CN113527260A

CN113527260A - Compound capable of degrading STAT3 enzyme, preparation method and pharmaceutical application thereof

Info

Publication number: CN113527260A
Application number: CN202110222225.1A
Authority: CN
Inventors: 张晨; 王健民; 吴守涛; 叶飞; 李瑶; 严庞科
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2020-04-21
Filing date: 2021-03-03
Publication date: 2021-10-22

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in STAT3 related diseases such as tumors. B-L-K (I).

Description

Compound capable of degrading STAT3 enzyme, preparation method and pharmaceutical application thereof

Technical Field

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in STAT3 related diseases such as tumors.

Background

A Signal Transducer and Activator of Transcription (STAT) protein is a protein that binds to DNA. The STAT protein can respond to various extracellular cytokine and growth factor signals, and further serve as a signal molecule to transmit signals to cell nucleus to participate in regulation and control of gene expression. Currently, 7 STAT subtypes, namely STAT 1, STAT 2, STAT3, STAT 4, STAT 5a, STAT 5b, and STAT 6, are found, which generally consist of 850 amino acid residues, 750-.

STAT3, one of the STAT family members, has a number of important roles in regulating cell growth, differentiation and apoptosis, as well as angiogenesis. Under normal physiological conditions, the activation of STAT3 protein is tightly controlled; the protein is over-activated and expressed at high levels in cells of various tumors (e.g., breast cancer, ovarian cancer, head and neck squamous cell carcinoma, prostate cancer, malignant melanoma, multiple myeloma, brain tumor, non-small cell lung cancer, various leukemias, etc.) (Huynh, j.et al., nat. rev.cancer.,2019,19, 82-96).

PROTAC (protein targeting chimera) molecules are bifunctional compounds capable of simultaneously combining targeting proteins and E3 ubiquitin ligase, and the compounds can be recognized by proteasomes of cells to cause degradation of the targeting proteins and effectively reduce the content of the targeting proteins in the cells. By introducing ligands capable of binding different target proteins into the ProTAC molecule, the application of the PROTAC technology to the treatment of various diseases becomes possible, and the technology has attracted much attention in recent years.

The application of Protac technology to STAT3 protein, which shows degradation, has been reported in the literature (Bai et al, Cancer cell.2019,36,498-511). The novel PROTAC drug combined with STAT3 protein and E3 ubiquitin ligase is developed for treating diseases related to STAT3, and has wide application prospect.

Disclosure of Invention

The STAT3 inhibitor which is novel in structure, good in drug effect, high in bioavailability and safer is developed and used for treating STAT3 related diseases such as tumors or autoimmune system diseases.

The PROTAC compound which has novel structure, good drug effect, high bioavailability and higher safety and can inhibit or degrade the inhibitor of STAT3 and E3 ubiquitin ligase is developed and used for treating STAT3 related diseases such as tumors or autoimmune system diseases.

The invention relates to a compound or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),

B-L-K(I)

in certain embodiments, L is selected from

-Cy1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Cy3-Cy4-, s1 or s2 are each independently selected from 0, 1,2, 3 or 4, and s1+ s2 is equal to or less than 4;

in certain embodiments, L is selected from

s1 or s2 are each independently selected from 0, 1,2, 3, and s1+ s2 is equal to or less than 4;

in certain embodiments, L is selected from

In certain embodiments, L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Cy3-Cy 4-;

in certain embodiments, each of G1, G2, Cy1, Cy2, Cy3, Cy4 is independently selected from 4-7 membered heteromonocyclic ring, 5-10 membered heterobicyclic ring, 6-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered heteroaryl, 5-10 membered benzocycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, benzocycloalkyl, spirocycloalkyl, bridged cycloalkyl, heteromonocyclic, fused ring, heterospirocyclic, or bridged ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH, H, F, Br, I, OH, COOH, and G₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Substituted by alkoxy, said hetero-monocyclic ring,The hetero-fused, hetero-spiro or hetero-bridged ring contains 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, each G1, G2, Cy1, Cy2, Cy3, or Cy4 is independently selected from a 4-7 membered azamonocyclic ring, a 4-7 membered monocycloalkyl ring, a 5-10 membered azabicyclic ring, a 7-10 membered nitrogenous bridged ring, or a 6-12 membered nitrogenous heterocyclic spiro ring, said monocycloalkyl, heteromonocyclic, heterocyclic, bridged ring, or heterocyclic spiro ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH, F, Cl, Br, H, OH, o₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

in certain embodiments, each G1, G2, Cy1, Cy2, Cy3, or Cy4 is independently selected from one of the following substituted or unsubstituted groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinyl, cyclopentaietitidinyl, cyclopentaieticanyl, cyclohexyloazetidinyl, azetidinyl, azetidinoazetidinyl, azetidinyl, azetidinoheteroazetidinyl, azetidinyl, azetidinoazetidinyl, azetidinyl, cyclopentaizetidinyl, azetidinyl, cyclopentaizacetyl, azetidinyl, morpholinoazetidinyl, and azetidinyl, Azacyclopentylpiperidine, azacyclohexapentyl-azetidinyl, azacyclohexapentyl, azetidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclohexyl(ii) a spiroazacyclopentyl group, a cyclohexylspiroazacyclohexyl group, an azetidinylspiroazetidinyl group, an azetidinylspiroazacyclopentyl group, an azetidinylspiroazacyclobutyl group, an azetidinylspiroazetidinyl group, an azetidinylspiroazacyclopentyl group, an azetidinylspiroazacyclohexyl group, a cyclobutylspiropiperidine group, a cyclopentylspiropiperidine group, a cyclohexylspiropiperidine group, an azetidinylspiropiperidine group, a cyclohexylspiropiperidine group, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof,

When substituted, is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、COOH、 CN、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in certain embodiments, each G1, G2, Cy1, Cy2, Cy3, or Cy4 is independently selected from one of the following substituted or unsubstituted groups:

when substituted, is optionally further substituted with 0 to 4 substituents selected from H, F, CF₃Methyl, hydroxymethyl, COOH, CN or NH₂Substituted with the substituent(s);

in certain embodiments, L is selected from

Wherein the left side is connected with B; in certain embodiments, L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

in certain embodiments, L is selected from

Wherein the left side is connected with B;

in certain embodiments, B is selected from

Ring C is selected from 6-10 membered aryl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, A is selected from a bond, -C_1-4Alkylene-, -C_1-4Alkylene group C (O) -, -C (O) C_1-4alkylene-or-C ═ O-, said alkylene optionally being further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH, D is selected from a bond, a,

Each X is independently selected from CR^b3Or N, R^b1Each independently selected from H, F, Cl, Br, I, OH, NH₂、NO₂、NO、CN、COOH、C(O)NH₂、-S(O)₂NH₂、-NHS(O)₂R^C1、 -N(OH)S(O)₂C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further selected from H, F, Cl, Br, I, OH, C by 0 to 4_1-4Alkyl or C_1-4Substituted by substituents of alkoxy radicals, R^c1Each independently selected from C_1-4Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-7 membered cycloalkyl or 4-7 membered heterocyclyl, said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl being optionally further selected from H, F, Cl, Br, I, OH, C, by 0 to 4_1-4Alkyl or C_1-4Alkoxy, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, R^b2Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、COOH、C(O)NH₂、C(O)NHNH₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) -C_1-4Alkyl, 6-10 membered aryl, 3-7 membered cycloalkyl or 4-7 membered heterocyclyl, said alkyl, alkoxy, aryl, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH or C (O) NH₂Said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N, R^b3Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NH-C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH, R^b4Each independently selected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH or phenyl, R^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、 CN、C(O)NH₂、COOH、-NH-C_1-4Alkyl, -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) C_1-4Alkyl, -C (O) OC_1-4Alkyl, -C (O) NHC_1-4Alkyl or-C (O) N (C)_1-4Alkyl radical)₂Said alkyl or alkoxy is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH or NH₂Each of m1 or m2 is independently selected from 1,2 or 3, each of n1 is independently selected from 0, 1,2, 3, 4 or 5, each of n2, n3 or n5 is independently selected from 0, 1,2 or 3;

in certain embodiments, ring C is selected from a benzene ring, thiazole, furan, thiophene, pyrrole, oxazole, imidazole or pyrazole, and A is selected from a bond, methylene, ethylene, propylene, -CH₂C(O)-、-C(O)CH₂-、-CH₂CH₂C(O)-、-C(O)CH₂CH₂-or-co-, said methylene, ethylene or propylene being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH, D is selected from the group consisting of a bond, a,

Each X is independently selected from CR^b3Or N, R^b1Each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、NO₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -NHS (O)₂CH₃、-NHS(O)₂CH₂CH₃、-NHS(O)₂-cyclopropyl or-NHS (O)₂-phenyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl or phenyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, methyl or methoxy, R^b2Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、COOH、C(O)NH₂、C(O)NHNH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -C (O) CH₃、-C(O)CH₂CH₃Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl groups being optionally further selected from H, F, Cl, Br, I, OH, COOH or C (O) NH by 0 to 4₂Is substituted by a substituent of (A), R^b3Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、 COOH、-NHCH₃、-NHCH₂CH₃Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH, R is a hydrogen atom, and R is a hydrogen atom^b4Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I or OH, R is optionally substituted by a substituent selected from the group consisting of^b5Each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NHCH₃、 -NHCH₂CH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy, -C (O) CH₃、-C(O)CH₂CH₃、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)NHCH₃、- C(O)NHCH₂CH₃、-C(O)NHCH₃or-C (O) N (CH)₂CH₃)₂The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropylThe alkoxy is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH or NH₂Each n1 is independently selected from 0, 1,2, 3, 4 or 5, each n2, n3 or n5 is independently selected from 0, 1,2 or 3;

in certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In some instancesIn one embodiment, K is selected from

Each of rings E or F is independently selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N, R^k2Each independently selected from CH₂、C＝O、S＝O、SO₂，R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、CN、COOH、C_1-4Alkyl or C_1-4Alkoxy radical, R^k5Is selected from C ═ O or

p1 or p2 are each independently selected from 0, 1,2, 3 or 4;

in certain embodiments, K is selected from

R^k2Each independently selected from CH₂、C＝O、S＝O、SO₂，R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、CN、COOH、C_1-4Alkyl or C_1-4Alkoxy radical, R^k5Is selected from C ═ O or

p1 or p2 are each independently selected from 0, 1,2, 3 or 4;

in certain embodiments, K is selected from

R^k2Each independently selected from CH₂Or C ═ O, R^k1、R^k3Or R^k4Each independently selected from H, CH₃F, Cl, Br, I, OH or NH₂P1 or p2 are each independently selected from 0, 1 or 2;

in certain embodiments, K is selected from

In certain embodiments, K is selected from

In certain embodiments, K is selected from

As a first embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

l is selected from

Or L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy 3-or-Cy 1-Cy2-Cy3-Cy 4-;

G₁、G₂cy1, Cy2, Cy3, Cy4 are each independently selected from 4-7 membered heteromonocyclic ring, 5-10 membered heteroaryl, 5-10 membered heterofused ring, 6-12 membered heterospiro ring, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered fused cycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl or 6-10 membered aryl, which aryl, heteroaryl, cycloalkyl, fused cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heteromonocyclic ring, fused ring, heterospiro ring or heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH, OH, COOH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

b is selected from

Ring C is selected from 6-10 membered aryl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

a is selected from the group consisting of a bond, -C_1-4Alkylene-, -C_1-4Alkylene group C (O) -, -C (O) C_1-4alkylene-or-C ═ O-, said alkylene optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

d is selected from a bond,

Each X is independently selected from CR^b3Or N;

R^b1each independently selected from H, F, Cl, Br, I, OH, NH₂、NO₂、NO、CN、COOH、C(O)NH₂、 -S(O)₂NH₂、-NHS(O)₂R^C1、-N(OH)S(O)₂C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further selected from H, F, Cl, Br, I, OH, C by 0 to 4_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^c1each independently selected from C_1-4Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-7 membered cycloalkyl or 4-7 membered heterocyclyl, said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl being optionally further selected from H, F, Cl, Br, I, OH, C, by 0 to 4_1-4Alkyl or C_1-4Alkoxy, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^b2each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、COOH、C(O)NH₂、C(O)NHNH₂、 C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) -C_1-4Alkyl, 6-10 membered aryl, 3-7 membered cycloalkyl or 4-7 membered heterocyclyl, said alkyl, alkoxy, aryl, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH or C (O) NH₂Said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^b3each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NH-C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R^b4each independently selected from H, C_1-4Alkyl or C_3-6Cycloalkyl, said alkyl or cycloalkyl optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH or phenyl;

R^b5each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NH-C_1-4Alkyl, -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C (O))C_1-4Alkyl, -C (O) OC_1-4Alkyl, -C (O) NHC_1-4Alkyl or-C (O) N (C)_1-4Alkyl radical)₂Said alkyl or alkoxy is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH or NH₂Substituted with the substituent(s);

k is selected from

Ring E or F are each independently selected from a phenyl ring or a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from O, S, N;

R^k2each independently selected from CH₂、C＝O、S＝O、SO₂；

R^k1、R^k3Or R^k4Each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、CN、COOH、C_1-4Alkyl or C_1-4An alkoxy group;

R^k5is selected from C ═ O or

p1 or p2 are each independently selected from 0, 1,2, 3 or 4;

s1 or s2 are each independently selected from 0, 1,2, 3 or 4, and s1+ s2 is equal to or less than 4;

m1 or m2 are each independently selected from 1,2 or 3;

each n1 is independently selected from 0, 1,2, 3, 4 or 5;

n2, n3 or n5 are each independently selected from 0, 1,2 or 3.

As a second embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

l is selected from

Or L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy 3-or-Cy 1-Cy2-Cy3-Cy 4-;

g1, G2, Cy1, Cy2, Cy3 or Cy4 are each independently selected from 4-7 membered azamonocyclic ring, 4-7 membered monocycloalkyl, 5-10 membered azabicyclic ring, 7-10 membered nitrogen-containing heterobridged ring or 6-12 membered nitrogen-containing heterospiro ring, said monocycloalkyl, heteromonocyclic, heterofused ring, heterobridged ring or heterospiro ring being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、 C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

k is selected from

The remaining group definitions are consistent with the first embodiment of the present invention.

