CN113461670A - Novel compounds as inhibitors of rearrangement kinase during transfection - Google Patents
Novel compounds as inhibitors of rearrangement kinase during transfection Download PDFInfo
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- CN113461670A CN113461670A CN202010242796.7A CN202010242796A CN113461670A CN 113461670 A CN113461670 A CN 113461670A CN 202010242796 A CN202010242796 A CN 202010242796A CN 113461670 A CN113461670 A CN 113461670A
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Abstract
The present invention relates to compoundsPharmaceutical compositions containing them and processes for their preparation and their use as inhibitors of Rearrangement (RET) kinase during transfection. The compound is shown as a formula I, or pharmaceutically acceptable salts, prodrugs, isomers and stable isotope derivatives 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
Technical Field
The present invention relates to compounds, pharmaceutical compositions containing them and their use as inhibitors of Rearrangement (RET) kinase during transfection. 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 four glial cell-derived neurotrophic factor (GDNF) family receptor alpha (GFR α) 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. A study of 26 small samples of cabozantinib on RET treatment was performed with a primary endpoint ORR of 28% and median time for PFS of 5.5 months, whereas 19 patients on treatment were dose adjusted for adverse events 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. Cancer Discovery.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 stable isotope derivative or a pharmaceutically acceptable salt thereof:
wherein:
X1is CR1Or N; preferably CH or N;
X2is CH or N;
provided that X is1、X2At most 1 in the totalIs N;
Y1is CR2Or N; preferably CH or N; most preferably N;
Y2is CR3Or N; preferably CH or N; most preferably CH;
Y3is CR4Or N; preferably CH or N;
Y4is CR5Or N; preferably CH or N; most preferably CH;
provided that Y is1、Y2、Y3And Y4At most 2 of them are N;
one of the following conditions is preferred: y is1-Y4Are not all N; y alone1Or Y2Is N; y is1And Y2Are both N; or Y1And Y3Are both N;
further preferred is one of the following conditions: y alone1Or Y2Is N; or Y1And Y3Are both N; most preferably one of the following conditions: y is1Is N, Y2、Y3And Y4Are all CH; or Y1And Y3
Is N, Y2And Y4Is CH;
R1-R5each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, -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)mNR7R8or-NR9S(O)mNR7R8Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl OR alkynyl is optionally substituted with one OR more substituents selected from halogen, cyano, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, -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)mNR11R12or-NR13S(O)mNR11R12Substituted with the substituent(s); preferably, R1-R5Each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR6or-NR7R8(ii) a Further preferably, R1-R5Each independently selected from hydrogen, halogen or C1-C4 alkyl; most preferably, R1-R5Are all hydrogen;
a is selected from hydrogen, halogen, cyano or C1-C8 alkyl; preferably, A is selected from hydrogen, halogen, cyano or C1-C6 alkyl; further preferably, A is selected from hydrogen, cyano or C1-C4 alkyl; most preferably, a is hydrogen;
b is selected from hydrogen, halogen, cyano, C1-C4 alkyl, -OR14Or Ar optionally substituted1(ii) a Preferably, B is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1(ii) a Most preferably, B is selected from hydrogen, halogen, -OR14Or R15 ;
R14Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl, or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; preferably, R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; further preferably, R14Selected from C1-C4 alkyl, C3-C6 cycloalkyl or 4-6 member heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl are optionally substitutedSubstituted with one or more substituents selected from halogen, hydroxy, 4-6 membered heterocyclyl optionally substituted with C1-C4 alkyl; most preferably, R14Is C1-C4 alkyl optionally substituted with 1-methylpiperidin-4-yl;
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, Ar1Selected from 5 or 6 membered heteroaryl containing two ring N atoms; further preferably, Ar1Selected from 5-membered heteroaryl containing two ring N atoms; most preferably, Ar1Is R15 ;
Ar1Optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl are optionally substituted with one OR more substituents selected from the group consisting of halogen, cyano, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, -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);
R15selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl or heteroaryl; preferably, R15Selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclyl; further preferably, R15Selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl or a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; most preferably, R15Is C1-C4 alkyl;
d is selected from 4-8 membered heterocyclylene, 6-8 membered fused heterocyclylene or 7-11 membered spiroheterocyclylene containing 1-3 heteroatoms selected from N, O; preferably, D is selected from 4-6-membered heterocyclylene containing 1-2N or 6-8-membered heterocyclylene containing 1-2N; most preferably, D is selected from:
D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino or C1-C8 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C8 alkyl) amino,N- (C1-C8 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-8 membered heterocyclyl optionally substituted by halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C8 alkyl; preferably, D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl)-N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C6 alkyl; further preferably, D is optionally substituted with one substituent selected from hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: hydroxy, mono-or di (C1-C4 alkyl) amino,N- (C1-C4 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with (C1-C4 alkyl) carbonyl or C1-C6 alkyl; most preferably, D is optionally substituted with one substituent selected from hydroxy, amino or C1-C4 alkyl optionally substituted with one substituent selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl; wherein forAnd, if the substituent is hydroxy, it is substituted at its 3-position; if the substituent is other than hydroxyl, the substituent is substituted at the 4-position; for theThe substituent is hydroxyl or amino, and is substituted at the 4-position;
e is selected from amino, NHC (O) RX、-C(O)Ry、、-OR6、-NR7R8、-OC(O)NR7R8、-C(O)OR6、-C(O)NR7R8、-NR9C(O)NR7R8、-S(O)mR6、-NR9S(O)mR6、-SR6、-S(O)mNR7R8、-NR9S(O)mNR7R8or-CH2-Ar2(ii) a Preferably, E is selected from amino, heteroaryloxy, -NHC (O) RX、-SO2(C1-C8) alkyl, -C (O) Ry、or-CH2-Ar2(ii) a Further preferably, E is selected from amino, pyridyloxy, -NHC (O) RX、SO2(C1-C6) alkyl, -C (O) Ry、or-CH2-Ar2;
Most preferably, when D isWhen E is selected from amino, -NHC (O) RXor-SO2(C1-C4) alkyl; when D isWhen E is pyridine-2-oxyl; when D is When E is selected from-C (O) Ry、、-SO2(C1-C4) alkyl, or-CH2-Ar2;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl; preferably, RXSelected from C1-C6 alkoxy, optionally substituted 6-membered aryl, optionally substituted 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C6 alkyl, optionally substituted 1 or 2 heteroatoms selected from N, O, S4-6 membered heterocyclyl of a heteroatom of (a), C3-C6 cycloalkyl or amino optionally substituted with C1-C6 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C6 alkoxy or C3-C6 cycloalkyl; most preferably, RXSelected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl; preferably, RySelected from optionally substituted amino, C1-C6 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C6 cycloalkyl, said substituents being selected from C1-C6 alkyl optionally substituted with aryl; most preferably, RySelected from amino optionally substituted with C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, or C3-C6 cycloalkyl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino or C1-C8 alkoxy; preferably, Ar2Selected from the group consisting of optionally mono-or disubstituted 5-6 membered aryl or heteroaryl, said substituents being selected from the group consisting of halogen, C1-C6 alkoxy; most preferably, Ar2Selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen, C1-C4 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl or hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group; preferably, Rm、RnEach independently selected from hydrogen, hydroxy, C1-C6 alkyl or hydroxy C1-C6 alkyl, or Rm、RnCarbon attached theretoThe atoms taken together form a C3-C6 cycloalkyl group; most preferably, Rm、RnEach independently selected from hydrogen, hydroxy or hydroxy C1-C4 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a cyclopropyl group;
R6、R7、R8、R9、R10、R11、R12、R13each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
r is selected from 0, 1,2 or 3; preferably, r is selected from 0, 1 or 2;
m is selected from 1 or 2.
Preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, as described hereinbefore, which is useful as a selective RET kinase inhibitor, wherein
X1Is CR1Or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N;
Y2is CR3Or N;
Y3is CR4Or N;
Y4is CR5Or N;
and one of the following conditions is satisfied: y is1-Y4Are not all N; y alone1Or Y2Is N; y is1And Y2Are both N; or Y1And Y3Are both N;
R1-R5each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8;
A is selected from hydrogen, halogen, cyano or C1-C6 alkyl;
b is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl, or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 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;
Ar1optionally substituted by one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8;
D is selected from a 4-6 membered heterocyclylene group containing 1-2N or a 6-8 membered heterocyclylene group containing 1-2N, and when X is2When is CH, D is notOr;
D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino, or C1-C8 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C8 alkyl) amino,N- (C1-C8 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-8 membered heterocyclyl optionally substituted by halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C8 alkyl;
e is selected from amino, NHC (O) RX、-C(O)Ry、、-OR6、-NR7R8、-OC(O)NR7R8、-C(O)OR6、-C(O)NR7R8、-NR9C(O)NR7R8、-S(O)mR6、-NR9S(O)mR6、-SR6、-S(O)mNR7R8、-NR9S(O)mNR7R8or-CH2-Ar2;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino or C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogenHydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
R6、R7、R8、R9each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
m is 1 or 2;
r is 0, 1,2 or 3.
Further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof as described hereinbefore, which is useful as a selective RET kinase inhibitor, wherein
X1Is CR1Or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N;
Y2is CR3Or N;
Y3is CR4Or N;
Y4is CR5Or N;
and one of the following conditions is satisfied: y is1-Y4Are not all N; y alone1Or Y2Is N; y is1And Y2Are both N; or Y1And Y3Are both N;
R1-R5each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR6or-NR7R8;
A is selected from hydrogen, halogen, cyano or C1-C6 alkyl;
b is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl are optionally substitutedSubstituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, or 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
Ar1selected from 5 or 6 membered heteroaryl containing two ring N atoms;
Ar1optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8;
D is selected from a 4-6 membered heterocyclylene group containing 1-2N or a 6-8 membered heterocyclylene group containing 1-2N, and when X is2When is CH, D is notOr;
D is optionally substituted with one substituent selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C8 alkyl, wherein said alkyl is optionally substituted with one substituent selected from the group consisting of: halogen, hydroxy, mono-or di (C1-C8 alkyl) amino,N- (C1-C8 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-8 membered heterocyclyl optionally substituted by halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C8 alkyl;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino, C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
R6、R7、R8、R9each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
m is 1 or 2;
r is 0, 1,2 or 3.
Still further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof as described hereinbefore, wherein the compound is useful as a selective RET kinase inhibitor
X1Is CR1Or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N;
Y2is CR3Or N;
Y3is CR4Or N;
Y4is CR5Or N;
and one of the following conditions is satisfied: y is1-Y4Are not all N; y alone1Or Y2Is N; or Y1And Y3Are both N;
R1-R5each independently selected from hydrogen, halogen or C1-C4 alkyl;
a is selected from hydrogen, cyano or C1-C4 alkyl;
b is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
Ar1selected from 5-membered heteroaryl containing two ring N atoms;
Ar1optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8;
D is selected from a 4-6 membered heterocyclylene group containing 1-2N or a 6-8 membered heterocyclylene group containing 1-2N, and when X is2When is CH, D is notOr;
D is optionally substituted with one substituent selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from the group consisting of: halogen, hydroxy, mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C6 alkyl;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino, C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
R6、R7、R8、R9each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
m is 1 or 2;
r is 0, 1,2 or 3.
Still further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof as described hereinbefore, wherein the compound is useful as a selective RET kinase inhibitor
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CH or N;
Y2is CH or N;
Y3is CH or N;
Y4is CH or N;
and one of the following conditions is satisfied: y is1、Y2、Y3And Y4Are all CH; y alone1Or Y2Is N; or Y1And Y3Are both N;
a is hydrogen;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
R15selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O, S, aryl or heteroaryl;
d is selected from:
D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C6 alkyl;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from optionally arylatedC1-C8 alkyl substituted by aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino or C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
r is 0, 1,2 or 3.
Still further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof as described hereinbefore, wherein the compound is useful as a selective RET kinase inhibitor
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CH or N;
Y2is CH or N;
Y3is CH or N;
Y4is CH or N;
and one of the following conditions is satisfied: y is1、Y2、Y3And Y4Are all CH; y alone1Or Y2Is N; or Y1And Y3Are both N;
a is hydrogen;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
R15selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl, or a mixture containing4-8 membered heterocyclyl with 1-2 heteroatoms selected from N, O, S;
d is selected from:
D is optionally substituted with one substituent selected from hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkyl) carbonylamino, 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, acetyl;
RXSelected from C1-C6 alkoxy, optionally substituted 6-membered aryl, optionally substituted 5-6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C6 alkyl, optionally substituted 4-6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C6 cycloalkyl or amino optionally substituted with C1-C6 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C6 alkoxy or C3-C6 cycloalkyl;
Ryselected from optionally substituted amino, C1-C6 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C6 cycloalkyl, said substituents being selected from optionally substituted arylSubstituted C1-C6 alkyl;
Ar2selected from 5-6 membered aryl or heteroaryl optionally mono-or disubstituted, said substituents being selected from halogen or C1-C6 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C6 alkyl or hydroxy C1-C6 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl group;
r is 0, 1,2 or 3.
Still further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof as described hereinbefore, wherein the compound is useful as a selective RET kinase inhibitor
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
a is hydrogen;
R14Selected from C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl, wherein said alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, 4-6 membered heterocyclyl optionally substituted with C1-C4 alkyl;
R15selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl, or a 4-6 membered heterocyclyl containing 1-2 heteroatoms each independently selected from N, O or S;
d is selected from:
D is optionally substituted with one substituent selected from hydroxy, amino or C1-C4 alkyl optionally substituted with one substituent selected from hydroxy, di (C1-C4 alkyl) amino,N-acetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
RXSelected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
Ryselected from amino optionally substituted with C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, or C3-C6 cycloalkyl;
Ar2selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen or C1-C4 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy C1-C4 alkyl, or Rm、RnTo which it is connectedThe attached carbon atoms together form a cyclopropyl group;
r is 0, 1 or 2.
Still further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof as described hereinbefore, wherein the compound is useful as a selective RET kinase inhibitor
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
a is hydrogen;
R14Selected from the group consisting of C1-C4 alkyl optionally substituted with 1-methylpiperidin-4-yl;
R15is C1-C4 alkyl;
d is selected from
D is optionally substituted with one substituent selected from hydroxy, amino or C1-C4 alkyl optionally substituted with one substituent selected from hydroxy, di (C1-C4 alkyl) aminoA base,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
wherein forAnd, if the substituent is hydroxy, it is substituted at its 3-position; if the substituent is other than hydroxyl, the substituent is substituted at the 4-position; for theThe substituent is hydroxyl or amino, and is substituted at the 4-position;
RXSelected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituent is selected from halogen, hydroxyl, C1-C4 alkoxy or C3-C6 cycloalkyl group;
Ryselected from amino optionally substituted with C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, or C3-C6 cycloalkyl;
Ar2selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen, C1-C4 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy C1-C4 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a cyclopropyl group;
r is 0, 1 or 2.
Still further preferably, the present invention provides a compound represented by formula (I), an isomer, a prodrug, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof as described hereinbefore, which is useful as a selective RET kinase inhibitor, 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, excipient, and optionally further comprising one or more other RET kinase inhibitors.
The invention also relates to the use of a compound of formula (I) as described in any one of the embodiments of the invention or an isomer, prodrug, stable isotopic derivative or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as an inhibitor of RET kinase.
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, in particular 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 present 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) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of the embodiments of the present invention, as a therapeutic and/or prophylactic agent for RET kinase-mediated diseases (e.g., tumor, etc.). Said tumor is especially hematological malignancy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, brain glioma.
Another aspect of the present invention relates to a pharmaceutical composition for treating and/or preventing a RET kinase-mediated disease (e.g., tumor, etc.), comprising a compound of formula (I) as described in any one of the embodiments of the present invention or its isomer, prodrug, stable isotopic derivative or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, excipient, and optionally further comprising one or more other RET kinase inhibitors.
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 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg 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 method
The invention also provides a method for preparing the compound. The compounds of the present invention can be prepared by various methods known in the art. For example, the compounds of the present invention can be synthesized as shown in schemes 1-10.
Scheme 1
R16Selected from C1-C4 alkyl;
P1and P2Each independently selected from halogen, such as chlorine, bromine, iodine, and the like;
the first step is as follows:
adding base (such as sodium bicarbonate) and R into solvent selected from 1, 4-dioxane, tetrahydrofuran or water16OCOCl, and reacting at room temperature or under oil bath heating (20-50 ℃) to obtain 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) atmosphere16OH, nitrine 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 (IV) and R in an anhydrous solvent (such as anhydrous toluene) under an inert gas (such as nitrogen or argon) atmosphere16OH, azidodiphenylphosphate and base (e.g. anhydrous)Triethylamine) is added, the mixture is heated in an oil bath, and Curtius rearrangement reaction is carried out at the temperature of 60-80 ℃ to obtain a compound (III);
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 ice bath, 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:
reacting compound (VII), lithium diisopropylamide andN,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
P1、P2、P3Each independently selected from halogen, such as chlorine, bromine, iodine, and the like;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
PG1selected from tert-butyloxycarbonyl;
R17selected from hydrogen, hydroxy;
R18selected from hydrogen, amino or C1-C4 alkyl optionally substituted with one selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
R19selected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
R20、R21each independently selected from hydrogen, C1-C4 alkyl;
the first step is as follows:
starting material (IX) (P)1Is chlorine, P2Bromine or iodine) and N-substituted pyrazole borate (or boric acid) are dissolved in a solvent (dioxane and water), a palladium complex such as tetrakis (triphenylphosphine) palladium is used as a catalyst, sodium carbonate or potassium carbonate is used as an alkali, the mixture is heated in an oil bath under the protection of nitrogen or argon, the mixture is stirred for 2 to 12 hours at the temperature of 70 to 100 ℃, and Suzuki coupling reaction is carried out to obtain a compound (X);
the second step is that:
dissolving the starting material (X), borate (or boronic acid) (XI) in a solvent (dioxane orN,NDimethylformamide with water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as catalyst, with potassium carbonate or phosphoric acidTaking potassium as alkali, heating in oil bath or microwave under the protection of nitrogen or argon, stirring at 90-140 ℃ for 1-12 hours, and carrying out Suzuki coupling reaction to obtain a compound (XIV);
the third step:
preparation of pinacol borate ester: dissolving a starting material (X) and pinacol diboron in a solvent (such as dioxane), using a palladium complex such as 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride as a catalyst or using 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:
dissolving the starting material (XII), the 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, stirring at 90-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction 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:
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 (XVI) is obtained;
the seventh step:
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 (XVII) is obtained;
eighth step:
starting material (IX) (P)1Is bromine or iodine, P2Dissolving chlorine) and 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, stirring for 2-12 hours at the temperature of 50-100 ℃, and carrying out Suzuki coupling reaction to obtain a compound (XVIII);
the ninth step:
starting material (XVIII),N-substituted pyrazole boronic acid esters (or boronic acids) in solvents (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, stirring at 90-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction to obtain a compound (XIV).
