 (s, 1H), 6.95 (s, 1H), 6.69 (d,J= 8.8 Hz, 1H), 5.28 (d,J= 2.4 Hz, 2H), 4.32-4.19 (m, 4H), 3.62-3.52 (m,8H), 1.49 (s, 9H), 1.37-1.20 (m, 6H)。

The fourth step

7- ((Acetyloxycarbonyl) amino) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazolin-1 (2)H) -Carboxylic acid ethyl ester

Ethyl 5- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -7- ((acetoxycarbonyl) amino) quinazoline-1 (2H) -carboxylate 134d (0.35 g, 0.63 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2.5 mL) was added at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction solution was desolventized under reduced pressure, and the residue was dissolved in methylene chloride/methanol (10: 1) and washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure to give the target product ethyl 7- ((acetoxycarbonyl) amino) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazoline-1 (2H) -carboxylate 134e (0.25 g, crude, yellow solid). The crude product was directly subjected to the next reaction.

MS m/z (ESI): 453 [M + 1]；

The fifth step

7- ((Acetyloxycarbonyl) amino) -5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) quinazolin-1 (2)H) -Carboxylic acid ethyl ester

The compound 7- ((acetoxycarbonyl) amino) -5- (6- (piperazin-1-yl) pyridin-3-yl) quinazolin-1 (2)H) Ethyl carboxylate 134e (crude, 0.25 g) and m-fluorobenzaldehyde (0.21 g, 1.66 mmol) were dissolved in methanol (5 mL), sodium borohydride acetate (0.70 g, 3.32 mmol) was added at room temperature, the reaction was stirred at 50 ℃ for 12 hours, the reaction solution was diluted with dichloromethane (100 mL), quenched with saturated aqueous ammonium chloride (50 mL), after separation, the aqueous phase was extracted with dichloromethane (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, desolventized under reduced pressure, and the residue was used as a solventSilica gel plate preparation and purification (dichloromethane/methanol 20:1) are carried out to obtain the target product 7- ((acetoxycarbonyl) amino) -5- (6- (4- (3-fluorobenzyl) piperazine-1-yl) pyridine-3-yl) quinazoline-1 (2)H) Ethyl carboxylate 134f (0.15 g, yellow solid). Two-step yield: 45 percent.

MS m/z(ESI): 561 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 8.18-8.14 (m, 2H), 7.88-7.85 (m, 2H), 7.74 (d,J= 8.8 Hz, 1H), 7.49 (d,J= 8.0 Hz, 1H), 7.18-7.11 (m, 2H), 7.03-6.99 (m,1H), 6.70 (d,J= 8.8 Hz, 1H), 5.30 (s, 2H), 4.32-4.18 (m, 4H), 3.87 (s, 2H),3.75-3.72 (m, 4H), 2.82-2.79 (m, 4H), 1.35-1.30 (m, 6H)。

The sixth step

5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) quinazolin-7-amine

The compound 7- ((acetoxycarbonyl) amino) -5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) quinazolin-1 (2)H) Ethyl carboxylate 134f (0.15 g, 0.27 mmol) and potassium hydroxide (0.30 g, 5.38 mmol) were dissolved in ethanol (4 mL) and water (4 mL) and reacted at 80 ℃ for 1 hour, and then potassium ferricyanide (0.44 g, 1.34 mmol) was added thereto and reacted at 80 ℃ for 2 hours. The reaction mixture was filtered, the filter cake was washed with dichloromethane/methanol (10: 1, 50 mL), the filtrates were combined, the layers were separated, and the aqueous phase was extracted with dichloromethane/methanol (10: 1, 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give 134g (0.10 g, brown solid) of the desired product 5-bromoquinazolin-7-amine in 90% yield.

MS m/z (ESI): 415 [M + 1]；

Seventh step

5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7-iodoquinazoline

134g (0.10 g, 0.24 mmol) of the compound 5-bromoquinazolin-7-amine was dissolved in 10% hydrochloric acid solution (6 mL), an aqueous solution (2 mL) of sodium nitrite (50 mg, 0.73 mmol) was added dropwise in an ice bath, and after the mixture was stirred at low temperature for 30 minutes, an aqueous solution (2 mL) of potassium iodide (0.20 g, 1.21 mmol) was added dropwise thereto, followed by reaction at 45 ℃ for 2 hours. The reaction was quenched with saturated aqueous sodium sulfite (5 mL) and aqueous sodium bicarbonate (5 mL) to pH 8, respectively. The mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the desired product 5-bromo-7-iodoquinazoline 134h (30 mg, yellow solid) in 24% yield.

MS m/z (ESI): 526 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.43 (s, 1H), 9.31 (s, 1H), 8.45 (s, 1H), 8.30(s, 1H), 7.86 (s, 1H), 7.60 (d,J= 7.6 Hz, 1H), 7.31-7.27 (m, 1H), 7.14-7.12(m, 2H), 6.99 (t,J= 7.6 Hz, 1H), 6.78 (d,J= 8.6 Hz, 1H), 3.71-3.68 (m,4H), 3.59 (s, 2H), 2.63-2.61 (m, 4H)。

Eighth step

The compound 5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7-iodoquinazoline 134h (3 mg, 0.01 mmol), 1-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (3 mg, 0.02 mmol), tetrakis (triphenylphosphine) palladium (3 mg, 0.01 mmol) and potassium carbonate (3 mg, 0.02 mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.5 mL) and stirred under nitrogen at 100 ℃ in an oil bath for 1 hour. The reaction solution was filtered, and the filtrate was desolventized under reduced pressure to purify the reaction solution by plate preparation (dichloromethane: methanol = 10: 1) to obtain the target product 7- (1-cyclopropyl-1)H-pyrazol-4-yl) -5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) quinazoline 134 (3 mg, yellow solid), yield: 80 percent.

MS m/z (ESI): 506 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.35 (d,J= 2.0Hz, 1H), 8.05 (s, 1H), 7.94 (d,J= 5.2 Hz, 2H), 7.67-7.64 (m, 2H), 7.16-7.16(m, 3H), 7.00-6.96 (m, 1H), 6.80 (d,J= 8.8 Hz, 1H), 3.71-3.66 (m, 4H), 3.59(s, 2H), 2.62 (d,J= 4.8 Hz, 4H), 2.24-2.20 (m, 1H), 1.21-1.06 (m, 4H)。

Synthetic procedures for examples 135 to 139 reference the eighth procedure of example 134: substitution of 1-cyclopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1 with different boronic estersH-a pyrazole.