As a third embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

l is selected from

Or L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy 3-or-Cy 1-Cy2-Cy3-Cy 4-;

g1, G2, Cy1, Cy2, Cy3 or Cy4 are each independently selected from one of the following substituted or unsubstituted groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azepinyl, piperidine, morpholine, piperazine, cyclopropyloazepinyl, cyclobutyloazepinyl, cyclopentoazepinyl, cyclopentaazepinyl, and cyclopentaazepinyl,Cyclopentoazetidicyclopentyl, cyclopentoazetidicyclohexyl, cyclopentylpiperidine, cyclohexyloazetidinyl, azetidinylbetazetidinyl, azetidinylcoazetidinyl, azetidineiderinyl, azetidinobutyl, azetidinobutynyl, azetidinozetidinyl, azetidinylcerazetidinyl, azetidinylcoazetidinyl, cyclopentaspiralkyl, cyclopentaspiralceazepinyl, cyclopentaspiralzetidinyl, cyclopentaspiralkyl, cyclopentaspiralkyi, and cyclopentaspiralkyl, Cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclohexylspiropiperidine, azetidinyl spiropiperidine, azetidinyl spiroazetidinyl spiropiperidine, azetidinyl spiroheterocycloalkyl, and so,

ring C is selected from benzene ring, thiazole, furan, thiophene, pyrrole, oxazole, imidazole or pyrazole;

a is selected from the group consisting of a bond, methylene, ethylene, propylene, -CH₂C(O)-、-C(O)CH₂-、-CH₂CH₂C(O)-、-C(O)CH₂CH₂-or-co-, said methylene, ethylene or propylene being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

d is selected from a bond,

Each X is independently selected from CR^b3Or N;

R^b1each independently selected from H, F, Cl, Br, I, OH, NH₂、CF₃、NO₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -NHS (O)₂CH₃、-NHS(O)₂CH₂CH₃、-NHS(O)₂-cyclopropyl or-NHS (O)₂-phenyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl or phenyl being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, methyl or methoxy;

R^b2each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、COOH、C(O)NH₂、C(O)NHNH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -C (O) CH₃、-C(O)CH₂CH₃Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl groups being optionally further selected from H, F, Cl, Br, I, OH, COOH or C (O) NH by 0 to 4₂Substituted with the substituent(s);

R^b3each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NHCH₃、- NHCH₂CH₃Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R^b4each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R^b5each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NHCH₃、- NHCH₂CH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy, -C (O) CH₃、-C(O)CH₂CH₃、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)NHCH₃、- C(O)NHCH₂CH₃、-C(O)NHCH₃or-C (O) N (CH)₂CH₃)₂Said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH or NH₂Substituted with the substituent(s);

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

R^k1、R^k3or R^k4Each independently selected from H, CH₃F, Cl, Br, I, OH or NH₂；

p1 or p2 are each independently selected from 0, 1 or 2;

each n1 is independently selected from 0, 1,2, 3, 4 or 5;

n2, n3 or n5 are each independently selected from 0, 1,2 or 3;

the remaining radical definitions are in accordance with either the first or second embodiment of the present invention.

As a fourth embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

l is selected from

Or L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy 3-or-Cy 1-Cy2-Cy3-Cy 4-;

g1, G2, Cy1, Cy2, Cy3 or Cy4 are each independently selected from one of the following substituted or unsubstituted groups:

k is selected from

B is selected from

The remaining group definitions are consistent with any of the first, second or third embodiments of the present invention.

As a fifth embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein,

l is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

the remaining group definitions are consistent with any of the first, second, third or fourth embodiments of the present invention.

As a sixth embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein,

k is selected from

The remaining group definitions are consistent with any of the first, second, third, fourth or fifth embodiments of the present invention.

As a seventh embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

k is selected from

The remaining group definitions are consistent with any of the first, second, third, fourth, fifth or sixth embodiments of the present invention.

As an eighth embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

b is selected from

The remaining group definitions are consistent with any of the first, second, third, fourth, fifth, sixth or seventh embodiments of the present invention.

As a ninth embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

b is selected from

As a tenth embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

b is selected from

As an eleventh embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

b is selected from

As a twelfth embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,

b is selected from

As an embodiment of the present invention, a compound represented by general formula (I) or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, is selected from one of the following structures:

。

some embodiments of the present invention relate to a compound of formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein the salt is selected from trifluoroacetate.

The invention relates to a pharmaceutical composition, which comprises the compound or stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to application of a compound shown as a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof in preparing a medicament for treating diseases related to STAT3 activity or expression quantity.

The invention relates to application of a compound shown as a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof in preparing a medicament for treating diseases related to STAT3 inhibition or degradation.

The invention relates to application of the compound or the stereoisomer, the deuterogen, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof, which is characterized in that the disease is selected from tumors, preferably brain tumors, lymphatic system tumors, ovarian cancers, endometrial cancers, cervical cancers, breast cancers, bladder cancers, prostatic cancers, gastric cancers, colon cancers, laryngeal cancers, nasopharyngeal cancers, liver cancers, skin cancers, bone cancers, blood cancers, head and neck squamous cell cancers, glioma, melanoma, leukemia, non-small cell lung cancers, lung adenocarcinoma, squamous lung cancers, pancreatic cancers, liver cancers, skin cancers or epithelial cell cancers.

The first synthesis method comprises the following steps:

the general formula (Z-1) and the general formula (Z-4) are subjected to nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Ia);

the general formula (Z-1) and the general formula (Z-2) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-3), if the reaction site of the general formula (Z-3) has an amino protecting group, the amino protecting group is removed and then the reaction site is subjected to nucleophilic substitution reaction or coupling with the general formula (Z-4) to obtain a corresponding general formula (Ib);

the general formula (Z-2) and the general formula (Z-5) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-21), the general formula (Z-21) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-6), and if an amino protecting group is arranged at the reaction position of the general formula (Z-21), the amino protecting group is removed and then the general formula (Z-1) is subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-6); the general formula (Z-3) and the general formula (Z-5) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-6); if the reaction site of the general formula (Z-6) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain the corresponding general formula (Ic);

the general formula (Z-21) and the general formula (Z-7) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-22), the general formula (Z-22) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-8), and if an amino protecting group is arranged at the reaction position of the general formula (Z-22), the amino protecting group is removed and then the general formula (Z-1) is subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-8); the general formula (Z-6) and the general formula (Z-7) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-8), if the reaction site of the general formula (Z-8) has an amino protecting group, the amino protecting group is removed and then the reaction site is subjected to nucleophilic substitution reaction or coupling with the general formula (Z-4) to obtain a corresponding general formula (Id);

the general formula (Z-22) and the general formula (Z-9) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-23), the general formula (Z-23) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-10), if an amino protecting group is arranged at the reaction position of the general formula (Z-23), the amino protecting group is removed, and then the general formula (Z-1) is subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-10); obtaining a corresponding general formula (Z-10) by the general formula (Z-8) and the general formula (Z-9) through reductive amination, nucleophilic substitution reaction or coupling reaction, and obtaining a corresponding general formula (Ie) by removing an amino protecting group and then performing nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) if the reaction site of the general formula (Z-10) has the amino protecting group;

and a second synthesis method comprises the following steps:

route 1:

route 2:

route 3:

route 4:

route 1: if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-11); the general formula (Ib) is obtained by the general formula (Z-11) and the general formula (Z-1) through reductive amination, nucleophilic substitution reaction or coupling reaction;

route 2: if the reaction site of the general formula (Z-5) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-12); if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-12) to obtain a corresponding general formula (Z-13); or if the reaction site of the general formula (Z-21) has an amino protecting group, removing the amino protecting group and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain the corresponding general formula (Z-13); the general formula (Z-13) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a general formula (Ic);

route 3: if the reaction site of the general formula (Z-7) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-14); if the reaction site of the general formula (Z-5) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-14) to obtain a corresponding general formula (Z-15); if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-15) to obtain a general formula (Z-16); or if the reaction site of the general formula (Z-22) has an amino protecting group, removing the amino protecting group and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain the corresponding general formula (Z-16); or the general formula (Z-16) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain the general formula (Id);

route 4: if the reaction site of the general formula (Z-9) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-17); if the reaction site of the general formula (Z-7) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-17) to obtain a corresponding general formula (Z-18); if the reaction site of the general formula (Z-5) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-18) to obtain a general formula (Z-19); if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out reductive amination, nucleophilic substitution reaction or coupling reaction with the general formula (Z-19) to obtain a general formula (Z-20); or if the reaction site of the general formula (Z-23) has an amino protecting group, removing the amino protecting group and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain the corresponding general formula (Z-20); the general formula (Z-20) and the general formula (Z-1) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a general formula (Ie);

the definition of each substituent is the same as that of the synthesis method I.

The third synthesis method comprises the following steps:

R₁₃、R₁₄each independently selected from H, (═ O), -CHO, F, Cl, Br, I, OTf, OMs, OTs, or an amino protecting group, preferably Boc;

R₁₁selected from H, F, Cl, Br, I;

R₁₂is selected from NH₂、F、Cl、Br、I、OTf、OH；

Obtaining the corresponding general formula (Z-27) by the coupling reaction, the nucleophilic substitution reaction or the condensation reaction of the general formula (Z-24) and the general formula (Z-26), and if the reaction site of the general formula (Z-26) has an amino protecting group, removing the amino protecting group and then obtaining the corresponding general formula (Z-27) by the coupling reaction, the nucleophilic substitution reaction or the condensation reaction of the general formula (Z-24);

if the reaction site of the general formula (Z-27) has an amino protecting group, the amino protecting group is removed and then the general formula (Z-25) is subjected to coupling reaction or nucleophilic substitution reaction to obtain the corresponding general formula (If).

The synthesis method comprises the following steps:

R₁₃、R₁₄each independently selected from H, (═ O), -CHO, F, Cl, Br, I, OTf, OMs, OTs or an amino protecting group, preferably Boc;

R₁₁selected from H, F, Cl, Br, I;

R₁₂is selected from NH₂、F、Cl、Br、I、OTf、OH；

Obtaining a corresponding general formula (Z-28) through coupling reaction or nucleophilic substitution reaction between the general formula (Z-25) and the general formula (Z-26), and if the reaction site of the general formula (Z-26) has an amino protecting group, removing the amino protecting group and then obtaining the corresponding general formula (Z-28) through coupling reaction or nucleophilic substitution reaction with the general formula (Z-25);

obtaining a corresponding general formula (If) by the general formula (Z-28) and the general formula (Z-24) through coupling reaction, nucleophilic substitution reaction or condensation reaction, and If the reaction site of the general formula (Z-28) has an amino protecting group, removing the amino protecting group and then obtaining the corresponding general formula (If) by the coupling reaction, the nucleophilic substitution reaction or condensation reaction with the general formula (Z-25);

the definition of each substituent is the same as that of the third synthesis method.

Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"halogen" means F, Cl, Br or I.

"halo-substituted" refers to F, Cl, Br, or I substitution, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "halogen-substituted" is simply referred to as "halo".

"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; alkyl groups, as used herein, are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.

"heteroalkyl" means that 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH)₂)v-X(CH₂)v- X(CH₂) v-H (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, a heteroatom including but not limited to N, O or S, and at least 1X is selected from a heteroatom, and either N or S in a heteroatom can be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.

"alkylene" refers to a substituted or unsubstituted, straight and branched chain, divalent saturated hydrocarbon radical, including- (CH)₂)_v- (v is an integer of 1 to 10), examples of the alkylene group include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

"Heteroalkylidene" means a substituted or unsubstituted alkylene group in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH)₂)v-X(CH₂)v- X(CH₂) v-, v is an integer from 1 to 5, each X is independently selected from the group consisting of a bond, N, O or S, and at least 1X is selected from the group consisting of N, O or S.

"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having from 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. Cycloalkyl as found herein, is as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl groups may be attached to a heteroatom or carbon atom, heterocycloalkyl groups may be attached to an aromatic ring or to a non-aromatic ring, heterocycloalkyl groups may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, morpholinyl, hexahydropyrimidyl, piperazinyl. The heterocycloalkyl radical may be monovalent, divalent, trivalent or tetravalent

"alkenyl" means a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group having at least 1, and typically 1,2 or 3 carbon double bonds, the backbone including, but not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; alkenyl groups are present herein, the definition of which is consistent with the present definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.

"alkynyl" refers to substituted or unsubstituted, straight and branched chain, monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, including, but not limited to, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, and examples of alkynyl include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.

"alkoxy" means a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, the carbocyclyl may be attached to the aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, and mixtures thereof,

"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system, and includesOptionally substituted N, S in the ring of the heterocyclyl containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, dihydropyranyl, spirocyclo-pyridyl, spiro-pyridyl, spirocyclo-pyridyl, oxacycloheptyl, azanyl, pyridyl, oxathianyl, thianyl, thienyl, pyridyl, etc, Benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] groups]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

"Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclic" refers to a polycyclic group that shares a single atom (referred to as a spiro atom) between substituted or unsubstituted monocyclic rings, and the number of ring atoms in the spiro ring system includes, but is not limited to, groups containing 5 to 20, 6 to 14, 6 to 12, 6 to 10, where one or more of the ringsMay contain 0 or more (including but not limited to 1,2, 3 or 4) double bonds, and optionally may contain 0 to 5 double bonds selected from N, O or S (═ O)_nA heteroatom of (a).

The "spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.

"fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1,2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (═ O)_nOr O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

the "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.

"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly linked, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S (═ O)_nOr O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include

Cubic alkane,Adamantane. The "bridge ring" or "bridge ring group" may be monovalent, divalent, trivalent or tetravalent.

"carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic" refers to a "spiro" ring whose ring system consists of only carbon atoms. The "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospiro" group, as referred to herein, is defined in accordance with the definition of spiro.

"carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. "carbocyclic ring", "fused carbocyclic ring group", "fused carbocyclic group", or "fused carbocyclic group" as used herein, is defined in accordance with fused rings.