Scheme 3:
the first step is as follows:
dissolving 8-aminoquinoline (XIX) in dichloromethane, sequentially adding triethylamine and benzoyl chloride, and reacting at 25 ℃ for 1 hour to obtain the final productN- (quinolin-8-yl) benzamide (XX);
the second step is that:
will be provided withN- (Quinolin-8-Yl) benzamide (XX) is added to water in portionsNBromosuccinimide, and reacting at 25 ℃ for 15 hours. To obtainN- (5-bromoquinolin-8-yl) benzamide (XXI);
the third step:
will be provided withN- (5-bromoquinolin-8-yl) benzamide (XXI) is dissolved in ethanol, and 1M ethanol solution of sodium hydroxide is added with stirring at 25 ℃ and stirred at 85 ℃ for 15 hours to give 5-bromo-8-aminoquinoline (XXII);
the fourth step:
dissolving 5-bromo-8-aminoquinoline (XXII) in acetonitrile, addingN-chlorosuccinimide, stirring at 80 ℃ for 6 hours, to give 5-bromo-7-chloro-8-aminoquinoline (XXIII);
the fifth step:
5-bromo-7-chloro-8-aminoquinoline (XXIII) 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, stirred at 65 ℃ for 4 hours, and the mixture is poured into saturated aqueous sodium hydroxide solution (3L) to obtain 5-bromo-7-chloroquinoline (XXIV).
Scheme 4
P3Selected from halogens such as chlorine, bromine, iodine, and the like;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
PG1selected from tert-butyloxycarbonyl;
R15selected from C1-C4 alkyl;
R17selected from hydrogen, hydroxy;
R18selected from amino or C1-C4 alkyl, wherein said alkyl is optionally substituted with one group selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
R19selected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
the first step is as follows:
dissolving a starting material (XXIV) and 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, stirring at 50-100 ℃ for 2-12 hours, and carrying out Suzuki coupling reaction to obtain a compound (XXV);
the second step is that:
starting material (XXV),N-substituted pyrazole boronic acid esters (or boronic acids) in solvents (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, stirring at 90-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction to obtain a compound (XXVI);
the third step:
deprotection of t-butyloxycarbonyl using trifluoroacetic acid or hydrochloric acid as the acid; PG is carried out in solvent such as dichloromethane or dioxane1The deprotection reaction is carried out at the temperature of 0-25 ℃ to obtain a compound (XXVII);
the fourth step:
dissolving the starting material (XXVII) 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 (XXVII) with the corresponding carboxylic acid in a solvent (tetrahydrofuran, dichloromethane orN,NDimethylformamide, etc.)Adding a condensing agent such as 2- (7-benzotriazole oxide)N,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 (XXVIII) is obtained;
the fifth step:
dissolving an initial raw material (XXIV) and pinacol diboron 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 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 (XXIX), wherein a crude product is used for the next step without purification;
and a sixth step:
dissolving the starting material 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (XXIX), the 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, stirring at 90-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction to obtain a compound (XXV).
Scheme 5
P3Selected from halogens such as chlorine, bromine, iodine, and the like;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
PG1selected from tert-butyloxycarbonyl;
R17selected from hydrogen, hydroxy;
R18selected from amino or C1-C4 alkyl, wherein said alkyl is optionally substituted with one group selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-ylGeneration;
R19selected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
the first step is as follows:
dissolving 2-chloro-4-ethoxy-6-fluorobenzaldehyde (XXX) in dimethyl sulfoxide, adding potassium carbonate and formamidine acetate while stirring, and stirring at 110 ℃ for 6 hours to obtain 5-chloro-7-ethoxyquinazoline (XXXI);
the second step is that:
the starting material 5-chloro-7-ethoxyquinazoline (XXXI), boronic ester (or boronic acid) (XI) is dissolved 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, stirring at 90-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction to obtain a compound (XXXIII);
the third step:
dissolving 5-chloro-7-ethoxyquinazoline (XXXI) and pinacol diboron serving as starting raw materials 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, 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 (XXXII);
the fourth step:
dissolving the starting material (XXXII), the heterocyclic aryl halide (XIII) in a solvent (dioxane orN,NDimethylformamide with water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as catalyst, using potassium carbonate or potassium phosphate as base, under nitrogen or argon protection, in an oil bath orHeating by microwave, stirring for 1-12 hours at the temperature of 90-140 ℃, and carrying out Suzuki coupling reaction to obtain a compound (XXXIII);
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 (XXXIV);
and a sixth step:
the starting material (XXXIV) 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 (XXXV) can be obtained.
Scheme 6
Y1Is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
PG1selected from tert-butyloxycarbonyl;
R17selected from hydrogen, hydroxy;
R18selected from amino or C1-C4 alkyl, wherein said alkyl is optionally substituted with one group selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
R19selected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected fromFrom halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
the first step is as follows: the starting material 5, 7-dichloro-1, 6-naphthyridine (synthesis reference: PCT int. appl., 2011134971) (XXXVI), boronic ester (or boronic acid) (XI) was dissolved in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst or tris (dibenzylideneacetone) dipalladium as a catalyst, tricyclohexylphosphine as a ligand, using potassium carbonate or potassium phosphate as a base, stirring for 12-16 hours at a temperature of 80-90 ℃ by oil bath or microwave heating under the protection of nitrogen or argon, and carrying out Suzuki coupling reaction to obtain a compound (XXXVII);
the second step is that:
starting material (XXXVII) is introduced,N-methylpyrazole boronate (or boronic acid) is dissolved 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, stirring at 120-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction to obtain a compound (XXXVIII);
the third step:
PG1deprotection of, for example, t-butyloxycarbonyl group using a hydrogen chloride dioxane solution or a hydrogen chloride ethyl acetate solution as an acid; carrying out reaction in solvents such as methanol, ethyl acetate or dioxane and the like at the temperature of 0-25 ℃;
the fourth step:
the starting material (XXXIX) 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 (XXXX) can be obtained.
Scheme 7
Y1Is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
PG1selected from tert-butyloxycarbonyl;
R14selected from C1-C4 alkyl or C1-C4 alkyl optionally substituted with 1-methylpiperidin-4-yl;
R17selected from hydrogen, hydroxy;
R18selected from amino or C1-C4 alkyl, wherein said alkyl is optionally substituted with one group selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
R19selected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
the first step is as follows:
starting material XXXVII (R)14Ethyl) is dissolved in a sodium ethoxide ethanol solution prepared in situ using sodium and ethanol, heated in an oil bath and stirred at 100 ℃ for about 16 hours to give compound (XXXXI); or
Dissolving starting materials XXXVII and 1-methyl-4-piperidine methanol in 1, 4-dioxane, using a metal complex such as tris (dibenzylideneacetone) dipalladium as a catalyst and cesium carbonate as a base, bubbling the reaction solution with nitrogen for ten minutes, and stirring by microwave heating at 110 ℃ for 1 hour under the protection of nitrogen to obtain a compound (XXXXI);
the second step is that:
PG1deprotection of, for example, t-butyloxycarbonyl group using a hydrogen chloride ethyl acetate solution as an acid; in a solvent such as ethyl acetate and the like, the reaction is carried out at the temperature of 0-25 ℃;
the third step:
the starting material (XXXXII) 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 (XXXIII) can be obtained.
Scheme 8
Y1Is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
PG1selected from tert-butyloxycarbonyl;
R19selected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
R22selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen, C1-C4 alkoxy;
R23selected from C1-C4 alkyl;
the first step is as follows:
starting material 5, 7-dichloro-1, 6-naphthyridine (synthetic ginseng)Examination: PCT int, appl., 2011134971) (XXXVI), borate (or boronic acid) (XXXXIV) are dissolved in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst or tris (dibenzylideneacetone) dipalladium as a catalyst, tricyclohexylphosphine as a ligand, using potassium carbonate or potassium phosphate as a base, stirring for 12-16 hours at a temperature of 80-90 ℃ by oil bath or microwave heating under the protection of nitrogen or argon, and carrying out Suzuki coupling reaction to obtain a compound (XXXXXV);
the second step is that:
starting material (XXXXV),N-methylpyrazole boronate (or boronic acid) is dissolved in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium phosphate as a base, heating in an oil bath or microwave under the protection of nitrogen or argon, stirring at 120-140 ℃ for 1-12 hours, and performing Suzuki coupling reaction to obtain a compound (XXXXVI);
the third step:
PG1deprotection of, for example, t-butyloxycarbonyl group using a hydrogen chloride dioxane solution or a hydrogen chloride ethyl acetate solution as an acid; carrying out reaction in a solvent such as methanol, ethyl acetate or dioxane at 0-25 ℃ to obtain a compound (XXXXVI);
the fourth step:
dissolving the starting material (XXXXVI) and corresponding aldehyde or ketone in a solvent (methanol, ethanol or 1, 2-dichloroethane, etc.), adding a reducing agent such as sodium triacetoxyborohydride, etc., and heating and stirring at room temperature of 20-50 ℃ or in an oil bath for 12-48 hours to obtain the compound (XXXXVIII).
The fifth step:
the starting material (XXXXVI) 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 (XXXXIX) can be obtained.
And a sixth step:
dissolving the starting material (XXXXVI) with the corresponding carboxylic acid in a solvent (CN,NDimethylformamide etc.), alkylsulfonyl chloride R is added23S(O)2Adding base such as triethylamine and the like into the Cl, and stirring the mixture for 15 minutes to 18 hours at room temperature; compound (XXXXX) can be obtained.
Scheme 9
R23Selected from C1-C4 alkyl;
the first step is as follows:
the starting materials 5, 7-dichloro-1, 6-naphthyridine (synthesis reference: PCT int. appl. 2011134971) (XXXVI), boronic ester (or boronic acid) (XXXXXI) were dissolved in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst or tris (dibenzylideneacetone) dipalladium as a catalyst, tricyclohexylphosphine as a ligand, potassium carbonate or potassium phosphate as a base, and stirring at 80-90 ℃ for 12-16 hours under the protection of nitrogen or argon, so as to perform Suzuki coupling reaction, thereby obtaining a compound (XXXXXII);
the second step is that:
starting material (XXXXXII),N-methylpyrazole boronate (or boronic acid) is dissolved in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using potassium phosphate as a base, stirring at 120-140 ℃ for 1-12 hours under the protection of nitrogen or argon, and carrying out Suzuki coupling reaction to obtain a compound (XXXXXIII).
Scheme 10
R17Selected from hydrogen, hydroxy or amino;
the first step is as follows:
dissolving the starting material (XXXXXIV) inN,NIn dimethylformamideAdding sodium hydrogen, stirring at room temperature for half an hour, then adding 2-fluoropyridine, and stirring at 80-90 ℃ for 4-16 hours to obtain a compound (XXXXXV);
the second step is that:
starting materials (XXXXXV), 5-bromo-2-fluoropyridine andN,Ndissolving diisopropylethylamine in dimethyl sulfoxide, and stirring at 90-110 ℃ for 10-20 hours to obtain a compound (XXXXXVI);
the third step:
dissolving a starting material (XXXXVI), pinacol diboron, potassium acetate and 1,1' -bis diphenylphosphino ferrocene palladium dichloride in dioxane under the protection of nitrogen, stirring for 4-10 hours at 80-100 ℃, cooling the obtained mixture to room temperature, adding 5, 7-dichloro-1, 6-naphthyridine (the synthesis reference: PCT int, appl., 2011134971) (XXXVI) and a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst or tris (dibenzylideneacetone) dipalladium as a catalyst under the protection of nitrogen, taking tricyclohexylphosphine as a ligand, taking potassium carbonate or potassium phosphate as a base, adding water, stirring for 12-20 hours at 80-90 ℃, and carrying out Suzuki coupling reaction to obtain a compound (XXXXXVII);
the fourth step:
starting material (XXXXXVII),N-methylpyrazole boronate (or boronic acid) is dissolved in a solvent (dioxane orN,NDimethylformamide and water), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst and potassium phosphate as a base, stirring at 130-150 ℃ for 2-12 hours under the protection of nitrogen or argon, and carrying out Suzuki coupling reaction to obtain a compound (XXXXXVIII).
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
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 4-to 5-membered, 5-to 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 present invention, the term "nitro" means NO2A group.
In the present invention, the term "hydroxyl group" means an-OH group.
In the present invention, the term "amino" refers to-NH2A group. One or two hydrogens on the amino group may be replaced by an alkyl group having the meaning as described above to form a mono-or dialkylamino group.
In the present invention, the term "carbonyl group" meansA group. One side of the carbon on the carbonyl group is attached to an alkyl group, which has the meaning as described above, to form an alkylcarbonyl group.
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 "heteroaryloxy" refers to a heteroaryl group attached through an oxygen bridge, said heteroaryl group having the meaning as described hereinbefore.
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, "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" described herein are those described in Berge, et al, "Pharmaceutically 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 (. delta.) are reported as PPM (parts per million). NMR was performed by a Bruker AVANCE III-400MHz spectrometer. Suitable solvents are selected from deuterated chloroform (CDCl)3) 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 ZORBAX XDB-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 Acros Organics, Aldrich Chemical Company, Shaoshi Chemical technology (Accela ChemBio Inc), Shanghai Bidi medicine, Shanghai Aladdin chemistry, Shanghai Michelle chemistry, Bailinger chemistry, Annaige chemistry, and the like.
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 anigi 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 23
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
First step of
((3S,4S) -1- (5-Bromopyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamic acid tert-butyl ester
The compound 2-fluoro-5-bromopyridine (1.08 g, 5.00 mmol) ((3)S,4S) -3-hydroxypiperidin-4-yl) carbamic acid tert-butyl ester (synthesis reference: WO 2004058144A 2) (1.18 g, 5.00 mmol) andN,Ndiisopropylethylamine (1.29 g, 10.00 mmol) was dissolved in dimethyl sulfoxide (10 mL) and heated to 90 ℃ for reaction overnight. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), the organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified with silica gel column (ethyl acetate/petroleum ether = 2: 3) to obtain the objective product (3)S,4S) -tert-butyl 1- (5-bromopyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (1.40 g, yellow solid). Yield: 75.4 percent. MS m/z (ESI) 372&374 [M + 1];
Second step of
((3S,4S) -1- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamic acid tert-butyl ester
Compound ((3)S,4S) -1- (5-bromopyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamic acidTert-butyl ester (0.15 g, 0.54 mmol), 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (synthesis reference: WO 2017032840A 1) (0.15 g, 0.54 mmol), tetrakis (triphenylphosphine) palladium (20 mg, 0.05 mmol), potassium carbonate (75 mg, 0.54 mmol) were dissolved in dioxane (6 mL) and water (1 mL), and stirred under nitrogen in an oil bath at 80 ℃ for 2 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (50 mL), and the organic phase was washed with water (10 mL) and saturated brine (10 mL). Drying over anhydrous sodium sulfate, filtering, desolventizing under reduced pressure, and separating the residue by silica gel column chromatography (dichloromethane: methanol = 100: 0 to 9: 1) to obtain the objective product ((3)S,4S) -tert-butyl 1- (5- (7-chloroquinolin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (0.11 g, yellow liquid), yield: 90 percent. MS M/z (ESI) 455 [ M + 1];
The third step
(3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Compound ((3)S,4S) -1- (5- (7-Chloroquinolin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamic acid tert-butyl ester (0.11 g, 0.24 mmol), 1-methyl-1HPyrazole-4-boronic acid pinacol ester (0.10 g, 0.48 mmol), tetrakis (triphenylphosphine) palladium (20 mg, 0.02 mmol), potassium phosphate (0.10 g, 0.48 mmol) dissolved in dioxane (4 mL) and water (1 mL), stirred under nitrogen atmosphere in an oil bath at 120 ℃ overnight, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL), the organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, desolventized under reduced pressure, and the residue was chromatographed on silica gel column (dichloromethane: methanol = 100: 0 to 20: 1) to give the desired product (3) (3: methanol = 100: 0 to 20: 1)S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-tert-buty-lester) carbamate (0.12 g, yellow solid), yield: 99 percent;
MS m/z (ESI): 501 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 4.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.18-8.16 (m, 2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.60-7.58 (m, 1H), 7.31-7.29 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.90-4.88 (m, 1H), 4.50-4.43 (m, 2H), 3.98 (s, 3H), 3.63-3.57 (m, 2H), 3.49-3.47 (m, 2H), 3.00-2.87 (m, 1H), 2.14-2.10 (m, 1H), 1.47 (s, 9H);
the fourth step
(3S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-3-ol
Reacting a compound (3)S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.11 g, 0.22 mmol) was dissolved in dioxane (4 mL, 16 mmol, 4M) of hydrochloric acid and stirred at room temperature for 30 minutes. The reaction mixture was desolventized under reduced pressure, neutralized with a saturated aqueous solution of sodium hydrogencarbonate (3 mL), extracted with ethyl acetate (10 mL), and the organic phase was washed with saturated brine (4 mL. times.3). Drying with anhydrous sodium sulfate, filtering, and desolventizing under reduced pressure to obtain target product (3)S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-3-ol (70 mg, yellow solid), yield: 80 percent. MS M/z (ESI) 401 [ M + 1]];
The fifth step
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
The compounds o-chlorobenzoic acid (4 mg, 0.02 mmol), triethylamine (5 mg, 0.05 mmol) and 2- (7-benzotriazole oxide)N,N, N', N'-Tetramethyluronium hexafluorophosphate (7 mg, 0.02 mmol) was dissolved inN,NDimethylformamide (1 mL), stirred at room temperature for 5 minutes. Adding (3)S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-3-ol (5 mg, 0.01 mmol), and stirring at room temperature was continued for 10 minutes. The reaction mixture was washed with saturated sodium hydroxide solution (2 mL), extracted with ethyl acetate (10 mL), and the organic phase was washed with water (20 mL) and saturated brine(20 mL), drying with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain the target product 2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide (2.7 mg, white solid), yield: 42%;