Example 135

7- (1-Ethyl-1)H-pyrazol-4-yl) -5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) quinazoline

MS m/z (ESI): 494 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.28 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.68-7.65 (m, 2H), 7.15-7.13 (m, 3H), 7.00-6.96 (m, 1H), 6.80 (d,J= 8.8 Hz, 1H), 4.30-4.24 (m, 2H),3.70 (t,J= 4.8 Hz, 4H), 3.59 (s, 2H), 2.62 (d,J= 4.8 Hz, 4H), 1.33-1.31(m, 3H)。

Example 136

2- (4- (5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) quinazolin-7-yl) -1H-pyrazol-1-yl) ethan-1-ol

MS m/z (ESI): 510 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.36 (s, 1H), 9.27 (s, 1H), 8.35 (d,J= 2.0Hz, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.66-7.64 (m, 2H), 7.34-7.28 (m, 1H), 7.15-7.12 (m, 2H), 7.00-6.96 (m, 1H), 6.80 (d,J= 8.8 Hz, 1H),4.36-4.33 (m, 4H), 3.69 (t,J= 4.8 Hz, 4H), 3.59 (s, 2H), 2.62 (d,J= 4.8Hz, 4H)。

Example 137

5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) quinazolines

MS m/z (ESI): 550 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.37 (s, 1H), 9.29 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.71-7.69 (m, 1H), 7.48-7.44 (m, 1H), 7.16-7.13 (m, 2H), 7.00-6.97 (m, 2H), 6.81 (d,J= 8.8 Hz, 1H),4.30-4.28 (m, 1H), 4.17-4.10 (m, 4H), 3.71-3.69 (m, 4H), 3.61-3.56 (m, 4H),3.49 (s, 2H), 2.13-1.95 (m, 4H)。

Example 138

5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-3-yl) quinazolines

MS m/z (ESI): 480 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.41 (s, 1H), 9.30 (s, 1H), 8.38 (d,J= 2.4Hz, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.70-7.67 (m, 1H), 7.54-7.52 (m, 1H),7.47-7.46 (m, 1H), 7.36-7.34 (m, 1H), 7.16-7.11 (m, 2H), 6.83-6.78 (m, 2H),4.01 (s, 2H), 3.71-3.70 (m, 4H), 3.49 (s, 3H), 2.63-2.61 (m, 4H)。

Example 139

7- (1, 5-dimethyl-1)H-pyrazol-4-yl) -5- (6- (4- (3-fluorobenzyl) piperazin-1-yl) pyridin-3-yl) quinazoline

MS m/z (ESI): 494 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.41 (s, 1H), 9.30 (s, 1H), 8.36 (d,J= 2.4Hz, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.63-7.61 (m, 1H), 7.56-7.52 (m, 1H),7.49-7.45 (m, 2H), 7.15-7.09 (m, 2H), 6.81 (d,J= 8.8 Hz, 1H), 3.91 (s, 2H),3.83-3.49 (m, 4H), 3.70 (s, 3H), 2.62 (s, 3H), 2.36-2.20 (m, 4H)。

Example 140

7-ethoxy-5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) quinazoline

First step of

2-chloro-4-ethoxy-6-fluorobenzaldehyde

The compound 2-chloro-6-fluoro-4-hydroxybenzaldehyde 140a (1.74 g, 10.00 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (2.76 g, 20.00 mmol) and iodoethane (2.34 g, 15.00 mmol) were added with stirring, stirred at 50 ℃ for 2 hours, cooled to room temperature, extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, spun-dried, and purified on silica gel column (petroleum ether: ethyl acetate = 10: 1) to give 2-chloro-4-ethoxy-6-fluorobenzaldehyde 140b (1.82 g, white solid) in 90% yield.

MS m/z (ESI): 203 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 10.32 (s, 1H), 6.78 (s, 1H), 6.59-6.55 (m, 1H),4.10 (q,J= 6.8 Hz, 2H), 1.45 (t,J= 6.8 Hz, 3H)。

Second step of

5-chloro-7-ethoxyquinazoline

The compound 2-chloro-4-ethoxy-6-fluorobenzaldehyde 140b (1.01 g, 5.00 mmol) was dissolved in dimethyl sulfoxide (30 mL), potassium carbonate (2.07 g, 15.00 mmol) and formamidine acetate (1.04 g, 10.00 mmol) were added with stirring, stirred at 110 ℃ for 6 hours, cooled to room temperature, extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, spun-dried, and purified with silica gel column (petroleum ether: ethyl acetate = 20:1) to give 5-chloro-7-ethoxyquinazoline 140c (0.36 g, yellow solid) in 35% yield.

MS m/z (ESI): 209 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.56 (s, 1H), 9.25 (s, 1H), 7.33 (s, 1H), 7.21(s, 1H), 4.21 (q,J= 6.8 Hz, 2H), 1.51 (t,J= 6.8 Hz, 3H)。

The third step

{1- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl ] -4-methylpiperidin-4-yl } carbamic acid tert-butyl ester

The compound 4- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-yl]Piperazine-1-carboxylic acid tert-butyl ester (0.19 g, 0.50 mmol), 5-chloro-7-ethoxyquinazoline 140c (52 mg, 0.25 mmol), potassium phosphate (0.14 g, 1.00 mmol) were dissolved inN,N-dimethylformamide (5 mL) and water (1 mL), tetrakis (triphenylphosphine) palladium (58 mg, 0.05 mmol) was added under nitrogen, heated to 120 ℃ and stirred for 8 h cooling to room temperature, ethyl acetate was added for extraction (30 mL), the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, spun dry and purified on silica gel plates (dichloromethane/methanol = 40: 1) to give the desired product 4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl]Piperazine-1-carboxylic acid tert-butyl ester 140d (30 mg, 0.07 mmol, yellow solid), yield: 29 percent.

MS m/z (ESI): 436 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.24 (s, 1H), 9.20 (s, 1H), 8.30 (s, 1H), 7.63(d,J= 8.8 Hz, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 6.78 (d,J= 8.8 Hz, 1H),4.25 (q,J= 6.8 Hz, 2H), 3.68-3.64 (m, 4H), 3.61-3.57 (m, 4H), 1.54-1.50 (m,12H)。

The fourth step

4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl ] piperazine hydrochloride

Compound 4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl ] piperazine-1-carboxylic acid tert-butyl ester 140d (30 mg, 0.07 mmol) was dissolved in hydrogen chloride (4M, 20mmol, 5mL in methanol) and stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation under reduced pressure to give the target compound 4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl ] piperazine hydrochloride 140e (26 mg, 0.07 mmol, yellow solid), yield: 100 percent.

MS m/z (ESI): 336 [M + 1]；

The fifth step

4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl ] piperazine hydrochloride 140e (5 mg, 0.015 mmol), m-fluorobenzaldehyde (12 mg, 0.1 mmol) were dissolved in methanol (1 mL), and sodium cyanoborohydride (6 mg, 0.1 mmol) was added with stirring and stirred at room temperature overnight. 2mL of saturated ammonium chloride solution was added, stirred for 10 minutes, extracted with dichloromethane (5 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Purification on silica gel (dichloromethane: methanol = 30: 1) afforded 7-ethoxy-5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) quinazoline 140 (3 mg, white solid) in 46% yield.