"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. "Carbobridged ring", "bridged carbocyclyl", or "carbobridyclyl" as used herein, is defined in accordance with the definition of bridged ring.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein, is defined consistent with the definition of heterocycle.

"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. The term "fused ring" as used herein refers to a "fused ring," fused ring group, "fused heterocyclic group," or "fused ring group," which is defined as being fused.

"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospiro, "heterospiro ring", "spiro heterocyclic" or "heterospiro ring" as used herein is consistent with spiro rings.

"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The term "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group", as used herein, is defined in accordance with the bridged ring.

"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single or fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include a benzene ring, a naphthalene ring, a substituted naphthalene group, a substituted or substituted naphthalene group, a substituted benzene or substituted benzene ring, a substituted benzene or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene ring, or substituted benzene ring, a substituted benzene,

The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is located on the aryl ring.

"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (═ O)_nAnd n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include

Heteroaryl, as used herein, is defined in accordance with the present definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is on the heteroaryl ring.

The "5-membered and 5-membered heteroaromatic ring" means a 5-and 5-membered fused heteroaromatic ring in which at least 1 ring of 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity, and non-limiting examples include pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiophene rings, pyrazolothiophene rings.

"5 and 6 membered heteroaromatic ring" means a 5 and 6 membered fused heteroaromatic ring wherein at least 1 ring of the 2 fused rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include benzo 5 membered heteroaryl, 6 membered heteroaromatic ring and 5 membered heteroaromatic ring.

"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH)₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)- NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed.

"contains 1 to 5 heteroatoms selected from O, S, N" means containing 1,2, 3, 4 or 5 heteroatoms selected from O, S, N.

"0 to X substituents selected from …" means substituted with 0, 1,2, 3 … X substituents selected from …, X being selected from any integer between 1 and 10. If "substituted with 0 to 4 substituents selected from …" is intended to mean substituted with 0, 1,2, 3, or 4 substituents selected from …. If "substituted with 0 to 5 substituents selected from …" is meant substituted with 0, 1,2, 3, 4, or 5 substituents selected from …. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1,2, 3 or 4 substituents selected from H or F.

X-Y membered rings (X is selected from integers less than Y greater than 3 and Y is selected from any integer between 4 and 12) include X +1, X +2, X +3, X +4 … Y membered rings. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.

"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. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuteroides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.

"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"tautomer" refers to functional group isomers resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-enol isomers, and the like.

"optional" or "optionally" or "selective" or "selectively" 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 and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.

“IC₅₀"is a pairThe concentration of drug or inhibitor required for a given biological process (or for a component of the process such as an enzyme, receptor, cell, etc.) to inhibit half.

Detailed Description

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from compounds described in the commercial chemicals and/or chemical literature. "commercial chemicals" are obtained from regular commercial sources, and suppliers include: tatan science and technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical engineering, Shaoshao chemical technology, Nanjing Yashi, Yaogongkang and Bailingwei science and technology.

References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley-Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.

Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃₎Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);

the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4 mm-0.5 mm;

the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.

Intermediate 1:

2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine

2-chloro-N-[2-(4-nitrophenyl)ethyl]quinazolin-4-amine

The first step is as follows: 2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine

2-chloro-N-[2-(4-nitrophenyl)ethyl]quinazolin-4-amine

2, 4-dichloroquinazoline (4g,20.10mmol) and 4-nitrophenylethylamine hydrochloride (4.08g,20.13mmol) were charged into a 500mL single-neck round-bottom flask and dissolved in 200mL of tetrahydrofuran. Cooling in ice-water bath, cooling the internal temperature to 5-10 ℃, adding 6mL of triethylamine, removing the ice-water bath, heating to room temperature, and stirring overnight. TLC was used to monitor the reaction of the starting material almost completely, and the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was dissolved in 300mL of ethyl acetate, and the organic phase was washed once with 250mL of water and 250mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give 2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (intermediate 1) as a yellow-white solid (4g, yield: 60.5%).

MS m/z(ESI):329.1[M+H]⁺

Intermediate 2:

n- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide N- (4- (2- ((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide

The first step is as follows: [2- (4-Nitrophenyl) ethyl ] carbamic acid tert-butyl ester (2-1)

tert-butyl(4-nitrophenethyl)carbamate

4-Nitrophenylethylamine hydrochloride (10g,49.5mmol) and di-tert-butyl dicarbonate (11.87g,54.5mmol) were weighed into a 500mL single-neck round-bottom flask, dissolved in 200mL tetrahydrofuran and 100mL of saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was extracted with 300mL of ethyl acetate, washed with 250mL of water and 250mL of saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude tert-butyl [2- (4-nitrophenyl) ethyl ] carbamate (2-1) was isolated and purified by column chromatography on silica gel to give a yellowish white solid (8.5g, yield: 64.59%).

MS m/z(ESI):267.3[M+H]⁺

The second step is that: (4-Aminophenylethyl) carbamic acid tert-butyl ester (2-2)

tert-butyl(4-aminophenethyl)carbamate

[2- (4-Nitrophenyl) ethyl ] carbamic acid tert-butyl ester (2-1) (8.5g,31.9mmol) was weighed into a 500mL single-neck round-bottom flask, 150mL of methanol and 1g of palladium on carbon (10 wt%) were added, and after replacement with hydrogen, the atmosphere was maintained under hydrogen, and the mixture was stirred at room temperature overnight. Filtering, concentrating the filtrate under reduced pressure to remove methanol to obtain crude product. The crude product was purified by silica gel column chromatography to give tert-butyl (4-aminophenylethyl) carbamate (2-2) as a pink solid (5.7g, yield: 76%).

MS m/z(ESI):237.32[M+H]⁺

The third step: (4- (Methanesulfonamido) phenethyl) carbamic acid tert-butyl ester (2-3)

tert-butyl(4-(methylsulfonamido)phenethyl)carbamate

Tert-butyl (4-aminophenylethyl) carbamate (2-2) (5.7g,24.15mmol) was weighed into a 250mL single-neck round-bottom flask, dissolved by adding 100mL dichloromethane, cooled in an ice-water bath, and methanesulfonyl chloride (2.48g,21.73mmol) was added dropwise and reacted for 30min under an ice-water bath. 100mL of water was added to the reaction mixture, followed by liquid separation and organic phase concentration under reduced pressure to remove methylene chloride and obtain a crude product, which was subjected to silica gel column chromatography to obtain tert-butyl (4- (methylsulfonylamino) phenethyl) carbamate (2-3) as a white solid (6.1g, yield: 80.4%).

MS m/z(ESI):315.24[M+H]⁺

The fourth step: n- (4- (2-aminoethyl) phenyl) methanesulfonamide (2-4)

N-(4-(2-aminoethyl)phenyl)methanesulfonamide

100mL of tert-butyl (4- (methylsulfonamido) phenethyl) carbamate (2-3) (5g,15.92mmol) was weighed into a single-neck round-bottom flask, dissolved by adding 50mL of 3M HCl/EA, reacted at room temperature for 3 hours, and monitored by TLC for completion. The reaction solution is concentrated to obtain a crude product which is directly put into the next step.

MS m/z(ESI):215.3[M+H]⁺

The fifth step: n- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (intermediate)

2)N-(4-(2-((2-chloroquinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide

2, 4-dichloroquinazoline (2.69g,13.6mmol) and the crude N- (4- (2-aminoethyl) phenyl) methanesulfonamide (2-4) from the previous step were added to a 250mL single neck round bottom flask and dissolved in 200mL tetrahydrofuran. Cooling in ice-water bath, cooling the internal temperature to 5-10 ℃, adding 6mL of triethylamine, removing the ice-water bath, heating to room temperature, and stirring overnight. TLC was used to monitor the completion of the reaction, and the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was dissolved in 300mL of ethyl acetate, washed with 250mL of water and 250mL of saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel to give N- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (intermediate 2) as a pale yellow solid (3.89g, yield: 76.1%).

MS m/z(ESI):377.1[M+H]⁺

Example 1:

2- (2, 6-dioxo-3-piperidinyl) -5- [2- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] ethynyl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[2-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3- yl]thynyl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (1a)

tert-butyl 3-ethynylazetidine-1-carboxylate

3-formyl azetidine-1-carboxylic acid tert-butyl ester (10g,53.99mmol) was dissolved in 200mL of methanol in a 500mL single-neck round-bottom flask, cooled to 5-10 ℃ in an ice-water bath, added sequentially with (1-diazo-2-oxopropyl) dimethyl phosphonate (14.33g,64.79mmol) and potassium carbonate (29.85,215.96mmol), warmed to room temperature and stirred for 3-4 hours, and the reaction was monitored by TLC for completion. Diluting with 200mL ethyl acetate, suction-filtering with a sand core funnel, washing the filter cake with 100mL ethyl acetate, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (1a) as colorless oily substance (9.2g, yield: 94%).

MS m/z(ESI):126.2[M-55]⁺

The second step is that: 3- [2- [2- (2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5-yl ] ethynyl ] azetidine-1-carboxylic acid tert-butyl ester (1b)

tert-butyl3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]ethynyl]azetidine-1- carboxylate

5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (see WO2009145899 for synthetic method) (1.7 g,5.04mmol) was weighed and dissolved in a 100mL single-neck round-bottom flask with 15mL tetrahydrofuran and 3mL DMF, followed by addition of tert-butyl 3-ethynylazetidine-1-carboxylate (1a) (1.37g,7.56mmol), palladium-ditriphenylphosphine dichloride (350mg, 0.504mmol), cuprous iodide (97mg,0.504mmol) and triethylamine (2.55g,25.21mmol), and heating to 75 ℃ under nitrogen atmosphere overnight. The residue was concentrated under reduced pressure to remove tetrahydrofuran, 20mL of water was added to the residue, extracted with ethyl acetate (25 mL. times.2), the organic phases were combined, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give tert-butyl 3- [2- [2- (2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5-yl ] ethynyl ] azetidine-1-carboxylate (1b), as a tan solid (1.8g, yield: 81.6%).

Ms m/z(ESI):436.2[M-1]^-

In the third step, 5- [2- (azetidin-3-yl) ethynyl ] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (1c)

5-[2-(azetidin-3-yl)ethynyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

Tert-butyl 3- [2- [2- (2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5-yl ] ethynyl ] azetidine-1-carboxylate (1b) (0.2g,0.457mmol) was weighed into a 100mL single-neck round-bottom flask containing 10mL of 3N HCl ethyl acetate solution, stirred at room temperature for two hours, and concentrated under reduced pressure to give the hydrochloride salt of 5- [2- (azetidin-3-yl) ethynyl ] -2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (1c) as a pale yellow solid (0.14g, yield: 90.78%).

MS m/z(ESI):338.1[M+1]⁺

The fourth step: 2- (2, 6-dioxo-3-piperidinyl) -5- [2- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] ethynyl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 1)

Intermediate 1(0.091g,0.277mmol) of 2-chloro-N- [2- (-nitrophenyl) ethyl ] quinazolin-4-amine was weighed, dissolved in 15mL of dimethylsulfoxide in a 100mL single-neck round-bottom flask, and 5- [2- (azetidin-3-yl) ethynyl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (1c) (0.124g,0.332mmol) and N, N-diisopropylethylamine (0.358g,2.77mmol) were added in that order and heated to 90 ℃ for 6 hours. Adding 45mL of water for quenching reaction, adding ethyl acetate (30mL of x 3) for extraction, combining organic phases, washing with saturated saline solution (45mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and separating and purifying the crude product by preparing a liquid phase (a mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- (2, 6-dioxo-3-piperidyl) -5- [2- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] ethynyl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 1), yellow-white solid (37mg, yield: 15.59%).

¹H NMR(400MHz,DMSO-d₆)δ11.12(s,1H),9.67(t,1H),8.24–8.15(m,3H),8.02–7.92 (m,3H),7.83(t,1H),7.62–7.54(m,3H),7.46(t,1H),5.17(dd,1H),4.76–4.61(m,2H),4.46–4.32 (m,2H),4.12–4.00(m,1H),3.86(dd,2H),3.15(t,2H),2.96–2.83(m,1H),2.66–2.51(m,2H), 2.13–2.02(m,1H).

MS m/z(ESI):630.2[M+1]⁺

Example 2:

2- (2, 6-dioxo-3-piperidinyl) -5- [2- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] ethynyl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[2-[1-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin- 3-yl]azetidin-3-yl]ethynyl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 3-ethynylazetidine (2a)

3-ethynylazetidine

1a (2.77g,15.28mmol) was added to a 250mL single neck round bottom flask containing 40mL 3N HCl ethyl acetate and the reaction stirred at room temperature for 4 hours. Concentration under reduced pressure gave 3-ethynylazetidine (2a) as a hydrochloride salt as a white solid (1.74g, yield: 96.83%).

MS m/z(ESI):82.2[M+H]⁺

The second step is that: 3- (3-ethynylazetidin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (2b)

tert-butyl 3-(3-ethynylazetidin-1-yl)azetidine-1-carboxylate

3-ethynylazetidine (2a) (1.74g,14.80mmol) was weighed, dissolved in 100mL of 1, 2-dichloroethane in a 250mL single-neck round-bottom flask, 3mL of triethylamine was added, followed by the sequential addition of tert-butyl 3-oxaazetidine-1-carboxylate (6.33g,37.00mmol), acetic acid (3.11g,51.80mmol) and 6g of anhydrous sodium sulfate, heated to 60 ℃ for 2 hours, cooled to room temperature, added in portions with sodium triacetoxyborohydride (18.82g,88.79mmol), and reacted at room temperature overnight. Adding 50mL of water, then carrying out layering, sequentially washing an organic phase with 50mL of saturated sodium bicarbonate solution, 50mL of water and 50mL of saturated saline solution once respectively, drying the organic phase with anhydrous sodium sulfate, filtering the mixture, concentrating the mixture under reduced pressure to obtain a crude product, and carrying out silica gel column chromatography purification on the crude product to obtain 3- (3-ethynylazetidin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (2b) and colorless oily substances (3.33g, 95.22%).

