TW202336013A - Sos1 degradation agent, and preparation method and application thereof - Google Patents

Abstract

The invention discloses an SOS1 degrading agent, a preparation method and application thereof. Specifically, the present invention discloses a compound of formula I: S-L-E(I); wherein L is a linking chain, which connects S and E through a covalent bond; E is a small molecule ligand of E3 ubiquitin ligase complex. The compounds of formula I of the present invention can degrade and/or inhibit SOS1 protein in cells, and can be used for the treatment and/or prevention of related diseases or disorders mediated by SOS1 or caused by the interaction of SOS1 and Ras or SOS1 and Rac.

Description

SOS1 Degradation agent and its preparation method and application

The present invention belongs to the field of medical technology. Specifically, the present invention relates to a SOS1 degradation agent, its preparation method and its application as a therapeutic agent for preventing and/or treating cancer.

This application claims the priority of Chinese patent application 2022102017001 with a filing date of 2022/3/2, and the priority of Chinese patent application 2022104313828 with a filing date of 2022/4/22. This application cites the full text of the above-mentioned Chinese patent application.

SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells. As a key protein in signaling pathways, SOS1 plays an important regulatory role in many signal transduction pathways in cells, such as participating in the regulation of Ras and Rac signaling pathway. SOS1 is composed of 1333 amino acids and contains a proline-rich domain (PxxP) at its C-terminus, which can interact with growth factor receptor-bound protein 2 (growth factor receptor-bound protein) in the Ras pathway. 2, Grb2) combine to form a complex of Grb2 and SOS1, thereby bringing SOS1 to the cell membrane near the Ras protein. SOS1 catalyzes the combination of Ras and GTP, promotes the activation of Ras, and then activates multiple downstream signaling pathways, such as Ras-Raf -Mek-Erk, Ras-PI3K-AKT-mTOR. PxxP can also combine with the SH3 (Src homology 3) domain of E3B1 and other proteins in the Rac pathway to form an EPS8-E3B1-SOS1 complex. The EPS8-E3B1-SOS1 complex connects to actin filaments through EPS8, causing GTP conversion, thereby activating Rac, and subsequently activating signaling pathways such as JNK and MAPK.

The Ras mutated gene is considered to be a major oncogene with a high incidence of human cancer. Studies have shown that 20-30% of tumor patients have Ras mutations, of which KRas mutations account for 85%, NRas and HRas account for 12% each. and 3%. However, due to the picomole affinity of GTP for its binding site and the smooth surface of Ras protein, which lacks other suitable binding pockets, it is considered extremely challenging to directly act on Ras to inhibit its activity.

Abnormal expression or mutation of SOS1 is also closely related to the occurrence of clinical diseases. Studies have shown that SOS1 mutations exist in patients with NS and CFC. HGF1 is a rare autosomal dominant disease, and its cause is also related to mutations in the PxxP domain of SOS1. In addition, abnormal expression or mutations of SOS1 are associated with cancer. The occurrence is also related.

WO2018172250A1, WO2020173935A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, WO2019122129A1 and EP3558979A1 disclose several types of SOS1 inhibitors, but so far, there are no relevant reports on SOS1 degrading agents. Proteolysis Targeting Chimeria (PROTAC) is a technology that is different from traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity, while PROTAC is a heterogeneous A bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein, through the connecting chain, and the other end is an E3 ubiquitin ligase ligand that can recognize the E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein in the body and E3 ubiquitin ligase, bringing the target protein and E3 ubiquitin ligase closer to form a ternary complex. After ubiquitinating the target protein, the target protein is degraded through the ubiquitin-proteasome pathway in the body. Compared with traditional small molecule inhibitors, PROTAC only needs to bring the target protein closer to the E3 ubiquitin ligase to degrade the substrate. This mode of action allows this technology to be applied to some undruggable targets; on the other hand, PROTAC only needs to bring the target protein closer to the E3 ubiquitin ligase to degrade the substrate. On the other hand, after the target protein is degraded, PROTAC molecules can be released to continue to participate in the degradation process of the next protein. Therefore, this catalytic degradation effect allows efficient degradation to be achieved with a smaller dose of PROTAC drugs; On the one hand, traditional small molecule inhibitors are prone to drug resistance, often due to point mutations that cause the small molecule inhibitor to lose its inhibitory effect on the target. PROTAC can directly degrade the target protein and can, to a certain extent, By avoiding resistance caused by point mutations. Therefore, compared with traditional small molecule inhibitors, using PROTAC technology to develop new small molecule drugs has high advantages and feasibility.

The invention provides compounds of formula I, and/or their stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or their pharmaceutically acceptable of salt S-L-E Ⅰ in: S is a small molecule compound that can inhibit the activity of SOS1 protein or bind to SOS1 protein; L is the connecting chain, which connects S and E through covalent bonds; E is a small molecule ligand of the E3 ubiquitin ligase complex.

The invention provides compounds of formula I, and/or their stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or their pharmaceutically acceptable of salt S-L-E Ⅰ S, L and E are as defined below.

Preferably, in certain embodiments of the present invention, S is S1: S1 wherein in S1: R ₁ is selected from hydrogen, halogen, -OH, -CN, -NO ₂ , C ₁ -C ₆ alkyl mercapto or -NR _a R _b , and the R _a and R _b are each independent is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ heterocycloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ - C ₈ cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl, -COOH, -COOR _c ; the R _c is -C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₈ ring Alkyl or -C ₄ -C ₈ cycloalkenyl; R ₁ is -NS(O)(R _d )(R _e ), and R _d and R _e are each independently C ₁ -C ₆ alkyl, C _{R 1 _ _ _ _ _ _ _} is -NHC(O)-(C ₁ -C ₆ alkyl), -NHC(O)-NR _a R _b , and the R _a and R _b are each independently hydrogen, -C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -NH-(CH ₂ ) _k -NH-C(O)-R _aa , and R _aa is C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl (for example, R _aa is C ₁ -C ₆ alkyl), and k is 1 or 2; R ₁ is -NH -(CH ₂ ) _i -R _f , i is 0, 1 or 2 and R _f is 4-7 membered heterocycloalkyl, heteroaryl, C ₁ -C ₆ alkylsulfonyl group; in addition, the above The C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, 4-7 membered heterocycloalkyl group and heteroaryl group are optionally selected from halogen, -OH, oxygen by 1, 2 or 3 Generation, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, 4-7 membered heterocycloalkyl , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylsulfonyl, phenyl, benzyl, heteroaryl, -( CH ₂ )-Heteroaryl, -NHC(O)(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkoxy, phenoxy, heteroaryloxy or -NR _a R _b group substitution; the R _a and R _b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -O- (CH ₂ ) _z -phenyl, -O-(CH ₂ ) _z - (4-7 membered heterocycloalkyl), -O-(CH ₂ ) _z -heteroaryl, z is 0, 1 or 2. The phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted by -OH, heterocycloalkyl or heterocycloalkenyl, and can be substituted by methyl or oxo group; or R ₁ is , , , , , , , , , , , , or , or two adjacent R _1s together with their respective connected carbon atoms form a 5-7-membered cycloalkyl group or a 5-7-membered heterocycloalkyl group; and the x is 1, 2 or 3; A ₁ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl (such as phenyl) or heteroaryl (such as thienyl); R ₂ is hydrogen, -OH, oxo, halogen, -CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₃ -C ₈ cycloalkoxy, -C ₃ -C ₈ halocycloalkoxy, -C ₄ -C ₈ cycloalkenyl, 4-7 membered heterocycloalkyl, -O-CH ₂ -4-7 membered heterocycloalkyl, 5-10 Metaheterocyclic alkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ alkylsulfonyl group; R ₂ is -NR _a R _b , and R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl or -C(O)C ₁ - C ₃ alkyl; R ₂ is -C(O)NR _a R _b , and R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is -C(O)OR _g , and the R _g is hydrogen or C ₁ -C ₆ alkyl; R ₂ is -OR _h ; the R _h is C ₁ -C ₆ alkyl; R ₂ is -(CH ₂ ) NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ - C ₈ cycloalkyl; and w is 1, 2, 3 or 4 (for example, said w is 1, 2 or 3); said A ₂ (R ₃ ) _Y is hydrogen; or A ₂ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl (such as phenyl) or heteroaryl, and R ₃ is hydrogen, halogen, -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₇ -C ₈ cycloalkynyl, 4-7 membered heterocycle Alkyl, 5-10 membered heterocyclic alkenyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, Heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally selected by 1, 2 or 3 from halogen, -OH, oxo, -CN, -C ₁ -C ₆ alkyl, Substituted with -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ haloalkyl, phenyl, heteroaryl or -C(O)NR _i R _j , where R _i and R _j are each independent is hydrogen or C ₁ -C ₆ alkyl; or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl The base is optionally substituted by _-NRkRl , and the _Rk and _Rl are each independently hydrogen _, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylsulfonyl, phenyl, heteroaryl, -CH ₂ -C(O)-R _m , -C(O)R _p or 4-7 yuan Heterocycloalkyl, and each of the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl groups is independently optionally selected from 1, 2 or 3 C ₁ -C ₆ haloalkyl, -OH, oxo, phenyl, -CN, C ₁ -C ₆ alkoxy or heteroaryl substituted, and the heteroaryl is optionally substituted by methyl; and the R _m is a bicyclic heteroaryl group, C ₁ -C ₆ alkoxy group or -NR _n R _o , and the R _n and R _o are each independently hydrogen, a C ₁ -C ₆ alkyl group or a phenyl group, and the alkyl group The base is optionally substituted by C ₁ -C ₆ alkoxy or phenyl, or -NR _n R _o is a 4-7 membered azacycloalkyl group, and the azacycloalkyl group is connected to other parts of the molecule through N atoms, and It also contains 1 or more heteroatoms selected from N or O; the R _p is selected from C ₁ -C ₆ alkoxy, optionally 1, 2 or 3 selected from -OH or C ₁ - C ₆ alkoxy substituted C ₁ -C ₆ alkyl, monocyclic or bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R _p is -CH ₂ -NR _q R _r , the R _q and R _r is each independently selected from hydrogen, phenyl or C ₁ -C ₆ alkyl optionally substituted by F; or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl _, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by -NR _s R _t , which is a 4-7 membered nitrogen heterocycle connected to other parts of _the molecule through a nitrogen atom The alkyl group or the 6-10 membered nitrogen spirocycloalkyl group connected to other parts of the molecule through the nitrogen atom, and further includes up to two heteroatoms selected from N or O, and optionally 1, 2 or 3 Substituted with a substituent selected from -OH, oxo group, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR _z , where R _z is C ₁ -C ₆ alkyl base, halogen, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ N(C ₁ -C ₆ alkyl) ₂ , -C(O)NR _a R _b , each of the R _a and R _b Independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; or R ₃ is C(O)R _v , -C(O)NH ₂ , -C(O)NHR _v , -C(O)NR _v R _w , -C(O)OR _v , the R _v and R _w are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, phenyl or -(CH ₂ ) ₂ NR _x R _y , the R _x and R _y are each independently hydrogen, C ₁ -C ₄ alkyl or -(CH ₂ ) ₂ N(CH ₃ ) ₂ ; or R ₃ is -NH ₂ , -NHR _z , -NR _z R _za , -NHC(O)R _z , -NHC(O)OR _z , -NHS(O) ₂ R _z , 4-7 Yuanheterocycloalkyl, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, the R _z and R _za are each independently C ₁ -C ₄ alkyl, C ₁ - C ₄ haloalkyl or phenyl; or R ₃ is C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, -O(CH ₂ ) _s -C ₃ -C ₈ cycloalkyl, -O( CH ₂ ) _s -phenyl, -O(CH ₂ ) _s -heterocycloalkyl, -O(CH ₂ ) _s -heteroaryl, the s is 0, 1, 2 or 3; or R ₃ is - S(O) ₂ R _z , -S(O) ₂ NH ₂ , -S(O) ₂ NHR _z , -S(O) ₂ NR _z R _za , the R _z and R _za are each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl; Y is 0, 1, 2, 3, 4 or 5 (for example, Y is 0, 1, 2 or 3); L' is a bond, - (CH ₂ ) _k -, -O(CH ₂ ) _k -, -(CH ₂ ) _k -O- or -O-(CH ₂ ) _k -O- (for example, L' is a bond, -(CH ₂ ) _k - or -O(CH ₂ ) _k -), the k is 0, 1, 2 or 3, or L' is -CH=CH-(CH ₂ ) _n -, the n is 0, 1 or 2 ; R ₄ and R ₅ are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkoxy, the alkyl group , alkoxy, cycloalkyl and cycloalkoxy are optionally replaced by cyano, hydroxyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or Halogen substitution.