MS m/z (ESI): 539&541 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.90-8.89 (m, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.80 (s, 1H), 7.77-7.75 (m, 1H), 7.66-7.64 (m, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.45-7.35 (m, 3H), 7.33-7.30 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 6.4 Hz, 1H), 4.20-4.15 (m, 1H), 4.00 (s, 3H), 3.73-2.99 (m, 5H), 2.05-2.00 (m, 2H)。
example 44
2-chloro-N- (4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) -6-fluorobenzamide
First step of
1- (5-Bromopyridin-2-yl) -4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylic acid methyl ester
The compound 2-fluoro-5-bromopyridine (0.61 g, 3.49 mmol), methyl 4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylate (0.90 g, 3.49 mmol), potassium carbonate (1.60 g, 13.94 mmol) and dimethyl sulfoxide (15 mL) were mixed and stirred at 100 ℃ for 16 hours. After cooling to room temperature, the mixture was slowly poured into water (40 mL), extracted with ethyl acetate (50 mL. times.3), and the organic phase was washed with water (50 mL. times.3) and saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to give methyl 1- (5-bromopyridin-2-yl) -4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylate (1.10 g, crude product). Used directly in the next step. MS M/z (ESI) 414&416 [ M + 1 ];
second step of
(1- (5-Bromopyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) carbamic acid tert-butyl ester
The compound methyl 1- (5-bromopyridin-2-yl) -4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylate (0.25 g, 0.60 mmol) was dissolved in tetrahydrofuran (3 mL), a solution of lithium borohydride in tetrahydrofuran (2 mL, 2M) was added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of water (20 mL), extracted with ethyl acetate (20 mL. times.3), and the organic phase was washed with water (20 mL. times.3) and saturated brine (20 mL. times.3). Drying over anhydrous sodium sulfate, filtering to remove the drying agent, desolventizing the filtrate under reduced pressure, and purifying the residue with a silica gel chromatography column (petroleum ether: ethyl acetate = 100: 0-4: 6) to obtain the target product tert-butyl (1- (5-bromopyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) carbamate (0.14 g, white solid) in yield: 56 percent. MS M/z (ESI) 386&388 [ M + 1 ];
the third step
(1- (5-Bromopyridin-2-yl) -4-formylpiperidin-4-yl) carbamic acid tert-butyl ester
Compound (1- (5-bromopyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) carbamic acid tert-butyl ester (0.93 g, 2.59 mmol) was dissolved in dichloromethane (10 mL), and dess-martin reagent (1.65 g, 3.89 mmol) was added in portions and stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated sodium sulfite solution (5 mL), extracted with dichloromethane (20 mL), and the organic phase was washed with water (20 mL) and saturated brine (20 mL). Dried over anhydrous sodium sulfate, filtered, and exsolution under reduced pressure to give the desired product tert-butyl (1- (5-bromopyridin-2-yl) -4-formylpiperidin-4-yl) carbamate (0.68 g, white solid), yield: 68 percent;
MS m/z (ESI): 384&386 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.55-7.52 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.92 (s, 1H), 3.94-3.88 (m, 2H), 3.36-3.33 (m, 2H), 2.04-1.98 (m, 2H), 1.87-1.84 (m, 2H), 1.45 (s, 9H);
the fourth step
(1- (5-Bromopyridin-2-yl) -4- ((4-ethylpiperazin-1-yl) methyl) piperidin-4-yl) carbamic acid tert-butyl ester
The compound (1- (5-bromopyridin-2-yl) -4-formylpiperidin-4-yl) carbamic acid tert-butyl ester (0.60 g, 1.60 mmol) and 2-ethylpiperazine (0.34 g, 3.00 mmol) were dissolved in tetrahydrofuran (15 mL), and tetraethyltitanate (0.94 g, 4.16 mmol) was added thereto, followed by stirring at room temperature for 30 minutes, followed by addition of sodium borohydride acetate (0.85 g, 4.00 mmol), and reaction at 50 ℃ for 3 hours. The reaction mixture was diluted with dichloromethane/methanol (10: 1, 200 mL), water (5 mL) was added, the mixture was stirred vigorously for 15 minutes, the mixture was filtered, the filter cake was washed with dichloromethane (40 mL. times.3), and the organic phases were combined and washed with water (20 mL) and saturated brine (20 mL). Drying with anhydrous sodium sulfate, filtering to remove the drying agent, and desolventizing under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give the objective product tert-butyl 1- (5-bromopyridin-2-yl) -4- ((4-ethylpiperazin-1-yl) methyl) piperidin-4-yl) carbamate (0.53 g, yellow oil), yield: 70 percent. MS M/z (ESI) 482&484 [ M + 1 ];
the fifth step
(1- (5- (7-Chloroquinolin-5-yl) piperidin-2-yl) -4- ((4-ethylpiperazin-1-yl) methyl) piperidin-4-yl) carbamic acid tert-butyl ester
Tert-butyl 7-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (0.17 g, 0.60 mmol), (1- (5-bromopyridin-2-yl) -4- ((4-ethylpiperazin-1-yl) methyl) piperidin-4-yl) carbamate (0.20 g, 0.41 mmol) and dioxane (10 mL), water (2 mL) were mixed, potassium carbonate (0.17 g, 1.23 mmol) and tetrakis (triphenylphosphine) palladium (47 mg, 0.041 mmol) were added under argon protection, replaced three times with argon, and stirred at 80 ℃ for 5 hours under argon protection. After cooling to room temperature and desolventizing under reduced pressure, the residue was extracted with ethyl acetate (15 mL. times.3) by adding water (20 mL), and the organic phase was washed with saturated brine (20 mL. times.3). Drying over anhydrous sodium sulfate, filtering to remove the drying agent, desolventizing under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (dichloromethane: methanol = 100: 0-15: 1) to give the target product tert-butyl (1- (5- (7-chloroquinolin-5-yl) piperidin-2-yl) -4- ((4-ethylpiperazin-1-yl) methyl) piperidin-4-yl) carbamate (0.10 g, yellow solid) in yield: and 43 percent. MS M/z (ESI) 565&567 [ M + 1 ];
the sixth step
(4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
The compound (tert-butyl 1- (5- (7-chloroquinolin-5-yl) piperidin-2-yl) -4- ((4-ethylpiperazin-1-yl) methyl) piperidin-4-yl) carbamate (0.10 g, 0.18 mmol), 1-methyl-1HPyrazole-4-boronic acid pinacol ester (75 mg, 0.36 mmol) and dioxane (6 mL) and water (1 mL) were mixed and 35 mL of block was added, potassium carbonate (75 mg, 0.54 mmol) and tetrakis (triphenylphosphine) palladium (21 mg, 0.018 mmol) were added under argon, argon was replaced three times, and stirring was carried out at 140 ℃ for 3 hours under argon. After cooling to room temperature and desolventizing under reduced pressure, the residue was extracted with ethyl acetate (15 mL. times.3) by adding water (20 mL), and the organic phase was washed with saturated brine (20 mL. times.2). Drying with anhydrous sodium sulfate, filtering to remove the drying agent, desolventizing under reduced pressure to obtain crude product, and purifying with silica gel preparation plate (dichloromethane/methanol = 12: 1) to obtain target product (4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1-yl) methyl)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (50 mg, yellow solid), yield: 45 percent. MS M/z (ESI) 611 [ M + 1];
Seventh step
4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-amine
Mixing compound (4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (50 mg, 0.082 mmol) and methanolic hydrogen chloride solution (6 mL, 24 mmol, 4M) were mixed and stirred at room temperature for 1 hour. Removing solvent under reduced pressure, adding saturated solution of sodium bicarbonate (10 mL), extracting with dichloromethane (10 mL × 4), washing organic phase with saturated saline (20 mL), drying with anhydrous sodium sulfate, filtering to remove drying agent, and removing solvent under reduced pressure to obtain target product 4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-amine (35 mg, yellow solid), which was used in the next reaction without purification. MS M/z (ESI) 511M + 1];
Eighth step
2-chloro-N- (4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) -6-fluorobenzamide
Mixing compound 4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-amine (6.0 mg, 0.012 mmol), 2-chloro-6-fluorobenzoic acid (2.6 mg, 0.015 mmol), 2- (7-benzotriazole oxide) -substituted benzeneN,N,N',N' -tetramethyluronium hexafluorophosphate (6.8 mg, 0.018 mmol), triethylamine (3 mg, 0.03 mmol) andN,Ndimethylformamide (2 mL) and stirred at room temperature for 1 hour. Water (20 mL) was added to dilute the mixture, the mixture was extracted with dichloromethane (20 mL. times.4), and the organic phase was washed with saturated brine (20 mL. times.2). Drying over anhydrous sodium sulfate, filtering to remove the drying agent, and purifying the residue from the preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)2O25% -50%) to obtain the target product 2-chloro-N- (4- ((4-ethylpiperazin-1-yl) methyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) quinolin-5-yl) pyridin-2-yl) piperidin-4-yl) -6-fluorobenzamide (2.2 mg, white solid), yield: 28%;
MS m/z (ESI): 667&669 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.92-8.90 (m, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.27 (s, 1H), 8.26-8.18 (m, 2H), 7.94 (s, 1H), 7.82 (s, 1H), 7.67-7.59 (m, 2H), 7.38-7.30 (m, 2H), 7.09-7.06 (m, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 4.34-4.18 (m, 2H), 4.00 (s, 3H), 3.40-3.27 (m, 2H), 3.17-3.01 (m, 10H), 2.98 (s, 2H), 2.54-2.41 (m, 2H), 1.82-1.69 (m, 2H), 1.40-1.31 (m, 3H)。
example 142
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) Pyridin-2-yl) piperidin-4-yl) benzamides
First step of
((3S,4S) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamic acid tert-butyl ester
The compound 5, 7-dichloro-1, 6-naphthyridine (synthetic reference: PCT int. appl., 2011134971) (45 mg, 0.23 mmol), (6- ((3)S,4S) -4-carbamic acid tert-butyl ester-3-hydroxypiperidin-1-yl) pyridin-3-yl) boronic acid (crude) and potassium carbonate (89 mg, 0.65 mmol) were added to 1, 4-dioxane (5 mL) and water (1 mL), tetrakis (triphenylphosphine) palladium (25 mg, 0.022 mmol) was added under nitrogen protection, and the reaction was carried out at 90 ℃ for 12 hours. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (10 mL. times.3) and saturated brine (10 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified on preparative silica gel plates (petroleum ether/ethyl acetate 1:1) to give the desired product ((3)S,4S) Tert-butyl 1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (60 mg, yellow solid) in 61% yield;
MS m/z (ESI): 456&458 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.07 (dd, J = 4.2, 1.6 Hz, 1H), 8.50-8.46 (m, 2H), 7.96-7.88 (m, 2H), 7.70-7.61 (m, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.78 (d, J = 6.4 Hz, 1H), 4.59-4.42 (m, 2H), 3.66-3.59 (m, 1H), 3.56-3.42 (m, 1H), 3.02-2.88 (m, 2H), 2.10-2.05 (m, 2H), 1.47 (s, 9H);
second step of
((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Adding compound (((3)S,4S) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) Carbamic acid tert-butyl ester (25 mg, 0.055 mmol), 1-methyl-1HPyrazole-4-boronic acid pinacol ester (29 mg, 0.137 mmol) and potassium phosphate (33 mg, 0.165 mmol) were dissolved in dioxane (2 mL) and water (0.5 mL), tetrakis (triphenylphosphine) palladium (7 mg, 0.006 mmol) was added under nitrogen protection, and the mixture was microwave-reacted at 140 ℃ for 1.5 hours. The reaction mixture was diluted with methylene chloride/methanol (20: 1, 50 mL), washed with saturated brine (5 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified on a preparative silica gel plate (dichloromethane/methanol 25: 1) to give the desired product ((3)S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (15 mg, yellow solid). Yield: 54 percent. MS M/z (ESI) 502 [ M + 1];
The third step
(3S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-3-ol
Compound ((3)S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (15 mg, 0.030 mmol) was dissolved in ethyl acetate (2 mL) and ethyl acetate hydrochloride solution (8 mL, 16 mmL, 2M) was added at room temperature. The reaction was stirred at room temperature for 0.5 hour. The reaction solution was desolventized under reduced pressure, and the residue was dissolved in methylene chloride/methanol (10: 1) and adjusted to pH 8-9 with triethylamine. After the mixture is evaporated and desolventized, a yellow solid crude product is obtained and is directly used for the next reaction. MS M/z (ESI) 402 [ M + 1 [)];
The fourth step
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
Reacting a compound (3)S,4S) -4-amino-1- (5- (7- (1-methyl-1)HPyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-3-ol (crude, 0.030 mmol), 2-chlorobenzoic acid (7 mg, 0.045 mmol) and triethylamine (6 mg, 0.06 mmol) were dissolved in dioxaneMethyl chloride (2 mL), 2- (7-benzotriazole oxide) is added at room temperatureN,N,N',N' -tetramethyluronium hexafluorophosphate (17 mg, 0.045 mmol), the reaction was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with water (20 mL), extracted with dichloromethane (20 mL. times.2), and the combined organic phases were washed with saturated brine (20 mL. times.2). Drying with anhydrous sodium sulfate, filtering, desolventizing under reduced pressure, purifying the residue with a preparative silica gel plate (dichloromethane/methanol 30: 1) to obtain the target product 2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide (10 mg, yellow solid). Yield: 62 percent;
MS m/z (ESI): 540&542 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.00 (m, 1H), 8.57 (d, J = 3.2 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.98-7.95 (m, 2H), 7.75-7.73 (m, 1H), 7.42-7.35 (m, 3H), 6.91 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 6.8 Hz, 1H), 4.65-4.53 (m, 2H), 4.27-4.25 (m, 1H), 4.17-4.15 (m, 1H), 3.99 (s, 3H), 3.77-3.71 (m, 1H), 3.30-3.24 (m, 1H), 2.96-2.90 (m, 1H), 2.32-2.27 (m, 1H)。
synthetic procedures for examples 143 to 167 reference example 142, the last step, in which 2-chlorobenzoic acid was replaced by a different acid:
example 168
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-4-yl) benzamide
First step of
(6-((3S,4S) -4- ((tert-butoxycarbonyl) amino) -3-hydroxypiperidin-1-yl) pyrazin-3-yl) boronic acid
Will (3)S,4S) Tert-butyl (1- (5-bromopyrazin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (first step of synthesis reference example 23) (0.52 g, 1.40 mmol), pinacol diboron (0.71 g, 2.80 mmol) were dissolved in 1, 4-dioxane (20 mL), tris (dibenzylideneacetone) dipalladium (0.14 g, 0.15 mmol), tricyclohexylphosphine (84 mg, 0.30 mmol) and potassium acetate (0.41 g, 4.20 mmol) were added, the reaction solution was bubbled with nitrogen for ten minutes, and stirred at 95 ℃ for 2 hours under nitrogen protection. The reaction solution is dried in a rotating way to obtain a crude product (6- ((3)S,4S) -4- ((tert-butoxycarbonyl) amino) -3-hydroxypiperidin-1-yl) pyrazin-3-yl) boronic acid (1.20 g, crude) was used directly in the next step without purification. MS M/z (ESI) 339 [ M + 1]];
Second step of
((3S,4S) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyrazin-2-yl) -3-hydroxypiperidin-4-yl) carbamic acid tert-butyl ester
Will (6- ((3)S,4S) -4- ((tert-butoxycarbonyl) amino) -3-hydroxypyrazin-1-yl) pyridin-3-yl) boronic acid (120 g, crude), 5, 7-dichloro-1, 6-naphthyridine (synthesis reference: PCT int, appl., 2011134971) (0.30 g, 1.50 mmol) was dissolved in 1, 4-dioxane (5 mL) and water (1 mL), tris (dibenzylideneacetone) dipalladium (92 mg, 0.10 mmol), tricyclohexylphosphine (56 mg, 0.20 mmol) and potassium carbonate (0.62 g, 4.50 mmol) were added, and the reaction solution was bubbled with nitrogen for ten minutes, and stirred at 90 ℃ for 14 hours under nitrogen. Cooled to room temperature, diluted with dichloromethane (100 mL), the organic phase washed with water (20 mL. times.3) and saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered, desolventized under reduced pressure, and the crude product purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to give ((3: 1)S,4S) -tert-butyl 1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyrazin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (0.28 g, yellow solid) yield 43.7%;
MS m/z (ESI): 457&459 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.39 (d, J = 8.8 Hz, 1H), 9.06-9.04 (m, 1H), 9.00 (s, 1H), 8.26 (s, 1H), 8.19-8.16 (m, 1H), 7.94 (s, 1H), 4.76-4.74 (m, 1H), 4.58-4.52 (m, 2H), 3.55-3.48 (m, 1H), 3.06-2.80 (m, 2H), 2.12-2.07 (m, 1H), 1.57-1.51 (m, 1H), 1.47 (s, 9H);
the third step
((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Will ((3)S,4S) -tert-butyl 1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyrazin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (0.28 g, 0.62 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (0.26 g, 1.24 mmol), dissolved inN,NDimethylacetamide (5 mL) and water (1 mL), and the reaction solution was bubbled with nitrogen for ten minutes, and heated and stirred at 120 ℃ for 4 hours under nitrogen blanket. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL) and the organic phase was washed with water (20 mL) and saturated brine (20 mL). Drying with anhydrous sodium sulfate, filtering, removing solvent under reduced pressure, and separating the crude product with silica gelColumn purification (dichloromethane: methanol = 40: 1) yielded the objective product ((3)S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (100 mg, yellow solid) yield 32.7%;
MS m/z (ESI): 503 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 8.8 Hz, 1H), 9.13 (s, 1H), 8.99-8.97 (m, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.44-7.40 (m, 1H), 4.89-4.87 (m, 1H), 4.57-4.53 (m, 2H), 3.97 (s, 3H), 3.54-3.51 (m, 1H), 3.09-2.94 (m, 2H), 2.15-2.11 (m, 1H), 1.59-1.51 (m, 1H), 1.47 (s, 9H);
the fourth step
(3S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-3-ol hydrochloride
Will ((3)S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.10 g, 0.20 mmol) was dissolved in dioxane hydrochloride solution (5 mL, 20 mmol, 4M) and stirred at room temperature for 1 hour. The reaction liquid is dried in a rotating way to obtain a crude product (3)S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-3-ol hydrochloride (110 mg, crude) was used directly in the next step without purification. MS M/z (ESI) 403 [ M + 1]];
The fifth step
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-4-yl) benzamide
Reacting a compound (3)S,4S) -4-amino-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-3-ol hydrochloride (crude, 0.004 mmol), 2-chlorobenzoic acid (1 mg, 0.006 mmol) and triethylamine (1 mg, 0.008 mmol) were dissolved in dichloromethane (1 mL), and 2- (7-benzotriazole oxide) -one was added at room temperatureN,N,N',N' -tetramethylureaHexafluorophosphate (2.3 mg, 0.006 mmol) was stirred at room temperature for 0.5 h. The reaction mixture was diluted with water (5 mL), extracted with dichloromethane (10 mL. times.2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, desolventized under reduced pressure, and the residue was purified with preparative silica gel plate (dichloromethane/methanol 25: 1) to give the desired product, 2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyrazin-2-yl) piperidin-4-yl) benzamide (1.2 mg, yellow solid). Yield: 50 percent;
MS m/z (ESI): 541&543 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 7.8 Hz, 1H), 9.10 (d, J = 1.2 Hz, 1H), 9.01-9.00 (m, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.79-7.73 (m, 1H), 7.45-7.36 (m, 3H), 6.45 (d, J = 6.8 Hz, 1H), 4.68-4.56 (m, 2H), 4.30-4.17 (m, 1H), 4.00 (s, 3H), 3.81-3.68 (m, 1H), 3.18-3.06 (m, 2H), 2.29-2.26 (m, 1H), 2.01-1.98 (m, 1H)。
synthetic procedures for examples 169 to 181 reference is made to the last step of example 27, in which 2-chlorobenzoic acid is replaced by a different acid:
example 183
2-chloro-N- (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
First step of
(1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Tert-butyl (1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamate (third step of Synthesis reference example 168) (38 mg, 0.09 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (37 mg, 0.18 mmol) dissolvedN,NTo dimethylformamide (4 mL), tetrakis (triphenylphosphine) palladium (10 mg, 0.009 mmol) and potassium phosphate (57 mg, 0.27 mmol) were added in this order, and the mixture was heated to 140 ℃ under nitrogen for 6 hours. The reaction mixture was cooled to room temperature, poured into water (20 mL), extracted with ethyl acetate (25 mL × 3), the organic phases were combined, washed with saturated brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography (dichloromethane: methanol = 15: 1) to obtain the objective compound (1- (5- (7- (1-methyl-1: 1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (37 mg, white solid) yield 84.7%;
MS m/z (ESI): 486 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.57 (m, 1H), 8.44-8.42 (m, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.96-7.95 (m, 2H), 7.38-7.35 (m, 1H), 6.83 (d, J= 8.8 Hz, 1H), 4.53-4.52 (m, 1H), 4.37-4.35 (m, 2H), 3.99 (s, 3H), 3.77-3.76 (m, 1H), 3.14-3.08 (m, 2H), 2.10-2.05 (m, 4H), 1.47 (s, 9H);
second step of
(1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amino hydrochloride
(1- (5- (7- (1-methyl-1))HTert-butyl (10 mg, 0.02 mmol) of (E) -pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamate was dissolved in methanol (3 mL), and dioxane hydrochloride solution (3 mL, 12 mmol, 4M) was added to react at room temperature for 30 minutes. Reaction ofThe solution was concentrated to give crude (1- (5- (7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amino hydrochloride (crude, 10 mg, yellow solid) as the title compound, which was directly charged to the next step. MS M/z (ESI) 386 [ M + 1]];
The third step
2-chloro-N- (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
O-chlorobenzoic acid (6 mg, 0.04 mmol), 2- (7-benzotriazole oxide)N,N,N',N'Tetramethyluronium hexafluorophosphate (16 mg, 0.04 mmol) and triethylamine (0.1 mL) were dissolved in dichloromethane (5 mL), and (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amino hydrochloride (10 mg, 0.02 mmol), and the reaction was stirred at room temperature for 1 hour. Diluting with dichloromethane (20 mL), washing the organic phase with saturated brine (25 mL), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying by thin layer chromatography (dichloromethane: methanol = 15: 1) to obtain 2-chloro-N- (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide (8.0 mg, yellow solid), yield 76.5%;
MS m/z (ESI): 524&526 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.01-9.00 (m, 1H), 8.59-8.58 (m, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.98-7.95 (m, 2H), 7.69-7.66 (m, 1H), 7.41-7.32 (m, 4H), 6.87 (d, J = 8.8 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 4.43-4.34 (m, 3H), 3.99 (s, 3H), 3.27-3.21 (m, 2H), 2.23-2.21 (m, 2H), 1.67-1.62 (m, 2H)。
synthetic procedures for examples 184 to 203 reference is made to the last step of example 183 in which 2-chlorobenzoic acid is replaced by a different acid:
example 205
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
First step of
((3S,4S) -3-hydroxy-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Will ((3)S,4S) Tert-butyl (46 mg, 0.10 mmol) of (E) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamate, 1-methyl-4-piperidinemethanol (65 mg, 0.05 mmol) was dissolved in 1, 4-dioxane (1.5 mL), tris (dibenzylideneacetone) dipalladium (9.2 mg, 0.01 mmol) and cesium carbonate (98 mg, 0.30 mmol) were added, and the reaction solution was bubbled with nitrogen for ten minutes, and stirred under nitrogen at 110 ℃ under microwave heating for 1 hour. The mixture was diluted with dichloromethane (20 mL) and washed with saturated brine (20 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was desolventized under reduced pressure. The residue was purified by a silica gel column (dichloromethane: methanol = 15: 1) to obtain the objective product ((3)S,4S) -3-hydroxy-1- (5- (7- ((1-methylpiperidine)-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (8 mg, yellow solid) yield 20.2%;
MS m/z (ESI): 549 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.8 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.34 (s, 1H), 7.91-7.88 (m, 1H), 7.30-7.27 (m, 1H), 7.20 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.78-4.48 (m, 3H), 4.33 (d, J = 6.0 Hz, 2H), 3.66-3.51 (m, 4H), 3.02-2.89 (m, 2H), 2.76-2.70 (m, 5H), 2.13-2.04 (m, 4H), 1.92-1.84 (m, 2H), 1.47 (s, 9H);
second step of
(3S,4S) -4-amino-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-3-ol
Will ((3)S,4S) Tert-butyl (8 mg, 0.02 mmol) 3-hydroxy-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamate was dissolved in dioxane hydrochloride solution (1 mL, 4 mmol, 4M) and stirred at room temperature for 1 hour. Adding triethylamine into the reaction solution for neutralization, and spin-drying to obtain a crude product (3)S,4S) -4-amino-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-3-ol (10 mg, crude) was used directly in the next step without purification. MS M/z (ESI) 449 [ M + 1]];
The third step
2-chloro-N-((3S,4S) -3-hydroxy-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
The target product 2-chloro-substituted benzene was synthesized according to the third procedure of example 183N-((3S,4S) -3-hydroxy-1- (5- (7- ((1-methylpiperidin-4-yl) methoxy) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide;
MS m/z (ESI): 587&589 [M + 1];
1H NMR (400 MHz, CD3OD) δ 8.95-8.93 (m, 1H), 8.53-8.49 (m, 2H), 7.97-7.94 (m, 1H), 7.46-7.36 (m, 5H), 7.16 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 4.65-4.58 (m, 1H), 4.42-4.39 (m, 3H), 4.11-4.05 (m, 1H), 3.67-3.62 (m, 1H), 3.54-3.48 (m, 2H), 3.21-3.13 (m, 1H), 3.07-2.97 (m, 2H), 2.86 (s, 3H), 2.17-2.10 (m, 4H), 1.75-1.61 (m, 4H)。
the synthetic procedures for examples 206 to 211 refer to the last step of example 205, in which 2-chlorobenzoic acid was replaced by a different acid:
example 212
2-chloro-N- (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
First step of
(1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid ethyl ester
Adding metallic sodium (0.23 g, 10 mmol) into absolute ethyl alcohol (5 mL), stirring at room temperature for 20 minutes, adding tert-butyl (1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridine-2-yl) piperidine-4-yl) carbamate (20 mg, 0.046 mmol), heating to 80 ℃ for reaction for 2 hours, continuing heating to 100 ℃ for reaction for 16 hours, and directly feeding the crude ethyl (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridine-2-yl) piperidine-4-yl) carbamate reaction liquid to the next step. MS M/z (ESI) 408 [ M + 1 ];
second step of
(1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amine
To a solution of crude ethyl (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamate (crude, 0.046 mmol) in ethanol (5 mL) was added water (3 mL), sodium hydroxide (5 mg, 0.09 mmol) and the reaction was allowed to warm to 120 ℃ for 5 hours. The reaction was spin dried, ethyl acetate (50 mL) was added, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amine (crude, 20 mg) which was directly fed to the next step. MS M/z (ESI) 350 [ M + 1 ];
the third step
2-chloro-N- (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide
O-chlorobenzoic acid (18 mg, 0.12 mmol), 2- (7-benzotriazole oxide)N,N,N',N'Tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol), triethylamine (10 mg, 0.10 mmol) were dissolved in dichloromethane (5 mL), and (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amine (crude, 20 mg, 0.06 mmol) was added and the reaction was stirred at room temperature for 1 hour. Diluting with dichloromethane (20 mL), washing the organic phase with saturated brine (25 mL), drying over anhydrous sodium sulfate, filtering and concentrating, and purifying the residue as a liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)2O25% -50%) to obtain the target product 2-chloro-N- (1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) benzamide (2.5 mg, yellow solid) in a three-step total yield of 8.5%;
MS m/z (ESI): 488&490 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.97-7.94 (m, 1H), 7.69-7.67 (m, 1H), 7.40-7.33 (m, 4H), 7.25-7.21 (m, 1H), 6.86 (d, J = 9.2 Hz, 1H), 6.16 (d, J = 7.6 Hz, 1H), 4.49-4.39 (m, 5H), 3.27-3.21 (m, 2H), 2.24-2.22 (m, 2H), 1.65-1.62 (m, 2H), 1.27-1.23 (m, 3H)。
example 213
2-chloro-N-((3S,4S) -1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) benzamides
First step of
((3S,4S) -1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl)) pyridin-2-yl) -3-hydroxypiperidin-4-yl) amine
To absolute ethanol (5 mL) was added metallic sodium (0.23 g, 10 mmol), stirred at room temperature for 20 minutes, and added ((3)S,4S) Tert-butyl (1- (5- (7-chloro-1, 6-naphthyridin-5-yl)) pyridin-2-yl) -3-hydroxypiperidin-4-yl) carbamate (first step of Synthesis reference example 142) (20 mg, 0.046 mmol), and was reacted at 90 ℃ for 16 hours. Concentrated under reduced pressure, ethyl acetate (20 mL) and water (20 mL) were added to the residue, extracted with ethyl acetate (20 mL. times.2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure to give ((3S,4S) -1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl)) pyridin-2-yl) -3-hydroxypiperidin-4-yl) amine (crede, 20 mg), and the reaction mixture was directly charged to the next step. MS M/z (ESI) 366 [ M + 1]];
Second step of
2-chloro-N-((3S,4S) -1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) benzamide
O-chlorobenzoic acid (10 mg, 0.055 mmol), 2- (7-benzotriazole oxide)N,N,N',N'Tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) and triethylamine (0.1 mL) were dissolved in dichloromethane (3 mL), and ((3 mL)S,4S) -1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl)) pyridin-2-yl) -3-hydroxypiperidin-4-yl) amine (crude, 20 mg), and the reaction was stirred at room temperature for 30 minutes. Dichloromethane (20 mL) was added for dilution and washing was performed with aqueous lithium hydroxide (10 mL, 1M) and saturated brine (20 mL. times.2). Drying with anhydrous sodium sulfate, filtering, desolventizing under reduced pressure, and purifying the residue with liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)2O20% -50%) to obtain the target product 2-chloro-N-((3S,4S) -1- (5- (7-ethoxy-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) benzamide (2.0 mg, yellow solid) in a two-step overall yield of 9.9%;
MS m/z (ESI): 504&506 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.95-8.94 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.96-7.93 (m, 1H), 7.77-7.75 (m, 1H), 7.43-7.35 (m, 3H), 7.25-7.23 (m, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.40 (d, J = 6.4 Hz, 1H), 4.64-4.61 (m, 1H), 4.56-4.50 (m, 1H), 4.49-4.43 (m, 2H), 4.19-4.15 (m, 1H), 4.06-4.04 (m, 1H), 3.73-3.66 (m, 1H), 3.10-2.99 (m, 2H), 2.23-2.21 (m, 1H), 1.72-1.65 (m, 1H), 1.50-1.45 (m, 3H)。
example 214
5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridine formate
First step of
4- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -1-piperazine-1-carboxylic acid tert-butyl ester
Tert-butyl (1- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) -1-piperazin-1-yl) carboxylate (0.17 g, 0.45 mmol), 5, 7-dichloro-1, 6-naphthyridine (60 mg, 0.3 mmol) were dissolved in dioxane (6 mL), tetrakis (triphenylphosphine) palladium (35 mg, 0.03 mmol) and potassium carbonate (0.12 g, 0.90 mmol) were added in that order, and the mixture was heated to 85 ℃ under nitrogen for 16 hours. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated and then diluted with dichloromethane (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, desolventized under reduced pressure, and purified by silica gel preparative plate (petroleum ether: ethyl acetate = 1: 1.5) to obtain the target compound, tert-butyl 4- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -1-piperazine-1-carboxylate (110 mg, yellow solid) in 86.0% yield. MS M/z (ESI) 427&429 [ M + 1 ];
1H NMR (400 MHz, CDCl3) δ 9.08-9.06 (m, 1H), 8.51-8.48 (m, 2H), 7.98-7.95 (m, 1H), 7.92 (s, 1H), 7.48-7.45 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.70-3.68 (m, 4H), 3.60-3.56 (m, 4H), 1.49 (s, 9H);
second step of
4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -1-piperazine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -1-piperazine-1-carboxylate (0.11 g, 0.26 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-carboxylate (1.11 g, 0.26 mmol)HPyrazole (0.11 g, 0.52 mmol) dissolvedN,NTo dimethylacetamide (4 mL), tetrakis (triphenylphosphine) palladium (30 mg, 0.026 mmol) and potassium phosphate (0.17 g, 0.78 mmol) were added in that order, and the mixture was heated to 140 ℃ under nitrogen for 6 hours. The reaction mixture was cooled to room temperature, poured into water (40 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, desolventized under reduced pressure, and purified by silica gel preparative plate (dichloromethane: methanol = 15: 1) to obtain the objective compound 4- (5- (7- (1-methyl-1: 1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -1-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, yellow solid) yield 97.8%;
MS m/z (ESI): 472 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.01 (m, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.43-8.41 (m, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 8.00-7.96 (m, 2H), 7.39-7.36 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.91-3.68 (m, 4H), 3.61-3.59 (m, 4H), 1.51 (s, 9H);
the third step
(1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amino hydrochloride
4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -1-piperazine-1-carboxylic acid tert-butyl ester (0.12 g,0.25 mmol) was dissolved in methanol (5 mL), and dioxane hydrochloride solution (5 mL, 20 mmol, 4M) was added to the solution to react at room temperature for 1.5 hours. The reaction solution is concentrated to obtain the crude product of the target compound (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amino hydrochloride (crude, yellow solid) was directly dosed to the next step. MS M/z (ESI) 372 [ M + 1]];
The fourth step
5- (6- (4- (3-fluorophenylmethyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridine formate
(1- (5- (7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) amino hydrochloride (crude, 0.07 mmol) was dissolved in methanol (10 mL), triethylamine (10 mg, 0.10 mmol) was added, the mixture was stirred for 10 minutes, methanol (10 mL) was added after concentration to dissolve, m-fluorobenzaldehyde (16 mg, 0.11 mmol) and sodium borohydride (47 mg, 0.21 mmol) were sequentially added, and after completion of the addition, the reaction was carried out at room temperature for 48 hours. The reaction mixture was concentrated, and then dissolved in methylene chloride (25 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolventized under reduced pressure, and the residue was purified by preparative liquid phase purification (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H2O25% -50%) to obtain the target product 5- (6- (4- (3-fluorobenzyl) piperazine-1-yl) pyridine-3-yl) -7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridine formate (15 mg, yellow solid), yield 50.6%;
MS m/z (ESI): 480 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.01 (m, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.45-8.43 (m, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.98-7.96 (m, 2H), 7.41-7.38 (m, 1H), 7.36-7.30 (m, 1H), 7.18-7.13 (m, 2H), 7.04-7.02 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 3.99 (s, 3H), 3.79-3.77 (m, 4H), 3.72 (m, 2H), 2.74 (t, J = 4.8 Hz, 4H)。
synthesis of examples 215 to 222 reference was made to the synthesis procedure of example 214:
example 223
2- (5-Fluoropyridin-2-yl) -1- (4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one
Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) -1, 6-naphthyridine hydrochloride (20 mg, 0.05 mmol) and triethylamine (10 mg, 0.10 mmol) were dissolved in dichloromethane (2 mL), and 2- (5-fluoropyridin-2-yl) acetic acid (8 mg, 0.05 mmol), 2- (7-oxybenzotriazole) -N,N,N',N' -tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol), quenched with 10 mL of water, the organic phase separated, the aqueous phase extracted with dichloromethane (10 mL. times.2), and the combined organic phases washed with saturated brine (20 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified from the preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H2O ((0.1% TFA) 25% -55%) to obtain the target product 2- (5-fluoropyridin-2-yl) -1- (4- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one (5 mg, yellow solid). Yield: 19 percent;
MS m/z (ESI):509 [M + 1];
1H NMR (400 MHz, DMSO-d 6 ) δ 9.06-9.05 (m, 1H), 8.56-8.54 (m, 1H), 8.50-8.49 (m, 1H), 8.45 (s, 1H), 8.43-8.41 (m, 1H), 8.18 (s, 1H), 8.06(s, 1H), 8.03-8.00 (m, 1H), 7.72-7.67 (m, 1H), 7.56-7.53 (m, 1H), 7.43-7.40 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.99 (s, 2H), 3.92 (s, 3H), 3.75-3.58 (m, 8H)。
synthesis procedures for examples 224 to 255 reference example 223 synthesis: wherein 2- (5-fluoropyridin-2-yl) acetic acid is substituted with different acids:
example 256
5- (6- (4- (ethylsulfonyl) piperazin-1-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridines
Reacting the compound 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) -1, 6-naphthyridine hydrochloride (third step of synthetic reference example 214) (20 mg, 0.054 mmol) was dissolved inN,NTo dimethylformamide (2 mL), triethylamine (16 mg, 0.162 mmol) and ethylsulfonyl chloride (9 mg, 0.064 mmol) were added in this order, and after the addition was completed, the mixture was magnetically stirred at 25 ℃For 15 minutes. Water (10 mL) was added for quenching, the mixture was extracted with dichloromethane (10 mL. times.2), and the combined organic phases were washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)2O(0.5 % NH4OH) 15% -35%) to obtain the target product 5- (6- (4- (ethylsulfonyl) piperazine-1-yl) pyridine-3-yl) -7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridine (11.4 mg, yellow solid), yield: 46 percent;
MS m/z (ESI): 464 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.03-8.99 (m, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 8.00-7.90 (m, 2H), 7.45-7.40 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 3.85-3.74 (m, 4H), 3.50-3.41 (m, 4H), 3.02-2.95 (m, 2H), 1.47-1.40 (m, 3H)。
example 257
N-benzyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperazine-1-carboxamide
Benzylamine (11 mg, 0.10 mmol) and triethylamine (25 mg, 0.25 mmol) were dissolved in dichloromethane (5 mL), phenyl chloroformate (16 mg, 0.10 mmol) was added, and stirring was performed at room temperature for 10 minutes, followed by addition of 7- (1-methyl-1H-pyrazol-4-yl) -5- (6- (piperazin-1-yl) pyridin-3-yl) -1, 6-phthalazinium hydrochloride (third step of synthesis reference example 214) (20 mg, 0.05 mmol). The temperature is raised to 60 ℃ for reaction for 5 hours. The solution was removed under reduced pressure, the residue was dissolved in ethyl acetate (20 mL), washed with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)2O(0.5 % NH4OH)15 %-35%) to obtain the target productN-benzyl-4- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperazine-1-carboxamide (7 mg, yellow solid), yield: 28.2 percent;
MS m/z (ESI):505 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.04-8.97 (m, 1H), 8.57 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 12.0 Hz, 2H), 8.01-7.95 (m, 2H), 7.44-7.25 (m, 6H), 6.83 (d, J = 8.0 Hz, 1H), 4.46 (s, 2H), 3.99 (s, 3H), 3.80-3.72 (m, 4H), 3.63-3.59 (m, 4H)。
synthesis of example 258 reference was made to the procedure of example 257:
synthetic procedures of examples 259 to 283 the synthesis of example 223 was referenced.