MS m/z(ESI):237.2[M+H]⁺

The third step: tert-butyl 3- [3- [2- [2- (2, 6-dioxo-3-piperidinyl) -1], 3-dioxoisoindolin-5-yl ] ethynyl ] azetidin-1-yl ] azetidine-1-carboxylate (2c)

tert-butyl3-[3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]ethynyl]azetidin-1- yl]azetidine-1-carboxylate

5-bromo-2- (2, 6-dioxo-3-piperidyl) isoindoline-1, 3-dione (1g,2.97mmol) was weighed out and dissolved in 20mL tetrahydrofuran in a 100mL single-neck round-bottom flask, tert-butyl 3- (3-ethynylazetidin-1-yl) azetidine-1-carboxylate (2b) (1.4g,5.93mmol), palladium bistriphenylphosphine dichloride (208mg,0.297mmol), cuprous iodide (57mg,0.297mmol) and triethylamine (1.5g,14.83mmol) were added in this order, and the mixture was heated to 75 ℃ under nitrogen atmosphere for reaction overnight. The residue was concentrated under reduced pressure to remove tetrahydrofuran, 20mL of water was added to the residue, extracted with ethyl acetate (25 mL. times.2), the organic phases were combined, washed once with 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel to give t-butyl 3- [3- [2- [2- (2, 6-dioxo-3-piperidinyl) -1], 3-dioxoisoindolin-5-yl ] ethynyl ] azetidin-1-yl ] azetidin-1-carboxylate (2c) as a tan solid (1g, yield: 77.07%).

MS m/z(ESI):491.2[M-H]^-

The fourth step: 5- [2- [1- (azetidin-3-yl) azetidin-3-yl ] ethynyl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (2d)

5-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

Tert-butyl 3- [3- [2- [2- (2, 6-dioxo-3-piperidyl) -1], 3-dioxoisoindolin-5-yl ] ethynyl ] azetidin-1-yl ] azetidine-1-carboxylate (2c) (0.505g,1.03mmol) was weighed out and dissolved in a 50mL single-neck round-bottom flask with 12mL of dichloromethane, 6mL of trifluoroacetic acid was added and reacted at room temperature for 3 hours. Concentration under reduced pressure gave 5- [2- [1- (azetidin-3-yl) azetidin-3-yl ] ethynyl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (2d) as a crude pale yellow solid (402mg, yield: 100%) which was used directly in the next step.

MS m/z(ESI):393.2[M+H]⁺

The fifth step: 2- (2, 6-dioxo-3-piperidinyl) -5- [2- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] ethynyl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 2)

Intermediate 1(0.200g,0.608mmol) of 2-chloro-N- [2- (-nitrophenyl) ethyl ] quinazolin-4-amine was weighed, dissolved in 15mL of dimethylsulfoxide in a 100mL single-neck round-bottom flask, followed by the addition of 5- [2- [1- (azetidin-3-yl) azetidin-3-yl ] ethynyl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (2d) (0.402g,1.02mmol) and N, N-diisopropylethylamine (0.786g,6.08mmol), and heated to 80 ℃ for reaction overnight. Adding 45mL of water to quench the reaction, adding ethyl acetate (30mL x 3) to extract, combining organic phases, washing with saturated saline (45mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and separating and purifying the crude product by preparing a liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to obtain 2-

(2, 6-dioxo-3-piperidinyl) -5- [2- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] ethynyl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 2), yellow-white solid (52mg, yield: 8.32%).

¹H NMR(400MHz,DMSO-d₆)δ11.13(s,1H),9.68(t,1H),8.24–8.11(m,3H),7.96–7.80 (m,4H),7.60–7.51(m,3H),7.46(t,1H),5.16(dd,1H),4.57-4.46(m2H),4.36-4.20(m,5H),4.12- 4.01(m,2H),3.95-3.80(m,3H),3.14(t,2H),2.97–2.81(m,1H),2.66–2.51(m,2H),2.13–2.02 (m,1H).

MS m/z(ESI):685.3[M+H]⁺

Example 3:

2- (2, 6-dioxo-3-piperidinyl) -5- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[3-[2-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2- yl]ethynyl]azetidin-1-yl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 3- [2- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidine-1-carboxylic acid tert-butyl ester (3a)

tert-butyl3-[2-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]ethynyl]azetidine-1-carboxylate

2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine intermediate 1(0.3g,0.912mmol) was weighed and dissolved in 15mL of N, N-dimethylformamide in a 50mL single-neck round-bottom flask, followed by the addition of 1a (0.827g,4.56mmol), palladium tetratriphenylphosphine (105mg,0.091mmol), cuprous iodide (35mg,0.183mmol) and triethylamine (0.277g,2.74mmol), and heated to 100 ℃ under nitrogen overnight. Adding 45mL of water, extracting with ethyl acetate (35mL x 3), combining organic phases, washing with 40mL of saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography to obtain 3- [2- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidine-1-carboxylic acid tert-butyl ester (3a), a tan solid (0.346g, yield: 80.07%).

MS m/z(ESI):474.3[M+H]⁺

The second step is that: 2- [2- (azetidin-3-yl) ethynyl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (3b)

2-[2-(azetidin-3-yl)ethynyl]-N-[2-(4-nitrophenyl)ethyl]quinazolin-4-amine

Tert-butyl 3- [2- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidine-1-carboxylate (3a) (0.346g,0.731mmol) was weighed out and dissolved in a 50mL single-neck round-bottom flask with 12mL of dichloromethane, and 6mL of trifluoroacetic acid was added and reacted at room temperature for 3 hours. Concentration under reduced pressure gave the trifluoroacetate salt of 2- [2- (azetidin-3-yl) ethynyl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (3b) as a crude pale yellow solid (0.272mg, yield: 100%) which was used directly in the next step.

MS m/z(ESI):374.2[M+H]⁺

The third step: 2- (2, 6-dioxo-3-piperidinyl) -5- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 3)

2-(2,6-dioxo-3-piperidyl)-5-[3-[2-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2- yl]ethynyl]azetidin-1-yl]isoindoline-1,3-dione；bis-2,2,2-trifluoroacetic acid

The trifluoroacetate salt of 2- [2- (azetidin-3-yl) ethynyl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (3b) (0.272g,0.728mmol) was weighed out and dissolved in 15mL of dimethylsulfoxide in a 100mL single neck round bottom flask, followed by the addition of 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (0.262g,0.947mmol) and N, N-diisopropylethylamine (0.941g,7.28mmol) and heating to 95 ℃ overnight. Adding 45mL of water for quenching reaction, adding ethyl acetate (30mL of x 3) for extraction, combining organic phases, washing with saturated saline solution (45mL), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product, and separating and purifying the crude product by preparing a liquid phase (a mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- (2, 6-dioxo-3-piperidyl) -5- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 3), pale yellow solid (50mg, yield: 7.92%).

¹H NMR(400MHz,DMSO-d₆)δ11.06(s,1H),9.37–9.08(m,1H),8.27(d,1H),8.20–8.10 (m,2H),7.93–7.85(m,1H),7.73–7.60(m,3H),7.60–7.52(m,2H),6.93(d,1H),6.77(dd,1H), 5.08(dd,1H),4.45(t,2H),4.15(t,2H),4.10-4.10(m,1H),3.89(dd,2H),3.15(t,2H),2.96–2.82 (m,1H),2.68–2.51(m,2H),2.12–1.96(m,1H).

MS m/z(ESI):630.0[M+H]⁺

Example 4:

2- (2, 6-dioxo-3-piperidyl) -5- [3- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] nonanidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 4)

2-(2,6-dioxo-3-piperidyl)-5-[3-[3-[2-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2- yl]ethynyl]azetidin-1-yl]azetidin-1-yl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 3- [3- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester (4a)

tert-butyl 3-[3-[2-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]ethynyl]azetidin-1- yl]azetidine-1-carboxylate

2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine intermediate 1(0.3g,0.912mmol) was weighed and dissolved in 15mL of N, N-dimethylformamide in a 50mL single neck round bottom flask, followed by the addition of 2b (1.08g,4.56mmol), palladium tetratriphenylphosphine (105mg,0.091mmol), cuprous iodide (35mg,0.183mmol) and triethylamine (0.277g,2.74mmol), and heated to 100 ℃ under nitrogen overnight. 45mL of water was added, extraction was performed with ethyl acetate (35 mL. times.3), the organic phases were combined, washed with 40mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give tert-butyl 3- [3- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidin-1-yl ] azetidine-1-carboxylate (4a), as a tan solid (0.106g, yield: 21.97%).

MS m/z(ESI):529.3[M+H]⁺

The second step is that: 2- [2- [1- (azetidin-3-yl) azetidin-3-yl ] ethynyl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (4b)

2-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]-N-[2-(4-nitrophenyl)ethyl]quinazolin-4-amine

Tert-butyl 3- [3- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] azetidin-1-yl ] azetidine-1-carboxylate (4a) (0.106g,0.201mmol) was weighed out, dissolved in 12mL of dichloromethane in a 50mL single-neck round-bottom flask, and reacted at room temperature for 3 hours with 6mL of trifluoroacetic acid. Concentration under reduced pressure gave the trifluoroacetate salt of 2- [2- [1- (azetidin-3-yl) azetidin-3-yl ] ethynyl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (4b) as a crude pale yellow solid (0.86mg, yield: 100%) which was used directly in the next step.

The third step: 2- (2, 6-dioxo-3-piperidyl) -5- [3- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] nonanidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 4)

2- [2- [1- (azetidin-3-yl) azetidin-3-yl ] ethynyl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (4b) (0.086g,0.201mmol) was weighed, dissolved in 15mL of dimethylsulfoxide in a 100mL single-neck round-bottom flask, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (0.072g,0.261mmol) and N, N-diisopropylethylamine (0.260g,2.01mmol) were added sequentially and heated to 85 ℃ for reaction overnight. Adding 45mL of water to quench the reaction, adding ethyl acetate (30mL x 3) to extract, combining organic phases, washing with saturated saline (45mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and separating and purifying the crude product by preparing a liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to obtain 2-

(2, 6-dioxo-3-piperidinyl) -5- [3- [3- [2- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] ethynyl ] nonanidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 4), pale yellow solid (63mg, yield: 30.51%).

¹H NMR(400MHz,DMSO-d₆)δ11.07(s,1H),8.94–8.81(m,1H),8.24(d,1H),8.20–8.12 (m,2H),7.89–7.80(m,1H),7.73–7.65(m,2H),7.62–7.51(m,3H),6.90(d,1H),6.75(dd,1H), 5.07(dd,1H),4.51–4.41(m,3H),4.34–4.21(m,4H),4.15-3.98(m,3H),3.84(dd,2H),3.14(t, 2H),2.96–2.81(m,1H),2.65–2.51(m,2H),2.09–1.94(m,1H).

MS m/z(ESI):685.3[M+H]⁺

Example 5:

The first step is as follows: 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (5a)

tert-butyl 4-ethynylpiperidine-1-carboxylate

4-formylpiperidine-1-carboxylic acid tert-butyl ester (10g,46.95mmol) was dissolved in 200mL of methanol in a 500mL single-neck round-bottom flask, cooled to 5-10 ℃ in an ice-water bath, and dimethyl (1-diazo-2-oxopropyl) phosphonate (12.46g, 56.34mmol) and potassium carbonate (25.92,187.8mmol) were added in sequence, the reaction was stirred at room temperature for 3-4 hours, and the reaction was monitored by TLC for completion. Diluting with 200mL of ethyl acetate, suction-filtering with a sand core funnel, washing the filter cake with 100mL of ethyl acetate, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (5a) as colorless oily substance (8.92g, yield: 91%).

MS m/z(ESI):154.2[M-55]⁺

The second step is that: 4- (((4- ((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) ethynyl) piperidine-1-carboxylic acid tert-butyl ester (5b)

tert-butyl4-((4-((4-(methylsulfonamido)phenethyl)amino)quinazolin-2-yl)ethynyl)piperidine-1- carboxylate

Weighing 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (5a) (1.1g,5.42mmol), dissolving in a 100mL single-neck round-bottom flask with 15mL tetrahydrofuran and 3mL DMF, adding N- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (intermediate 2) (1.36g,3.61mmol), palladium (363mg,0.542 mmol) ditriphenylphosphine dichloride, cuprous iodide (104mg,0.42mmol) and triethylamine (2.55g,25.21mmol) in sequence, heating to 75 ℃ under nitrogen atmosphere for reaction overnight, concentrating under reduced pressure to remove tetrahydrofuran, adding 20mL water to the residue, extracting with ethyl acetate (25mL x 2), combining the organic phases, washing with 30mL saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, purifying by silica gel column chromatography to obtain 4- (((4- ((4- (methylsulfonamido) Phenethyl) amino) quinazolin-2-yl) ethynyl) piperidine-1-carboxylic acid tert-butyl ester (5b), a tan solid (1.49g, yield: 75.2%).

Ms m/z(ESI):550.6[M+1]^-

In the third step, N- (4- (2- ((2- (piperidin-4-ylethynyl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (5c)

N-(4-(2-((2-(piperidin-4-ylethynyl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide

Tert-butyl 4- (((4- ((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) ethynyl) piperidine-1-carboxylate (5b) (0.4g,0.73mmol) was added to a 100mL single neck round bottom flask containing 10mL of a 3N HCl ethyl acetate solution, stirred at room temperature for two hours, and concentrated under reduced pressure to give the hydrochloride of N- (4- (2- ((2- (piperidin-4-ylethynyl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (5c) as a pale yellow solid (0.29g, yield: 87.9%).

MS m/z(ESI):450.6[M+1]⁺

Step four N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5-yl ] -4-piperidyl ] ethynyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide trifluoroacetate (compound 5)

N-[4-[2-[[2-[2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4- piperidyl]ethynyl]quinazolin-4-yl]amino]ethyl]phenyl]methanesulfonamide

The hydrochloride salt of N- (4- (2- ((2- (piperidin-4-ylethynyl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (5c) (0.29g,0.65mmol) was weighed out and dissolved in a 100mL single-neck round-bottom flask with 15mL of dimethyl sulfoxide, and 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (synthesis method WO2009145899) (0.36g, 1.3mmol) and N, N-diisopropylethylamine (0.358g,2.77mmol) were added in this order and heated to 90 ℃ for 6 hours. The reaction was quenched with 45mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with saturated brine (45mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was isolated and purified by preparative liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to give N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5-yl ] -4-piperidinyl ] ethynyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide trifluoroacetate (compound 5) as an off-white solid (21mg, yield: 5.49%).