Preferably, in certain embodiments of the present invention, R ₄ and R ₅ in S1 are each independently methyl.

In some embodiments, in the definition of each group of S1, the R _a and R _b appearing at any place are each independently hydrogen or C ₁ -C ₆ alkyl.

In some embodiments, in the definition of each group of S1, the R _d and R _e appearing at any place are each independently hydrogen or C ₁ -C ₆ alkyl.

In certain embodiments of the present invention, in S1, R ₅ is a C ₁ -C ₆ alkyl group, such as methyl.

In certain embodiments of the present invention, in S1, R ₄ is a C ₁ -C ₆ alkyl group, such as methyl.

In certain embodiments of the present invention, in S1, R ₁ is hydrogen or C ₁ -C ₆ alkoxy.

In certain embodiments of the present invention, in S1, A ₁ is an aryl group or a heteroaryl group.

In certain embodiments of the present invention, in S1, A ₁ is an aryl group, such as phenyl.

In certain embodiments of the present invention, in S1, A ₁ is heteroaryl, such as thienyl.

In certain embodiments of the present invention, in S1, R ₂ is hydrogen, halogen, C ₁ -C ₆ alkyl or -C ₁ -C ₆ haloalkyl.

In some embodiments of the present invention, in S1, L' is a bond.

In certain embodiments of the present invention, in S1, A ₂ (R ₃ ) _Y is hydrogen.

In certain embodiments of the present invention, in S1, A ₂ is an aryl group, such as phenyl.

In certain embodiments of the present invention, in the S1, R ₃ is hydrogen, halogen or C ₁ -C ₆ alkyl, and the alkyl is optionally substituted by -NR _k R ₁ ; each of the R _k and R ₁ Independently hydrogen or C ₁ -C ₆ alkyl. In certain embodiments of the present invention, in the S7, R ₃ is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl groups are replaced by -NR _k R ₁ ; the R _k is methyl Or ethyl, R _l is hydrogen, methyl or ethyl.

In certain embodiments of the present invention, in S1, R ₃ is hydrogen, Cl, -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ .

In some embodiments of the present invention, in S1, A ₁ is an aryl group, L' is a bond, and A ₂ (R ₃ ) _Y is hydrogen.

In some embodiments of the present invention, in S1, A ₁ is a heteroaryl group, L' is a bond, A ₂ is an aryl group, R ₃ is hydrogen, halogen or C ₁ -C ₆ alkyl group, and the alkyl group Optionally substituted by _-NRkRl ; the _Rk and _Rl are each independently hydrogen or C ₁ -C ₆ alkyl _.

In some embodiments of the present invention, the S is S1': S1' wherein, in S1', R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , L', A ₁ , A ₂ , w, x and Y are defined as described in S1.

In some embodiments of the present invention, the S is S1'': S1'' wherein, in S1'', the definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , L', A ₁ , A ₂ , w and Y are as described in S1.

In certain embodiments of the present invention, in S1' or S1'', R ₁ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy is optionally substituted by C ₁ -C ₆ alkoxy (eg methoxy).

In certain embodiments of the present invention, in S1' or S1'', R ₁ is hydrogen, methyl, methoxy or .

In some embodiments of the present invention, among S1 and S1', The fragment is .

In certain embodiments of the present invention, the S is -X-S1', and the structure of S1' is as described above; X is O, NH or S, preferably O.

In certain embodiments of the present invention, the S is -X-S1'', and the structure of S1'' is as described above; X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S is S1a S1a wherein in S1a: R ₁ is selected from hydrogen, -OCH ₃ , -OCH ₂ CH ₃ , , -CH ₂ OH, -C(O)OH, -C(O)OCH ₃ , -Br, -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ CH(CH ₃ ) ₂ , -O(CH ₂ ) ₃ CH ₃ , -O(CH ₂ ) ₂ OCH ₃ , , -O(CH ₂ )-phenyl, -N=S(O)(CH ₃ ) ₂ , -CH ₃ , cyclopropyl, -N(CH ₃ ) ₂ , -NHCH ₃ , -NH ₂ , , , , , , , -C(CH ₃ ) ₂ -OH, , , -NH(CH ₂ )-NH-C(O)CH ₃ , -NH(CH ₂ )-morpholine, -NH-C(O)CH ₃ , -NH-C(O)NHCH ₃ , -NH- C(O)-N(CH ₃ ) ₂ , nitro group, -NH-S(O) ₂ CH ₃ , -N=S(O)(CH ₃ ) ₂ , hydroxyl group, -O-(CH ₂ ) ₂ - S(O) ₂ CH ₃ ,-F, , , , , , , , , , , , , , , , cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azetidinyl, piperidinyl, piperazyl, oxetane, oxygen Thietanyl, oxetanyl, thietanyl, thietanyl, thietanyl, azetidinyloxy, azetidinyloxy, Piperidyloxy, piperidyloxy, oxetaneoxy, oxolaneoxy, oxaneoxy, thietaneoxy, thiolaneoxy base, thianeoxy group, , , , , , , , , , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ OH, , , -OCH ₂ CH ₂ NC(O)CH ₃ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ OH, , , , , , -SCH ₃ , -N(CH ₃ ) ₂ , ,or ; x is 1 or 2; A ₁ is selected from , , , , , , , , , , , , , , , , , , , , , , , , or ; R ₂ is selected from: hydrogen, hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH ₂ )CH ₃ , -C(CH ₃ )(= CH ₂ )CH ₃ , -CH=CH(CH ₂ ) ₂ CH ₃ , -CH=CHCH ₃ , -CH=CH-cyclopropyl, -C(O)NH ₂ , -C(O)OCH ₃ , - S(O) ₂ CH ₃ , -OCH ₃ , -CH ₂ NH _{2 ,} trifluoromethyl, methyl, trifluoromethoxy, or halogen (F, Cl, Br), -NH ₂ , -NHC(O )CH ₃ , -NHCH ₂ CH ₃ or -NHCH(CH ₃ ) ₂ ; w is 1, 2 or 3; A ₂ is selected from , , , , , , , , , , , , , , , , , , , , , , or ; R ³ is selected from -C(O)NH(CH ₂ ) ₂ CH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NH ₂ , -C(O)NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , -CH ₂ C(O)NH ₂ , hydrogen, -F, -Cl, -Br, cyano, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , -CH ₂ CN, -CH(CH ₃ )-NH ₂ , -CH=CH-CN, -C(O)-OH, -C(O)OCH ₃ , -C(O)CH ₃ , -C( CH ₃ ) ₂ -C(O)-OCH ₃ , -C(CH ₃ ) ₂ -CN, oxo group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, -NH ₂ , -NH-C( O)CH ₃ , -NH-S(O) ₂ CH ₃ , -NH-C(O)OC(CH ₃ ) ₃ , , , , , , -S(O) ₂ CH ₃ , -S(O) ₂ NCH ₃ , -S(O) ₂ NH ₂ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCF ₃ , , -OCH ₂ cyclopropyl, -OCH ₃ , -O(CH ₂ ) ₃ CH ₃ , -OCH ₂ phenyl, -O-phenyl, -(CH ₂ )-OH, -(CH ₂ ) ₂ -OH , -(CH ₂ )-OCH ₃ , -(CH ₂ )-OCH ₂ CH ₃ , -CH(OH)-CH ₂ -phenyl, -CH(OH)-CH ₂ CH ₃ , -CH(OH)- CH ₂ CH ₂ CH ₃ , -CH(OH)-CH ₂ CH ₂ CH ₂ CH ₃ , -CH(OH)-CH(CH ₃ ) ₂ , -CH(OH)-phenyl, -CH(OH)- CN, -CH(OH)-CH ₂ -OH, -CH(OH)-CF ₃ , -CH(OH)-(CH ₂ ) ₂ -phenyl, , -CH(NH ₂ )-CH ₂ -C(O)OH, -CH ₂ -NH-S(O) ₂ -CH ₃ , -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ - NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -NH-CH ₂ CH ₃ , -CH(CH ₃ )-NH ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ - NH ₂ , -CH ₂ NH-CH ₂ -phenyl, -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH-cyclopropyl, -CH ₂ NH-cyclobutyl, -CH ₂ NH-cyclo Pentyl, -CH ₂ NH-pyridyl, -CH ₂ NH-phenyl, -CH ₂ NH-(CH ₂ ) ₂ -OH, -CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -OH, - CH ₂ NH-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CF ₃ , -CH ₂ N(CH ₃ )-CH ₂ - CF ₂ H, -CH ₂ NH-CH ₂ -CF ₂ H, -CH ₂ NH-(CH ₂ ) ₂ -OCH ₃ , , , , , , , , , , , , , , , , , , , , , , , , , -CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₂ NOH , -CH ₂ NH-C(O)-CH ₂ OCH ₃ , -CH(CH ₃ )NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₃ , , -CH ₂ NHCH ₂ -C(O)-NH ₂ , -CH ₂ NHCH ₂ -C(O)-(CH ₃ ) ₂ , -CH ₂ NHCH ₂ -C(O)-OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₃ , -CH ₂ NHCH ₂ -C(O)-NH(CH ₂ ) ₂ -OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₂ -phenyl, , -CH ₂ NHCH ₂ -C(O)-NH-phenyl, ,-CH ₂ NH-C(O)-CH ₂ NH-phenyl, , , , Or -CH ₂ NH-C(O)-CH ₂ NH-CH ₂ CF ₃ ; Y is 1 or 2; L' is a bond, -(CH ₂ ) _k - or -O(CH ₂ ) _k -, as described k is 1 or 2, or L' is -CH=CH-(CH ₂ ) _n -, and n is 0, 1 or 2.