MS m/z (ESI): 444 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.25 (s, 1H), 9.20 (s, 1H), 8.31 (s, 1H), 7.61(d,J= 8.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.17-7.12 (m, 3H), 6.99-.6.97 (m,1H), 6.77 (d,J= 8.8 Hz, 1H), 4.25 (q,J= 6.8 Hz, 2H), 3.70-3.68 (m, 4H),3.65 (s, 2H), 2.63-2.61 (m, 4H), 1.52 (t,J= 6.8 Hz , 3H)。

Example 141

1- (4- (5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylethane-1-one

4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl ] piperazine hydrochloride 140e (5 mg, 0.015 mmol), triethylamine (4 mg, 0.04 mmol) were dissolved in dichloromethane (2 mL), 2-phenylacetyl chloride (3 mg, 0.02 mmol) was added with stirring, stirred at room temperature for 10 minutes, 2mL of a saturated lithium hydroxide solution was added with stirring for 10 minutes, extracted with dichloromethane (5 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry, silica gel plate purified (dichloromethane: methanol = 30: 1) to give 1- (4- (5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2-phenylethane-1-one 141 (1.5 mg, white solid), yield 22%.

MS m/z (ESI): 454 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.22 (s, 1H), 9.20 (s, 1H), 8.29 (s, 1H), 7.63(d,J= 8.8 Hz, 1H), 7.36-7.28 (m, 6H), 7.17 (s, 1H), 6.75 (d,J= 8.8 Hz,1H), 4.26 (q,J= 6.8 Hz, 2H), 3.94-3.82 (m, 4H), 3.63-3.61 (m, 4H), 3.54-3.52 (m, 2H), 1.52 (t,J= 6.8 Hz , 3H)。

Example 142

(2, 5-difluorophenyl) (4- (5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) methanone

Example 142 was synthesized according to the procedure of example 141, in which phenylacetic acid was substituted with 2, 5-difluorobenzoic acid to give the desired product (2, 5-difluorophenyl) (4- (5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) methanone 142.

MS m/z (ESI): 476 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.24 (s, 1H), 9.21 (s, 1H), 8.32 (s, 1H), 7.65(d,J= 8.8 Hz, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.16-7.10 (m, 3H), 6.82 (d,J= 8.8 Hz, 1H), 4.27 (q,J= 6.8 Hz, 2H), 3.97-3.95 (m, 2H), 3.79-3.70 (m,4H), 3.53-3.51 (m, 2H), 1.53 (t,J= 6.8 Hz , 3H)。

Example 143

1- (4- (5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (5-fluoropyridin-2-yl) ethan-1-one

Example 143 was synthesized according to the procedure of example 141, in which phenylacetic acid was substituted with 2- (5-fluoropyridin-2-yl) acetic acid to give the objective product 1- (4- (5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl) piperazin-1-yl) -2- (5-fluoropyridin-2-yl) ethan-1-one 143.

MS m/z (ESI): 473 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.23 (s, 1H), 9.20 (s, 1H), 8.63 (s, 1H), 8.31(s, 1H), 7.63 (d,J= 8.8 Hz, 1H), 7.41-7.39 (m, 2H), 7.29 (s, 1H), 7.17 (s,1H), 6.79 (d,J= 8.8 Hz, 1H), 4.25 (q,J=6.8 Hz, 2H), 3.98 (s, 2H), 3.81-3.79 (m, 4H), 3.61-3.59 (m, 4H), 1.53 (t,J= 6.8 Hz , 3H)。

Example 144

1- (4- (5- (7-ethoxyquinazolin-5-yl) pyrazin-2-yl) piperazin-1-yl) -2-phenylethane-1-one

First step of

7-ethoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline

The compound 5-chloro-7-ethoxyquinazoline 140c (0.12 g, 0.60 mmol), pinacol diboron (0.23 g, 0.90 mmol), tricyclohexylphosphorus (56 mg, 0.20 mmol), potassium acetate (0.20 g, 2.00 mmol) were dissolved in waterN,N-dimethylformamide (10 mL), tris (dibenzylideneacetone) dipalladium (92 mg, 0.10 mmol) was added under nitrogen, heated to 85 ℃ and stirred for 4 hours. Cooling to room temperature to obtain crude 7-ethoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline 144a, and directly carrying out the next step by a one-pot method。

MS m/z (ESI): 301 [M + 1]；

Second step of

4- [5- (7-ethoxyquinazolin-5-yl) pyrazin-2-yl ] piperazine-1-carboxylic acid tert-butyl ester

The compound 7-ethoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline 144a (0.18 g, 0.60 mmol), 4- (5-bromopyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester 70b (0.21 g, 0.60 mmol), potassium phosphate (0.28 g, 2.00 mmol) were dissolved in waterN,N-dimethylformamide (10 mL) and water (2 mL), tetrakis (triphenylphosphine) palladium (58 mg, 0.05 mmol) was added under nitrogen, heated to 80 ℃ and stirred for 8 h cooling to room temperature, ethyl acetate was added for extraction (50 mL), the organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, spun dry and purified on silica gel plates (dichloromethane/methanol = 30: 1) to give the desired product 4- [5- (7-ethoxyquinazolin-5-yl) pyridin-2-yl]Piperazine-1-carboxylic acid tert-butyl ester 144b (60 mg, 0.14mmol, yellow solid), yield: 24 percent.

MS m/z (ESI): 437 [M + 1]；

The third step

7-ethoxy-5- [5- (piperazin-1-yl) pyrazin-2-yl ] quinazoline

The compound 4- [5- (7-ethoxy quinazoline-5-yl) pyridine-2-yl]Piperazine-1-carboxylic acid tert-butyl ester 144b (60 mg, 0.14 mmol) was dissolved in hydrogen chloride (5 mL, 20mmol, 4M in methanol) and stirred at room temperature for 2 hours. Spin-dry, dilute with water (20 mL), add 0.5NAdjusting the pH value to 8-10 by using sodium hydroxide, extracting with dichloromethane (30 mL), washing an organic phase with saturated saline solution (30 mL), drying with anhydrous sodium sulfate, filtering, spin-drying, preparing a silica gel plate, and purifying (dichloromethane/methanol =8: 1) to obtain the target compound 7-ethoxy-5- [5- (piperazin-1-yl) pyrazin-2-yl]Quinazoline 144c (28 mg, 0.08mmol, yellow solid), yield: 57 percent.