MS m/z(ESI):706.7[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.06(s,1H),9.60(s,1H),8.30(d,1H),7.90(t,1H),7.78– 7.58(m,3H),7.39(d,1H),7.29(dd,1H),7.27–6.95(m,5H),5.07(dd,1H),3.94–3.74(m,3H), 3.44–3.34(m,2H),3.20-3.10(m,1H),2.99–2.53(m,9H),2.12–1.95(m,3H),1.85–1.69(m, 2H).

Example 6

N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidyl) ] -1, 3-dioxoisoindolin-5-yl ] pyrrolidin-3-yl ] ethynyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide; trifluoroacetate salt N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] pyrrolidin-3-yl ] ethyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanolfynamide-trifluoroacetic acid

The first step is as follows: 3-ethynylpyrrolidine-1-carboxylic acid tert-butyl ester (6a)

tert-butyl 3-ethynylpyrrolidine-1-carboxylate

3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (6g,30.15mmol) was dissolved in 200mL of methanol in a 500mL single-neck round-bottom flask, cooled to 5-10 ℃ in an ice-water bath, and dimethyl (1-diazo-2-oxopropyl) phosphonate (8.11g, 36.18mmol) and potassium carbonate (25.92,187.8mmol) were added in sequence, the reaction was stirred at room temperature for 3-4 hours, and the reaction was monitored by TLC for completion. Diluting with 200mL of ethyl acetate, suction-filtering with a sand core funnel, washing the filter cake with 100mL of ethyl acetate, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (6a) as colorless oily substance (5.66g, yield: 96.4%).

MS m/z(ESI):140.2[M-55]⁺

The second step is that: 3- (((4- ((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) ethynyl) pyrrolidine-1-carboxylic acid tert-butyl ester (6b)

tert-butyl3-((4-((4-(methylsulfonamido)phenethyl)amino)quinazolin-2-yl)ethynyl)pyrrolidine-1- carboxylate

Weighing 3-ethynylpyrrolidine-1-carboxylic acid tert-butyl ester (6a) (1.1g,5.64mmol), dissolving in a 100mL single-neck round-bottom flask with 15mL tetrahydrofuran and 3mL DMF, adding N- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (intermediate 2) (1.41g,3.76mmol), palladium (369mg,0.564 mmol), cuprous iodide (104mg,0.42mmol) and triethylamine (2.55g,25.21mmol) in sequence, heating to 75 deg.C under nitrogen atmosphere for reaction overnight, concentrating under reduced pressure to remove tetrahydrofuran, adding 20mL water to the residue, extracting with ethyl acetate (25mL x 2), combining the organic phases, washing with 30mL saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, purifying by silica gel column chromatography to obtain 3- (((4- ((4- (methylsulfonamido) Phenethyl) amino) quinazolin-2-yl) ethynyl) pyrrolidine-1-carboxylic acid tert-butyl ester (6b), a tan solid (1.53g, yield: 76.2%).

Ms m/z(ESI):536.6[M+1]^-

In the third step, N- (4- (2- ((2- (pyrrolidin-3-ylethynyl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (6c)

N-(4-(2-((2-(pyrrolidin-3-ylethynyl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide

Tert-butyl 3- (((4- ((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) ethynyl) pyrrolidine-1-carboxylate (6b) (0.4g,0.75mmol) was added to a 100mL single neck round bottom flask containing 10mL of 3N HCl ethyl acetate solution, stirred at room temperature for two hours, and concentrated under reduced pressure to give N- (4- (2- ((2- (pyrrolidin-3-ylethynyl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (6c) as a pale yellow solid (0.30g, yield: 87.9%).

MS m/z(ESI):436.6[M+1]⁺

A fourth step of N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidyl) ] -1, 3-dioxoisoindolin-5-yl ] pyrrolidin-3-yl ] ethynyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide; trifluoroacetate salt N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] pyrrolidin-3-yl ] ethyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanolfynamide-trifluoroacetic acid

The hydrochloride salt of N- (4- (2- ((2- (pyrrolidin-3-ylethynyl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (6c) (0.30g,0.69mmol) was weighed out and dissolved in 15mL of dimethylsulfoxide in a 100mL single neck round bottom flask, and 5-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (synthesis see WO2009145899) (0.38g, 1.38mmol) and N, N-diisopropylethylamine (0.358g,2.77mmol) were added in this order and heated to 90 ℃ for 6 hours. The reaction was quenched with 45mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with saturated brine (45mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was isolated and purified by preparative liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to give N- [4- [2- [ [2- [2- [1- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxoisoindolin-5-yl ] -4-piperidinyl ] ethynyl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide trifluoroacetate (compound 6) as an off-white solid (18mg, yield: 4.65%).

MS m/z(ESI):692.7[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.05(s,1H),9.60(s,1H),8.28(d,1H),7.87(t,1H),7.73– 7.56(m,3H),7.28–6.96(m,6H),6.91(dd,1H),5.06(dd,1H),3.93–3.50(m,6H),3.01–2.83(m, 7H),2.69–2.54(m,3H),2.30–2.16(m,1H),2.07–1.97(m,1H).

Example 7:

2- (2, 6-dioxo-3-piperidinyl) -5- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[4-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3- yl]piperazin-1-yl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 4- (1-benzyloxycarbonyl azetidin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (7a)

tert-butyl 4-(1-benzyloxycarbonylazetidin-3-yl)piperazine-1-carboxylate

1-Boc-piperazine (10g,53.69mmol) was weighed, dissolved in 200mL of 1, 2-dichloroethane in a 500mL single-neck round-bottom flask, and then benzyl 3-oxaazetidine-1-carboxylate (27.54g,134.22mmol), acetic acid (6.45g,107.38mmol) and 20g of anhydrous sodium sulfate were added in this order, heated to 65 ℃ for reaction for 2 hours, cooled to room temperature, added in portions with sodium triacetoxyborohydride (68.27 g,322.14mmol) and reacted at room temperature overnight. After the completion of the TLC monitoring reaction, 200mL of water was added and the layers were separated. The organic phase was washed with 300mL of a saturated sodium bicarbonate solution, 300mL of water and 300mL of a saturated saline solution in this order once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give tert-butyl 4- (1-benzyloxycarbonyl azetidin-3-yl) piperazine-1-carboxylate (1a) as a colorless oil (17.3g, yield: 85.82%).

MS m/z(ESI):376.2[M+H]⁺

The second step is that: 4- (azetidin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (7b)

tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate

Tert-butyl 4- (1-benzyloxycarbonylazetidin-3-yl) piperazine-1-carboxylate 7a (6g,15.98mmol) was dissolved in a 250mL single-neck round-bottom flask with 100mL of methanol, 1.2g of 10% Pd/C was weighed and added to the reaction, and the reaction was stirred at room temperature for 5 hours under a hydrogen atmosphere after hydrogen substitution. The reaction mixture was filtered with a sand-core funnel, the filter cake was washed with 40mL of methanol, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- (azetidin-3-yl) piperazine-1-carboxylate (7b) as a colorless oily substance (3.5g, yield: 90.8%).

MS m/z(ESI):242.2[M+H]⁺

The third step: 4- [1- [4- [2- [4- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazine-1-carboxylic acid tert-butyl ester (7c)

tert-butyl4-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3-yl]piperazine-1- carboxylate

Tert-butyl 4- (azetidin-3-yl) piperazine-1-carboxylate (7b) (0.1g,0.414mmol) was weighed and dissolved in 10mL of dimethyl sulfoxide in a 100mL single-neck round-bottom flask, and 2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine intermediate 1(0.15g,0.456mmol) and N, N-diisopropylethylamine (0.27g,2.07mmol) were weighed and added to the reaction and heated to 120 ℃ for 10 hours. The reaction was quenched with 30mL of water, extracted with ethyl acetate (3X 25mL), the organic phases were combined, washed once with 45mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, purified by silica gel column chromatography to give tert-butyl 4- [1- [4- [2- [4- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazine-1-carboxylate (1c) as a brown solid (0.18g, yield: 81.9%).

MS m/z(ESI):534.3[M+H]⁺

The fourth step: n- [2- (4-Nitrophenyl) ethyl ] -2- (3-piperazin-1-yl azetidin-1-yl) quinazolin-4-amine (7d)

N-[2-(4-nitrophenyl)ethyl]-2-(3-piperazin-1-ylazetidin-1-yl)quinazolin-4-amine

Tert-butyl 4- [1- [4- [2- [4- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazine-1-carboxylate (7c) (0.181g,0.339mmol) was weighed, dissolved in 10mL of dichloromethane in a 100mL single-neck round-bottom flask, and reacted at room temperature for 2 hours with 5mL of trifluoroacetic acid. The solvent and a part of trifluoroacetic acid were removed by concentration under reduced pressure, the residue was dissolved in 20mL of dichloromethane, saturated aqueous sodium bicarbonate solution and aqueous ammonia were added to adjust pH 9-10, dichloromethane was extracted (2 × 20mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude N- [2- (4-nitrophenyl) ethyl ] -2- (3-piperazin-1-ylazetidin-1-yl) quinazolin-4-amine (7d) as a brown solid (0.15g, yield: 99.3%).

MS m/z(ESI):434.2[M+H]⁺

The fifth step: 2- (2, 6-dioxo-3-piperidinyl) -5- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 7)

N- [2- (4-Nitrophenyl) ethyl ] -2- (3-piperazin-1-ylazetidin-1-yl) quinazolin-4-amine (7d) (0.15g, 0.34mmol) was dissolved in 15mL of dimethylsulfoxide in a 100mL single neck round bottom flask, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (synthetic method see WO2017197056) (0.125g,0.452mmol) and N, N-diisopropylethylamine (0.486g,3.76mmol) were sequentially weighed into the reaction and heated to 90 ℃ for 6 hours. Adding 45mL of water for quenching reaction, extracting with ethyl acetate (30mL of x 3), combining organic phases, washing once with saturated saline solution (45mL), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product, and separating and purifying the crude product by a preparation liquid phase (a mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- (2, 6-dioxo-3-piperidyl) -5- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 7) as a pale yellow solid (78mg, yield: 20.21%).

¹H NMR(400MHz,DMSO-d₆)δ11.07(s,1H),9.64(t,1H),8.24–8.14(m,3H),7.83(t,1H), 7.73(d,1H),7.62–7.53(m,3H),7.50–7.41(m,2H),7.34(dd,1H),5.09(dd,1H),4.53–4.43(m, 2H),4.41–4.31(m,2H),3.93–3.83(m,2H),3.82–3.72(m,1H),3.71–3.54(m,4H),3.16(t,2H), 3.01–2.77(m,5H),2.65–2.52(m,2H),2.10–1.93(m,1H).

MS m/z(ESI):690.3[M+H]⁺

Example 8:

2- (2, 6-dioxo-3-piperidinyl) -5- [7- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonanan-2-yl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[7-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3- yl]-2,7-diazaspiro[3.5]nonan-2-yl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 7- (1-benzyloxycarbonylazetidin-3-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (8a)

tert-butyl 7-(1-benzyloxycarbonylazetidin-3-yl)-2,7-diazaspiro[3.5]nonane-

2-carboxylate

Weighing 2-tert-butoxycarbonyl-2, 7-diazaspiro [3.5] nonane (1g,4.42mmol), dissolving in a 100mL single-neck round-bottom flask with 50mL of 1, 2-dichloroethane, sequentially weighing benzyl 3-oxazetidine-1-carboxylate (2.27g,11.05mmol), acetic acid (531mg,8.84mmol) and 4g anhydrous sodium sulfate, adding to the reaction, heating to 65 ℃ for 2 hours, cooling to room temperature, adding sodium triacetoxyborohydride (5.62g,26.51mmol) in portions, and reacting at room temperature overnight. Adding 40mL of water, layering, washing the organic phase with 30mL of saturated sodium bicarbonate solution, 30mL of water and 30mL of saturated saline solution in sequence, washing once respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to give tert-butyl 7- (1-benzyloxycarbonylazetidin-3-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (8a) as a colorless oil (1.73g, yield: 94.22%).

Ms m/z(ESI):416.3[M+H]⁺

The second step is that: 7- (azetidin-3-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (8b)

tert-butyl 7-(azetidin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Tert-butyl 7- (1-benzyloxycarbonylazetidin-3-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (8a) (1.73g, 4.16mmol) was weighed out, dissolved in 40mL of methanol in a 100mL single-neck round-bottom flask, added with 350mg of palladium on carbon (10 wt%), replaced with hydrogen, and allowed to react overnight at room temperature under a hydrogen atmosphere. Celite filtration, cake washing with 25mL methanol, filtrate under reduced pressure concentration to 7- (azetidin-3-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (8b) crude (1.23 g).

MS m/z(ESI):282.3[M+H]⁺

The third step: 7- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (8c)

tert-butyl 7-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate

2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine intermediate 1(0.15g,0.456mmol) was weighed, dissolved in 15mL of dimethyl sulfoxide in a 100mL single-neck round-bottom flask, followed by the addition of tert-butyl 7- (azetidin-3-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (8b) (0.18g,0.639mmol) and N, N-diisopropylethylamine (0.59g,4.56mmol), and heated to 100 ℃ for overnight reaction. The reaction was quenched with 45mL of water, extracted with ethyl acetate (3X 30mL), the organic phases combined, washed once with 45mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give tert-butyl 7- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonane-2-carboxylate (8c) as a brown solid (0.173g, yield: 66%).

MS m/z(ESI):574.3[M+H]⁺

The fourth step: 2- [3- (2, 7-diazaspiro [3.5] nonanan-7-yl) azetidin-1-yl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (8d)

2-[3-(2,7-diazaspiro[3.5]nonan-7-yl)azetidin-1-yl]-N-[2-(4-nitrophenyl)ethyl]quinazolin-4- amine

Tert-butyl 7- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonane-2-carboxylate (8c) (0.173g,0.302mmol) was weighed out, dissolved in a 100mL single-neck round-bottom flask with 10mL of dichloromethane, 4mL of trifluoroacetic acid was measured and added to the reaction and allowed to react at room temperature for 2 hours. Concentration under reduced pressure gave 2- [3- (2, 7-diazaspiro [3.5] nonanan-7-yl) azetidin-1-yl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (8d) as a crude tan solid (0.142g, yield: 99.4%).