In some embodiments, in S1a, R ₂ is selected from: hydrogen, hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH ₂ )CH _3. -C(CH ₃ )(=CH ₂ )CH ₃ , -CH=CH(CH ₂ ) ₂ CH ₃ , -CH=CHCH ₃ , -CH=CH-cyclopropyl, -C(O)NH ₂ , -C(O)OCH ₃ , -S(O) ₂ CH ₃ , -OCH ₃ , -CH ₂ NH ₂ , trifluoromethyl, methyl, trifluoromethoxy, halogen (F, Cl, Br) .

In some embodiments of the present invention, in S1a, w is 1 or 2.

In certain embodiments of the present invention, in S1a, R ₁ is hydrogen, -CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ CH(CH ₃ ) ₂ or -O(CH ₂ ) ₃ CH ₃ , for example -OCH ₃ .

In some embodiments of the present invention, in S1a, A ₁ is or .

In some embodiments of the present invention, in S1a, A ₁ is .

In certain embodiments of the present invention, in S1a, R ₂ is hydrogen, halogen, -NH ₂ , C ₁ -C ₆ alkyl or -C ₁ -C ₆ haloalkyl.

In some embodiments of the present invention, in S1a, L' is a bond.

In certain embodiments of the present invention, in S1a, A ₂ (R ₃ ) _Y is hydrogen.

In some embodiments of the present invention, in S1a, A ₂ is .

In certain embodiments of the present invention, in S1a, R ₃ is hydrogen, -F, -Cl, -Br, -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -NH-CH ₂ CH ₃ .

In certain embodiments of the present invention, in S1a, R ₃ is hydrogen, Cl, -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ .

In some embodiments of the present invention, in S1a, A ₁ is or , L' is a bond, A ₂ (R ₃ ) _Y is hydrogen.

In some embodiments of the present invention, in S1a, A ₁ is , L' is the key, A ₂ is , R ₃ is hydrogen, -F, -Cl, -Br, -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ or - CH ₂ -NH-CH ₂ CH ₃ .

In some embodiments of the present invention, the S is S1a': S1a' wherein, in said S1a', the definitions of R ₁ , R ₂ , R ₃ , L', A ₁ , A ₂ , w, x and Y are as described in S1 or S1a.

In some embodiments of the present invention, the S is S1a'': S1a'' wherein, in S1a'', the definitions of R ₁ , R ₂ , R ₃ , L', A ₁ , A ₂ , w and Y are as described in S1 or S1a.

In certain embodiments of the present invention, in S1a' and S1a'', R ₁ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy is optionally substituted by C ₁ -C ₆ alkoxy (eg methoxy).

In certain embodiments of the present invention, in S1a' and S1a'', R ₁ is hydrogen, methyl, methoxy or .

In some embodiments of the present invention, among S1a, S1a' and S1a'', The fragment is .

In certain embodiments of the present invention, the S is -X-S1a', and the structure of S1a' is as described above; X is O, NH or S, preferably O.

In certain embodiments of the present invention, the S is -X-S1a'', and the structure of S1a'' is as described above; X is O, NH or S, preferably O.

More preferably, in certain embodiments of the present invention, the S1 is a specific compound of Example 1 (Example 1) to Example 458 (Example 458) in WO2018172250A1 (the entire text of which is incorporated herein by reference).