MS m/z (ESI): 337 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.66 (s, 1H), 9.20 (s, 1H), 8.51 (s, 1H), 8.28(s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.26 (q,J= 6.8 Hz, 2H), 3.71-3.68 (m,4H), 3.06-3.03 (m, 4H), 1.52 (t,J= 6.8 Hz, 3H)。

The fourth step

1- {4- [5- (7-ethoxyquinazolin-5-yl) pyrazin-2-yl ] piperazin-1-yl } -2-phenylethanone

The compound 7-ethoxy-5- [5- (piperazin-1-yl) pyrazin-2-yl ] quinazoline 144c (5 mg, 0.015 mmol) was dissolved in dichloromethane (2 mL), triethylamine (5 mg, 0.05 mmol) and phenylacetyl chloride (3 mg, 0.02 mmol) were added with stirring, stirred at room temperature for 0.5 h, spun dry and purified using silica gel plates (dichloromethane: methanol = 15: 1) to give 1- {4- [5- (7-ethoxyquinazolin-5-yl) pyrazin-2-yl ] piperazin-1-yl } -2-phenylethanone 144 (5.3 mg, yellow solid) in 78% yield.

MS m/z (ESI): 455 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.63 (s, 1H), 9.20 (s, 1H), 8.39 (s, 1H), 8.25(s, 1H), 7.34-7.28 (m, 7H), 4.25 (q,J= 6.8 Hz, 2H), 3.85-3.82 (m, 4H),3.71-3.68 (m, 2H), 3.65-3.63 (m, 2H), 3.55-3.53 (m, 2H), 1.54 (t,J= 6.8 Hz, 3H)。

Example 145

4- (5- (7-ethoxyquinazolin-5-yl) pyrazin-2-yl) -N-isobutylpiperazine-1-carboxamide

7-ethoxy-5- (5- (piperazin-1-yl) pyrazin-2-yl) quinazoline 144c (10 mg, 0.03 mmol) was dissolved in tetrahydrofuran (6 mL), triethylamine (10 mg, 0.10 mmol) was added,N,N'carbonyl bis (1,2, 4-triazole) (6 mg, 0.04 mmol), after which the reaction was carried out at room temperature for 30 minutes. Isobutylamine (5 mg, 0.06 mmol) was added, stirred at room temperature overnight and then heated to 50 ℃ for reaction for 3 hours. The reaction mixture was concentrated and dissolved in 20mL of methylene chlorideWashing with saturated sodium chloride (20 mL), drying over anhydrous sodium sulfate, concentrating, purifying with silica gel plate (dichloromethane: methanol = 20:1) to obtain 4- (5- (7-ethoxyquinazolin-5-yl) pyrazin-2-yl) -NIsobutylpiperazine-1-carboxamide 145 (pale yellow solid, 4 mg) in 30.6% yield.

MS m/z (ESI): 436 [M + 1]；

¹H NMR (400 MHz, CDCl₃) 9.65 (s, 1H), 9.21 (s, 1H), 8.41 (s, 1H), 8.29(s, 1H), 7.37 (d,J= 2.0 Hz, 1H), 7.32 (d,J= 2.0 Hz, 1H), 4.60-4.56 (m,1H), 4.29-4.24 (m, 2H), 3.81-3.78 (m, 4H), 3.63-3.60 (m, 4H), 3.13-3.10 (m,2H), 1.53 (t,J= 6.8 Hz, 3H), 1.21-1.19 (m, 1H), 0.94 (d,J= 6.8 Hz, 6H)。

Biological experiments

Activity inhibition assay for RET kinase

Evaluation of the Effect of Compounds of the invention on RET kinase Activity Using in vitro kinase assay

The experimental methods are summarized as follows:

the in vitro activity of RET kinase was determined by measuring the phosphorylation level of substrates in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, cat # 62TK0 PEC.) the reaction buffer contains the components of the kit's own enzyme reaction buffer (1 ×), 5mM MgCl₂1mM DTT; human recombinant RET protein (cat 11997) was purchased from Cassia and diluted to 0.1 ng/. mu.l of kinase solution with reaction buffer; substrate reaction

The solution comprised 0.66. mu.M biotin-labeled tyrosine kinase substrate and 12. mu.M ATP diluted with reaction buffer; the detection buffer included 0.1 ng/. mu.l Eu3+ -labeled caged antibody-diluted with reaction buffer and 41.25nM streptavidin-labeled XL 665.

Compounds were diluted to 25 μ M in 100% DMSO at solution, then serially diluted 4-fold with DMSO to a minimum concentration of 1.5nM, each concentration point being diluted 40-fold with reaction buffer.

mu.L of the compound solution and 2. mu.L of RET kinase solution were added to 384-well test plates (Corning, cat. No. 4512), mixed well, and incubated at room temperature for 15 minutes. Subsequently, 4. mu.L of the substrate reaction solution was added and the reaction mixture was incubated at room temperature for 60 minutes. Then, 10. mu.L of a detection buffer equal in volume to the reaction was added, mixed well and left to stand at room temperature for 30 minutes, and then the progress of the reaction was detected at wavelengths of 620nm and 665nm using an Envision plate reader (Perkin Elmer). 665/620, and the phosphorylation degree of the substrate, thereby detecting the activity of RET kinase. In this experiment, the group without RET kinase protein was taken as 100% inhibition, and the group with RET kinase protein but without compound was taken as 0% inhibition. The percent inhibition of RET kinase activity by a compound can be calculated using the following formula:

compound IC₅₀Values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:

Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

wherein Y is the inhibition percentage, X is the logarithm value of the concentration of the compound to be detected, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.

Activity inhibition assay for RET M918T

In vitro kinase assay to assess the effect of the compounds of the invention on the activity of RET M918T

The experimental methods are summarized as follows:

the in vitro activity of RET M918T was determined by measuring the phosphorylation level of a substrate in the kinase reaction using the HTRF kinase detection kit (Cisbio, cat # 62TK0 PEC.) the reaction buffer contains the following components: the kit-of-matter enzyme reaction buffer (1 ×), 5mM MgCl₂1mM DTT; human recombinant RET M918T protein (cat # PV 6217) was purchased from Thermo Fish, and diluted to 0.35 ng/. mu.l of kinase solution with reaction buffer; the substrate reaction solution comprises a biotin-labeled tyrosine kinase substrate diluted to 0.9. mu.M and 18. mu.M ATP with a reaction buffer; the detection buffer included dilution with reaction buffer to 0.1 ng/. mu. lEu³⁺Labeled cage antibody and 56.25nM streptavidin labeled XL 665.