Example 284
3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1]Heptane-6-yl) (piperidin-4-yl) methanone hydrochloride
First step of
4- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carbonyl) piperidine-1-carboxylic acid tert-butyl ester
The compound 1- (5- (7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-amine (15 mg, 0.04 mmol) was dissolved in methylene chloride (2 mL), and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (12 mg, 0.05 mmol), 2- (7-oxybenzotriazole) -N,N,N',N' -tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol),N,NDiisopropylethylamine (11 mg, 0.08 mmol), stirred at room temperature for 0.5 h. It was diluted with methylene chloride (20 mL) and washed with water (20 mL. times.2) and saturated brine (20 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified from the preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, CH)3CN/H2O ((0.1% TFA) 15% -30%) to obtain the target product 4- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carbonyl) piperidine-1-carboxylic acid tert-butyl ester (8.6 mg, yellow solid). Yield: 36 percent. MS m/z (ESI): 595 [ M + 1]];
Second step of
3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) (piperidin-4-yl) methanone hydrochloride
Compound 4- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-carbonyl) piperidine-1-carboxylic acid tert-butyl ester (8.6 mg, 0.01 mmol) was dissolved in 1, 4-dioxane solution (2 mL, 8.00 mmol, 4M) of hydrochloric acid and reacted at room temperature for 1 hour. The reaction solution is directly concentrated, and then,the target product 3- (5- (7- (1-methyl-1) is obtainedH-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-yl) (piperidin-4-yl) methanone hydrochloride (5.4 mg, yellow solid). Yield: 78 percent;
MS m/z (ESI):495 [M + 1];
1H NMR (400 MHz, CD3OD) δ 9.38-9.37 (m, 1H), 9.33-9.29 (m, 1H), 8.65-8.52 (m, 3H), 8.31 (s, 1H), 8.21 (s, 1H), 8.12-8.08 (m, 1H), 7.62-7.56 (m, 1H), 4.74-4.68 (m, 1H), 4.27-4.22 (m, 1H), 4.03 (s, 3H), 3.46-3.44 (m, 2H), 3.10-3.04 (m, 4H), 2.71-2.67 (m, 1H), 2.17-2.14 (m, 4H), 1.93-1.89 (m, 4H);
synthesis of example 285 reference was made to the procedure of example 257:
example 286
6- (3-chlorophenylmethyl) -3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (Heptane)
Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (crude, 0.17 mmol) was dissolved in 1, 2-dichloroethane (2 mL), and 3-chlorobenzaldehyde (29 mg, 0.20 mmol) and sodium borohydride acetate (72 mg, 0.34 mmol) were added and reacted at room temperature for 8 hours. The reaction was quenched by addition of saturated ammonium chloride solution, the organic phase was separated and the aqueous phase was extracted with dichloromethane (10 mL. times.2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified from the preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, CH)3CN/H2O ((0.1% TFA) 25% -55%) to obtain the target product 6- (3-chlorophenylmethyl) -3- (5- (7- (1-methyl-)1H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane (3 mg, yellow solid). Yield: 3 percent;
MS m/z (ESI):508&510 [M + 1];
1H NMR (400 MHz, CD3OD) δ 8.93-8.92 (m, 1H), 8.48-8.47 (m, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 8.01-7.98 (m, 1H), 7.91 (s, 1H), 7.49-7.46 (m, 1H), 7.36 (s, 1H), 7.30-7.19 (m, 3H), 7.05-7.02 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.03-3.98 (m, 1H), 3.90 (s, 3H), 3.87-3.84 (m, 2H), 3.72-3.66 (m, 3H), 2.11-2.07 (m, 1H), 1.71-1.69 (m, 1H), 1.52-1.49 (m, 2H)。
synthesis of example 287 referring to the procedure of example 286:
example 288
2- (5-Fluoropyridin-2-yl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl) ethan-1-one
First step of
3- (5-Bromopyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
The compound 5-bromo-2-fluoropyridine (4.9 g, 28.2 mmol), 3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (2.00 g, 9.40 mmol) andN,Ndiisopropylethylamine (3.60 g, 28.20 mmol) was added to dimethyl sulfoxide (5 mL) and the reaction was allowed to warm to 100 ℃ overnight. It was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL. times.3) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Separating and purifying the residue by a silica gel column (10-20% ethyl acetate/petroleum ether) to obtain a target product 3- (5-bromopyridine-2-yl) -3, 8-diAzabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (3.10 g, white solid), yield: 89.5 percent;
MS m/z (ESI): 368&370 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 4.0 Hz, 1H), 7.52 (dd, J = 8.0, 4.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 4.46-4.52 (m, 2H), 3.88-3.58 (m, 2H), 3.26-3.03 (m, 2H), 2.041.76 (m, 4H), 1.45 (s, 9H);
second step of
3- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
The compound, tert-butyl 3- (5-bromopyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (3.10 g, 8.40 mmol), pinacol diboron (3.20 g, 12.60 mmol), potassium acetate (1.70 g, 16.80 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.61 g, 0.80 mmol) were added to dioxane (30 mL), vacuum-pumped and nitrogen-replaced three times, and the temperature was raised to 90 ℃ for 4 hours. After cooling to room temperature, 5, 7-dichloro-1, 6-naphthyridine (1.70 g, 8.40 mmol), tetrakis (triphenylphosphine) palladium (0.97 g, 0.80 mmol), anhydrous potassium carbonate (2.30 g, 16.60 mmol) and water (6 mL) were added, and the mixture was heated to 85 ℃ for reaction overnight under a nitrogen atmosphere. Concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by a silica gel column (20 to 70% ethyl acetate/petroleum ether) to obtain the target product, tert-butyl 3- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.90 g, yellow solid). Yield: 49.8 percent;
MS m/z (ESI): 452&454 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.08 (d, J = 4.0 Hz, 1H), 8.56-8.46 (m, 2H), 7.93 (s, 1H), 7.72- 7.63 (m, 1H), 7.59-7.52 (m, 1H), 6.84-6.76 (m, 1H) 4.45-4.42 (m, 2H), 4.23- 3.96 (m, 2H), 3.27 (s, 2H), 2.00-1.98 (m, 2H), 1.85-1.75 (m, 2H), 1.50 (s, 9H);
the third step
3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester
The compound 3- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (1.90 g, 4.20 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (1.70 g, 8.40 mmol), potassium phosphate (1.80 g, 8.40 mmol) and palladium tetratriphenylphosphine (0.49 g, 0.40 mmol) were addedN,NA mixed solution of diformylacetamide (8 mL) and water (2 mL) was evacuated and replaced with nitrogen three times, and the temperature was raised to 140 ℃ to react for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated brine (80 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Separating and purifying the residue with silica gel column (20-100% ethyl acetate/petroleum ether) to obtain the target product 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (1.40 g, yellow solid). Yield: 66.8 percent;
MS m/z (ESI): 498 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.05-9.00 (m, 1H), 8.62-8.58 (m, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.72-7.63 (m, 1H), 7.59-7.52 (m, 2H), 6.84-6.76 (m, 1H), 4.44 (s, 2H), 4.28-4.06 (m, 2H), 3.99 (s, 3H), 3.27 (s, 2H), 2.04-1.98 (m, 2H), 1.86-1.78 (m, 2H), 1.50 (s, 9H);
the fourth step
5- (6- (3, 8-diazabicyclo [3.2.1]]Oct-3-yl) pyridin-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridine hydrochloride
Compound 3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (1.40 g, 2.80 mmol) was dissolved in a solution of hydrogen chloride in 1, 4-dioxane (5 mL, 20.00 mmol, 4M) and stirred at room temperature for 1 hour. Concentrating under reduced pressure to obtain 5- (6- (3, 8-diazabicyclo)[3.2.1]Oct-3-yl) pyridin-3-yl) -7- (1-methyl-1HPyrazol-4-yl) -1, 6-naphthyridine hydrochloride (1.20 g, yellow solid), crude. MS M/z (ESI) 398 [ M + 1]];
The fifth step
2- (5-Fluoropyridin-2-yl) -1- (3- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl) ethan-1-one
The compound 5- (6- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) pyridin-3-yl-7- (1-methyl-1H-pyrazol-4-yl) -1, 6-naphthyridine hydrochloride (17 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), and 2- (5-fluoropyridin-2-yl) acetic acid (8 mg, 0.05 mmol) and 2- (7-benzotriazole oxide) were addedN,N,N',N' -tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol),N,NDiisopropylethylamine (11 mg, 0.08 mmol), and stirred at room temperature for 0.5 hour. After diluting with dichloromethane (20 mL), the mixture was washed with saturated brine (20 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified from the preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, CH)3CN/H2O ((0.1% TFA) 20% -40%) gave the desired product 2- (5-fluoropyridin-2-yl) -1- (3- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Octane-8-yl) ethan-1-one (6 mg, yellow solid). Yield: 28%;
MS m/z (ESI):535 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.01 (m, 1H), 8.58-8.57 (m, 1H), 8.42-8.40 (m, 2H), 8.12 (s, 1H), 8.06 (s, 1H), 7.96-7.94 (m, 2H), 7.47-7.35 (m, 3H), 6.76 (d, J = 8.4 Hz, 1H), 4.90 (s, 1H), 4.67 (s, 1H), 4.25-4.22 (m, 1H), 4.05-3.90 (m, 3H), 3.99 (s, 3H), 3.21-3.18 (m, 1H), 3.01-2.98 (m, 1H), 1.96-1.81 (m, 4H)。
synthetic procedures for examples 289 to 320 were synthesized with reference to example 288: wherein 2- (5-fluoropyridin-2-yl) acetic acid is substituted with different acids:
synthesis procedures for examples 321 to 322 were as described in example 286.
The synthesis procedures for examples 323 to 324 were synthesized by reference to example 288.
Synthetic procedures for examples 325 to 365 were synthesized by referring to example 183.
Example 366
3-chloro-N- (4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) -2-carbamoylpyridine
First step of
(4- (hydroxymethyl) -1- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Tert-butyl (1- (5-bromo-2-yl) -4- (hydroxymethyl) pyridin-2-yl) piperidin-4-yl) carbamate (second step of Synthesis reference example 44) (1.00 g, 2.6 mmol) and pinacol ester diboron (0.99 g, 3.9 mmol) were dissolved in dioxane (30 mL), and bis (triphenylphosphine) palladium dichloride (0.19 g, 0.26 mmol), potassium acetate (0.51 g, 5.2 mmol) were added in order, and heated to 90 ℃ under nitrogen for 8 hours. After the reaction solution is cooled to room temperature, the crude dioxane solution is directly fed into the next step. MS M/z (ESI) 434 [ M + 1 ];
second step of
(1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) carbamic acid tert-butyl ester
To a solution of tert-butyl (4- (hydroxymethyl) -1- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) piperidin-4-yl) carbamate (1.14 g, 2.6 mmol) in dioxane (30 mL) was added 5, 7-dichloro-1, 6-naphthyridine (0.52 g, 2.6 mmol), tetrakis (triphenylphosphine) palladium (0.30 g, 0.26 mmol), potassium carbonate (0.90 g, 6.5 mmol) and water (6 mL) in that order. The mixture is heated to 85 ℃ under the protection of nitrogen and reacted for 16 hours. The reaction mixture was cooled to room temperature, and then diluted with ethyl acetate (50 mL) and water (20 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL. times.2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate) to give the objective compound tert-butyl 1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) carbamate (0.65 g, yellow solid) in 53.2% yield. MS M/z (ESI) 470 & 472 [ M + 1 ];
the third step
(4- (hydroxymethyl) -1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
Tert-butyl (1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) carbamate (0.65 g, 1.39 mmol),1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (0.58 g, 2.8 mmol) dissolvedN,NTo dimethylacetamide (10 mL), tetrakis (triphenylphosphine) palladium (0.16 g, 0.14 mmol), potassium phosphate (0.89 g, 4.17 mmol) and water (2 mL) were added in that order. The mixture is heated to 140 ℃ under the protection of nitrogen and reacted for 4 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, washed with saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 3) to give the objective compound (4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.42 g, white solid) yield 58.8%;
MS m/z (ESI): 516 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.98-8.97 (m, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.93-7.92 (m, 2H), 7.37-7.33 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.98 (s, 1H), 4.06-4.01 (m, 2H), 3.97 (s, 3H), 3.77 (s, 2H), 3.40-3.35 (m, 2H), 2.14-2.10 (m, 2H), 1.83-1.76 (m, 2H), 1.45 (s, 9H);
the fourth step
4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-amine
(4- (hydroxymethyl) -1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.28 g, 0.54 mmol) was dissolved in methanol (3 mL), and dioxane hydrochloride solution (3 mL, 12.00 mmol, 4M) was added to react at room temperature for 3 hours. Concentrating the reaction solution, adding dichloromethane (15 mL) and triethylamine to adjust the pH value to 8-9, and concentrating again to obtain the crude product of the target compound 4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-amine (crude, 0.45 g, yellow solid) was directly dosed to the next step. MS M/z (ESI) 416 [ M + 1]];
The fifth step
3-chloro-N- (4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) -2-carbamoylpyridine
3-chloro-o-picolinic acid (10 mg, 0.06 mmol), 2- (7-benzotriazole oxide)N,N,N',N' -tetramethyluronium hexafluorophosphate (27 mg, 0.072 mmol), triethylamine (20 mg, 0.20 mmol) were dissolved inN,N-dimethylformamide (4 mL), stirred at room temperature for 10 minutes, and added with 4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-amine (crude, 80 mg, 0.096 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated, methylene chloride (20 mL) was added, and the mixture was washed with 1M sodium hydroxide solution (5 mL, 5 mmol) and saturated brine (25 mL) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is prepared and purified by high performance liquid chromatography to obtain the target compound 3-chloro-N- (4- (hydroxymethyl) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) -2-carbamoylpyridine (28 mg, yellow solid) yield 52.6%;
MS m/z (ESI): 555 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.01 (m, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.47-8.44 (m, 2H), 8.17 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.99-7.96 (m, 2H), 7.86-7.83 (m, 1H), 7.42-7.38 (m, 2H), 6.88 (d, J = 8.8 Hz, 1H), 4.16-4.12 (m, 2H), 3.99 (s, 3H), 3.94 (s, 2H), 3.51-3.46 (m, 2H), 2.35-2.31 (m, 2H), 1.95-1.89 (m, 2H)。
synthetic procedures for examples 367 to 371 were synthesized with reference to example 366.
The synthesis of example 372 refers to the procedure of example 44.
Example 373
3-fluoro-N- (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-yl) -2-carbamoylpyridine
First step of
(6- (4- ((tert-butoxycarbonyl) amino) -4- (methoxycarbonyl) piperidin-1-yl) pyridin-3-yl) boronic acid
The compound methyl 1- (5-bromopyridin-2-yl) -4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylate (first step of synthesis reference example 44) (4.60 g, 11.14 mmol) was added to 1, 4-dioxane (50 mL) and pinacol ester diboron (4.24 g, 16.71 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (1.22 g, 1.67 mmol) and potassium acetate (3.27 g, 33.41 mmol) were added in portions. After the addition was complete, argon was replaced three times, magnetically stirred at 90 ℃ and condensed under reflux for 3 hours. Cooled to room temperature and desolventized under reduced pressure to give the desired product (6- (4- ((tert-butoxycarbonyl) amino) -4- (methoxycarbonyl) piperidin-1-yl) pyridin-3-yl) boronic acid (crude) which mixture was used in the next reaction without purification. MS m/z (ESI): 380 [ M + 1 ];
second step of
4- ((tert-Butoxycarbonyl) amino) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidine-4-carboxylic acid methyl ester
The compound (6- (4- ((tert-butoxycarbonyl) amino) -4- (methoxycarbonyl) piperidin-1-yl) pyridin-3-yl) boronic acid (crude, 11.14 mmol), 5, 7-dichloro-1, 6-naphthyridine (2.65 g, 13.37 mmol), tetrakis (triphenylphosphine) palladium (1.92 g, 1.67 mmol), anhydrous potassium carbonate (3.07 g, 22.28 mmol), 1, 4-dioxane (50 mL) and water (5 mL) were mixed and added to a 250 mL one-neck flask, argon was replaced three times, magnetic stirring was conducted at 120 ℃ and reflux was condensed for 16 hours. After cooling to room temperature, 100 mL of water was added for quenching, extraction was performed with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was desolventized under reduced pressure, and the residue was purified by a chromatographic silica gel column (petroleum ether/ethyl acetate = 100: 1 to 7: 3) to obtain the objective 4- ((tert-butoxycarbonyl) amino) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidine-4-carboxylic acid methyl ester (3.20 g, yellow oil). Yield: 58 percent;
MS m/z (ESI): 498&500 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.08-9.06 (m, 1H), 8.53-8.47 (m, 2H), 7.95 (m, 1H), 7.91 (s, 1H), 7.18 (s, 1H), 6.84 (d, J = 8.9 Hz, 1H), 4.85 (s, 1H), 4.14-4.12 (m, 4H), 3.76 (s, 3H), 3.44-3.42 (m, 2H), 2.21-3.19 (m, 2H), 1.46 (s, 9H);
the third step
4- ((tert-butoxycarbonyl) amino) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidine-4-carboxylic acid methyl ester
The compound methyl 4- ((tert-butoxycarbonyl) amino) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidine-4-carboxylate (3.20 g, 6.43 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (1.6 g, 7.71 mmol), tetrakis (triphenylphosphine) palladium (1.11 g, 0.96 mmol), anhydrous potassium carbonate (1.77 g, 12.85 mmol),N,Ndimethylacetamide (50 mL) was added in a 250 mL single-neck flask with mixing, argon was replaced three times, magnetic stirring was carried out at 120 ℃ and reflux condensation was carried out for 8 hours. After cooling to room temperature, 100 mL of water was added for quenching, extraction was performed with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was desolventized under reduced pressure, and the residue was purified by a chromatographic silica gel column (dichloromethane/methanol = 100: 1 to 9: 1) to obtain the objective 4- ((tert-butoxycarbonyl) amino) -1- (5- (7- (1-methyl-1) amino) -1- (5-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidine-4-carboxylic acid methyl ester (2.77 g, yellow oil). Yield: 79 percent;
MS m/z (ESI): 544 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.00 (m, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.98-7.96 (m, 2H), 7.38-7.36 (m, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.91 (s, 1H), 4.18-4.09 (m, 2H), 3.99 (s, 3H), 3.76 (s, 3H), 3.55-3.34 (m, 4H), 2.26-2.18 (m, 2H), 1.46 (s, 9H);
the fourth step
(4- (hydroxymethyl) -1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester
The compound 4- ((tert-butoxycarbonyl) amino) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidine-4-carboxylic acid methyl ester (1.00 g, 1.842 mmol) was added to tetrahydrofuran (10 mL) followed by slow addition of lithium aluminum hydride (70 mg, 1.841 mmol) in portions at 0 ℃ after magnetic stirring at 0 ℃ for 0.5 h. Quenched by addition of water (30 mL), extracted with ethyl acetate (30 mL. times.3), the organic phases were combined and washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was desolventized under reduced pressure, and the residue was purified by a column chromatography silica gel (dichloromethane/methanol = 100: 1 to 9: 1) to obtain the objective product (4- (hydroxymethyl) -1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.70 g, yellow solid). Yield: 74 percent;
MS m/z (ESI): 516 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.00 (m, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.16-8.05 (m, 2H), 8.00-7.87 (m, 2H), 7.39-7.32 (m, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.68 (s, 1H), 4.03-4.01 (m, 2H), 3.99 (s, 3H), 3.78 (s, 2H), 3.49-3.36 (m, 2H), 2.12-1.99 (m, 2H), 1.86-1.75 (m, 2H), 1.46 (s, 9H);
the fifth step
(4-formyl-1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl esterButyl ester
The compound (4- (hydroxymethyl) -1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.70 g, 1.359 mmol) was added to dichloromethane (10 mL) followed by dessimutan oxidant (69 mg, 1.631 mmol) and magnetic stirring was performed at room temperature for 1 hour. After addition of a saturated aqueous sodium sulfite solution (15 mL), a saturated aqueous sodium hydrogencarbonate solution (35 mL) was added thereto, followed by extraction with ethyl acetate (50 mL. times.3). The organic phases were combined and washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was desolventized under reduced pressure to give the desired product (4-formyl-1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.60 g, yellow oil). Yield: 86 percent;
MS m/z (ESI): 514 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 9.03-8.98 (m, 1H), 8.59-8.57 (m, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.11-8.09 (m, 2H), 8.00-7.95 (m, 2H), 7.39-7.33 (m, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.66 (s, 1H), 4.20-4.06 (m, 2H), 3.99 (s, 3H), 3.21-3.18 (m, 2H), 2.14-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.43 (s, 9H);
the sixth step
(7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-yl) carbamic acid tert-butyl ester
The compound (4-formyl-1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (0.12 g, 1.167 mmol) was dissolved in 1, 2-dichloroethane (10 mL), and morpholine (0.15 g, 1.400 mmol), zinc chloride (0.79 g, 5.835 mmol) and sodium cyanoborohydride (0.15 g, 2.334 mmol) were added sequentially and stirred at room temperature for 3 hours. Quenched with water (30 mL), extracted with dichloromethane (30 mL. times.3), the combined organic phases were washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate is decompressed and exsolution is carried out, and residue is obtainedPurifying the residue with silica gel column chromatography (dichloromethane/methanol = 100: 1-9: 1) to obtain target product (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-yl) carbamic acid tert-butyl ester (0.30 g, yellow oil). Yield: 44%;
MS m/z (ESI): 585 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.00 (m, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.11-8.09 (m, 2H), 7.99-7.92 (m, 2H), 7.39-7.27 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.61 (s, 1H), 4.13-4.11 (m, 4H), 3.99 (s, 3H), 3.70-3.68 (m, 4H), 3.25-3.23 (m, , 4H), 2.86-2.84 (m, 2H), 2.60-2.55 (m, 4H), 1.45 (s, 9H);
seventh step
1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-amine hydrochloride
The compound (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-yl) carbamic acid tert-butyl ester (15 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL) and methanol (0.5 mL), dioxane hydrochloride (1 mL, 4.00 mmol, 4M) was added at room temperature, and the reaction was stirred at 25 ℃ for 30 minutes. The reaction solution is decompressed and desolventized to obtain crude product 1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-amine hydrochloride directly for the next reaction. MS M/z (ESI) 485 [ M + 1 [)];
Eighth step
3-fluoro-N- (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-yl) -2-carbamoylpyridine
Compound 1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-amine hydrochloride (crude, 0.03 mmol), 3-fluoropyridine-2-carboxylic acid (7 mg, 0.036 mmol) and triethylamine (10 mg, 0.09 mmol) were dissolved in waterN,N-dimethylformylAdding 2- (7-benzotriazole oxide) into amine (2 mL) at room temperatureN,N,N',N' -tetramethyluronium hexafluorophosphate (18 mg, 0.045 mmol), was magnetically stirred at 25 ℃ for 1 hour. Quench with water (20 mL) and extract with dichloromethane (30 mL. times.3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is prepared by preparative high performance liquid chromatography to obtain the target product 3-fluorine-N- (1- (5- (7- (1-methyl-1))H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- ((morpholin-4-yl) methyl) piperidin-4-yl) -2-carbamoylpyridine (6.8 mg, yellow solid). Yield: 38 percent;
MS m/z (ESI): 608 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.03-9.01 (m, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.47-8.39 (m, 2H), 8.14-8.05 (m, 2H), 7.96 (s, 2H), 7.61-7.55 (m, 1H), 7.52 (s, 1H), 7.39-7.37 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.29 (s, 2H), 3.99 (s, 3H), 3.78-3.76 (m, 4H), 3.32-3.30 (m, 2H), 3.12-3.10 (m, 2H), 2.85-2.83 (m, 4H), 2.64-2.62 (m, 2H), 1.84-1.82 (m, 2H)。
synthetic procedures of examples 374 to 412 reference was made to the synthesis of example 373.