Preferably, in certain embodiments of the present invention, S is S2: S2 wherein in S2: R ₁ is hydrogen, halogen, -OH, -CN, -NO ₂ , C ₁ -C ₆ alkyl mercapto or -NR _a R _b ; each of R _a and R _b is independently Hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ heterocycloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C _8- cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl, -COOH, -COOR _c ; the R _c is -C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl group or -C ₄ -C ₈ cycloalkenyl; R ₁ is -NS(O)(R _d )(R _e ), and R _d and R _e are each independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl; R ₁ is -NHC(O)-(C ₁ -C ₆ alkyl) , -NHC(O)-NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl base; R ₁ is -NH-(CH ₂ ) _k -NH-C(O)-( C ₁ -C ₆ alkyl), and the k is 1 or 2; R ₁ is -NH-(CH ₂ ) _i -R _f , the i is 0, 1 or 2 and R _f is a 4-7 membered heterocycloalkyl group, heteroaryl group, C ₁ -C ₆ alkylsulfonyl group; in addition, the above C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally selected from halogen, -OH, oxo, -CN, - by 1, 2 or 3 NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, 4-7 membered heterocycloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH ₂ )-heteroaryl group substitution, -NHC(O)(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkoxy, phenoxy, heteroaryloxy or -NR _a R _b ; the R _a and R _b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -O-(CH ₂ ) _z - Phenyl, -O-(CH ₂ ) _z - (4-7 membered heterocycloalkyl), -O-(CH ₂ ) _z -heteroaryl, the z is 0, 1 or 2, the phenyl , heterocycloalkyl and heteroaryl are optionally substituted from -OH, heterocycloalkyl or heterocycloalkenyl, and can be substituted by methyl or oxo; or R ₁ is , , , , the L ₂ a is C(O), L ₂ b is a bond or C ₁ -C ₆ alkylene group, and X ₂ is , , , Rx ₂ is , or , or R ₁ is , , , , , , , , , , , , or ; Or two adjacent R _1s together with their respective connected carbon atoms form a 5-7-membered cycloalkyl group or a 5-7-membered heterocycloalkyl group; and the x is 1, 2, 3 or 4 (for example, the (x is 1, 2 or 3); A ₁ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R ₂ is hydrogen, -OH, oxo, halogen, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₃ -C ₈ Cycloalkoxy, -C ₃ -C ₈ halocycloalkoxy, -C ₄ -C ₈ cycloalkenyl, 4-7-membered heterocycloalkyl, -O-CH ₂ -4-7-membered heterocycloalkyl Base, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ alkylsulfonyl; R ₂ is -NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ - C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is -C(O)NR _a R _{b ,} and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is -C(O)OR _g , and the R _g is hydrogen or C ₁ -C ₆ alkyl; R ₂ is -OR _h ; the R _h is C ₁ -C ₆ alkyl; R ₂ is -(CH ₂ )NR _a R _b , and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; and w is 1, 2, 3 or 4 (for example, the w is 1 or 2); the A ₂ (R ₃ ) _Y is hydrogen; or A ₂ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and R ₃ is hydrogen, halogen, -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ cycloalkynyl, 4 -7-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl Aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally selected from halogen, -OH, oxo, -CN, -C ₁ - by 1, 2 or 3 Substituted by C ₆ alkyl, -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ haloalkyl, phenyl, heteroaryl or -C(O)NR _i R _j , the R _i and R _j is each independently hydrogen or C ₁ -C ₆ alkyl; or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkyne The base and heterocyclic alkenyl are optionally substituted by -NR _k R _l , and the R _k and R _l are each independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylsulfonyl, phenyl, heteroaryl, -CH ₂ -C(O)-R _m , -C(O)R _p Or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 selected from C ₁ -C ₆ haloalkyl, -OH, oxo, phenyl, -CN, C ₁ -C ₆ alkoxy or heteroaryl substituted, and the heteroaryl is optionally substituted by methyl Substituted; and the R _m is a bicyclic heteroaryl group, a C ₁ -C ₆ alkoxy group or -NR _n R _o , and the R _n and R _o are each independently hydrogen, a C ₁ -C ₆ alkyl group or benzene base, the alkyl group is optionally substituted by a C ₁ -C ₆ alkoxy group or phenyl group, or -NR _n R _o is a 4-7 membered azacycloalkyl group, and the azacycloalkyl group is connected through an N atom other parts of the molecule, and also contains 1 or more heteroatoms selected from N or O; the R _p is selected from C ₁ -C ₆ alkoxy, optionally 1, 2 or 3 selected from - OH or C ₁ -C ₆ alkoxy substituted C ₁ -C ₆ alkyl, monocyclic or bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R _p is -CH ₂ -NR _q R _r , so The R _q and R _r are each independently selected from hydrogen, phenyl or C ₁ -C ₆ alkyl optionally substituted by F; or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by -NR _s R _t , where -NR _s R _t is 4- connected to other parts of the molecule through a nitrogen atom A 7-membered nitrogen heterocycloalkyl group or a 6-10 membered nitrogen spirocycloalkyl group connected to other parts of the molecule through a nitrogen atom, and further including up to two heteroatoms selected from N or O, optionally substituted by 1 , 2 or 3 substituents selected from -OH, oxo group, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR _z , the R _z is C ₁ -C ₆ alkyl, halogen, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ N(C ₁ -C ₆ alkyl) ₂ , -C(O)NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; or R ₃ is C(O)R _v , -C (O)NH ₂ , -C(O)NHR _v , -C(O)NR _v R _w , -C(O)OR _v , the R _v and R _w are each independently hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ haloalkyl, phenyl or -(CH ₂ ) ₂ NR _x R _y , the R _x and R _y are each independently hydrogen, C ₁ -C ₄ alkyl or -(CH ₂ ) ₂ NH(CH ₃ ) ₂ ; or R ₃ is -NH ₂ , -NHR _z , -NR _z R _za , -NHC(O) R _z , -NHC(O)OR _z , -NHS(O) ₂ R _z , 4-7 membered heterocycloalkyl, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, the R _z and R _za are each independently C ₁ -C ₄ alkyl base, C ₁ -C ₄ haloalkyl or phenyl; or R ₃ is C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, -O(CH ₂ ) _s -C ₃ -C ₈ cycloalkyl base, -O(CH ₂ ) _s -phenyl, -O(CH ₂ ) _s -heterocycloalkyl, -O(CH ₂ ) _s -heteroaryl, the s is 0, 1, 2 or 3; Or R ₃ is -S(O) ₂ R _z , -S(O) ₂ NH ₂ , -S(O) ₂ NHR _z , -S(O) ₂ NR _z R _za , and the R _z and R _za are respectively Independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl; Y is 0, 1, 2, 3, 4 or 5 (for example, Y is 0, 1, 2 or 3) ; L' is a bond, -(CH ₂ ) _k -, -O(CH ₂ ) _k -, -(CH ₂ ) _k -O- or -O-(CH ₂ ) _k -O- (for example, the L ' is a bond, -(CH ₂ ) _k - or -O(CH ₂ ) _k -), and k is 0, 1, 2 or 3, or L' is -CH=CH-(CH ₂ ) _n -, The n is 0, 1 or 2; R ₄ and R ₅ are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ Cycloalkoxy group, the alkyl group, alkoxy group, cycloalkyl group and cycloalkoxy group are optionally replaced by cyano group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkoxy or halogen substitution; T and V are both N, or T is C and V is N, or T is N and V is C.

Preferably, in certain embodiments of the present invention, R ₄ and R ₅ in S2 are each independently methyl.

In some embodiments, in the definition of each group of S2, the R _a and R _b appearing at any place are each independently hydrogen or C ₁ -C ₆ alkyl.

In some embodiments of the present invention, in S2, both T and V are N.

In some embodiments of the present invention, in S2, T is C and V is N.

In some embodiments of the present invention, in S2, T is N and V is C.

In certain embodiments of the present invention, in S2, R ₅ is a C ₁ -C ₆ alkyl group, such as methyl.

In certain embodiments of the present invention, in S2, R ₄ is a C ₁ -C ₆ alkyl group, such as methyl.

In certain embodiments of the present invention, in S2, R ₁ is hydrogen or C ₁ -C ₆ alkoxy.

In certain embodiments of the present invention, in S2, A ₁ is an aryl group or a heteroaryl group.

In certain embodiments of the present invention, in S2, A ₁ is an aryl group, such as phenyl.

In certain embodiments of the present invention, in S2, A ₁ is heteroaryl, such as thienyl.

In certain embodiments of the present invention, in S2, R ₂ is hydrogen, halogen, C ₁ -C ₆ alkyl or -C ₁ -C ₆ haloalkyl.

In some embodiments of the present invention, in S2, L' is a bond.

In certain embodiments of the present invention, in S2, A ₂ (R ₃ ) _Y is hydrogen.

In certain embodiments of the present invention, in S2, A ₂ is an aryl group, such as phenyl.

In certain embodiments of the present invention, in the S2, R ₃ is hydrogen, halogen or C ₁ -C ₆ alkyl, and the alkyl is optionally substituted by -NR _k R ₁ ; each of the R _k and R ₁ Independently hydrogen or C ₁ -C ₆ alkyl. In certain embodiments of the present invention, in the S7, R ₃ is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl groups are replaced by -NR _k R ₁ ; the R _k is methyl Or ethyl, R _l is hydrogen, methyl or ethyl.

In certain embodiments of the present invention, in the S2, R ₃ is hydrogen, Cl, -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ .

In certain embodiments of the present invention, in S2, A ₁ is an aryl group, L' is a bond, and A ₂ (R ₃ ) _Y is hydrogen.

In some embodiments of the present invention, in S2, A ₁ is a heteroaryl group, L' is a bond, A ₂ is an aryl group, R ₃ is hydrogen, halogen or C ₁ -C ₆ alkyl group, and the alkyl group Optionally substituted by _-NRkRl ; the _Rk and _Rl are each independently hydrogen or C ₁ -C ₆ alkyl _.

In some embodiments of the present invention, the S is S2': S2' wherein, in said S2', T, V, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , L', A ₁ , A ₂ , w, x and Y are defined as described in S2 .

In some embodiments of the present invention, the S is S2'': S2'' wherein, in S2'', the definitions of R ₂ , R ₃ , R ₄ , R ₅ , L', A ₁ , A ₂ , w and Y are as described in S2.

In certain embodiments of the present invention, among the S2, S2' and S2'', R ₁ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups are optionally substituted by C ₁ -C ₆ alkoxy groups (eg methoxy).

In certain embodiments of the present invention, among the S2, S2' and S2'', R ₁ is hydrogen, methyl, methoxy or .

In certain embodiments of the present invention, among S2 and S2', The fragment is .

In certain embodiments of the present invention, the S is -X-S2', and the structure of S2' is as described above; X is O, NH or S, preferably O.