MS m/z(ESI):474.2[M+H]⁺

The fifth step: 2- (2, 6-dioxo-3-piperidinyl) -5- [7- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonanan-2-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 8)

2- [3- (2, 7-diazaspiro [3.5] nonanan-7-yl) azetidin-1-yl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (8d) (0.142g,0.300mmol) was weighed, dissolved in a 100mL single-neck round-bottom flask with 15mL of dimethyl sulfoxide, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (116mg,0.420mmol) and N, N-diisopropylethylamine (390mg,3.02mmol) were weighed and added to the reaction and heated to 95 ℃ for 6 hours. Adding 45mL of water to quench the reaction, adding ethyl acetate (30mL x 3) for extraction, combining organic phases, washing once with saturated saline (45mL), drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product. Separating and purifying the crude product by preparing a liquid phase (a mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- (2, 6-dioxo-3-piperidyl) -5- [7- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonanan-2-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 8), pale yellow solid (46mg, yield: 12.9%).

¹H NMR(400MHz,CD₃OD)δ8.20–8.13(m,2H),8.05(d,1H),7.87–7.79(m,1H),7.65(d, 1H),7.55–7.43(m,4H),6.85(d,1H),6.68(dd,1H),5.06(dd,1H),4.73–4.58(m,4H),4.24–4.13 (m,1H),3.99(t,2H),3.90(s,4H),3.30–3.10(m,6H),2.91–2.63(m,3H),2.30–2.15(m,4H), 2.15–2.04(m,1H).

MS m/z(ESI):730.3[M+H]⁺

Example 9:

2- (2, 6-dioxo-3-piperidinyl) -5- [4- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[4-[1-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin- 3-yl]azetidin-3-yl]piperazin-1-yl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows:

4- [1- (1-benzyloxycarbonyl azetidin-3-yl) azetidin-3-yl ] piperazine-1-carboxylic acid tert-butyl ester (9a)

tert-butyl4-[1-(1-benzyloxycarbonylazetidin-3-yl)azetidin-3-yl]piperazine-1-carboxylate

Tert-butyl 4- (azetidin-3-yl) piperazine-1-carboxylate (7b) (3.5g,14.50mmol) was weighed, dissolved in a 250mL single-neck round-bottom flask with 60mL1, 2-dichloroethane, and 3-oxazetidine-1-carboxylate (7.44g,36.26 mmol), acetic acid (1.74g,29.01mmol) and 7g anhydrous sodium sulfate were sequentially weighed and added to the reaction, heated to 65 ℃ for 2 hours, cooled to room temperature, and sodium triacetoxyborohydride (18.44g,87.02mmol) was weighed and added to the reaction in portions and allowed to react at room temperature overnight. The mixture was separated by adding 80mL of water, and the organic phase was washed once with 80mL of a saturated sodium bicarbonate solution, 80mL of water and 80mL of a saturated saline solution in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated and purified by silica gel column chromatography to give tert-butyl 4- [1- (1-benzyloxycarbonyl azetidin-3-yl) azetidin-3-yl ] piperazine-1-carboxylate (9a) as a white solid (5g, yield: 80.1%).

MS m/z(ESI):431.2[M+H]⁺

The second step is that: 4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazine-1-carboxylic acid tert-butyl ester (9b)

tert-butyl 4-[1-(azetidin-3-yl)azetidin-3-yl]piperazine-1-carboxylate

Tert-butyl 4- [1- (1-benzyloxycarbonylazetidin-3-yl) azetidin-3-yl ] piperazine-1-carboxylate (9a) (0.626g,1.45mmol) was weighed out, dissolved in a 100mL single-neck round-bottom flask with 30mL of methanol, and 130mg of palladium on carbon (10 wt%) was weighed out and added to the reaction, replaced with hydrogen and kept under a hydrogen atmosphere, and reacted at room temperature overnight. After filtration through Celite, the filter cake was washed with 25mL of methanol, and the filtrate was concentrated under reduced pressure to give crude tert-butyl 4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazine-1-carboxylate (9b) as a white solid (0.42g, yield: 97.45%).

MS m/z(ESI):297.2[M+H]⁺

The third step: 4- [1- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazine-1-carboxylic acid tert-butyl ester (9c)

tert-butyl4-[1-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3-yl]azetidin-3- yl]piperazine-1-carboxylate

2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine intermediate 1(0.15g,0.456mmol) was weighed, dissolved in 15mL of dimethyl sulfoxide in a 100mL single-neck round-bottom flask R1, and tert-butyl 4- [1- (azetidin-3-yl) azetidin-3-yl ] piperazine-1-carboxylate (9b) (190mg,0.641mmol) and N, N-diisopropylethylamine (590mg,4.56mmol) were sequentially weighed and added to the reaction and heated to 100 ℃ for reaction overnight. The reaction was quenched with 45mL of water, extracted with ethyl acetate (3X 30mL), the organic phases were combined, washed once with 45mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was isolated and purified by silica gel column chromatography to give tert-butyl 4- [1- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazine-1-carboxylate (9c) as a brown solid (0.14g, yield: 52.12%).

MS m/z(ESI):589.3[M+H]⁺

The fourth step: n- [2- (4-Nitrophenyl) ethyl ] -2- [3- (3-piperazin-1-yl azetidin-1-yl) azetidin-1-yl ] quinazolin-4-amine (9d)

N-[2-(4-nitrophenyl)ethyl]-2-[3-(3-piperazin-1-ylazetidin-1-yl)azetidin-1-yl]quinazolin-4-amine

Tert-butyl 4- [1- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazine-1-carboxylate (9c) (0.14g,0.238mmol) was weighed out, dissolved in a 50mL single-neck round-bottom flask with 7.5mL of dichloromethane, 2.5mL of trifluoroacetic acid was measured and added to the reaction and reacted at room temperature for 3 hours. Concentration under reduced pressure gave crude N- [2- (4-nitrophenyl) ethyl ] -2- [3- (3-piperazin-1-yl azetidin-1-yl) azetidin-1-yl ] quinazolin-4-amine (9d) as a brown solid (0.116g, yield: 100%).

The fifth step: 2- (2, 6-dioxo-3-piperidinyl) -5- [4- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 9)

2-(2,6-dioxo-3-piperidyl)-5-[4-[1-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin- 3-yl]azetidin-3-yl]piperazin-1-yl]isoindoline-1,3-dione；penta-2,2,2-trifluoroacetic acid

N- [2- (4-Nitrophenyl) ethyl ] -2- [3- (3-piperazin-1-yl azetidin-1-yl) azetidin-1-yl ] quinazolin-4-amine (9d) (0.116g,0.237mmol) was weighed, dissolved in 15mL of dimethylsulfoxide in a 100mL single-neck round-bottom flask, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (92mg,0.333mmol) and N, N-diisopropylethylamine (310mg,2.4mmol) were weighed and added to the reaction and heated to 100 ℃ for reaction overnight. The reaction was quenched with 45mL of water, extracted with ethyl acetate (30mL x 3), the organic phases combined, washed once with saturated brine (45mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Separating and purifying the crude product by using a preparation liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- (2, 6-dioxo-3-piperidyl) -5- [4- [1- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 9) as a pale yellow solid (62mg, yield: 19.86%).

¹H NMR(400MHz,CD₃OD)δ8.18–8.11(m,2H),8.08–8.01(m,1H),7.87–7.77(m,1H), 7.69(d,1H),7.55–7.42(m,4H),7.36(d,1H),7.25(dd,1H),5.08(dd,1H),4.62(dd,2H),4.48– 4.32(m,3H),4.31–4.20(m,2H),4.13–4.02(m,2H),3.96(t,2H),3.68–3.51(m,5H),3.18(t, 2H),2.96–2.62(m,7H),2.16–2.07(m,1H).

MS m/z(ESI):745.2[M+H]⁺

Example 10:

2- (2, 6-dioxo-3-piperidinyl) -5- [3- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] azetidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetic acid salt

2-(2,6-dioxo-3-piperidyl)-5-[3-[4-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin- 3-yl]piperazin-1-yl]azetidin-1-yl]isoindoline-1,3-dione；2,2,2-trifluoroacetic acid

The first step is as follows: 3-piperazin-1-yl-azetidine-1-carboxylic acid benzyl ester (10a)

benzyl 3-piperazin-1-ylazetidine-1-carboxylate

Tert-butyl 4- (1-benzyloxycarbonylazetidin-3-yl) piperazine-1-carboxylate (7a) (5.3g,14.12mmol) was weighed out, dissolved in 30mL of dichloromethane in a 100mL single-neck round-bottom flask, and reacted at room temperature for 3 hours with the addition of 10mL of trifluoroacetic acid. Concentration under reduced pressure gave crude benzyl 3-piperazin-1-yl-azetidine-1-carboxylate (10a) as a white solid (3.89g, yield: 100%).

MS m/z(ESI):276.2[M+H]⁺

The second step is that: benzyl 3- [4- (1-tert-butoxycarbonylazetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylate (10b)

benzyl3-[4-(1-tert-butoxycarbonylazetidin-3-yl)piperazin-1-yl]azetidine-1-carboxylate

Benzyl 3-piperazin-1-yl-azetidine-1-carboxylate (10a) (3.89g,14.13mmol) was weighed, dissolved in 80mL of 1, 2-dichloroethane in a 250mL single-neck round-bottom flask, followed by addition of 1-Boc-3-azetidinone (6.05g,35.32mmol), acetic acid (1.70g,28.25mmol) and 7g of anhydrous sodium sulfate, heating to 65 ℃ for 2 hours, cooling to room temperature, and sodium triacetoxyborohydride (17.96g,84.76mmol) was weighed, added in portions, and reacted at room temperature overnight. 80mL of water was added thereto, followed by liquid separation, and the organic phase was washed once with 80mL of a saturated sodium bicarbonate solution, 80mL of water and 80mL of a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography to give benzyl 3- [4- (1-t-butoxycarbonylazetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylate (10b) as a white solid (4.50g, yield: 74.0%).

MS m/z(ESI):431.2[M+H]⁺

The third step: 3- [4- (azetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester (10c)

tert-butyl 3-[4-(azetidin-3-yl)piperazin-1-yl]azetidine-1-carboxylate

Benzyl 3- [4- (1-tert-butoxycarbonylazetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylate (10b) (0.645 g,1.5mmol) was weighed, dissolved in 30mL of methanol in a 100mL single-neck round-bottom flask, and 130mg of palladium on carbon (10 wt%) was added, and reacted under hydrogen atmosphere at room temperature overnight after replacement with hydrogen. After filtration through Celite, the filter cake was washed with 25mL of methanol, and the filtrate was concentrated under reduced pressure to give crude tert-butyl 3- [4- (azetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylate (10c) as a white solid (0.44g, yield: 99%).

MS m/z(ESI):297.3[M+H]⁺

The fourth step: 3- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester (10d)

tert-butyl3-[4-[1-[4-[2-(4-nitrophenyl)ethylamino]quinazolin-2-yl]azetidin-3-yl]piperazin-1- yl]azetidine-1-carboxylate

2-chloro-N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine intermediate 1(0.20g,0.608mmol) was weighed, dissolved in 15mL of dimethyl sulfoxide in a 100mL single-neck round-bottom flask, followed by the addition of tert-butyl 3- [4- (azetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylate (10c) (252mg,0.852mmol) and N, N-diisopropylethylamine (786mg,6.08mmol), and heated to 100 ℃ for reaction overnight. The reaction was quenched with 45mL of water, extracted with ethyl acetate (3 × 30mL), the organic phases combined, washed once with 45mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by means of a silica gel column chromatography to give tert-butyl 3- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] azetidine-1-carboxylate (10d) as a brown solid (0.31g, yield: 86.56%).

MS m/z(ESI):589.4[M+H]⁺

The fifth step: 2- [3- [4- (azetidin-3-yl) piperazin-1-yl ] azetidin-1-yl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (10e)

2-[3-[4-(azetidin-3-yl)piperazin-1-yl]azetidin-1-yl]-N-[2-(4-nitrophenyl)ethyl]quinazolin-4- amine

Tert-butyl 3- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] azetidine-1-carboxylate (10d) (0.31g,0.526mmol) was weighed out, dissolved in a 50mL single-neck round-bottom flask with 15mL of dichloromethane, and reacted at room temperature for 3 hours with 5mL of trifluoroacetic acid. Concentration under reduced pressure gave crude 2- [3- [4- (azetidin-3-yl) piperazin-1-yl ] azetidin-1-yl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (10e) as a brown solid (0.257g, yield: 100%).

MS m/z(ESI):489.4[M+H]⁺

And a sixth step: 2- (2, 6-dioxo-3-piperidinyl) -5- [3- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] azetidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 10)

2- [3- [4- (azetidin-3-yl) piperazin-1-yl ] azetidin-1-yl ] -N- [2- (4-nitrophenyl) ethyl ] quinazolin-4-amine (10e) (0.257g,0.528mmol) was dissolved in 15mL of dimethylsulfoxide in a 100mL single-neck round-bottom flask, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (204mg,0.739mmol) and N, N-diisopropylethylamine (682mg,5.28mmol) were added sequentially and heated to 100 ℃ for reaction overnight. The reaction was quenched with 45mL of water, extracted with ethyl acetate (30mL x 3), the organic phases combined, washed once with saturated brine (45mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Separating and purifying the crude product by preparing a liquid phase (a mobile phase system: acetonitrile/0.1% TFA water) to obtain 2- (2, 6-dioxo-3-piperidyl) -5- [3- [4- [1- [4- [2- (4-nitrophenyl) ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] piperazin-1-yl ] azetidin-1-yl ] isoindoline-1, 3-dione; trifluoroacetate salt (Compound 10), pale yellow solid (110mg, yield: 15.9%).