Compounds were diluted to 10 μ M in 100% DMSO at solution, then serially diluted 4-fold with DMSO to a minimum concentration of 0.61nM, using reaction buffer for 40-fold dilutions at each concentration point.

mu.L of the compound solution and 2. mu.L of RET M918T kinase solution were added to 384-well assay plates (Corning, cat. No. 4512), mixed well, and incubated at room temperature for 15 minutes. Subsequently, 4. mu.L of the substrate reaction solution was added and the reaction mixture was incubated at room temperature for 40 minutes. Then, 10. mu.L of a detection buffer equal in volume to the reaction was added, mixed well and left to stand at room temperature for 30 minutes, and then the progress of the reaction was detected at wavelengths of 620nm and 665nm using an Envision plate reader (Perkin Elmer). 665/620, and the phosphorylation degree of the substrate, thereby detecting the activity of RET M918T kinase. In this experiment, 100% inhibition was obtained with the group without the addition of the RETM918T kinase protein, and 0% inhibition was obtained with the addition of the RET M918T kinase protein but without the addition of the compound. The percent inhibition of RET M918T activity by a compound can be calculated using the following equation:

percent inhibition =100-

Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

Activity inhibition assay for RET V804M

In vitro kinase assay to assess the effect of compounds of the invention on RET V804M activity

The experimental methods are summarized as follows:

the in vitro activity of RET V804M was determined by measuring the phosphorylation level of a substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase detection kit (Cisbio, cat # 62TK0 PEC). The reaction buffer contained the following components: the kit is provided with enzyme reaction bufferSolution (1 ×), 5mM MgCl₂1mM DTT and 0.08% Tween-20; human recombinant RET V804M protein (cat # PV 6223) was purchased from Thermo Fish, diluted to 0.15 ng/. mu.l of kinase solution with reaction buffer; the substrate reaction solution comprises a biotin-labeled tyrosine kinase substrate diluted to 0.9. mu.M and 8. mu.M ATP with a reaction buffer; the detection buffer solution comprises Eu diluted to 0.1 ng/mu l by reaction buffer solution³⁺Labeled cage antibody and 56.25nM streptavidin labeled XL 665.

mu.L of the compound solution and 2. mu.L of RET V804M kinase solution were added to 384-well assay plates (Corning, cat. No. 4512), mixed well, and incubated at room temperature for 15 minutes. Subsequently, 4. mu.L of the substrate reaction solution was added and the reaction mixture was incubated at room temperature for 30 minutes. Then, 10. mu.L of a detection buffer equal in volume to the reaction was added, mixed well and left to stand at room temperature for 30 minutes, and then the progress of the reaction was detected at wavelengths of 620nm and 665nm using an Envision plate reader (Perkin Elmer). 665/620, and the phosphorylation degree of the substrate, thereby detecting the activity of RET V804M kinase. In this experiment, 100% inhibition was obtained with the group without RETV804M kinase protein, and 0% inhibition was obtained with RET V804M kinase protein but without compound. The percent inhibition of RET V804M activity by a compound can be calculated using the following equation:

percent inhibition =100-

Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

Activity inhibition assay for RET V804L

In vitro kinase assay to assess the effect of compounds of the invention on RET V804L activity

The experimental methods are summarized as follows:

the in vitro activity of RET V804L was determined by measuring the phosphorylation level of a substrate in the kinase reaction using the HTRF kinase detection kit (Cisbio, cat # 62TK0 PEC.) the reaction buffer contains the following components: the kit-of-matter enzyme reaction buffer (1 ×), 5mM MgCl₂1mM DTT and 0.05% Tween-20; human recombinant RET V804L protein (cat. No. 14-758) was purchased from Merck, diluted to 0.05 ng/. mu.l of kinase solution with reaction buffer; the substrate reaction solution comprises a1 mu M biotin-labeled tyrosine kinase substrate and 8 mu M ATP diluted with a reaction buffer; the detection buffer solution comprises Eu diluted to 0.1 ng/mu l by reaction buffer solution³⁺Labeled cage antibody and 62.5nM streptavidin labeled XL 665.

Compounds were diluted to 100 μ M in 100% DMSO solutions, then serially diluted 4-fold with DMSO to a minimum concentration of 6.1nM, each concentration point diluted 40-fold with reaction buffer.

mu.L of the compound solution and 2. mu.L of RET V804L kinase solution were added to 384-well assay plates (Corning, cat. No. 4512), mixed well, and incubated at room temperature for 15 minutes. Subsequently, 4. mu.L of the substrate reaction solution was added and the reaction mixture was incubated at room temperature for 40 minutes. Then, 10. mu.L of a detection buffer equal in volume to the reaction was added, mixed well and left to stand at room temperature for 30 minutes, and then the progress of the reaction was detected at wavelengths of 620nm and 665nm using an Envision plate reader (Perkin Elmer). 665/620, and the phosphorylation degree of the substrate, thereby detecting the activity of RET V804L kinase. In this experiment, 100% inhibition was obtained with the group without RETV804L kinase protein, and 0% inhibition was obtained with RET V804L kinase protein but without compound. The percent inhibition of RET V804L activity by a compound can be calculated using the following equation:

percent inhibition =100-

Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

Activity inhibition assay for VEGFR2

In vitro kinase assay to assess the effect of the compounds of the invention on VEGFR2 activity

The experimental methods are summarized as follows:

the in vitro activity of RET V804L was determined by measuring the phosphorylation level of a substrate in the kinase reaction using the HTRF kinase detection kit (Cisbio, cat # 62TK0 PEC.) the reaction buffer contains the following components: the kit-of-matter enzyme reaction buffer (1 ×), 5mM MgCl₂、1mM DTT、1mM MnCl₂0.01% BSA and 0.05% Tween-20; the human recombinant VEGFR2 protein (cat 10012) was purchased from Yiqiao Shenzhou, and diluted to 0.3 ng/ul of kinase solution by using reaction buffer; the substrate reaction solution comprises a biotin-labeled tyrosine kinase substrate diluted to 0.3. mu.M and 3.5. mu.M ATP with a reaction buffer; the detection buffer solution comprises Eu diluted to 0.1 ng/mu l by reaction buffer solution³⁺Labeled cage antibody and 18.75nM streptavidin labeled XL 665.

Compounds were diluted to 1000 μ M in 100% DMSO at solution, then serially diluted 4-fold with DMSO to a minimum concentration of 0.06 μ M, each concentration point being diluted 40-fold with reaction buffer.

To a 384-well detection plate (Corning, Cat. 4512), 4. mu.L of the compound solution and 2. mu.L of the VEGFR2 kinase solution were added, mixed well, and then incubated at room temperature for 15 minutes. Subsequently, 4. mu.L of the substrate reaction solution was added and the reaction mixture was incubated at room temperature for 40 minutes. Then, 10. mu.L of a detection buffer equal in volume to the reaction was added, mixed well and left to stand at room temperature for 30 minutes, and then the progress of the reaction was detected at wavelengths of 620nm and 665nm using an Envision plate reader (Perkin Elmer). 665/620, and the phosphorylation degree of the substrate, thereby detecting the activity of VEGFR2 kinase. In this experiment, the VEGFR2 kinase protein group was not added as 100% inhibition, and the VEGFR2 kinase protein but the compound group was not added as 0% inhibition. The percent inhibition of VEGFR2 activity by a compound can be calculated using the following formula:

percent inhibition =100-

Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

Determination of half effective inhibitory concentration GI50 of Ba/F3 LMNA-NTRK1-G595R cells

The effect of the compounds of the present invention on the proliferation of Ba/F3 LMNA-NTRK1-G595R cells was evaluated using a luminescent cell viability assay.