In certain embodiments of the present invention, the S is -X-S2'', and the structure of S2'' is as described above; X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, S is S2a, S2a wherein in S2a: T and V are both N, or T is C and V is N, or T is N and V is C; R ₁ is selected from hydrogen, -OCH ₃ , -OCH ₂ CH ₃ , , -CH ₂ OH, -C(O)OH, -C(O)OCH ₃ , -Br, -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ CH(CH ₃ ) ₂ , -O(CH ₂ ) ₃ CH ₃ , -O(CH ₂ ) ₂ OCH ₃ , , -O(CH ₂ ) _z -phenyl, -N=S(O)(CH ₃ ) ₂ , -CH ₃ , cyclopropyl, -N(CH ₃ ) ₂ , -NHCH ₃ , -NH ₂ , , , , , , , -C(CH ₃ ) ₂ -OH, , , -NH(CH ₂ )-NH-C(O)CH ₃ , -NH(CH ₂ )-morpholine, -NH-C(O)CH ₃ , -NH-C(O)NHCH ₃ , -NH- C(O)-N(CH ₃ ) ₂ , nitro group, -NH-S(O) ₂ CH ₃ , -N=S(O)(CH ₃ ) ₂ , hydroxyl group, -O-(CH ₂ ) ₂ - S(O) ₂ CH ₃ ,-F, , , , , , , , , , , , , , , Cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azetidinyl, piperidinyl, piperazyl, oxetane, oxa Cyclopentyl, oxanyl, thietanyl, thiolyl, thietanyl, azetidinyloxy, azetidinyloxy, pipera Aldyloxy, piperayloxy, oxetanoxy, oxolanoxy, oxanyloxy, thietanyloxy, thiolyloxy , thiacyclohexaneoxy, , , , , , , , , , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ OH, , , -OCH ₂ CH ₂ NC(O)CH ₃ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ OH, , , , , , -SCH ₃ , -N(CH ₃ ) ₂ , ,or ; z is 1 or 2; x is 1 or 2; A ₁ is selected from , , , , , , , , , , , , , , , , , , , , , , , , or ; R ₂ is selected from: hydrogen, hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH ₂ )CH ₃ , -C(CH ₃ )(= CH ₂ )CH ₃ , -CH=CH(CH ₂ ) ₂ CH ₃ , -CH=CHCH ₃ , -CH=CH-cyclopropyl, -C(O)NH ₂ , trifluoromethyl, methyl, tris Fluoromethoxy, -C(O)OCH ₃ , -S(O) ₂ CH ₃ , -OCH ₃ , -CH ₂ NH ₂ or halogen (F, Cl, Br); w is 1, 2 or 3; A ₂ selected from , , , , , , , , , , , , , , , , , , , , , , or ; R ³ is selected from -C(O)NH(CH ₂ ) ₂ CH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NH ₂ , -C(O)NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , -CH ₂ C(O)NH ₂ , hydrogen, -F, -Cl, -Br, cyano, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , -CH ₂ CN, -CH(CH ₃ )-NH ₂ , -CH=CH-CN, -C(O)-OH, -C(O)OCH ₃ , -C(O)CH ₃ , -C( CH ₃ ) ₂ -C(O)-OCH ₃ , -C(CH ₃ ) ₂ -CN, oxo group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, -NH ₂ , -NH-C( O)CH ₃ , -NH-S(O) ₂ CH ₃ , -NH-C(O)OC(CH ₃ ) ₃ , , , , , , -S(O) ₂ CH ₃ , -S(O) ₂ NCH ₃ , -S(O) ₂ NH ₂ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCF ₃ , , -OCH ₂ cyclopropyl, -OCH ₃ , -O(CH ₂ ) ₃ CH ₃ , -OCH ₂ phenyl, -O-phenyl, -(CH ₂ )-OH, -(CH ₂ ) ₂ -OH , -(CH ₂ )-OCH ₃ , -(CH ₂ )-OCH ₂ CH ₃ , -CH(OH)-CH ₂ -phenyl, -CH(OH)-CH ₂ CH ₃ , -CH(OH)- CH ₂ CH ₂ CH ₃ , -CH(OH)-CH ₂ CH ₂ CH ₂ CH ₃ , -CH(OH)-CH(CH ₃ ) ₂ , -CH(OH)-phenyl, -CH(OH)- CN, -CH(OH)-CH ₂ -OH, -CH(OH)-CF ₃ , -CH(OH)-(CH ₂ ) ₂ -phenyl, , -CH(NH ₂ )-CH ₂ -C(O)OH, -CH ₂ -NH-S(O) ₂ -CH ₃ , -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ - NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -NH-CH ₂ CH ₃ , -CH(CH ₃ )-NH ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ - NH ₂ , -CH ₂ NH-CH ₂ -phenyl, -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH-cyclopropyl, -CH ₂ NH-cyclobutyl, -CH ₂ NH-cyclo Pentyl, -CH ₂ NH-pyridyl, -CH ₂ NH-phenyl, -CH ₂ NH-(CH ₂ ) ₂ -OH, -CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -OH, - CH ₂ NH-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CF ₃ , -CH ₂ N(CH ₃ )-CH ₂ - CF ₂ H, -CH ₂ NH-CH ₂ -CF ₂ H, -CH ₂ NH-(CH ₂ ) ₂ -OCH ₃ , , , , , , , , , , , , , , , , , , , , , , , , , -CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₂ NOH , -CH ₂ NH-C(O)-CH ₂ OCH ₃ , -CH(CH ₃ )NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₃ , , -CH ₂ NHCH ₂ -C(O)-NH ₂ , -CH ₂ NHCH ₂ -C(O)-(CH ₃ ) ₂ , -CH ₂ NHCH ₂ -C(O)-OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₃ , -CH ₂ NHCH ₂ -C(O)-NH(CH ₂ ) ₂ -OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₂ -phenyl, , -CH ₂ NHCH ₂ -C(O)-NH-phenyl, ,-CH ₂ NH-C(O)-CH ₂ NH-phenyl, , , , Or -CH ₂ NH-C(O)-CH ₂ NH-CH ₂ CF ₃ ; Y is 1 or 2; L' is a bond, -(CH ₂ ) _k - or -O(CH ₂ ) _k -, as described k is 1 or 2, or L' is -CH=CH-(CH ₂ ) _n , and n is 0 or 1.

More preferably, in certain embodiments of the present invention, the S2 is the specific compound of Example 1 (Example 1) to Example 100 (Example 100) in WO2019201848A1 (the entire text of which is incorporated herein by reference).

In some embodiments of the present invention, in S2a, w is 1 or 2.

In certain embodiments of the present invention, in the S2a, R ₁ is hydrogen, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ CH(CH ₃ ) ₂ or -O(CH ₂ ) ₃ CH ₃ , such as -OCH ₃ .

In some embodiments of the present invention, in S2a, A ₁ is or .

In some embodiments of the present invention, in S2a, A ₁ is .

In certain embodiments of the present invention, in the S2a, R ₂ is hydrogen, halogen, -NH ₂ , C ₁ -C ₆ alkyl or -C ₁ -C ₆ haloalkyl.

In some embodiments of the present invention, in S2a, L' is a bond.

In certain embodiments of the present invention, in S2a, A ₂ (R ₃ ) _Y is hydrogen.

In some embodiments of the present invention, in S2a, A ₂ is .

In certain embodiments of the present invention, in the S2a, R ₃ is hydrogen, -F, -Cl, -Br, -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ or -CH ₂ -NH-CH ₂ CH ₃ .

In certain embodiments of the present invention, in S2a, R ₃ is hydrogen, Cl, -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ .

In some embodiments of the present invention, in S2a, A ₁ is or , L' is a bond, A ₂ (R ₃ ) _Y is hydrogen.

In some embodiments of the present invention, in S2a, A ₁ is , L' is the key, A ₂ is , R ₃ is hydrogen, -F, -Cl, -Br, -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ or - CH ₂ -NH-CH ₂ CH ₃ .

In some embodiments of the present invention, the S is S2a', S2a' wherein, in said S2a', T, V, R ₁ , R ₂ , R ₃ , L', A ₁ , A ₂ , w, x and Y are defined as described in S2 or S2a.

In some embodiments of the present invention, the S is S2a'', S2a'' wherein, in said S2a'', T, V, R ₂ , R ₃ , L', A ₁ , A ₂ , w and Y are defined as described in S2 or S2a.

In certain embodiments of the present invention, in S2a' and S2a'', R ₁ is hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy is optionally substituted by C ₁ -C ₆ alkoxy (eg methoxy).

In certain embodiments of the present invention, in S2a' and S2a'', R ₁ is hydrogen, methyl, methoxy or .

In some embodiments of the present invention, among the S2a, S2a' and S2a'', The fragment is .

In certain embodiments of the present invention, the S is -X-S2a', and the structure of S2a' is as described above; X is O, NH or S, preferably O.

In certain embodiments of the present invention, the S is -X-S2a'', and the structure of S2a'' is as described above; X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S is S3: S3 wherein in S3: Q ¹ and Q ² are each independently CH or N; Q ³ , Q ⁴ and Q ⁷ are each independently C or N, at least one of Q ³ and Q ⁴ is C, and the Q ³ , Q ⁴ and Q ⁷ are not all N; Q ⁵ is CH, N, NH, O or S; Q ⁶ is CH, N, NH, N (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ heteroalkyl), N (3-7 membered cycloalkyl), N (3-7 membered heterocycle), O or S; the Q ¹ , Q ² , Q ³ , Q ⁴ , Q ⁵ , At least one of Q ⁶ and Q ⁷ is N, NH, O or S; R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -NHR _1a , -OR _1a , C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or -CN; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ cycloalkoxy is optionally substituted with a substituent selected from halogen, -NHR ^1a or -OR ^1a ; the R ^1a is hydrogen, C ₁ -C ₆ alkyl, 3-6 membered hetero Ring or C ₁ -C ₆ haloalkyl; L ² is selected from bond, -C(O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S(O) ₂ -, -S(O)-, -S(=O)(=NH)-, -S(=O)[=N(C ₁ -C ₆ alkyl)]-, -N(C ₁ -C ₆ Alkyl)-, -C(O)(CH ₂ ) _p -, -(CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R is selected from ² From hydrogen, halogen, -CN, -NO ₂ , C 1 -C ₆ alkylmercapto, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl _, C ₂ -C ₆ alkenyl, -NR ^2b R ^2c , -OR ^2a , 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; the C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered hetero Each aryl group is independently optionally selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OH, -OR ^2a , oxo, halogen, -C(O)R ^2a , -C (O)OR ^2a , -C(O)NR ^2b R ^2c , -CN, -NR ^2b R ^2c , 3-6-membered cycloalkyl, 3-7-membered heterocycloalkyl, 6-10-membered aryl or 5 -10-membered heteroaryl substituent substitution; the R ^2a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, or -(CH ₂ ) _r OCH ₃ , the r is 1, 2 or 3; the R ^2b is hydrogen or C ₁ -C ₆ alkyl; the R ^2c is hydrogen or C ₁ -C ₆ alkyl; R ² is -NHC(O )-(C ₁ -C ₆ alkyl), -NHC(O)-NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ hetero Cycloalkyl or C ₃ -C ₈ cycloalkyl (for example, R _a and R _b are each independently hydrogen or C ₁ -C ₆ alkyl); R ² is -NH-(CH ₂ ) _k -NH -C(O)-(C ₁ -C ₆ alkyl), the k is 1 or 2; R ² is -NH-(CH ₂ ) _i -R _f , the i is 0, 1 or 2 and R _f is 4-7 membered heterocycloalkyl, heteroaryl, C ₁ -C ₆ alkylsulfonyl group; R ³ and R ⁴ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy or C ₃ -C ₆ cycloalkoxy; at least one of R ³ and R ⁴ is not hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6 membered cycloalkyl group; the alkyl group, alkoxy group, cycloalkyl group and cycloalkoxy group are optionally substituted by cyano group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkoxy or halogen substituted; A is optionally substituted (e.g. optionally substituted by 1 or more R ₂ , R ₂ is defined as described in S1) 6-membered aryl or optionally substituted (e.g. Optionally substituted by 1 or more R ₂ , R ₂ is defined as described in S1) 5-6 membered heteroaryl.