Example 446
7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) -1, 6-naphthyridine
First step of
5-bromo-2- (4- (methylsulfonyl) piperidin-1-yl) pyridine
The compound 5-bromo-2-fluoropyridine (0.89 g, 5.06 mmol), 4- (methylsulfonyl) piperidine (0.75 g, 4.60 mmol) and potassium carbonate (1.27 g, 9.20 mmol) were dissolved in dimethyl sulfoxide (10 mL), reacted at 80 ℃ for 8 hours, and the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL. times.3). The combined organic phases were washed with water (50 mL. times.3) and saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate = 100: 1 to 3: 1) to give the desired product 5-bromo-2- (4- (methylsulfonyl) piperidin-1-yl) pyridine (0.62 g, yellow solid). Yield: 42%;
MS m/z (ESI):319&321 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 2.4 Hz, 1H), 7.56-7.53 (m, 1H), 6.59 (d, J = 9.0 Hz, 1H), 4.46-4.44 (m, 2H), 3.12-3.02 (m, 1H), 2.93-2.86 (m, 2H), 2.85 (s, 3H), 2.24-2.20 (m, 2H), 1.90-1.79 (m, 2H);
second step of
(6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) boronic acid
The compounds 5-bromo-2- (4- (methylsulfonyl) piperidin-1-yl) pyridine (0.62 g, 1.94 mmol), pinacol diboron (0.99 g, 3.89 mmol), potassium acetate (0.38 g, 3.88 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (15 mg, 0.02 mmol) and 1, 4-dioxane (20 mL) were added to a 100 mL single vial, after which time the gas was replaced with argon three times and the reaction was allowed to react at 90 ℃ for 4 hours. The crude (1.94 mmol) reaction solution of the target product (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) boronic acid thus obtained was used directly in the next step without post-treatment. MS m/z (ESI): 285 [ M + 1 ];
the third step
7-chloro-5- (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) -1, 6-naphthyridine
The compound (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) boronic acid (crude, 1.94 mmol) reaction solution, 5, 7-dichloro-1, 6-naphthyridine (0.42 g, 2.13 mmol), potassium carbonate (0.53 g, 3.88 mmol), tetrakis (triphenylphosphine) palladium (23 mg, 0.02 mmol) and water (4 mL) were added to a 100 mL single vial, after which time the gas was replaced with argon three times and the reaction was allowed to react at 100 ℃ for 6 hours. Cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined and washed with brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (dichloromethane/methanol = 100: 1 to 25: 1) to give the desired product 7-chloro-5- (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) -1, 6-naphthyridine (0.40 g, yellow solid). Yield: 51 percent. MS M/z (ESI) 403 & 405 [ M + 1 ];
the fourth step
7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) -1, 6-naphthyridine
The compound 7-chloro-5- (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) -1, 6-naphthyridine (20 mg, 0.05 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (13 mg, 0.06 mmol), potassium phosphate (22 mg, 0.10 mmol), tetrakis (triphenylphosphine) palladium (12 mg, 0.01 mmol) andN,N-dimethylacetamide (10 mL)/water (2 mL) mixed, replaced three times with argon and the reaction allowed to react at 120 ℃ for 2 hours. Water (50 mL) was added to dilute the solution, and the solution was extracted with ethyl acetate (50 mL. times.3). The organic phase was washed with water (50 mL. times.3) and saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified from the preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H2O ((0.1% TFA) 15% -40%) to obtain the target product 7- (1-methyl-1)H-pyrazol-4-yl) -5- (6- (4- (methylsulfonyl) piperidin-1-yl) pyridin-3-yl) -1, 6-naphthyridine (6.80 mg, yellow solid). Yield: 31 percent;
MS m/z (ESI): 449 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.02-9.01 (m, 1H), 8.59-8.58 (m, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.99-7.97 (m, 1H), 7.97 (s, 1H), 7.40-7.37 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.69-4.67 (m, 2H), 3.99 (s, 3H), 3.21-3.13 (m, 1H), 3.07-3.00 (m, 2H), 2.89 (s, 3H), 2.29-2.26 (m, 2H), 1.98-1.90 (m, 2H)。
synthetic procedures for examples 447 through 448 refer to the synthesis of example 446.
Example 449
(3S,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-amine
First step of
(3S,4S) -3- (1, 3-dioxoisoindolin-2-yl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
Will (3)S,4S) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 1.20 mmol), phthalic anhydride (0.18 g, 1.20 mmol), triethylamine (0.36 g, 3.60 mmol) andN,N-4-dimethylaminopyridine (12 mg, 0.10 mmol) was added to tetrahydrofuran (10 mL) and the reaction was allowed to warm to 70 ℃ overnight. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (30-50% ethyl acetate/petroleum ether) to obtain the objective product (3)S,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-amine (0.15 g, yellow solid). Yield: 36.5 percent;
MS m/z (ESI):355 [M + 23];
1H NMR (400 MHz, CDCl3) δ 7.88-7.83 (m, 2H), 7.78-7.72 (m, 2H), 5.08-4.94 (m, 1.5H), 4.66-4.56 (m, 1.5H), 4.02-3.80 (m, 3H), 2.23-2.21 (m, 1H), 1.47 (s, 9H);
second step of
2-(((3S,4S) -1- (tert-butoxycarbonyl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid
Will (3)S,4S) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.45 mmol) dissolved in anhydrous waterN,NDimethylacetamide (2 mL), and sodium hydride (60% dispersed in mineral oil, 54 mg, 1.35 mmol) was added. After stirring at room temperature for half an hour, 2-fluoropyridine (0.13 g, 1.35 mmol) was added and the reaction was allowed to warm to 80 ℃ for 4 hours. After cooling to room temperature, the reaction was also poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate (15 mL. times.3). The organic phases were combined, washed with saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the desired product 2- (((3)S,4S) -1- (tert-butoxycarbonyl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid (0.20 g,a black oil). And (5) crude product. MS m/z (ESI): 428 [ M + 1]];
The third step
2-((3S,4S) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) isoindoline-1, 3-dione hydrochloride
2- (((3)S,4S) -1- (tert-Butoxycarbonyl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid (0.20 g, 0.45 mmol) was dissolved in a solution of hydrogen chloride in methanol (5 mL, 20.00 mmol, 4M) and stirred at room temperature for 1 hour. Concentrating under reduced pressure to obtain target product 2- ((3)S,4S) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) isoindoline-1, 3-dione hydrochloride (crude, 0.45 mmol). And (5) crude product. MS m/z (ESI): 310 [ M + 1]];
The fourth step
2-((3S,4S) -1- (5-bromopyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) isoindoline-1, 3-dione
2- ((3)S,4S) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) isoindoline-1, 3-dione hydrochloride (crude, 0.45 mmol), 5-bromo-2-fluoropyridine (0.24 g, 1.35 mmol) andN,Ndiisopropylethylamine (0.35 g, 2.70 mmol) was dissolved in dimethyl sulfoxide (1 mL) and stirred overnight at 100 ℃. After cooling to room temperature, the reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. times.2). The organic phases were combined, washed with water (30 mL. times.2) and saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was desolventized under reduced pressure. The residue is separated and purified by a silica gel column to obtain the target product 2- ((3)S,4S) -1- (5-bromopyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) isoindoline-1, 3-dione (65 mg, white solid). Yield: 31.1 percent;
MS m/z (ESI):465 & 467 [M + 1];
1H NMR (400 MHz, CDCl3) δ 8.24-8.14 (m, 1H), 7.90-7.68 (m, 4H), 7.62-7.46 (m, 2H), 6.85-6.68 (m, 2H), 6.40-6.30 (m, 1H), 6.19-6.08 (m, 1H), 5.22-5.12 (m, 1H), 4.38-4.28 (m, 1H), 4.14-3.84 (m, 2H), 3.69-3.58 (m, 1H), 3.52-3.41 (m, 1H);
the fifth step
2-(((3S,4S) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid
Compound 2- ((3)S,4S) -1- (5-bromopyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) isoindoline-1, 3-dione (65 mg, 0.14 mmol), pinacol diboron (53 mg, 0.21 mmol), potassium acetate (28 mg, 0.28 mmol), 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (7 mg, 0.10 mmol) was added to dioxane (5 mL), replaced with nitrogen by vacuum, and the mixture was heated to 90 ℃ for 4 hours. After cooling to room temperature, 5, 7-dichloro-1, 6-naphthyridine (28 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (12 mg, 0.01 mmol), anhydrous potassium carbonate (38 mg, 0.28 mmol), and water (1 mL) were added. The temperature was raised to 85 ℃ and the reaction was carried out overnight under nitrogen atmosphere. Cooling to room temperature, and concentrating under reduced pressure to obtain product 2- (((3)S,4S) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid (0.20 g). And (3) obtaining a crude product. MS m/z (ESI): 567& 569 [M + 1];
The sixth step
2-(((3S,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid
2- (((3) of CompoundS,4S) -1- (5- (7-chloro-1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid (0.20 g, 0.14 mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole (58 mg, 0.28 mmol), potassium phosphate (59 mg, 0.28 mmol) and tetrakis (triphenylphosphine) palladium (12 mg, 0.01 mmol) were addedN,NA mixed solution of diformylacetamide/water (4/1, 2.5 mL) was purged with nitrogen three times under vacuum, and the temperature was raised to 140 ℃ for 4 hours. After cooling to room temperature, the reaction mixture was diluted by pouring into water (20 mL) and the aqueous phase was washed with dichloromethane (20 mL. times.2). Then concentrating the obtained water phase under reduced pressure to obtain the product 2- (((3)S,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-diazaHetaphthalen-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid (0.23 g, black oil). A crude product; MS M/z (ESI) 613 [ M + 1]];
Seventh step
(3S,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyrid-idin-2-yloxy) pyrrolidin-3-amine
2- (((3) of CompoundS,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyridin-2-yloxy) pyrrolidin-3-yl) carbamoyl) benzoic acid (0.23 g, 0.14 mmol) was dissolved in aqueous hydrochloric acid (6 mL, 18.00 mmol, 3M) and stirred at 50 ℃ for 3 hours. Concentrated under reduced pressure and the residue purified by preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H2O (0.5% HCOOH) 25% -40%) to obtain (3)S,4S) -1- (5- (7- (1-methyl-1)H-pyrazol-4-yl) -1, 6-naphthyridin-5-yl) pyridin-2-yl) -4- (pyrid-idin-2-yloxy) pyrrolidin-3-amine hydrochloride (1.8 mg, yellow solid), yield: 2.77 percent;
MS m/z (ESI): 465 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.04-8.98 (m, 1H), 8.60-8.56 (m, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.20-8.16 (m, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 8.00-7.89 (m, 2H), 7.63-7.56 (m, 1H), 7.42-7.33 (m, 1H), 6.94-6.88 (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.42-4.35 (m, 1H), 4.24-4.14 (m, 1H), 4.05-3.85 (m, 5H), 3.77-3.69 (m, 1H), 3.58-3.52 (m, 1H)。
synthesis procedures for examples 450 to 451 synthesis of reference example 449:
synthesis of example 461 reference was made to the synthesis procedure in example 223.
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 contained the following components: the kit was prepared from enzyme-containing reaction buffer (1X), 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; the substrate reaction solution comprises a biotin-labeled tyrosine kinase substrate diluted to 0.66. mu.M and 12. mu.M ATP with a 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 IC50The value is XLf from 8 concentration pointsit (ID Business Solutions ltd., UK) software is calculated 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 assay kit (Cisbio, cat # 62TK0 PEC). The reaction buffer contained the following components: the kit was prepared from enzyme-containing reaction buffer (1X), 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 solution comprises Eu diluted to 0.1 ng/mu l by reaction buffer solution3+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, the group without RET M918T kinase protein was taken as 100% inhibition, and the group with RET M918T kinase protein but without compound was taken as 0% inhibition. The percent inhibition of RET M918T activity by a compound can be calculated using the following equation:
percent inhibition = 100-.
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 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 was prepared from enzyme-containing reaction buffer (1X), 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.
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 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, the group without RET V804M kinase protein was taken as 100% inhibition, and the group with RET V804M kinase protein but without compound was taken as 0% inhibition. The percent inhibition of RET V804M activity by a compound can be calculated using the following equation:
percent inhibition = 100-.
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 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 assay kit (Cisbio, cat # 62TK0 PEC). The reaction buffer contained the following components: the kit was prepared from enzyme-containing reaction buffer (1X), 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 1 μ M biotin-labeled tyrosine kinase diluted with reaction bufferEnzyme substrate and 8 μ M ATP; 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, the group without RET V804L kinase protein was taken as 100% inhibition, and the group with RET V804L kinase protein but without compound was taken as 0% inhibition. The percent inhibition of RET V804L activity by a compound can be calculated using the following equation:
percent inhibition = 100-.
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 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:
detection kit Using HTRF kinase (Cisbio)Cat No. 62TK0 PEC), the in vitro activity of VEGFR2 was determined by measuring the phosphorylation level of substrates in the kinase reaction. The reaction buffer contained the following components: the kit was prepared from enzyme-containing reaction buffer (1X), 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-
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.
Half effective inhibitory concentration GI of Ba/F3 KIF5B-RET cells50Measurement of (2)
The effect of the compounds of the invention on Ba/F3 KIF5B-RET cell proliferation was evaluated using a luminescent cell viability test assay.
The experimental methods are summarized as follows:
the proliferation status of cells of Ba/F3 KIF5B-RET was determined using the CellTilter-glo (CTG) assay kit by detecting the indicator of viable cell metabolism, ATP, using a unique, stable luciferase, producing a luminescent signal proportional to the number of viable cells in the culture medium.
Ba/F3 KIF5B-RET cell (Nanjing Kebai, CBP 73195) was cultured in RPMI1640 medium (Thermofisiher, 12440053) containing 10% FBS (GBICO, 10099-141) and 100units/ml penicillin mixed solution (Thermofisiher, 15140122), the cultured cells were digested with 0.25% trypsin (Thermofisiher, 25200056), blown-off and seeded on white 384-well plates (Thermofisiher, 164610), 27. mu.L of medium containing 1000 cells was added to each well, and then the 384-well plates were placed in 5% CO-containing medium2The culture box is cultured overnight at 37 ℃. Compounds were dissolved and diluted to 5mM in 100% DMSO prior to 4-fold serial dilutions in DMSO to a minimum concentration of 0.31 μ M, with 50-fold dilutions using RPMI1640 medium at each concentration point. If the compound GI50The values are very low and the initial concentration of the 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-hole plate is placed at 37 ℃ and 5% CO2The incubation was continued for 72 hours, then taken out at room temperature for 30 minutes, the CTG reagent was also taken out and allowed to equilibrate to room temperature, 30. mu.L CTG reagent was added to each well, the plates were placed on a shaker with gentle shaking to ensure adequate cell lysis, the luminescence signal was allowed to stabilize for 10 minutes, and then the luminescence signal was read with an EnVision (Perkin Elmer). In addition, for correcting cell number, setting upT0Controls, including medium only blank and cell-added controls, the difference between the two was set as T0Control, obtained by adding CTG reagent before dosing.
The percent inhibition of Ba/F3 KIF5B-RET cell proliferation by the compound can be calculated by the following formula:
percent inhibition =100 { [ (signal) 100-Compound (I)-SignalNegative control)-T0 control]/[(signalPositive control-SignalNegative control)-T0 control]}。
Compound GI50Values 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 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.
Half-effective inhibitory concentration GI of LC-2/ad cells50Measurement of (2)
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 with 0.25% trypsin (containing EDTA) (Thermofisher, 25200056) and blown up and planted in white 384-well plates (Thermofisher,164610), adding 27. mu.l of IMDM complete medium containing 1000 cells per well, and placing 384 well plates in a 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 the compound GI50The values are very low and the initial concentration of the 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-hole plate is placed at 37 ℃ and 5% CO2The incubation was continued in the incubator, after 96 hours, the cells were removed and allowed to stand at room temperature for 30 minutes, the CTG reagent was also removed and allowed to equilibrate to room temperature, 15. mu.l of CTG reagent was added to each well, the plates were placed on a shaker for gentle shaking for 5 minutes to ensure adequate cell lysis, the luminescence signal was allowed to stabilize for 10 minutes and then read with an envision (perkin elmer). In addition, T is set simultaneously for correcting cell number0Controls, including medium only blank and cell-added controls, the difference between the two was set as T0Control, obtained by adding CTG reagent before dosing.
The percentage of inhibition of LC-2/ad cell proliferation by a compound can be calculated using the following formula:
percent inhibition =100 { [ (signal) 100-Compound (I)-SignalNegative control)-T0 control]/[(signalPositive control-SignalNegative control)-T0 control]}。
Compound GI50Values 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 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.
Half of TT cells are effectively inhibitedConcentration GI50Measurement of (2)
The effect of the compounds of the invention on TT cell proliferation was evaluated using a luminescent cell viability assay.
The experimental methods are summarized as follows:
cell proliferation of TT was measured using the CellTilter-glo (CTG) assay kit by detecting the indicator of viable cell metabolism ATP using a unique, stable luciferase, which generated a luminescent signal proportional to the number of viable cells in the culture medium.