The experimental methods are summarized as follows:

the proliferation status of cells of Ba/F3 LMNA-NTRK1-G595R was measured using the CellTilter-glo (CTG) assay kit by detecting the indicator of viable cell metabolism, ATP, using a unique, stable luciferase, which produces a luminescent signal proportional to the number of viable cells in the culture medium.

Ba/F3 LMNA-NTRK1-G595R cell (purchased from Conn. origin Bo-Chu) was cultured in RPMI1640 complete medium (Thermofish, 12440053,) containing 10% FBS (GBICO, 10099-141) and 100units/ml penicillin mixed solution (Thermofish, 15140122), when the coverage of the cells in the culture vessel reached 80-90%, the cells were digested and blown off with 0.25% trypsin (containing EDTA) (Thermofish, 25200056) and planted in white 384-well plates (Thermofish, 164610), 27. mu.l of RPMI1640 complete medium containing 1000 cells was added to each well, and then the 384-well plates were placed in RPMI1640 complete medium containing 5% CO₂The culture box is cultured overnight at 37 ℃. Compounds were dissolved and diluted to 1mM in 100% DMSO, followed by 4-fold serial dilutions in DMSO to a minimum concentration of 0.061 μ M, each concentration point was further diluted 50-fold using RPMI1640: F12(1:1) medium. If compound IC50 values are very low, the initial concentration of compound can be reduced. Add 3. mu.l of diluted compound to each well and mix by gentle centrifugation. Among these, the medium without cells was used as a negative control (100% inhibition), and the group with 0.2% DMSO was used as a positive control (0% inhibition). The 384 well plate was placed in an incubator at 37 ℃ with 5% CO2 for further cultivation, after 96 hours it was taken out and placed at room temperature for 30 minutes, the CTG reagent was also taken out and equilibrated to room temperature, 15. mu.l of CTG reagent was added to each well, placed on a shaker for gentle shaking for 5 minutes to ensure sufficient cell lysis, placed for 10 minutes to stabilize the luminescence signal, and then the luminescence signal was read with EnVision (Perkin Elmer). In addition, in order to correct the cell number, T0 controls including a blank control containing only the culture medium and a control added with cells were simultaneously set, and the difference between the two controls was set as a T0 control, which was obtained by adding CTG reagent before adding the drug.

The percentage of compound inhibition of cell proliferation by Ba/F3 LMNA-NTRK1-G595R can be calculated by the following formula:

percent inhibition =100 { [ (Signal compound-Signal negative control) -T0 control ]/[ (Signal positive control-Signal negative control) -T0 control ] }

Y = Bottom + (Top- Bottom)/(1+10^((LogIC50-X) * slope factor))

wherein Y is the percentage of inhibition, Bottom is the Bottom plate of the curve, Top is the Top plate of the curve, and X is the logarithm of the concentration of the compound to be measured.

Determination of half-effective inhibitory concentration of LC-2/ad cells GI50

The effect of the compounds of the invention on LC-2/ad cell proliferation was evaluated using a luminescent cell viability test assay.

The experimental methods are summarized as follows:

the cell proliferation status of LC-2/ad was measured using the CellTilter-glo (CTG) assay kit by detecting the indicator of viable cell metabolism, ATP, using a unique, stable luciferase, which produces a luminescent signal proportional to the number of viable cells in the culture medium.

LC-2/ad cells (purchased from Shanghai Xinyu Bio Inc.) were cultured in RPMI1640: F12(1:1) complete medium (Thermofisher, 72400047, 11765054) containing 10% FBS (GBICO, 10099-141) and 100units/ml streptomycin mixture (Thermofisher, 15140122), and when the coverage of the cells in the culture vessel reached 80-90%, they were digested and blown up with 0.25% trypsin (containing EDTA) (Thermofisher, 25200056) and planted in white 384-well plates (Thermofisher, 164610) containing 1000 cells, and 27. mu.l of IMDM complete medium was added to each well, and then the 384-well plates were cultured overnight at 37 ℃ in a culture box containing 5% CO 2. Compounds were dissolved and diluted to 1mM in 100% DMSO, followed by 4-fold serial dilutions in DMSO to a minimum concentration of 0.061 μ M, each concentration point was further diluted 50-fold using RPMI1640: F12(1:1) medium. If compound IC50 values are very low, the initial concentration of compound can be reduced. Add 3. mu.l of diluted compound to each well and mix by gentle centrifugation. Among these, the medium without cells was used as a negative control (100% inhibition), and the group with 0.2% DMSO was used as a positive control (0% inhibition). The 384 well plate was placed in an incubator at 37 ℃ with 5% CO2 for further incubation, after 96 hours it was removed and placed at room temperature for 30 minutes, the CTG reagent was also removed and equilibrated to room temperature, 15. mu.l of CTG reagent was added to each well, placed on a shaker for gentle shaking for 5 minutes to ensure adequate cell lysis, placed for 10 minutes to stabilize the luminescence signal, and then read with EnVision (Perkinelmer). In addition, in order to correct the cell number, T0 controls including a blank control containing only the culture medium and a control added with cells were simultaneously set, and the difference between the two controls was set as a T0 control, which was obtained by adding CTG reagent before adding the drug.

The percentage of inhibition of LC-2/ad cell proliferation by a compound can be calculated using the following formula:

Y = Bottom + (Top- Bottom)/(1+10^((LogIC50-X) * slope factor))

The results of the in vitro kinase assay are shown in Table 1 below, and the results of the cell assay are shown in Table 2.