Preferably, in certain embodiments of the present invention, the S is S3a, S3a wherein in S3a: Q ¹ and Q ² are each independently CH or N; Q ³ and Q ⁴ are each independently C or N, and at least one of Q ³ and Q ⁴ is C; Q ⁶ is CH, N, NH, O or S; Q ⁵ is CH, N, NH, O or S; at least one of Q ¹ , Q ² , Q ³ , Q ⁴ , Q ⁵ and Q ⁶ is N, NH, O Or S; R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, halogen, -OR ^1a , cyclopropyl or -CN; the R ^1a is hydrogen or C ₁ -C ₆ alkyl; L ² is selected from bond , -C(O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S(O) ₂ -, -C(O)(CH ₂ ) _p -, - (CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R ² is selected from hydrogen, -(CH ₂ ) _q CH ₃ , 3-14-membered cycloalkanes base, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; the q is an integer from 1 to 5; the 3-14 membered Cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl and 5-10-membered heteroaryl are each independently optionally selected from C ₁ -C ₆ alkane group, -OH, halogen, -C(O)R ^2a , -C(O)NR ^2b R ^2c substituents; the R ^2a is C ₁ -C ₆ alkyl or -(CH ₂ ) _r OCH ₃ , the r is 1, 2 or 3; the R ^2b is hydrogen or C ₁ -C ₆ alkyl; the R ^2c is hydrogen or C ₁ -C ₆ alkyl; R ³ and R ⁴ are each independently Hydrogen or C ₁ -C ₆ alkyl, at least one of R ³ and R ⁴ is not hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6 membered cycloalkyl group; A is Optionally substituted (for example, optionally 1 or more R ₂ substituted, R ₂ is as defined in S1) phenyl or optionally substituted (for example, optionally 1 or more R ₂ substituted, R ₂ Definition as described in S1) 5-6 membered heteroaryl.

More preferably, in certain embodiments of the present invention, the S3 is the specific compound of Example 1 (Example 1) to Example 103 (Example 103) in WO2020180768A1 (the entire text of which is incorporated herein by reference).

Preferably, in certain embodiments of the present invention, the S is S4: S4 wherein in S4: Q ¹ is CH or N; Q ⁴ is CH, C or N; each Q ² is independently CR ¹ or N, one of the Q ² is N and the other Q ² is CR ¹ ; Each Q ³ and Q ⁵ molecule is independently C(R ^QC ) ₂ , NR ^QN , C(O), O, S or SO ₂ , and the R ^QC is independently hydrogen, F, Cl, Br , or a 6-10-membered aryl group, each of the R ^QN is independently hydrogen, a C ₁ -C ₆ alkyl group or a 6-10-membered aryl group; the Q ¹ , Q ² , Q ³ , Q ⁴ , and Q At least one of ⁵ is N, NR ^QN , O or SO ₂ ; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; and when m is 0, n is not 0; R ¹ is selected from Hydrogen, C ₁ -C ₆ alkyl, halogen, -C(O)NHR ^1a , -NHR ^1a , -OR ^1a , cyclopropyl, azetidine or -CN; the C ₁ -C ₆ alkyl and azetidine is optionally substituted with a substituent selected from halogen, R ^1a , -NHR ^1a or -OR ^1a ; said R ^1a is hydrogen, C ₁ -C ₆ alkyl, cyclopropyl, 3- 6-membered heterocycle or C ₁ -C ₆ haloalkyl; L ² is selected from bond, -C(O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S( O) ₂ -, -S(O)-, -S(=O)(=NH)-, -S(=O)[=N(C ₁ -C ₆ alkyl)]-, -N(C ₁ -C ₆ alkyl)-, -C(O)(CH ₂ ) _p -, -(CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R ² is selected from hydrogen, C ₁ -C ₆ alkyl, -NR ^2b R ^2c , -OR ^2a , 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6 -10-membered aryl, 5-10-membered heteroaryl; the C ₁ -C ₆ alkyl, 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6 -The 10-membered aryl group and the 5-10-membered heteroaryl group are each independently optionally selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ methoxyalkyl, -OH, -OR ^2a , oxo group, halogen, =N, -C(O)R ^2a , -C(O)OR ^2a , -C(O)NR ^2b R ^2c , -S(O) ₂ R ^2a , -CN, -NR ^2b R ^2c , 3-6-membered cycloalkyl, 3-7-membered heterocycloalkyl, 6-10-membered aryl or 5-10-membered heteroaryl Substituent substitution; the R ^2a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, or -(CH ₂ ) _r OCH ₃ , and the r is 1, 2 or 3; The R ^2b is hydrogen or C ₁ -C ₆ alkyl; The R ^2c is hydrogen or C ₁ -C ₆ alkyl; R ³ and R ⁴ are each independently hydrogen, optionally Halogen, -OH substituted C ₁ -C ₆ alkyl, at least one of R ³ and R ⁴ is hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6 membered cycloalkyl group ; A is an optionally substituted (for example, optionally 1 or more R ₂ substituted, R ₂ is defined as described in S1) 6-membered aryl or optionally substituted (for example, optionally 1 or more R 2 ₂ substituted, R ₂ is defined as described in S1) 5-6 membered heteroaryl; provided that when for , , , , , , , , , , , , , , , or When, R ¹ is not hydrogen.

Preferably, in certain embodiments of the present invention, the S is S4a S4a wherein in S4a: Q ¹ is CH or N; Q ⁴ is CH, C or N; each Q ² is independently CR ¹ or N; each Q ³ and Q ⁵ molecule is independently C (R ^QC ) ₂ , NR ^QN , C(O), O, S or SO ₂ , each of the R ^QC is independently hydrogen, F, Cl, Br, or a 6-10 membered aryl group, each of the R ^QN is independently is hydrogen, C ₁ -C ₆ alkyl or 6-10 membered aryl group; at least one of Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ is N, NR ^QN , O or SO ₂ ; R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, halogen, cyclopropyl, cyano or -OR ^1a , said R ^1a is hydrogen or C ₁ -C ₆ alkyl; L ² is selected from bond, -C ( O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S(O) ₂ -, -C(O)(CH ₂ ) _p -, -(CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R ² is selected from hydrogen, -(CH ₂ ) _q CH ₃ , 3-14-membered cycloalkyl, 3- 14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; the q is a multiple of 1 to 5; the 3-14-membered cycloalkyl, 3-14-membered ring alkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl are each independently selected from C ₁ -C ₆ alkyl, hydroxyl, Halogen, -C(O)R ^2a or -C(O)NR ^2b R ^2c group substitution; the R ^2a is selected from C ₁ -C ₆ alkyl or -(CH ₂ ) _r OCH ₃ ; the r is 1, 2 or 3; R ^2b and R ^2c are each independently hydrogen or C ₁ -C ₆ alkyl; R ³ and R ⁴ are each independently hydrogen or C ₁ -C ₆ alkyl, and R At least one of ³ and R ⁴ is hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6-membered cycloalkyl group; A is optionally substituted (for example, optionally 1 or more R ₂ substituted, R ₂ is defined as described in S1) 6-membered aryl or optionally substituted (for example, optionally substituted with 1 or more R ₂ , R ₂ is defined as described in S1) 5-6 membered Heteroaryl.

Preferably, in certain embodiments of the present invention, R ³ and R ⁴ in S4a are each independently hydrogen or methyl, and at least one of R ³ and R ⁴ is hydrogen.

More preferably, in certain embodiments of the present invention, the S4 is the specific compound of Example 1 (Example 1) to Example 540 (Example 540) in WO2020180770A1 (the entire text of which is incorporated herein by reference).