TT cell (ATCC, CRL-1803) was cultured in F12K medium (Thermofisiher, 21127022) containing 10% FBS (GBICO, 10099-141) and 100units/ml penicillin-streptomycin mixture (Thermofisiher, 15140122), the cultured cells were digested with 0.25% trypsin (Thermofisiher, 25200056), blown-off and seeded on a white 384-well plate (Thermofisiher, 164610), 27. mu.L of the medium containing cells was added to each well, and then the 384-well plate was placed on a plate containing 5% CO2The culture box is cultured overnight at 37 ℃. Compounds were dissolved and diluted to 1mM in 100% DMSO prior to 4-fold serial dilutions to a minimum concentration of 0.061 μ M in DMSO, with 50-fold dilutions using F12K medium at each concentration point. If the compound GI50The values are very low and the initial concentration of the 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-hole plate is placed at 37 ℃ and 5% CO2The incubation was continued for 96 hours, after which time the cells were removed and allowed to stand at room temperature for 30 minutes, the CTG reagent was removed and allowed to equilibrate to room temperature, 30. mu.L of CTG reagent was added to each well, the plates were placed on a shaker with gentle shaking to ensure adequate cell lysis, the luminescence signal was allowed to stabilize for 10 minutes and then read with an envision (perkin Elmer). In addition, T is set simultaneously for correcting cell number0Controls, including medium only blank and cell-added controls, the difference between the two was set as T0Control, obtained by adding CTG reagent before dosing.
The percentage of inhibition of TT cell proliferation by the compound can be calculated by the following formula:
percent inhibition =100 { [ (signal) 100-Compound (I)-SignalNegative control)-T0 control]/[(signalPositive control-SignalNegative control)-T0 control]}
Compound GI50Values 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 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.
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) |
23 | 0.95 | 0.47 | 1.07 | ||
44 | 0.88 | ||||
142 | 2.47 | 0.99 | 1.31 | ||
143 | 0.21 | 0.48 | 3.52 | 44.19 | |
144 | 0.18 | 0.59 | 40.24 | ||
145 | 0.38 | 5.41 | 71.86 | ||
146 | 0.26 | 1.01 | |||
147 | 0.26 | 0.31 | 0.89 | 10.83 | |
148 | 1 | 6.94 | 36.67 | ||
149 | 1.66 | 6.27 | 64.56 | ||
150 | 1.67 | 8.69 | 30.47 | ||
151 | 3.38 | ||||
152 | 3.23 | 3.08 | 7.76 | 30.81 | |
153 | 0.27 | 0.23 | 0.52 | 21.70 | |
154 | 10.63 | ||||
155 | 2.32 | 1.93 | 2.87 | 14.55 | |
156 | 0.98 | 2.92 | 10.9 | ||
157 | 2.36 | 3.96 | 4.63 | 6.5 | |
158 | 34.65 | ||||
159 | 2.16 | 1.39 | 6.96 | 6.82 | |
160 | 2.02 | 2.19 | 5.45 | 17.29 | |
161 | 1.71 | 0.23 | 3.21 | 125.96 | |
162 | 0.06 | 0.05 | 0.66 | 7.58 | |
163 | 1.56 | ||||
164 | 0.62 | ||||
165 | 69.84 | ||||
166 | 79.86 | ||||
167 | 25.18 | ||||
168 | 0.47 | 1.32 | |||
169 | 1.13 | 0.29 | 1.30 | 292.72 | |
170 | 1.18 | 1.42 | |||
171 | 0.67 | 0.63 | 7.13 | 340.12 | |
172 | 1.37 | ||||
173 | 0.99 | 5.77 | |||
174 | 3.4 | ||||
175 | 0.29 | 0.28 | 1.34 | 221.57 | |
176 | 3.73 | 1.38 | 14.21 | 113.33 | |
177 | 3.74 | 1.05 | 17.94 | 38.86 | |
178 | 19.11 | ||||
179 | 0.29 | 0.06 | 1.84 | 206.82 | |
180 | 0.9 | 4.75 | 413.35 | ||
181 | 4.41 | ||||
183 | 0.24 | 0.11 | 2.53 | 41.63 | |
184 | 6.59 | ||||
185 | 1.18 | 2.46 | 81.63 | ||
186 | 3.94 | 1.59 | 9.63 | 201.11 | |
187 | 0.89 | 0.51 | 3.49 | 75.19 | |
188 | 1.93 | 0.44 | 3.80 | 45.91 | |
189 | 4.79 | ||||
190 | 3.47 | ||||
191 | 13.53 | ||||
192 | 0.18 | 0.21 | 1.96 | 84.52 | |
193 | 0.35 | 0.34 | 3.55 | 86.83 | |
194 | 1.32 | 1.81 | 9.84 | 53.95 | |
195 | 0.31 | 0.14 | 1.56 | 48.19 | |
196 | 5.31 | ||||
197 | 4.72 | ||||
198 | 1.48 | 1.22 | 9.98 | 80.83 | |
199 | 2.31 | ||||
200 | 15.08 | ||||
201 | 1.96 | 1.85 | 10.9 | 79.94 | |
202 | 4.68 | 2.31 | 25.51 | 169.82 | |
203 | 1.38 | 2.55 | 29.81 | 67.9 | |
205 | 1.97 | 4.79 | |||
206 | 8.91 | 14.55 | |||
207 | 3.47 | ||||
208 | 8.5 | ||||
209 | 8.2 | ||||
210 | 3.84 | ||||
211 | 1.53 | ||||
212 | 78.04 | ||||
213 | 25.34 | ||||
214 | 3.63 | 12.15 | |||
215 | 10.82 | ||||
216 | 2.82 | 0.43 | 4.33 | 93.79 | |
217 | 8.76 | ||||
218 | 7.83 | 39.83 | 194 | ||
219 | 9.55 | 23.1 | 119.28 | ||
220 | 12.6 | 34.62 | 160.37 | ||
221 | 14.37 | 48.34 | 81.68 | ||
222 | 6.01 | 22.57 | 144.73 | ||
223 | 4.92 | 46.76 | 95.63 | ||
224 | 4.47 | 22.96 | 104.97 | ||
225 | 13.9 | ||||
226 | 8.72 | ||||
227 | 30.7 | ||||
228 | 2.88 | 16.15 | 54.91 | ||
229 | 11.42 | ||||
230 | 5.85 | 12.62 | 36.94 | ||
231 | 9.24 | 28.22 | 33.17 | ||
232 | 16.21 | ||||
233 | 17.55 | ||||
234 | 8.57 | 22.25 | 68.82 | ||
235 | 0.35 | 20.93 | 32.31 | ||
236 | 11.77 | ||||
237 | 11.83 | ||||
238 | 23.18 | ||||
239 | 38.27 | ||||
240 | 10.37 | ||||
241 | 26.39 | ||||
242 | 7.59 | 67.38 | |||
243 | 6.2 | 29.5 | |||
244 | 25.18 | ||||
245 | 4.88 | 20.88 | 43.76 | ||
246 | 2.39 | 38.47 | |||
247 | 2.15 | 8.77 | 33.56 | ||
248 | 3.75 | 18.31 | 53.24 | ||
249 | 13.07 | ||||
250 | 24.42 | ||||
251 | 15.12 | ||||
252 | 6.61 | 64.47 | 32.24 | ||
253 | 16.86 | 59.7 | 47.96 | ||
254 | 22.91 | ||||
255 | 13.34 | 62.72 | 44.71 | ||
256 | 26.84 | ||||
257 | 15.45 | ||||
258 | 6.46 | 50.75 | 127.21 | ||
259 | 4.12 | 12.83 | 44.78 | ||
260 | 3.61 | 29.61 | |||
261 | 28.37 | ||||
262 | 26.39 | ||||
263 | 9.91 | ||||
264 | 11.95 | ||||
265 | 30.44 | ||||
266 | 33.69 | ||||
267 | 30.7 | ||||
268 | 4.63 | ||||
269 | 22.42 | ||||
270 | 16.67 | ||||
271 | 9.76 | ||||
272 | 14.02 | ||||
273 | 30.14 | ||||
274 | 14.62 | ||||
275 | 13.77 | ||||
276 | 74.39 | ||||
277 | 30.79 | ||||
278 | 53.71 | ||||
279 | 55.45 | ||||
280 | 26.39 | ||||
281 | 13.34 | 62.72 | 44.71 | ||
282 | 15.91 | 44.61 | 107.3 | ||
283 | 13.04 | 39.1 | 219.35 | ||
284 | 12.09 | ||||
285 | 17.69 | ||||
286 | 2.04 | 5.38 | 70.94 | ||
287 | 5.65 | 30.34 | 70.99 | ||
288 | 6.58 | 10.78 | 111.16 | ||
289 | 11.46 | 17.11 | 129.67 | ||
290 | 14.58 | 21.03 | 47.94 | ||
291 | 1.98 | 20.44 | 31.39 | ||
292 | 0.8 | ||||
293 | 10.74 | ||||
294 | 0.38 | 2.81 | 19.67 | ||
295 | 1.09 | 12.32 | 42.78 | ||
296 | 3.59 | 16.33 | 44.31 | ||
297 | 3.47 | 10.49 | 55.78 | ||
298 | 5.54 | 10.46 | 60.58 | ||
299 | 5.24 | 15.23 | 74.61 | ||
300 | 9.27 | 12.22 | 53.3 | ||
301 | 2.98 | 5.7 | 46.08 | ||
302 | 8.62 | 8.01 | 64.8 | ||
303 | 0.83 | 4.04 | 24.38 | ||
304 | 1.04 | 8.54 | 54.33 | ||
305 | 3.88 | 39.55 | 61.38 | ||
306 | 11.78 | ||||
307 | 8.92 | 21.02 | 131.75 | ||
308 | 17.57 | ||||
309 | 17.78 | ||||
310 | 18.29 | ||||
311 | 23.75 | ||||
312 | 10.64 | ||||
313 | 21.22 | ||||
314 | 16.86 | ||||
315 | 9.39 | 22.97 | 129.8 | ||
316 | 26 | ||||
317 | 15.12 | ||||
318 | 21.47 | ||||
319 | 3.01 | 79.11 | 460.54 | ||
320 | 26.92 | 19.42 | |||
321 | 4.57 | ||||
322 | 8.71 | ||||
323 | 7.69 | 13.8 | 36.55 | ||
324 | 9.24 | 17.91 | 21.84 | ||
325 | 3.06 | ||||
326 | 10.08 | ||||
327 | 2.91 | 10.51 | 28.79 | ||
328 | 3.22 | 5.2 | 61.96 | ||
329 | 7.05 | 47.67 | |||
330 | 2.34 | 6.06 | |||
331 | 1.64 | 4.47 | |||
332 | 0.82 | 1.31 | |||
333 | 10.25 | ||||
334 | 3.27 | 9.45 | |||
335 | 1.27 | 20.48 | 899.16 | ||
336 | 30.52 | ||||
337 | 1.47 | 16.26 | 966.39 | ||
338 | 1.59 | 12.58 | 679.27 | ||
339 | 23.9 | ||||
340 | 10.57 | ||||
341 | 7.1 | 497.75 | |||
342 | 64.14 | ||||
343 | 59.22 | ||||
344 | 64.02 | ||||
345 | 2.04 | 5.38 | 70.94 | ||
346 | 54.97 | ||||
347 | 7.04 | 20.09 | 50.67 | ||
348 | 11.99 | ||||
349 | 9.13 | 47.81 | 55.66 | ||
350 | 16.55 | ||||
351 | 22.74 | ||||
352 | 0.81 | 1.98 | 21.22 | ||
353 | 2.51 | ||||
354 | 3.96 | 157.23 | |||
355 | 3.04 | 196.25 | |||
356 | 1.14 | 105.32 | |||
357 | 37.56 | ||||
358 | 23.66 | ||||
359 | 20.44 | ||||
360 | 3.1 | 4.23 | |||
361 | 2.49 | 3.65 | |||
362 | 1.2 | 1.23 | |||
363 | 14.15 | ||||
364 | 13.74 | ||||
365 | 3.14 | 11.83 | |||
366 | 5.44 | ||||
367 | 19.02 | ||||
368 | 8.23 | 49.17 | 39.05 | ||
369 | 18.42 | 32.24 | 50.3 | ||
370 | 12.27 | ||||
371 | 26.39 | ||||
372 | 0.41 | 4.48 | 332.31 | ||
373 | 6.53 | 17.64 | 268.53 | ||
374 | 1.53 | 3.02 | 179.11 | ||
375 | 2.22 | 4.62 | 132.69 | ||
376 | 0.57 | 0.63 | 32.23 | ||
377 | 0.54 | 1.19 | 65.8 | ||
378 | 2.67 | ||||
379 | 5.07 | ||||
380 | 0.96 | 1.39 | 37.89 | ||
381 | 0.84 | 0.91 | 39.75 | ||
382 | 13.06 | 349.93 | |||
383 | 4.76 | 7.95 | 90.59 | ||
384 | 0.58 | 0.52 | 26.75 | ||
385 | 1.2 | 1.28 | 45.02 | ||
386 | 0.86 | 0.81 | 78.61 | ||
387 | 1.61 | 1.22 | 48.39 | ||
388 | 17.85 | 21.09 | 221.82 | ||
389 | 1.09 | 0.54 | 40.93 | ||
390 | 2.6 | ||||
391 | 6 | ||||
392 | 0.42 | 0.69 | 21.81 | ||
393 | 8.7 | ||||
394 | 0.87 | 1.13 | 142.77 | ||
395 | 2.52 | 2.37 | 99.44 | ||
396 | 1.05 | 9.86 | 44.03 | ||
397 | 1.82 | 2.95 | 32.87 | ||
398 | 0.56 | 0.59 | 45.47 | ||
399 | 0.63 | 0.94 | 37.58 | ||
400 | 3.11 | 4.16 | 51.76 | ||
401 | 1.7 | 6.25 | 92.39 | ||
402 | 1.46 | 3.39 | 58.8 | ||
403 | 0.77 | 1.68 | 78.19 | ||
404 | 2.30 | 19.0 | 182.05 | ||
405 | 0.85 | 2.15 | 67.61 | ||
406 | 1.42 | 6.65 | 58.84 | ||
407 | 9.16 | ||||
408 | 1.12 | 4.78 | 97.68 | ||
409 | 1.64 | 2.17 | 58.61 | ||
410 | 1.04 | 1.66 | 46.13 | ||
411 | 2.1 | 2.89 | 63.34 | ||
412 | 2.89 | 5.51 | 88.27 | ||
446 | 9.69 | 53.48 | 50.92 | ||
447 | 7.09 | 60.54 | |||
448 | 6.06 | 13.38 | 211.38 | ||
449 | 2 | 9.46 | 49.15 | ||
450 | 4.88 | 6.41 | 19.51 | ||
451 | 7.28 | ||||
461 | 2.66 | 13.58 | 36.67 |
Table 2: in vitro cell activity detection result
Compound numbering | Ba/F3_KIF5B-RET GI50 (nM) | LC-2/ad CCDC6 GI50 (nM) | TT C634W ATCC GI50 (nM) |
23 | 518.26 | 18.69 | |
142 | 24.78 | 5.02 | 7.97 |
143 | 244.26 | 12.08 | 5.36 |
144 | 27.94 | 8.09 | 4.52 |
145 | 702.15 | 10.43 | 9.31 |
146 | 231.74 | 21.04 | |
147 | 105.35 | 2.42 | 1.25 |
148 | 965.61 | 32.23 | 59.35 |
149 | 37.03 | 35.95 | |
150 | 855.75 | 32.05 | 82.99 |
151 | 559.84 | 59.45 | |
152 | 211.93 | 18.48 | 19.97 |
153 | 158.65 | 5.0 | 6.1 |
154 | 321.79 | 48.01 | |
155 | 136.42 | 37.28 | 18.59 |
156 | 67.51 | 25.07 | 7.75 |
157 | 312.54 | 30.85 | 27.89 |
158 | 556.06 | ||
159 | 135.49 | 22.36 | 18.39 |
160 | 173.65 | 17.9 | 16.84 |
161 | 324.77 | 29.84 | 14.26 |
162 | 103.51 | 1.55 | 0.98 |
164 | 720.31 | 21.1 | 19.54 |
165 | 1555.84 | ||
168 | 66.96 | ||
169 | 197.39 | 10.14 | 2.31 |
170 | 522.1 | 24.82 | 25.61 |
171 | 516.12 | 28.99 | 25.41 |
172 | 28.02 | ||
173 | 516.84 | 12.44 | |
174 | 318.77 | 31.31 | |
175 | 334.26 | 7.98 | 5.88 |
176 | 274.71 | 36.29 | 45.23 |
177 | 268.76 | 28.28 | 51.6 |
179 | 260.85 | 7.51 | 5.33 |
180 | 396.60 | 18.43 | |
181 | 883.77 | 66.68 | |
183 | 157.62 | 8.83 | 5.04 |
184 | 237.32 | 36.75 | |
185 | 136.02 | 13.41 | 7.67 |
186 | 229.57 | 34.43 | 12.22 |
187 | 241.42 | 14.79 | 9.83 |
188 | 192.05 | 15.42 | 19.3 |
189 | 362.33 | ||
190 | 321.38 | 37 | |
192 | 210.86 | 3.85 | 3.91 |
193 | 147.57 | 4.45 | 7.43 |
194 | 271.67 | 13.02 | 31.22 |
195 | 215.15 | 9.44 | 3.54 |
198 | 243.31 | 19.21 | 27.58 |
199 | 318.54 | 41.3 | |
201 | 277.11 | 17.52 | 42.56 |
202 | 187.4 | 27.64 | 47.68 |
203 | 215.55 | 25.4 | 38.01 |
205 | 42.8 | ||
206 | 898.33 | 70.89 | |
207 | 103.63 | ||
210 | 96.36 | ||
211 | 68.86 | ||
213 | 178.56 | ||
214 | 274.61 | 92.4 | |
215 | 601.01 | 230.46 | |
216 | 202.1 | 40.62 | 15.34 |
218 | 971.55 | ||
223 | 793.65 | ||
228 | 397.3 | ||
230 | 473.18 | 102.92 | 249.12 |
231 | 615.5 | 126.95 | 301.75 |
234 | 491.32 | 63.8 | 151.26 |
235 | 326.84 | 85.93 | 208.72 |
237 | 203.39 | 584.34 | |
242 | 888.52 | 198.36 | 469.38 |
243 | 903.01 | 158.22 | 214.51 |
245 | 386.43 | 93.42 | 233 |
246 | 865.63 | 146.35 | |
247 | 799.02 | 469.39 | 878.81 |
248 | 578.42 | 403.94 | 453.02 |
249 | 406.54 | 855.56 | |
252 | 343 | 258.82 | 426.81 |
253 | 887.99 | 401.30 | 791.34 |
255 | 617.08 | 362.79 | 700.30 |
259 | 638.64 | 44.61 | 135.88 |
260 | 871.38 | 229.90 | 369.14 |
271 | 968.26 | ||
275 | 234.94 | 548.45 | |
281 | 617.08 | 362.79 | 700.30 |
286 | 330.94 | 34.45 | 84.8 |
287 | 857.68 | 194.76 | 486.51 |
288 | 756.40 | 320.47 | 530.4 |
289 | 445.16 | 348.23 | 492.58 |
290 | 716.69 | 500.41 | 706.35 |
291 | 459.59 | 79.19 | 179.69 |
292 | 71.72 | 187.11 | |
293 | 688.03 | ||
294 | 277.87 | 136.85 | 176.79 |
295 | 589.70 | 45.39 | 328.88 |
296 | 417.86 | 360.56 | 297.38 |
297 | 494.17 | 354.23 | 252.55 |
298 | 415.28 | 354.77 | 207.53 |
299 | 436.13 | 315.01 | 450.7 |
300 | 323.69 | 330.95 | 349.79 |
301 | 377.79 | 294.01 | 227.15 |
302 | 713.96 | ||
303 | 422.3 | 354.78 | 362.22 |
304 | 348.09 | 316.17 | 277.7 |
305 | 991.95 | 262.44 | 430.52 |
308 | 774.67 | ||
309 | 903.56 | ||
310 | 598.31 | ||
311 | 656.03 | ||
312 | 794.56 | ||
313 | 646.35 | ||
314 | 583.37 | ||
315 | 651.85 | ||
316 | 708.98 | ||
317 | 216 | 298.86 | 438.62 |
318 | 514.63 | ||
320 | 467.99 | 488.48 | 778.82 |
322 | 344.87 | 732.16 | |
323 | 378.61 | 123.46 | |
324 | 746.25 | 290.41 | 425.1 |
327 | 493.06 | 69.78 | 171.7 |
329 | 933.23 | ||
332 | 563.19 | ||
345 | 330.94 | 34.45 | 84.8 |
347 | 285.11 | 63.74 | 136.98 |
349 | 614.76 | 191.09 | 330.19 |
352 | 619.78 | 99.14 | 425.4 |
353 | 677.96 | ||
354 | 939.15 | ||
356 | 942.56 | ||
362 | 879.96 | 144.85 | 127.41 |
366 | 146.98 | 143.05 | |
368 | 745.78 | 149.3 | 296.28 |
369 | 827.98 | 343.55 | 721.41 |
372 | 650.16 | ||
374 | 748.49 | ||
376 | 464.22 | 88.88 | 44.03 |
377 | 385.11 | 139.27 | 118.43 |
380 | 622.27 | 115.24 | |
381 | 787.76 | ||
383 | 831.02 | ||
384 | 772.76 | ||
386 | 228.50 | 150.29 | |
387 | 657.42 | 134.61 | 134.56 |
388 | |||
389 | 693.6 | 100.44 | 62.95 |
390 | 863.65 | ||
392 | 607.20 | 78.54 | 58.81 |
394 | 120.26 | 51.71 | |
395 | 203.92 | 96.59 | |
396 | 512.03 | 94.22 | 65.41 |
397 | 243.47 | 151.24 | |
398 | 736.92 | 52.86 | 27.56 |
399 | 636.95 | 91.1 | 38.26 |
400 | 467.94 | 517.93 | |
401 | 333.91 | 281.8 | |
402 | 311.63 | 278.06 | |
403 | 145.9 | 154.65 | |
404 | 811.76 | 188.48 | 203.78 |
405 | 641.09 | 77.65 | 58.63 |
406 | 717.75 | 135.01 | 173.48 |
407 | 828.47 | 244.87 | |
408 | 685.15 | 96.42 | 125.23 |
409 | 506.99 | 94.44 | 79.31 |
410 | 445.39 | 66.25 | 61.38 |
411 | 499.71 | 119.39 | 100.08 |
412 | 417.64 | 123.33 | 109.82 |
446 | 314.32 | 84.74 | 237.43 |
447 | 220.16 | 217.22 | 421.58 |
448 | 473.19 | 201.59 | 283.41 |
449 | 439.24 | 468.31 | 315.1 |
450 | 328.53 | 425.29 | 470.94 |
451 | 840.01 | 853.51 | |
461 | 466.35 | 57.4 | 159.11 |
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. Part of the compounds can also effectively inhibit the proliferation of Ba/F3_ KIF5B-RET tumor cells, LC-2/ad tumor cells and TT 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 (12)
1. A compound according to formula I, an isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof:
wherein:
X1is CR1Or N; preferably CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N; preferably CH or N; most preferably N;
Y2is CR3Or N; preferably CH or N; most preferably CH;
Y3is CR4Or N; preferably CH or N;
Y4is CR5Or N; preferably CH or N; most preferably CH;
provided that Y is1、Y2、Y3And Y4At most 2 of them are N;
one of the following conditions is preferred: y is1-Y4Are not all N; y alone1Or Y2Is N; y is1And Y2Are both N; or Y1And Y3Are both N;
further preferred is one of the following conditions: y alone1Or Y2Is N; or Y1And Y3Are both N; most preferably one of the following conditions: y is1Is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
R1-R5each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, -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)mNR7R8or-NR9S(O)mNR7R8Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl OR alkynyl is optionally substituted with one OR more substituents selected from halogen, cyano, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, -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)mNR11R12or-NR13S(O)mNR11R12Substituted with the substituent(s); preferably, R1-R5Each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR6or-NR7R8(ii) a Further preferably, R1-R5Each independently selected from hydrogen, halogen or C1-C4 alkyl; most preferably, R1-R5Are all hydrogen;
a is selected from hydrogen, halogen, cyano or C1-C8 alkyl; preferably, A is selected from hydrogen, halogen, cyano or C1-C6 alkyl; further preferably, A is selected from hydrogen, cyano or C1-C4 alkyl; most preferably, a is hydrogen;
b is selected from hydrogen, halogen, cyano, C1-C4 alkyl, -OR14Or Ar optionally substituted1(ii) a Preferably, B is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1(ii) a Most preferably, B is selected from hydrogen, halogen, -OR14Or R15 ;
R14Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl, or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; preferably, R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; further preferably, R14Selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, 4-6 membered heterocyclyl optionally substituted with C1-C4 alkyl; most preferably, R14Is C1-C4 alkyl optionally substituted with 1-methylpiperidin-4-yl;
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, Ar1Selected from 5 or 6 membered heteroaryl containing two ring N atoms; further preferably, Ar1Selected from 5-membered heteroaryl containing two ring N atoms; most preferably, Ar1Is composed of;
Ar1Optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl are optionally substituted with one OR more substituents selected from the group consisting of halogen, cyano, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, -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);