¹H NMR(400MHz,CD₃OD)δ8.21–8.11(m,2H),8.08–8.00(m,1H),7.85–7.76(m,1H), 7.68(d,1H),7.56–7.40(m,4H),6.91(d,1H),6.75(dd,1H),5.07(dd,1H),4.54–4.43(m,2H), 4.41–4.21(m,6H),4.20–4.08(m,1H),3.98(t,2H),3.80–3.68(m,1H),3.41–3.24(m,4H),3.18 (t,2H),3.08–2.63(m,7H),2.16–2.05(m,1H).

MS m/z(ESI):745.4[M+H]⁺

Example 11:

n- (4- (2- ((2- (4- (2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaisoindolin-5-yl) piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide; 2,2, 2-Trifluoroacetate (Compound 11)

N-(4-(2-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)quinazolin- 4-yl)amino)ethyl)phenyl)methanesulfonamide；2,2,2-trifluoroacic acid

The first step is as follows: 4- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (11a)

tert-butyl4-(4-((4-(methylsulfonamido)phenethyl)amino)quinazolin-2-yl)piperazine-1- carboxylate

Weighing N- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide intermediate 2(0.2g,0.534mmol), dissolving in a 100mL single-neck round-bottom flask with 10mL of N, N-dimethylformamide, sequentially weighing 1-Boc-piperazine (0.15g,0.798mmol) and N, N-diisopropylethylamine (0.21g,1.59mmol), adding into the reaction, heating to 100 ℃ for reaction for 5 hours, adding 30mL of water to quench the reaction, extracting with ethyl acetate (3x 25mL), combining the organic phases, washing with 45mL of saturated saline once, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, purifying by silica gel column chromatography to obtain 4- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (11a), brown solid (0.22g, yield 78.5%).

MS m/z(ESI):527.2[M+H]⁺

The second step is that: n- (4- (2- (((2- (piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (11b)

N-(4-(2-((2-(piperazin-1-yl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide

Weighing tert-butyl 4- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) piperazine-1-carboxylate (11a) (0.22g,0.418mmol), dissolving in a 100mL single-neck round-bottom flask with 10mL of dichloromethane, adding 3mL of trifluoroacetic acid, reacting at room temperature for 2 hours, concentrating under reduced pressure to remove the solvent and part of the trifluoroacetic acid, adding 20mL of dichloromethane to the residue to dissolve, adding saturated aqueous sodium bicarbonate solution and ammonia water to adjust pH to 9-10, extracting with dichloromethane (2x 20mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude N- (4- (2- (((2- (piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (11b), a brown solid (0.16g, yield: 89.8%).

MS m/z(ESI):427.2[M+H]⁺

The third step: n- (4- (2- ((2- (4- (2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaisoindolin-5-yl) piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide; 2,2, 2-Trifluoroacetate (Compound 11)

N-(4-(2-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)quinazolin- 4-yl)amino)ethyl)phenyl)methanesulfonamide；2,2,2-trifluoroacetic acid

Dissolving N- (4- (2- (((2- (piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (11b) (0.16g,0.375mmol) in 15mL of dimethylsulfoxide in a 100mL single-neck round-bottom flask, sequentially weighing 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (0.115g,0.413mmol) and N, N-diisopropylethylamine (0.486g,3.76mmol), adding to the reaction, heating to 90 ℃ for 6 hours, adding 45mL of water to quench the reaction, extracting with ethyl acetate (30mL x 3), combining the organic phases, washing once with saturated brine (45mL), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to give a crude product which was sent to preparation, separating and purifying the prepared liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to obtain N- (4- (2- ((2- (4- (2- (2, 6-dioxapiperidine-3-yl) -1, 3-dioxaisoindoline-5-yl) piperazine-1-yl) quinazoline-4-yl) amino) ethyl) phenyl) methanesulfonamide; 2,2, 2-Trifluoroacetate (Compound 11), pale yellow solid (69mg, yield: 23.15%)

¹H NMR(400MHz,DMSO-d₆)δ11.07(s,1H),9.67-9.54(m,2H),8.22(d,1H),7.83(t,1H), 7.75(d,1H),7.70(d,1H),7.50–7.39(m,2H),7.31(dd,1H),7.28–7.21(m,2H),7.20–7.13(m, 2H),5.09(dd,1H),4.13–3.94(m,4H),3.88-3.79(m,2H),3.79–3.70(m,4H),2.97(t,2H),2.93(s, 3H),2.91–2.82(m,1H),2.65–2.52(m,2H),2.11–1.94(m,1H).

MS m/z(ESI):683.2[M+H]⁺

Example 12:

n- (4- (2- ((2- (4- (1- (2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaisoindol-5-yl) azetidin-3-yl) piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide 2,2, 2-trifluoroacetate (Compound 12)

N-(4-(2-((2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin- 1-yl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide；2,2,2-trifluoroacetic acid

The first step is as follows: benzyl 4- (1- (tert-butoxycarbonyl) azetidin-3-yl) piperazine-1-carboxylate (12a)

benzyl 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate

1-Cbz-piperazine (5g,22.7mmol) was weighed and dissolved in 200mL of 1, 2-dichloroethane in a 500mL single-neck round-bottom flask, followed by addition of 1-Boc-3-oxaazetidinone (9.7g,56.81mmol) and acetic acid (6.45g,107.38mmol), stirring at room temperature for 30min, addition of sodium triacetoxyborohydride (16.8g,79.5mmol), and reaction at room temperature overnight. After the completion of the TLC monitoring reaction, 200mL of water was added and the layers were separated. The organic phase was washed once with 300mL of a saturated sodium bicarbonate solution, 300mL of water and 300mL of a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel to give benzyl 4- (1- (tert-butoxycarbonyl) azetidin-3-yl) piperazine-1-carboxylate (12a) as a colorless oil (6.31g, yield: 74.14%).

MS m/z(ESI):376.2[M+H]⁺

The second step is that: 3- (piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (12b)

tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate

Benzyl 4- (1- (tert-butoxycarbonyl) azetidin-3-yl) piperazine-1-carboxylate (6a) (1.0g,2.67mmol) was dissolved in 10mL of methanol in a 100mL single-neck round-bottom flask, 0.2g of Pd/C (10 wt%) was added, the mixture was replaced with hydrogen, and the reaction was stirred at room temperature for 5 hours while maintaining a hydrogen atmosphere. The reaction mixture was filtered with a sand-core funnel, the filter cake was washed with 40mL of methanol, and the filtrate was concentrated under reduced pressure to give tert-butyl 3- (piperazin-1-yl) azetidine-1-carboxylate (12b) as a colorless oil (0.50g, yield: 77.8%).

MS m/z(ESI):242.2[M+H]⁺

The third step: 3- (4- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (12c)

tert-butyl3-(4-(4-((4-(methylsulfonamido)phenethyl)amino)quinazolin-2-yl)piperazin-1- yl)azetidine-1-carboxylate

Weighing 3- (piperazine-1-yl) azetidine-1-carboxylic acid tert-butyl ester (12b) (0.12g,0.48mmol), dissolving in a 100mL single-neck round-bottom flask with 10mL of dimethyl sulfoxide, sequentially weighing N- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide intermediate 2(0.15g,0.398mmol) and N, N-diisopropylethylamine (0.27g,2.07mmol), adding into the reaction, heating to 100 deg.C, reacting for 10 hr, adding 30mL of water to quench the reaction, extracting with ethyl acetate (3x 25mL), combining organic phases, washing with 45mL of saturated saline solution once, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, purifying by silica gel column chromatography to obtain 3- (4- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) piperazine- 1-yl) azetidine-1-carboxylic acid tert-butyl ester (12c), brown solid (0.172g, yield: 74.5%).

MS m/z(ESI):582.3[M+H]⁺

The fourth step: n- (4- (2- ((2- (4- (azetidin-3-yl) piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (12d)

N-(4-(2-((2-(4-(azetidin-3-yl)piperazin-1-yl)quinazolin-4- yl)amino)ethyl)phenyl)methanesulfonamide

Weighing tert-butyl 3- (4- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) piperazin-1-yl) azetidine-1-carboxylate (12c) (0.172g,0.296mmol), dissolving in 10mL dichloromethane in a 100mL single-neck round-bottom flask, adding 3mL trifluoroacetic acid, reacting at room temperature for 2 hours, concentrating under reduced pressure to remove the solvent and part of the trifluoroacetic acid, dissolving the residue in 20mL dichloromethane, adding saturated aqueous sodium bicarbonate and ammonia water to adjust the pH to 9-10, extracting with dichloromethane (2X 20mL), combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain N- (4- (2- ((2- (3- (4- (azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) quinazolin-1-yl) quinazoline Lin-4-yl) amino) ethyl) phenyl) methanesulfonamide (12d) crude, brown solid (0.131g, yield: 92.3%).

MS m/z(ESI):482.3[M+H]⁺

The fifth step: n- (4- (2- ((2- (4- (1- (2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaisoindol-5-yl) azetidin-3-yl) piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide; trifluoroacetate salt (Compound 12)

N-(4-(2-((2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin- 1-yl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide 2,2,2-trifluoroacetic acid

N- (4- (2- ((2- (3- (4- (azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (12d) (0.131g,0.272mmol) was dissolved in a 100mL single neck round bottom flask with 15mL of dimethyl sulfoxide, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (0.113 g,0.409mmol) and N, N-diisopropylethylamine (0.486g,3.76mmol) were sequentially weighed into the reaction, heated to 90 ℃ and reacted for 6 hours. Adding 45mL of water for quenching reaction, extracting with ethyl acetate (30mL x 3), combining organic phases, washing once with saturated saline solution (45mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, separating and purifying the crude product by using a preparation liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to obtain N- (4- (2- ((2- (4- (1- (2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaisoindolyl-5-yl) azetidin-3-yl) piperazin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide; trifluoroacetate salt (Compound 12), pale yellow solid (81mg, yield: 35.1%)

¹H NMR(400MHz,CD₃OD)δ8.07(d,1H),7.81(t,1H),7.66(d,1H),7.59(d,1H),7.47(t, 1H),7.17(dd,4H),6.89(d,1H),6.73(dd,1H),5.06(dd,1H),4.35–4.26(m,2H),4.20–4.10(m, 2H),4.10–4.00(m,4H),3.96(t,2H),3.92–3.83(m,1H),3.10–2.96(m,6H),2.91(s,3H),2.87– 2.63(m,3H),2.17–2.05(m,1H).

MS m/z(ESI):793.3[M+H]⁺

Example 13:

n- (4- (2- ((2- (3- (4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide, trifluoroacetate (Compound 13)

N-(4-(2-((2-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3- yl)piperazin-1-yl)azetidin-1-yl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide；2,2,2- trifluoroacetic acid

The first step is as follows: 3- (4- (azetidin-3-yl) piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (13a)

tert-butyl 3-(4-(azetidin-3-yl)piperazin-1-yl)azetidine-1-carboxylate

Benzyl 3- [4- (1-tert-butoxycarbonylazetidin-3-yl) piperazin-1-yl ] azetidine-1-carboxylate (10b) (1g, 2.33mmol) was dissolved in 10mL of methanol in a 100mL single-neck round-bottom flask, and 0.2g of Pd/C (10 wt%) was added to the reaction, and the reaction was stirred at room temperature for 5 hours while maintaining a hydrogen atmosphere after hydrogen substitution. The reaction solution was filtered with a sand-core funnel, the filter cake was washed with 40mL of methanol, and the filtrate was concentrated under reduced pressure to give tert-butyl 3- (4- (azetidin-3-yl) piperazin-1-yl) azetidine-1-carboxylate (13a) as a colorless oil (0.54g, yield: 78.3%).

MS m/z(ESI):296.2[M+H]⁺

The second step is that: 3- (4- (1- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) azetidin-3-yl) piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (13b)

tert-butyl3-(4-(1-(4-((4-(methylsulfonamido)phenethyl)amino)quinazolin-2-yl)azetidin-3- yl)piperazin-1-yl)azetidine-1-carboxylate

Weighing 3- (4- (azetidin-3-yl) piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (13a) (0.12g,0.4 mmol) and dissolving in 10mL of dimethyl sulfoxide in a 100mL single-neck round-bottom flask, sequentially weighing N- (4- (2- (((2-chloroquinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide intermediate 2(0.1g,0.27mmol) and N, N-diisopropylethylamine (0.27g,2.07mmol), adding into the reaction, heating to 100 deg.C, reacting for 10 hours, adding 30mL of water to quench the reaction, extracting with ethyl acetate (3 × 25mL), combining the organic phases, washing once with 45mL of saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, purifying by silica gel column chromatography to obtain 3- (4- (1- (4- (((4- (methylsulfonyl) methanesulfonamide) Yl) phenethyl) amino) quinazolin-2-yl) azetidin-3-yl) piperazin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (13b), brown solid (0.158g, yield: 92.4%).

MS m/z(ESI):637.3[M+H]⁺

The third step: n- (4- (2- ((2- (3- (4- (azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (13c)

N-(4-(2-((2-(3-(4-(azetidin-3-yl)piperazin-1-yl)azetidin-1-yl)quinazolin-4- yl)amino)ethyl)phenyl)methanesulfonamide

Weighing tert-butyl 3- (4- (1- (4- (((4- (methylsulfonylamino) phenethyl) amino) quinazolin-2-yl) azetidin-3-yl) piperazin-1-yl) azetidine-1-carboxylate (13b) (0.158g,0.248mmol), dissolving in 10mL dichloromethane in a 100mL single-neck round-bottom flask, adding 3mL trifluoroacetic acid, reacting at room temperature for 2 hours, concentrating under reduced pressure to remove the solvent and part of the trifluoroacetic acid, adding 20mL dichloromethane to the residue to dissolve, adding saturated aqueous sodium bicarbonate solution and ammonia water to adjust the pH to 9-10, extracting with dichloromethane (2x 20mL), combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain N- (4- (2-

Crude ((2- (3- (4- (azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (13) as a brown solid (0.12g, yield: 90.2%).