Preferably, in certain embodiments of the present invention, the S is S5: S5 wherein in S5: R ¹ is hydrogen or R ^a1 ; R ^a1 is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ Alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ membered aryl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3 -10-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl and 5-10-membered heteroaryl are optionally substituted by 1 or more identical or different R ^b1 and/or R ^c1 ; each R ^b1 is each independently -OR ^c1 , -NR ^c1 R ^c1 , halogen, -CN, -C(O)R ^c1 , -C(O)OR ^c1 , -C(O)NR ^c1 R ^c1 , -S(O ) ₂ R ^c1 , -S(O) ₂ NR ^c1 R ^c1 , -NHC(O)R ^c1 , -N(C ₁ -C ₄ alkyl)C(O)R ^c1 , -NHC(O)OR ^c1 or -N(C ₁ -C ₄ alkyl)C(O)OR ^c1 ; each R ^c1 is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkene base, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered hetero Aryl; the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C _10- ring alkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more identical or different R ^d1 and/ or R ^e1 ; each R ^d1 is independently -OR ^e1 , -NR ^e1 R ^e1 , halogen, -CN, -C(O)R ^e1 , -C(O)OR ^e1 , -C(O)NR ^e1 R ^e1 , -S(O) ₂ R ^e1 , -S(O) ₂ NR ^e1 R ^e1 , -NHC(O)R ^e1 , -N(C ₁ -C ₄ alkyl)C(O)R ^e1 , - NHC(O)OR ^e1 or -N(C ₁ -C ₄ alkyl)C(O)OR ^e1 ; each R ^e1 is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ aromatic group or 5-10 membered heteroaryl; R ² is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl or halogen; Ring A is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 9-10 membered biheterocycloalkyl; p is 1, 2 or 3; each R ⁴ is independently hydrogen, hydroxyl, oxo, halogen, cyanide Base, C ₁ -C ₄ alkyl, -NH ₂ , C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ hydroxyalkyl, hydroxyl - C ₁ -C ₄ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 3-6 membered heterocycloalkyl, C ₃ -C ₆ hydroxycycloalkyl, 3-6 membered Heterocycloalkyl substituted C ₁ -C ₄ haloalkyl, 3-6 membered hetero substituted by hydroxyl, halogen, -NH ₂ , -S(O) ₂ -(C ₁ -C ₄ alkyl) or oxo group Cycloalkyl, and the oxo group is only substituted on the non-aromatic ring; R ⁴ is -NR _a R _b , and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ⁴ is -C(O)NR _a R _{b ,} and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ⁴ is -C(O)OR _g , and the R _g is hydrogen or C ₁ -C ₆ alkyl; R ⁴ is -OR _h ; The R _h is C ₁ -C ₆ alkyl; or R ⁴ is -(CH ₂ ) NR _a R _b , and the R _a and R _b are each independent hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ³ and R ⁵ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ Cycloalkyl or C ₃ -C ₆ cycloalkoxy, the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally replaced by cyano, hydroxyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or halogen substitution.

Preferably, in certain embodiments of the present invention, R ⁵ in S5 is methyl.

In some embodiments, in the definition of each group of S5, the R _a and R _b appearing at any place are each independently hydrogen or C ₁ -C ₆ alkyl.

In some embodiments of the present invention, the S is S5': S5' wherein in said S5', said R ² , R ³ , R ⁴ , R ⁵ , ring A and p are as defined and described in S5.

In certain embodiments of the present invention, the S is -X-S5', and the structure of S5' is as described above; X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S is S5a: S5a wherein the R ¹ , R ² , R ³ , R ⁴ , ring A and p are as defined and described in S5.

In some embodiments of the present invention, the S is S5a': S5a' wherein in said S5a', said R ² , R ³ , R ⁴ , R ⁵ , ring A and p are as defined and described in S5a.

In certain embodiments of the present invention, the S is -X-S5a', and the structure of S5a' is as described above; X is O, NH or S, preferably O.

More preferably, in certain embodiments of the present invention, the S5 is a specific compound from I-1 to I-179 in WO2019122129A1 (the entire text of which is incorporated herein by reference).

Preferably, in certain embodiments of the present invention, the S is S6: S6 wherein in S6: R ₂ is selected from hydrogen, halogen, -OH, -CN, -NO ₂ , C ₁ -C ₆ alkyl mercapto or -NR _a R _b , and the R _a and R _b are each independent is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ heterocycloalkoxy (for example ), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, 4-7 membered heterocycloalkyl (for example ), 5-10 membered heterocyclic alkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl, -COOH, -COOR _c ;The R _c is -C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or -C ₄ -C ₈ cycloalkenyl; R ₂ is -NS(O)(R _d )(R _e ), and R _d and R _e are each independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkyne base, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl; R ₂ is -NHC(O)-(C ₁ -C ₆ Alkyl), -NHC(O)-NR _a R _b , the R _a and R _b are each independently hydrogen, -C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ - C ₈ cycloalkyl; R ₂ is -NH-(CH ₂ ) _k -NH-C(O)-R _aa , said R _aa is C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl Or C ₃ -C ₈ cycloalkyl, and k is 1 or 2; R ₂ is -NH-(CH ₂ ) _i -R _f , the i is 0, 1 or 2 and R _f is 4-7 yuan hetero Cycloalkyl, heteroaryl, C ₁ -C ₆ alkylsulfonyl group; In addition, the above-mentioned C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 4-7 membered heterocycloalkyl and hetero The aryl group is optionally selected from halogen, -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, 4-7 membered heterocycloalkyl, C ₁ -C ₆ alkoxy, C 1 -C ₆ haloalkyl, C _{1 -C 6} haloalkoxy, C ₁ -C ₆ alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH ₂ )-heteroaryl, -NHC(O)(C ₁ -C ₆ alkyl), C ₃ -C ₈ Cycloalkoxy, phenoxy, heteroaryloxy or -NR _a R _b group substitution; the R _a and R _b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ - C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is -O-(CH ₂ ) _z -phenyl, -O-(CH ₂ ) _z - (4-7 membered heterocycloalkyl) , -O-(CH ₂ ) _z -heteroaryl, the z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl are optionally selected from -OH, heterocycloalkyl Or heterocycle alkenyl substituted, and can be substituted by methyl or oxo group; or R ₂ is , , , , , , , , , , , , or ; R ₁ is hydrogen or -OR ^A ; R ^A is hydrogen, C ₃ -C ₁₀ cycloalkyl or 3-10 membered heterocycloalkyl; the C ₃ -C ₁₀ cycloalkyl and 3-10 membered heterocycle The alkyl group is optionally substituted by one or more identical or different R ^a1 and/or R ^c1 ; each R ^a1 is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are independently are optionally substituted by one or more identical or different R ^b1 and/or R ^c1 ; each R ^b1 is independently -OR ^c1 , -NR ^c1 R ^c1 , halogen, -CN, -C(O )R ^c1 , -C(O)OR ^c1 , -C(O)NR ^c1 R ^c1 , -S(O) ₂ R ^c1 , -S(O) ₂ NR ^c1 R ^c1 , -NHC(O)R ^c1 , -N(C ₁ -C ₄ alkyl)C(O)R ^c1 , substituted by oxo group, and the oxo group is only substituted on the non-aromatic ring; each R ^c1 is independently hydrogen, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 Heteroaryl; or R ₁ is selected from C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl base; the C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally One or more R ^a2 and/or R ^b2 are substituted; each R ^a2 is independently selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by 1 or more R ^c2 and/or R ^b2 substitution; each R ^b2 is independently selected from -OR ^c2 , -NR ^c2 R ^c2 , halogen, -CN, -C(O)R ^c2 , -C(O)OR ^c2 , -C( O)NR ^c2 R ^c2 , -OC(O)R ^c2 , -S(O) ₂ R ^c2 , -S(O) ₂ NR ^c2 R ^c2 , -NHC(O)R ^c2 , -N(C ₁ -C _4Alkyl )C(O)R ^c2 , -NHC(O)OR ^c2 , oxo group, =NH, and the oxo group, =NH is only substituted on the non-aromatic ring; each R ^c2 is independent Selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 yuan hetero Cycloalkyl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ - C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by one or more R ^d2 and/or R ^e2 ; each R ^d2 is independently -OR ^e2 , -NR ^e2 R ^e2 , halogen, -CN, -C(O)R ^e2 , -C(O)OR ^e2 , -C(O)NR ^e2 R e2 , ^-S (O) ₂ R ^e2 , -S(O ) ₂ NR ^e2 R ^e2 , -NHC(O)R ^e2 , -N(C ₁ -C ₄ alkyl)C(O)R ^e2 , oxo group, the oxo group is only substituted on the non-aromatic ring; Each R ^e2 is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aromatic base, 3-10 membered heterocycloalkyl group or 5-10 membered heteroaryl group, the C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₁₀ Cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by 1 or more R ^f2 and/or R ^g2 ; each R ^f2 is independently Independently selected from -OR ^g2 , -NR ^g2 R ^g2 , halogen, -CN, -C(O)R ^g2 , -C(O)OR ^g2 , -C(O)NR ^g2 R ^g2 , -S(O) ₂ R ^g2 , -S(O) ₂ NR ^g2 R ^g2 , -NHC(O)R ^g2 , -N(C ₁ -C ₄ alkyl)C(O)R ^g2 , oxo group, the oxo group Only substituted on non-aromatic rings; each R ^g2 is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; or R ₁ is selected from C ₂ -C ₄ alkyl, C ₂ -C ₄ alkenyl; the C ₂ -C ₄ alkyl and C ₂ -C ₄ alkenyl are optionally substituted by R ^b3 ; R ^b3 is selected from -C(O)R ^c3 , -C(O)OR ^c3 , -C(O)NR ^c3 R ^c3 , -C(O)NHOR ^c3 or -C(O)N(C ₁ -C ₄ alkyl)OR ^c3 ; Each R ^c3 is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5 -10-membered heteroaryl is optionally substituted by one or more R ^d3 and/or R ^e3 ; each R ^d3 is independently selected from -OR ^e3 , -NR ^{e3 Re3} , halogen, -CN, -C( O)R ^e3 , -C(O)OR ^e3 , -C(O)NR ^e3 R ^e3 , -S(O) ₂ R ^e3 , -S(O) ₂ NR ^e3 R ^e3 , -NHC(O)R ^e3 , -N(C ₁ -C ₄ alkyl)C(O)R ^e3 , oxo group, the oxo group is only substituted on the non-aromatic ring; each R ^e3 is independently selected from hydrogen, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 Metaheteroaryl; R ₃ is selected from hydrogen, C ₁ -C ₄ alkyl, -O(C ₁ -C ₄ alkyl), -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N( C ₁ -C ₄ alkyl) ₂ or halogen; R ₅ is selected from hydrogen, hydroxyl or -NHR';R' is selected from hydrogen, C ₁ -C ₃ alkyl and -C(O)C ₁ -C ₃ alkyl ; R ₄ is selected from C ₁ -C ₄ alkyl, hydroxyl, oxo, cyano, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, hydroxyl-C ₁ -C ₄ haloalkyl, C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkane group, 3-6 membered hydroxyheterocycloalkyl, halogen or -SO ₂ -C ₁ -C ₄ alkyl; R ₆ is selected from hydrogen, C ₁ -C ₄ alkyl or halogen; or R ₄ and R ₆ are combined with them The attached carbon atoms together form an optionally substituted (e.g., unsubstituted or oxosubstituted) C ₅ -C ₆ cycloalkyl group (e.g., form ) and 5-6 membered heterocycloalkyl, the heteroatoms in the 5-6 membered heterocycloalkyl are selected from the group consisting of 1, 2, 3 or 4 independently selected from -NH, -O-, -S- and Heteroatom or heteroatom group of N; R ₇ and R ₈ are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkyl Oxy group, the alkyl group, alkoxy group, cycloalkyl group and cycloalkoxy group are optionally replaced by cyano group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₃ - C ₆ cycloalkoxy or halogen substitution.