R15selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl or heteroaryl; preferably, R15Selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkylOr a 4-8 membered heterocyclic group; further preferably, R15Selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl or a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; most preferably, R15Is C1-C4 alkyl;
d is selected from 4-8 membered heterocyclylene, 6-8 membered fused heterocyclylene or 7-11 membered spiroheterocyclylene containing 1-3 heteroatoms selected from N, O; preferably, D is selected from 4-6-membered heterocyclylene containing 1-2N or 6-8-membered heterocyclylene containing 1-2N; most preferably, D is selected from:
D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino or C1-C8 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C8 alkyl) amino,N- (C1-C8 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-8 membered heterocyclyl optionally substituted by halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C8 alkyl; preferably, D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C6 alkyl; further preferably, D is optionally one selected fromHydroxy, amino, or C1-C6 alkyl, wherein the alkyl is optionally substituted with one substituent selected from the group consisting of: hydroxy, mono-or di (C1-C4 alkyl) amino,N- (C1-C4 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with (C1-C4 alkyl) carbonyl or C1-C6 alkyl; most preferably, D is optionally substituted with one substituent selected from hydroxy, amino or C1-C4 alkyl optionally substituted with one substituent selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl; wherein forAnd, if the substituent is hydroxy, it is substituted at its 3-position; if the substituent is other than hydroxyl, the substituent is substituted at the 4-position; for theThe substituent is hydroxyl or amino, and is substituted at the 4-position;
e is selected from amino, NHC (O) RX、-C(O)Ry、、-OR6、-NR7R8、-OC(O)NR7R8、-C(O)OR6、-C(O)NR7R8、-NR9C(O)NR7R8、-S(O)mR6、-NR9S(O)mR6、-SR6、-S(O)mNR7R8、-NR9S(O)mNR7R8or-CH2-Ar2(ii) a Preferably, E is selected from amino, heteroaryloxy, -NHC (O) RX、-SO2(C1-C8) alkyl, -C (O) Ry、or-CH2-Ar2(ii) a Further excellenceOptionally, E is selected from amino, pyridyloxy, -NHC (O) RX、SO2(C1-C6) alkyl, -C (O) Ry、or-CH2-Ar2;
Most preferably, when D isWhen E is selected from amino, -NHC (O) RXor-SO2(C1-C4) alkyl; when D isWhen E is pyridine-2-oxyl; when D is、、、When E is selected from-C (O) Ry、、-SO2(C1-C4) alkyl, or-CH2-Ar2;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl; preferably, RXSelected from C1-C6 alkoxy,Optionally substituted 6-membered aryl, optionally substituted 5-6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C6 alkyl, optionally substituted 4-6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C6 cycloalkyl or amino optionally substituted with C1-C6 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C6 alkoxy or C3-C6 cycloalkyl; most preferably, RXSelected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl; preferably, RySelected from optionally substituted amino, C1-C6 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C6 cycloalkyl, said substituents being selected from C1-C6 alkyl optionally substituted with aryl; most preferably, RySelected from amino optionally substituted with C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, or C3-C6 cycloalkyl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino or C1-C8 alkoxy; preferably, Ar2Selected from the group consisting of optionally mono-or disubstituted 5-6 membered aryl or heteroaryl, said substituents being selected from the group consisting of halogen, C1-C6 alkoxy; most preferably, Ar2Selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen, C1-C4 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl or hydroxy C1-C8 alkyl, or Rm、RnTo carbon atoms bound theretoTogether form a C3-C8 cycloalkyl group; preferably, Rm、RnEach independently selected from hydrogen, hydroxy, C1-C6 alkyl or hydroxy C1-C6 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl group; most preferably, Rm、RnEach independently selected from hydrogen, hydroxy or hydroxy C1-C4 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a cyclopropyl group;
R6、R7、R8、R9、R10、R11、R12、R13each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
r is selected from 0, 1,2 or 3; preferably, r is selected from 0, 1 or 2;
m is selected from 1 or 2.
2. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CR1Or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N;
Y2is CR3Or N;
Y3is CR4Or N;
Y4is CR5Or N;
and one of the following conditions is satisfied: y is1-Y4Are not all N; y alone1Or Y2Is N; y is1And Y2Are both N; or Y1And Y3Are both N;
R1-R5each independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8;
A is selected from hydrogen, halogen, cyano or C1-C6 alkyl;
b is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl, or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 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;
Ar1optionally substituted by one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8;
D is selected from a 4-6 membered heterocyclylene group containing 1-2N or a 6-8 membered heterocyclylene group containing 1-2N, and when X is2When is CH, D is notOr;
D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino, or C1-C8 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C8 alkyl) amino,N- (C1-C8 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-8 membered heterocyclyl optionally substituted by halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C8 alkyl;
e is selected from amino, NHC (O) RX、-C(O)Ry、、-OR6、-NR7R8、-OC(O)NR7R8、-C(O)OR6、-C(O)NR7R8、-NR9C(O)NR7R8、-S(O)mR6、-NR9S(O)mR6、-SR6、-S(O)mNR7R8、-NR9S(O)mNR7R8or-CH2-Ar2;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino or C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
R6、R7、R8、R9each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
m is 1 or 2;
r is 0, 1,2 or 3.
3. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CR1Or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N;
Y2is CR3Or N;
Y3is CR4Or N;
Y4is CR5Or N;
and one of the following conditions is satisfied: y is1-Y4Are not all N; y alone1Or Y2Is N; y is1And Y2Are both N; or Y1And Y3Are both N;
R1-R5each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR6or-NR7R8;
A is selected from hydrogen, halogen, cyano or C1-C6 alkyl;
b is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl, or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, or 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
Ar1selected from 5 or 6 membered heteroaryl containing two ring N atoms;
Ar1optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8or-NR9S(O)mNR7R8;
D is selected from a 4-6 membered heterocyclylene group containing 1-2N or a 6-8 membered heterocyclylene group containing 1-2N, and when X is2When is CH, D is notOr;
D is optionally substituted with one substituent selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C8 alkyl, wherein said alkyl is optionally substituted with one substituent selected from the group consisting of: halogen, hydroxy, mono-or di (C1-C8 alkyl) amino,N- (C1-C8 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-8 membered heterocyclyl optionally substituted by halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C8 alkyl;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino, C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
R6、R7、R8、R9each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
m is 1 or 2;
r is 0, 1,2 or 3.
4. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CR1Or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CR2Or N;
Y2is CR3Or N;
Y3is CR4Or N;
Y4is CR5Or N;
and one of the following conditions is satisfied: y is1-Y4Are not all N; y alone1Or Y2Is N; or Y1And Y3Are both N;
R1-R5each independently selected from hydrogen, halogen or C1-C4 alkyl;
a is selected from hydrogen, cyano or C1-C4 alkyl;
b is selected from hydrogen, halogen, -OR14Or Ar optionally substituted1;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
Ar1selected from 5-membered heteroaryl containing two ring N atoms;
Ar1optionally substituted with one OR more substituents each independently selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, 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)mNR7R8;
D is selected from a 4-6 membered heterocyclylene group containing 1-2N or a 6-8 membered heterocyclylene group containing 1-2N, and when X is2When is CH, D is notOr;
D is optionally substituted with one substituent selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from the group consisting of: halogen, hydroxy, mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C6 alkyl;
RXSelected from C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkyl, or amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino, C1-C8 alkoxy;
Rm、RnEach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
R6、R7、R8、R9each independently selected from hydrogen, halogen, hydroxy, amino, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, heteroaryl, aryl, C2-C8 alkenyl, or C2-C8 alkynyl;
m is 1 or 2;
r is 0, 1,2 or 3.
5. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CH or N;
Y2is CH or N;
Y3is CH or N;
Y4is CH or N;
and one of the following conditions is satisfied: y is1、Y2、Y3And Y4Are all CH; y alone1Or Y2Is N; or Y1And Y3Are both N;
a is hydrogen;
R14Selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyanogenHydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
R15selected from hydrogen, C1-C8 alkyl, hydroxy C1-C8 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O, S, aryl or heteroaryl;
d is selected from:
D is optionally substituted with one substituent selected from halogen, cyano, hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: halogen, hydroxy, mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkylcarbonyl) amino, 4-6 membered heterocyclyl optionally substituted with halogen, hydroxy, (C1-C4 alkyl) carbonyl or C1-C6 alkyl;
RXSelected from the group consisting of C1-C8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl containing 1 or 2 heteroatoms selected from N, O, S, optionally substituted C1-C8 alkyl, optionally substituted 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C3-C8 cycloalkaneOr amino optionally substituted with C1-C8 alkyl; the optional substituents are selected from halogen, nitro, cyano, hydroxy, C1-C8 alkoxy or C3-C8 cycloalkyl;
Ryselected from optionally substituted amino, C1-C8 alkyl, 4-8 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C8 cycloalkyl, said substituents being selected from C1-C8 alkyl optionally substituted with aryl or heteroaryl;
Ar2is selected from optionally substituted aryl or heteroaryl, said substituents being selected from halogen, hydroxy, amino or C1-C8 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C8 alkyl, hydroxy C1-C8 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C8 cycloalkyl group;
r is 0, 1,2 or 3.
6. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is CH or N;
Y2is CH or N;
Y3is CH or N;
Y4is CH or N;
and one of the following conditions is satisfied: y is1、Y2、Y3And Y4Are all CH; y alone1Or Y2Is N; or Y1And Y3Are both N;
a is hydrogen;
R14Selected from hydrogen, C1-C6Alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclyl, wherein said alkyl, cycloalkyl, heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C3-C8 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl;
R15selected from hydrogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl, or a 4-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O, S;
d is selected from:
D is optionally substituted with one substituent selected from hydroxy, amino or C1-C6 alkyl, wherein said alkyl is optionally substituted with one substituent selected from: mono-or di (C1-C6 alkyl) amino,N- (C1-C6 alkyl) -N- (C1-C4 alkyl) carbonylamino, 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, acetyl;
RXSelected from the group consisting of C1-C6 alkoxy, optionally substituted 6-membered aryl, optionally substituted 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C6 alkyl, optionally substituted 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O4-6 membered heterocyclyl with 1 or 2 heteroatoms selected from N, O, S, C3-C6 cycloalkyl or amino optionally substituted with C1-C6 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C6 alkoxy or C3-C6 cycloalkyl;
Ryselected from optionally substituted amino, C1-C6 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, or C3-C6 cycloalkyl, said substituents being selected from C1-C6 alkyl optionally substituted with aryl;
Ar2selected from 5-6 membered aryl or heteroaryl optionally mono-or disubstituted, said substituents being selected from halogen or C1-C6 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy, C1-C6 alkyl or hydroxy C1-C6 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a C3-C6 cycloalkyl group;
r is 0, 1,2 or 3.
7. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
a is hydrogen;
R14Selected from C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl, wherein said alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, 4-6 membered heterocyclyl optionally substituted with C1-C4 alkyl;
R15selected from hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C3-C6 cycloalkyl, or a 4-6 membered heterocyclyl containing 1-2 heteroatoms each independently selected from N, O or S;
d is selected from:
D is optionally substituted with one substituent selected from hydroxy, amino or C1-C4 alkyl optionally substituted with one substituent selected from hydroxy, di (C1-C4 alkyl) amino,N-acetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
RXSelected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
Ryselected from the group consisting of1-C4 alkyl or benzyl substituted amino, C1-C4 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, or C3-C6 cycloalkyl;
Ar2selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen or C1-C4 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy C1-C4 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a cyclopropyl group;
r is 0, 1 or 2.
8. A compound of formula I according to claim 1, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
X1Is CH or N;
X2is CH or N;
provided that X is1、X2At most 1 of them is N;
Y1is N, Y2、Y3And Y4Are all CH; or Y1And Y3Is N, Y2And Y4Is CH;
a is hydrogen;
R14Selected from the group consisting of C1-C4 alkyl optionally substituted with 1-methylpiperidin-4-yl;
R15is C1-C4 alkyl;
d is selected from
D is optionally substituted with one substituent selected from hydroxy, amino or C1-C4 alkyl optionally substituted with one substituent selected from hydroxy, di (C1-C4 alkyl) amino,NAcetyl-N-methylamino, morpholin-4-yl, 1-ethylpiperazin-4-yl or 1-acetylpiperazin-4-yl;
wherein forAnd, if the substituent is hydroxy, it is substituted at its 3-position; if the substituent is other than hydroxyl, the substituent is substituted at the 4-position; for theThe substituent is hydroxyl or amino, and is substituted at the 4-position;
RXSelected from C1-C4 alkoxy, optionally mono-or di-substituted phenyl, optionally mono-or di-substituted pyridyl, 5-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, optionally substituted C1-C4 alkyl, optionally substituted 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, C3-C6 cycloalkyl, or amino optionally substituted with C1-C4 alkyl; the optional substituents are selected from halogen, hydroxy, C1-C4 alkoxy or C3-C6 cycloalkyl;
Ryselected from amino optionally substituted with C1-C4 alkyl or benzyl, C1-C4 alkyl, 4-6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, or C3-C6 cycloalkyl;
Ar2selected from the group consisting of optionally mono-or disubstituted phenyl, optionally mono-or disubstituted pyridinyl, said substituents being selected from the group consisting of halogen, C1-C4 alkoxy;
Rm、Rneach independently selected from hydrogen, hydroxy C1-C4 alkyl, or Rm、RnTogether with the carbon atom to which they are attached form a cyclopropyl group;
r is 0, 1 or 2.
10. Use of a compound of formula I, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the manufacture of a medicament for use as an inhibitor of RET kinase.
11. Use of a compound of formula I, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 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.
12. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 9, an isomer, prodrug, stable isotopic derivative or a pharmaceutically acceptable salt thereof, optionally one or more other RET kinase inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients.
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JP2014210769A (en) * | 2013-04-03 | 2014-11-13 | 株式会社ヤクルト本社 | Pim inhibitors containing thiazolidine derivatives or salts thereof as active ingredients |
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JP2014210769A (en) * | 2013-04-03 | 2014-11-13 | 株式会社ヤクルト本社 | Pim inhibitors containing thiazolidine derivatives or salts thereof as active ingredients |
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