MS m/z(ESI):537.3[M+H]⁺

The fourth step: n- (4- (2- ((2- (3- (4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide, trifluoroacetate (Compound 13)

N-(4-(2-((2-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3- yl)piperazin-1-yl)azetidin-1-yl)quinazolin-4-yl)amino)ethyl)phenyl)methanesulfonamide 2,2,2- trifluoroacetic acid

N- (4- (2- ((2- (3- (4- (azetidin-3-yl) piperazin-1-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide (13c) (0.12g,0.22mmol) was dissolved in a 100mL single neck round bottom flask with 15mL of dimethyl sulfoxide, and 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (0.093 g,0.34mmol) and N, N-diisopropylethylamine (0.486g,3.76mmol) were sequentially weighed into the reaction, heated to 90 ℃ and reacted for 6 hours. The reaction was quenched with 45mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases combined, washed once with saturated brine (45mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product which was isolated and purified by preparative liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to give N- (4- (2- ((2- (3- (4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-1-yl) quinazolin-4-yl) amino) ethyl) phenyl) methanesulfonamide, trifluoroacetate (compound 13), pale yellow solid (53mg, yield: 26.6%)

¹H NMR(400MHz,CD₃OD)δ8.09–8.01(m,1H),7.84–7.75(m,1H),7.69(d,1H),7.53– 7.39(m,2H),7.26–7.11(m,4H),6.92(d,1H),6.76(dd,1H),5.07(dd,1H),4.51–4.32(m,4H), 4.31–4.20(m,4H),4.19-4.10(m,1H),4.01–3.87(m,2H),3.78–3.66(m,1H),3.42–3.20(m, 4H),3.09–2.62(m,12H),2.15–2.05(m,1H).

MS m/z(ESI):793.3[M+H]⁺

Example 14:

n- [4- [2- [ [2- [3- [2- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5-yl ] -2, 7-diazaspiro [3.5] nonyl-7-yl ] azetidin-1-yl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide; trifluoroacetic acid salt

N-[4-[2-[[2-[3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,7- diazaspiro[3.5]nonan-7-yl]azetidin-1-yl]quinazolin-4-yl]amino]ethyl]phenyl]methanesulfonamide； 2,2,2-trifluoroacetic acid

The first step is as follows:

7- [1- [1- [4- [2- [4- (methanesulfonamido) phenyl ] ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester (14a)

tert-butyl 7-[1-[4-[2-[4-(methanesulfonamido)phenyl]ethylamino]quinazolin-2-yl]azetidin-3- yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

Intermediate 2(0.30g,0.796mmol) was weighed, dissolved in 10mL of dimethyl sulfoxide in a 50mL single neck round bottom flask, added sequentially with 8b (0.336g,1.19mmol) and N, N-diisopropylethylamine (0.514g,3.98mmol), and heated to 100 ℃ for reaction overnight. TLC monitored the reaction was complete, and 45mL water was added to quench the reaction, ethyl acetate extraction (3X 30mL) was performed, the organic phases were combined, washed once with 45mL saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel to give tert-butyl 7- [1- [1- [4- [2- [4- (methanesulfonamido) phenyl ] ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonane-2-carboxylate (14a), as brown solid (286mg, yield: 57.78%).

MS m/z(ESI):622.4[M+H]⁺

The second step is that: n- [4- [2- [ [2- [3- (2, 7-diazaspiro [3.5] nonan-7-yl ] azetidin-1-yl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide (14b)

N-[4-[2-[[2-[3-(2,7-diazaspiro[3.5]nonan-7-yl)azetidin-1-yl]quinazolin-4- yl]amino]ethyl]phenyl]methanesulfonamide

Tert-butyl 7- [1- [1- [4- [2- [4- (methanesulfonamido) phenyl ] ethylamino ] quinazolin-2-yl ] azetidin-3-yl ] -2, 7-diazaspiro [3.5] nonane-2-carboxylate (14a) (0.286g,0.460mmol) was weighed out, dissolved in a 50mL single-neck round-bottom flask with 15mL of dichloromethane, and reacted at room temperature for 3 hours with 5mL of trifluoroacetic acid. Sampling and detecting by TLC. TLC showed complete consumption of starting material. Vacuum concentrating to obtain crude N- [4- [2- [ [2- [3- (2, 7-diazaspiro [3.5] nonanan-7-yl ] azetidin-1-yl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide (14b), and brown solid (0.24g, yield: 100%) directly used in the next step.

The third step: n- [4- [2- [ [2- [3- [2- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxoisoindolin-5-yl ] -2, 7-diazaspiro [3.5] nonyl-7-yl ] azetidin-1-yl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide; trifluoroacetate salt (Compound 14)

N- [4- [2- [ [2- [3- (2, 7-diazaspiro [3.5] nonanan-7-yl ] azetidin-1-yl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide (14b) (0.24g,0.460mmol) was weighed out and dissolved in 10mL of dimethylsulfoxide in a 50mL single neck round bottom flask, 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (0.191g,0.690mmol) and N, N-diisopropylethylamine (0.594g,4.60mmol) were added in this order, heated to 100 ℃ overnight, quenched with 45mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed once with saturated brine (45mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and separating and purifying by preparing liquid phase (mobile phase system: acetonitrile/0.1% TFA water) to obtain N- [4- [2- [ [2- [3- [2- [2- (2, 6-dioxo-3-piperidyl) -1,3-dioxo-isoindolin-5-yl ] -2, 7-diazaspiro [3.5] nonyl-7-yl ] azetidin-1-yl ] quinazolin-4-yl ] amino ] ethyl ] phenyl ] methanesulfonamide; trifluoroacetate salt (Compound 14) as a pale yellow solid (85mg, yield: 14.97%).

¹H NMR(400MHz,DMSO-d₆)δ11.06(s,1H),9.74–9.59(m,2H),8.24(d,1H),7.84(t,1H), 7.68(d,1H),7.58(d,1H),7.47(t,1H),7.29–7.10(m,4H),6.78(d,1H),6.67(dd,1H),5.06(dd, 1H),4.68–4.40(m,4H),4.22–4.02(m,1H),3.87(s,4H),3.82-3.70(m,2H),3.66–3.32(m,4H), 3.00–2.91(m,5H),2.93-2.80(m,1H),2.65-2.50(m,2H),2.23–1.83(m,5H).

MS m/z(ESI):778.3[M+H]⁺

Biological test example

1. Cell proliferation inhibition assay

Prostate cancer cells LNCaP and PC3, both purchased from ATCC, wherein the LNCaP cell culture medium is RPMI 1640+ 10% FBS, the PC3 cell culture medium is F12K + 10% FBS, cultured at 37 deg.C, 5% CO₂An incubator. Cells in exponential growth phase were collected on the first day and the cell suspension was plated with medium at the corresponding concentrations to 3000/135. mu.L LNCaP cells and 5000/135. mu.L PC3 cells, and 135. mu.L cell suspension was added to 96-well cell culture plates per well and incubated overnight. Simultaneous paving of planks₀Wells, 1 column per cell, 5% CO at 37 ℃₂Incubate overnight. The next day 15. mu.L of different concentrations of compounds were added and cultured in incubators, 3 days for LNCaP cells and 5 days for PC3 cells. Detection of T by using CellTiter-Glo kit while adding medicine₀Plate, denoted as RLU₀. After the culture, 75. mu.L of CTG solution which is melted in advance and equilibrated to room temperature was added to each well according to the instructions of CellTiter-Glo kit (Promega, G7573), mixed by a microplate shaker for 2 minutes, left at room temperature for 10 minutes, and then measured for the fluorescence signal value by a microplate reader (PHERAStar FSX). As a result, the inhibition rate of each concentration of the compound was calculated by treating the compound according to the formula (1), and the concentration GI of the compound at a proliferation rate of 50% was calculated using origin9.2 software₅₀The value is obtained. Wherein RLU_compoundFor the drug treatment group readings, RLU_controlMean values for the solvent control group.

Growth％＝(RLU_compound-RLU₀)/(RLU_control-RLU₀)×100

TABLE 1 IC for inhibition of LNCaP cell proliferation₅₀Value of

Serial number	Compound numbering	IC₅₀(μM)
			1	Compound 3	0.265
2	Compound 4	0.406
			3	Compound 9	1.178
4	Compound 10	0.605

And (4) conclusion: the compound synthesized by the technology has good proliferation inhibition activity on prostate cancer cells LNCaP or PC 3.

Claims

1. A compound or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from a compound shown in a general formula (I),

B-L-K (I)

l is selected from

Or L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy 3-or-Cy 1-Cy2-Cy3-Cy 4-;

G₁、G₂cy1, Cy2, Cy3, Cy4 are each independently selected from 4-7 membered heteromonocyclic ring, 5-10 membered heterobicyclic ring, 6-12 membered heteromonocyclic ring, 7-10 membered heterobridged ring, 4-7 membered monocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, 6-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, bridged cycloalkyl, heteromonocyclic ring, heterobicyclic ring, heterospirocyclic ring or heterobridged ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH, OH, COOH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

b is selected from

d is selected from a bond,

Each X is independently selected from CR^b3Or N;

R^b1each independently selected from H, F, Cl, Br, I, OH, NH₂、NO₂、NO、CN、COOH、C(O)NH₂、-S(O)₂NH₂、-NHS(O)₂R^C1、-N(OH)S(O)₂C_1-4Alkyl radical, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further selected from H, F, Cl, Br, I, OH, C by 0 to 4_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R^b2each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、COOH、C(O)NH₂、C(O)NHNH₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) -C_1-4Alkyl, 6-10 membered aryl, 3-7 membered cycloalkyl or 4-7 membered heterocyclyl, said alkyl, alkoxy, aryl, cycloalkyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH or C (O) NH₂Said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;

R^b5each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NH-C_1-4Alkyl, -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) C_1-4Alkyl, -C (O) OC_1-4Alkyl, -C (O) NHC_1-4Alkyl or-C (O) N (C)_1-4Alkyl radical)₂Said alkyl or alkoxy is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH or NH₂Substituted with the substituent(s);

k is selected from

R^k2each independently selected from CH₂、C＝O、S＝O、SO₂；

R^k5is selected from C ═ O or

p1 or p2 are each independently selected from 0, 1,2, 3 or 4;

m1 or m2 are each independently selected from 1,2 or 3;

each n1 is independently selected from 0, 1,2, 3, 4 or 5;

n2, n3 or n5 are each independently selected from 0, 1,2 or 3.

2. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

G₁、G₂Cy1, Cy2, Cy3 or Cy4 are each independently selected from 4-7 membered azamonocyclic ring, 4-7 membered monocycloalkyl, 5-10 membered azabicyclic ring, 7-10 membered azabridged ring or 6-12 membered azaspiro ring, said monocycloalkyl, heteromonocyclic, heterobridged ring or heterospiro ring being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, COOH, CN, NH₂、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Alkoxy, said hetero-monocyclic, hetero-fused ring, hetero-spiro ring or hetero-bridged ring containing 1 to 4 heteroatoms selected from O, S, N;

k is selected from

3. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

G₁、G₂Cy1, Cy2, Cy3 or Cy4 are each independently selected from one of the following substituted or unsubstituted groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidine, morpholine, piperazine, cyclopropyloazetidinyl, cyclobutyloazetidinyl, cyclopentaietitidinyl, cyclopentaieticanyl, cyclohexyloazetidinyl, azetidinyl, azetidinoazetidinyl, azetidinyl, azetidinoheteroazetidinyl, azetidinyl, azetidinoazetidinyl, azetidinyl, cyclopentaizetidinyl, azetidinyl, cyclopentaizacetyl, azetidinyl, morpholinoazetidinyl, and azetidinyl, Azacyclopentylpiperidine, azacyclohexenyl-azetidinyl, azacyclohexenyl-cyclopentyl, azacyclohexenyl-cyclohexyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclobutyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl, and the like, Cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azaCyclobutyl spiropiperidines, aziridinyl spiropiperidines, azethylspiropiperidines, N-acetylspiropiperidines, N,

When substituted, is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH₂、COOH、CN、oxo、C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

d is selected from a bond,

Each X is independently selected from CR^b3Or N;

R^b2each independently selected from H, F, Cl, Br, I, OH,NH₂、CN、COOH、C(O)NH₂、C(O)NHNH₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -C (O) CH₃、-C(O)CH₂CH₃Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl groups being optionally further selected from H, F, Cl, Br, I, OH, COOH or C (O) NH by 0 to 4₂Substituted with the substituent(s);

R^b3each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NHCH₃、-NHCH₂CH₃Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy being optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

R^b5each independently selected from H, F, Cl, Br, I, OH, NH₂、CN、C(O)NH₂、COOH、-NHCH₃、-NHCH₂CH₃、-N(CH₃)₂、-N(CH₂CH₃)₂Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy, -C (O) CH₃、-C(O)CH₂CH₃、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)NHCH₃、-C(O)NHCH₂CH₃、-C(O)NHCH₃or-C (O) N (CH)₂CH₃)₂Said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyloxy group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH or NH₂Substituted with the substituent(s);

k is selected from

R^k2Each independently selected from CH₂Or C ═ O;

p1 or p2 are each independently selected from 0, 1 or 2.

4. The compound of claim 3, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

k is selected from

B is selected from

5. The compound of claim 4, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected with B;

or L is selected from

Wherein the left side is connected to B.

6. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

K is selected from

7. The compound of claim 6, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

K is selected from

8. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:

9. the compound according to any one of claims 1 to 8, or a stereoisomer, deuterode, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the salt is selected from trifluoroacetate.

10. A pharmaceutical composition comprising a compound of any one of claims 1-9, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

11. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with STAT3 activity or expression.

12. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with inhibition or degradation of STAT 3.

13. The use according to any one of claims 11 to 12, wherein the disease is selected from the group consisting of a tumor and cancer.

14. The use of claim 13, wherein the tumor or cancer is selected from brain tumor, lymphatic system tumor, ovarian cancer, endometrial cancer, cervical cancer, breast cancer, bladder cancer, prostate cancer, gastric cancer, colon cancer, laryngeal cancer, nasopharyngeal cancer, liver cancer, skin cancer, bone cancer, blood cancer, head and neck squamous cell carcinoma, glioma, melanoma, leukemia, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma, pancreatic cancer, liver cancer, skin cancer, or epithelial cell cancer.