Table 1: in vitro kinase Activity assay results

Compound numbering	RET IC50(nM)	RET V804M IC50 (nM)	RET V804L IC50 (nM)	RET M918T IC50 (nM)	VEGFR2 IC50 (nM)
						1	120.38	ND	ND	ND	ND
2	114	ND	ND	ND	ND
						3	4.86	1.10	3.21	10.97	734.86
4	9.28	ND	ND	ND	ND
						5	28.06	ND	ND	ND	ND
6	15.98	ND	ND	ND	ND
						7	18.57	ND	ND	ND	ND
8	10.32	ND	ND	ND	ND
						9	2.45	ND	ND	ND	ND
10	15.23	ND	ND	ND	ND
						11	13.18	ND	ND	ND	ND
12	8.75	ND	ND	ND	ND
						13	10.13	ND	ND	ND	ND
14	12.72	ND	ND	ND	ND
						15	20.56	ND	ND	ND	ND
16	50.13	ND	ND	ND	ND
						17	19.61	ND	ND	ND	ND
18	6.6	ND	ND	ND	ND
						19	26.38	ND	ND	ND	ND
20	30.5	ND	ND	ND	ND
						21	13.71	ND	ND	ND	ND
22	4.6	4.20	4.18	8.23	263.73
						23	7.69	ND	ND	ND	ND
24	2.62	6.06	ND	ND	163.88
						25	29	ND	ND	ND	ND
26	5.66	6.82	3.98	9.84	130.64
						27	4.74	10.61	ND	11.18	ND
28	36.94	ND	ND	ND	ND
						29	54.89	ND	ND	ND	ND
30	12.78	ND	ND	ND	ND
						31	12.46	ND	ND	ND	ND
32	12.25	ND	ND	ND	ND
						33	2.47	3.34	ND	4.32	180.99
34	3.99	4.47	3.05	9.09	ND
						35	20.78	ND	ND	ND	ND
36	1.65	3.06	16.47	3.75	265.32
						37	2.87	4.81	4.19	5.7	92.57
38	2.84	16.22	ND	17.23	ND
						39	4.82	6.87	3.3	9.43
40	11.98	ND	ND	ND	ND
						41	8.35	98.32	374.88	99.27	128.97
42	16.27	ND	ND	ND	ND
						43	58.06	ND	ND	ND	ND
44	171.54	ND	ND	ND	ND
						45	77.46	ND	ND	ND	ND
46	228.9	ND	ND	ND	ND
						47	73.1	ND	ND	ND	ND
48	4.61	73.93	333.42	103.58	181.13
						49	21.13	ND	ND	ND	ND
50	8.39	ND	ND	ND	ND
						51	36.55	ND	ND	ND	ND
52	33.17	ND	ND	ND	ND
						53	10.63	ND	ND	ND	ND
54	37.85	ND	ND	ND	ND
						55	114.66	ND	ND	ND	ND
56	112.91	ND	ND	ND	ND
						57	53.65	ND	ND	ND	ND
58	139.04	ND	ND	ND	ND
						59	83.99	ND	ND	ND	ND
60	155.03	ND	ND	ND	ND
						61	1.65	1.59	2.07	1.49	109.89
62	8.84	17.88	ND	22.33	413.83
						63	9.99	28.86	ND	16.25	182.95
64	189.78	ND	ND	ND	ND
						65	36.48	ND	ND	ND	ND
66	457.87	ND	ND	ND	ND
						67	76.56	ND	ND	ND	ND
68	131.23	ND	ND	ND	ND
						69	22.49	ND	ND	ND	ND
70	11.12	ND	ND	ND	ND
						71	3.72	5.84	13.96	ND	ND
72	9.52	19.76	41.05	ND	ND
						73	5.96	18.08	ND	13.33	726.17
74	114.18	ND	ND	ND	ND
						75	6.26	7.44	15.94	ND	ND
76	24.09	ND	ND	ND	359.05
						77	15.31	ND	ND	ND	ND
78	83.66	ND	ND	ND	ND
						79	19.67	ND	ND	ND	ND
80	18.11	ND	ND	ND	ND
						81	54.68	ND	ND	ND	ND
82	23.8	ND	ND	ND	ND
						83	89.22	ND	ND	ND	ND
84	39.77	ND	ND	ND	ND
						85	62.53	ND	ND	ND	ND
86	49.3	ND	ND	ND	ND
						87	85.53	ND	ND	ND	ND
88	49.4	ND	ND	ND	ND
						89	39.73	ND	ND	ND	ND
90	38.31	ND	ND	ND	ND
						91	55.68	ND	ND	ND	ND
92	40.46	ND	ND	ND	ND
						93	15.84	ND	ND	ND	ND
94	9.34	ND	ND	ND	ND
						95	10.15	ND	ND	ND	ND
96	17.24	ND	ND	ND	ND
						97	19.17	ND	ND	ND	ND
98	63.65	ND	ND	ND	ND
						99	26.94	ND	ND	ND	ND
100	23.26	ND	ND	ND	ND
						101	16.25	ND	ND	ND	ND
102	60.1	ND	ND	ND	ND
						103	10.86	ND	ND	ND	123.63
104	13.83	ND	ND	ND	ND
						105	31.93	ND	ND	ND	ND
106	28.79	ND	ND	ND	ND
						107	18.13	ND	ND	ND	ND
108	8.48	6.77	ND	9.56	217.54
						109	16.67	ND	ND	ND	ND
110	116.85	ND	ND	ND	ND
						111	44.21	ND	ND	ND	ND
112	78.86	ND	ND	ND	ND
						113	43.48	ND	ND	ND	ND
114	306.28	ND	ND	ND	ND
						115	145.95	ND	ND	ND	ND
116	53.76	ND	ND	ND	ND
						117	5.8	1.00	ND	10.97	108.69
118	17.14	ND	ND	ND	ND
						119	4.95	1.76	1.98	3.75	57.84
120	128.11	ND	ND	ND	ND
						121	11.96	ND	ND	ND	ND
122	10.22	ND	ND	ND	ND
						123	37.56	ND	ND	ND	ND
124	6.98	14.15	47.24	33.37	73.04
						125	26.93	ND	ND	ND	ND
126	136.31	ND	ND	ND	ND
						127	19.42	ND	ND	ND	ND
128	69.39	ND	ND	ND	ND
						129	2.29	1.5	8.85	7.66	337.48
130	2.64	1.38	6.38	5.77	204.75
						131	13.45	ND	ND	ND	ND
132	30.37	ND	ND	ND	ND
						133	69.07	ND	ND	ND	ND
134	122.95	ND	ND	ND	ND
						135	31.58	ND	ND	ND	ND
136	6.37	8.48	10.39	ND	ND
						137	57.52	ND	ND	ND	ND
138	158.85	ND	ND	ND	ND
						139	129.25	ND	ND	ND	ND
140	217.4	ND	ND	ND	ND
						141	84.23	ND	ND	ND	ND
142	137.57	ND	ND	ND	ND
						143	143.59	ND	ND	ND	ND
144	109.54	ND	ND	ND	ND
						145	254.74	ND	ND	ND	ND

Note: ND = not determined.

Table 2: in vitro cell activity detection result

Compound numbering	Ba/F3 LMNA-NTRK1-G595R GI50 (nM)	LC-2/ad GI50 (nM)
			3	410.97	106.58
34	612.18	93.37
			61	224.7	64.81
119	486.29	153.64
			129	556.36	84.2

From the above experimental results, it can be seen that the compounds of the embodiments of the present invention can effectively inhibit the activity of RET kinase, and can be used for treating RET kinase-mediated diseases, such as cancers, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and brain glioma. The partial compound can also effectively inhibit the proliferation of Ba/F3 LMNA-NTRK1-G595R tumor cells and LC-2/ad tumor cells.

It will be evident to those skilled in the art that the disclosure is not limited to the exemplary embodiments described above, and that it may be embodied in other specific forms without departing from the essential characteristics of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. A compound of formula (I), isomers, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts thereof:

wherein

X is selected from CR¹Or N; preferably selected from CH or N;

Y²selected from the group consisting of CR³Or N; preferably selected from CH or N; most preferably selected from CH;

Y⁴selected from the group consisting of CR⁵Or N; preferably selected from CH or N; most preferably selected from CH;

provided that Y is¹、Y²、Y³And Y⁴Up to 2N;

Or

d is a 4-8 membered heterocyclylene, 6-8 membered bridged heterocyclylene or 7-11 membered spiroheterocyclylene containing 1-3 heteroatoms selected from N or O; preferably a 4-to 6-membered heterocyclylene group containing two N,A 6-7 membered bridged heterocyclic group containing two N or a 7-11 membered spiroheterocyclic group containing two N; most preferably

、

、

；

、

、

、-C(O)R^x(ii) a Most preferably selected from hydrogen,

、

、-C(O)R^x；

R²¹and R²²Each independently selected from aryl or heteroaryl; said aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)N R¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²、-S(O)_mR¹⁰、-NR¹³S(O)_mR¹⁰、-SR¹⁰、-S(O)_mNR¹¹R¹²、-NR¹³S(O)_mNR¹¹R¹²Substituted with the substituent(s); preferably R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl, wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -O (CH)₂)_pR^y、-NR^vR^wSubstituted with the substituent(s);

R^yselected from hydrogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, and amino optionally mono-or di-substituted with C1-C8 alkyl; preferably selected from hydrogen, hydroxy, and amino optionally mono-or di-substituted with C1-C6 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

2. A compound shown as a formula (I), an isomer, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CR¹Or N;

Y¹selected from the group consisting of CR²Or N;

Y²selected from the group consisting of CR³Or N;

Y³selected from the group consisting of CR⁴Or N;

Y⁴selected from the group consisting of CR⁵Or N;

provided that Y is¹、 Y²、Y³And Y⁴Up to 2N;

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O) NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^yselected from hydrogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered heterocycle containing a heteroatom selected from N, O or SAnd amino optionally mono-or di-substituted with C1-C8 alkyl;

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

3. A compound shown as a formula (I), an isomer, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CR¹Or N;

Y¹selected from the group consisting of CR²Or N;

Y²selected from the group consisting of CR³Or N;

Y³selected from the group consisting of CR⁴Or N;

Y⁴selected from the group consisting of CR⁵Or N;

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R^yselected from hydrogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, and amino optionally mono-or di-substituted with C1-C8 alkyl;

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁹、R²⁰、R²³、R²⁴each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl optionally substituted with halogen or hydroxy, C1-C8 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, heteroaryl or aryl, C2-C8 alkenyl, C2-C8An alkynyl group; or

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

4. A compound shown as a formula (I), an isomer, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CR¹Or N;

Y¹selected from the group consisting of CR²Or N;

Y²selected from the group consisting of CR³Or N;

Y³selected from the group consisting of CR⁴Or N;

Y⁴selected from the group consisting of CR⁵Or N;

d is selected from

、

、

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O) NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

5. A compound shown as a formula (I), an isomer, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C6 alkyl, -OR¹⁴、-NR¹⁵R¹⁶；

d is selected from

、

、

e is selected from hydrogen, halogen, C1-C8 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from aryl or heteroaryl; wherein said aryl or heteroaryl is optionally substituted by one or more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、 -OC(O)N R¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^v、R^weach independently selected from hydrogen, C1-C8 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

6. A compound shown as formula (I), its isomer, prodrug and stable isotope derivative

A compound and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C6 alkyl, -OR¹⁴、-NR¹⁵R¹⁶；

R¹⁴、R¹⁵、R¹⁶Each independently selected from hydrogen, C1-C4 alkyl;

Or

；

d is selected from

、

、

e is selected from hydrogen, halogen, C1-C6 alkyl,

、

、-C(O)R^x；

R^yselected from hydrogen, halogen, hydroxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing a heteroatom selected from N, O or S, and amino optionally mono-or di-substituted with C1-C8 alkyl;

R^v、R^weach independently selected from hydrogen, C1-C6 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

7. A compound shown as a formula (I), an isomer, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C6 alkyl;

Or

；

d is selected from the following three heterocyclic rings

、

、

；

E is selected from hydrogen, halogen, C1-C4 alkyl,

、

、-C(O)R^x；

R²¹And R²²Each independently selected from phenyl, 2-pyridyl or 3-pyridyl, wherein said phenyl, 2-pyridyl or 3-pyridyl is optionally substituted with one or more substituents selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, -O (CH)₂)_pR^y、-NR^vR^w、-OC(O)NR¹¹R¹²、-C(O)OR¹⁰、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹⁰、-NR¹³C(O)NR¹¹R¹²Substituted with the substituent(s);

R^v、R^weach independently selected from hydrogen, C1-C6 alkyl;

m is selected from 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1,2 or 3.

8. A compound shown as formula (I), isomer, prodrug, stable isotope derivative and pharmaceutically acceptable salt thereof

Wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is selected from hydrogen, halogen, C1-C4 alkyl;

Or

；

d is selected from the following three heterocyclic rings

、

、

；

E is selected from hydrogen,

、

、-C(O)R^x；

R^v、R^weach independently selected from hydrogen, C1-C6 alkyl;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

9. A compound shown as formula (I), its isomer, prodrug and stable isotope derivative

A compound and a pharmaceutically acceptable salt thereof,

wherein

X is selected from CH or N;

Y¹selected from CH or N;

Y²is CH;

Y³selected from CH or N;

Y⁴is CH;

a is hydrogen;

Or

,

d is selected from the following three heterocyclic rings

、

、

；

E is selected fromHydrogen, hydrogen,

、

、-C(O)R^x；

R^v、R^weach independently selected from hydrogen, C1-C4 alkyl;

n is selected from 0 or 1;

p is selected from 0, 1,2 or 3.

10. The compound of claim 1, an isomer, a prodrug, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is:

。

11. use of a compound according to any one of claims 1-10, an isomer, prodrug, stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as an inhibitor of RET kinase.

12. Use of a compound according to any one of claims 1 to 10, an isomer, a prodrug, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a related disease mediated by RET kinase, such as a tumor selected from hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.

13. A pharmaceutical composition comprising a compound according to any one of claims 1-10, an isomer, prodrug, stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, optionally one or more other RET kinase inhibitors, and one or more pharmaceutically acceptable carriers, diluents, and excipients.