In some embodiments, in S6, when R ₄ and R ₆ together with the carbon atoms to which they are connected form optionally substituted C ₅ -C ₆ cycloalkyl and 5-6 membered heterocycloalkyl, the substitution Refers to being replaced by 1, 2, 3 or 4 =O.

In some embodiments, in S6, when R ₄ and R ₆ together with the carbon atoms to which they are connected form an optionally substituted 5-6 membered heterocycloalkyl group, the The fragment is ,For example .

In some embodiments, in S6, R ₁ is hydrogen or -OR ^A and ^RA is hydrogen.

In some embodiments, in S6, _R1 is hydrogen.

In some embodiments, in S6, R ₂ is hydrogen, C ₁ -C ₄ alkyl, -O(C ₁ -C ₄ alkyl), -NH ₂ , -NH(C ₁ -C ₄ alkyl ), -N(C ₁ -C ₄ alkyl) ₂ or halogen, the C ₁ -C ₄ alkyl and -O(C ₁ -C ₄ alkyl) are each independently optionally replaced by -O(C ₁ - C ₄ alkyl) substitution.

In some embodiments, in S6, R ₂ is hydrogen, C ₁ -C ₄ alkyl, -O(C ₁ -C ₄ alkyl), -NH ₂ , -NH(C ₁ -C ₄ alkyl ), -N(C ₁ -C ₄ alkyl) ₂ or halogen.

In some embodiments, in the S6, R ₂ is hydrogen, C ₁ -C ₄ alkyl or -O(C ₁ -C ₄ alkyl), and the -O(C ₁ -C ₄ alkyl) is any Optional substituted by -O(C ₁ -C ₄ alkyl).

In other embodiments, in said S6, R ₂ is , , , , , , , or .

In some embodiments, in S6, _R3 is hydrogen.

In some embodiments, in S6, R ₅ is hydrogen or -NHR'.

In some embodiments, in S6, R ₄ is a C ₁ -C ₄ haloalkyl group; R ₆ is hydrogen or halogen; or, R ₄ and R ₆ and the carbon atoms to which they are connected form a ring together so that in S6 The fragment is .

In some embodiments, in S6, R ₇ is C ₁ -C ₆ alkyl.

In some embodiments, in S6, R ₈ is C ₁ -C ₆ alkyl.

In some embodiments, in the S6, R ₁ is hydrogen or -OR ^A ; R ^A is hydrogen; R ₂ is hydrogen, C ₁ -C ₄ alkyl or -O(C ₁ -C ₄ alkyl) ( For example, methoxy), the -O(C ₁ -C ₄ alkyl) is optionally substituted by -O(C ₁ -C ₄ alkyl) (for example, methoxy); R ₃ is hydrogen; R ₅ is Hydrogen or -NHR';R' is selected from hydrogen, C ₁ -C ₃ alkyl and -C(O)C ₁ -C ₃ alkyl; R ₄ is C ₁ -C ₄ haloalkyl; R ₆ is hydrogen or halogen ; Or R ₄ and R ₆ form a ring together with the carbon atoms to which they are connected so that in S6 The fragment is ; R ₇ is C ₁ -C ₆ alkyl; R ₈ is C ₁ -C ₆ alkyl.

In some embodiments, in the S6, when R ₂ is a C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkyl group may be methyl.

In some embodiments, in the S6, when R ₂ is -O(C ₁ -C ₄ alkyl), the -O(C ₁ -C ₄ alkyl) may be -OCH ₃ .

In some embodiments, in S6, R ₂ is hydrogen, methyl, -OCH ₃ or .

In some embodiments, in S6, R ₂ is hydrogen, methyl or -OCH ₃ .

In some embodiments, in S6, _R3 is hydrogen.

In some embodiments, in the S6, when R' is a C ₁ -C ₃ alkyl group, the C ₁ -C ₃ alkyl group may be ethyl or isopropyl.

In some embodiments, in the S6, when R' is -C(O)C ₁ -C ₃ alkyl, the -C(O)C ₁ -C ₃ alkyl can be -C(O )CH ₃ .

In some embodiments, in S6, R ₅ is hydrogen or -NHR', wherein R' is hydrogen, ethyl, isopropyl or -C(O)CH ₃ .

In some preferred embodiments, in S6, R ₅ is -NHR', where R' is hydrogen.

In some embodiments, in S6, R ₄ is a C ₁ -C ₄ haloalkyl group; R ₆ is hydrogen or halogen; or R ₄ and R ₆ and the carbon atoms to which they are connected form a ring together so that in S6 The fragment is .

In some embodiments, in the S6, when R ₄ is a C ₁ -C ₄ haloalkyl group, the C ₁ -C ₄ haloalkyl group may be a C ₁ -C ₄ fluoroalkyl group, such as trifluoromethyl base.

In some embodiments, in S6, R ₇ is C ₁ -C ₆ alkyl.

In some embodiments, in the S6, when R ₇ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a methyl group.

In some embodiments, in S6, R ₈ is C ₁ -C ₆ alkyl.

In some embodiments, in the S6, when R ₈ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a methyl group.

In some embodiments, the S6 Fragments can be , or .

In some embodiments, the S6 The fragment is preferably .

In some embodiments, the S6 The fragment is preferably .

In some embodiments, the S6 Fragments can be , , , , or , preferably or .

In some preferred embodiments, the S6 The fragment is .

In some more preferred embodiments, the S6 The fragment is .

Preferably, in certain embodiments of the present invention, R ₈ in S6 is methyl.

In some embodiments of the present invention, the S is S6': S6' wherein in S6', R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

In some embodiments of the present invention, in S6 and S6', The fragment is .

In certain embodiments of the present invention, the S is -X-S6', and the structure of S6' is as described above; X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S is S6a: S6a wherein in S6a, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, in the S6 or S6a, R ¹ is hydrogen; R ² is selected from -O(C ₁ -C ₄ alkyl); R ³ is hydrogen; R ⁴ is C ₁ - C ₄ haloalkyl; R ⁵ is selected from -NH ₂ ; R ⁷ is selected from C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl.

Preferably, in certain embodiments of the present invention, the S is S6b: S6b wherein in S6b, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S is S6c: S6c wherein in S6c, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

In certain embodiments of the present invention, the S is -X-S6c, and the structure and definition of S6c are as described above; wherein, X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S is S6d: S6d wherein in S6d, X is O, NH or S, preferably O; R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S6 is a specific compound of I-1 to I-383 in WO2018115380A1 (the entire text of which is incorporated herein by reference). Preferably, in certain embodiments of the present invention, the S is S6e: S6e wherein in S6e, R ₂ , R ₃ and R ₇ are as defined and described in any scheme of S6.

Preferably, in certain embodiments of the present invention, the S is -X-S6e, and the structure and definition of S6e are as described above; wherein, X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, in the S6e, R ₂ is -O(C ₁ -C ₄ alkyl); R ₃ is hydrogen; R ₇ is C ₁ -C ₆ alkyl.

Preferably, in certain embodiments of the present invention, in the S6e, R ₂ is -OCH ₃ ; R ₃ is hydrogen; R ₇ is methyl.

In some embodiments of the present invention, the S6, S6', S6a or S6c is any of the following structures: , , , , , , , , .

Preferably, in certain embodiments of the present invention, the S6, S6', S6a or S6c is .

Preferably, in certain embodiments of the present invention, the S6, S6', S6a, S6c or S6e is .

In some embodiments of the present invention, the S is .

In some embodiments of the present invention, the S is S6'': S6'' wherein in S6'', R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined and described in S6.

In some embodiments of the present invention, the S is S6''': S6''' wherein in S6''', R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined and described in S6.

In some embodiments of the present invention, among S6'' and S6'''', The fragment is .

In certain embodiments of the present invention, the S is -X-S6''', and the structure of S6''' is as described above; where X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S6'' is .

Preferably, in certain embodiments of the present invention, the S is S6a'': S6a'' wherein in S6a'', R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S is S6b'': S6b'' wherein in S6b'', R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S is S6c'': S6c'' wherein in S6c'', R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S is -X-S6c'', and the structure and definition of S6c'' are as described above; wherein, X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, the S is S6d'': S6d'' wherein in S6d'', X is O, NH or S, preferably O; R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S is S6e'': S6e'' wherein in S6e'', R ₃ and R ₇ are as defined and described in S6.

Preferably, in certain embodiments of the present invention, the S is -X-S6e'', and the structure and definition of S6e'' are as above; wherein, X is O, NH or S, preferably O.

Preferably, in certain embodiments of the present invention, in the S6e'', R ₃ is hydrogen; R ₇ is C ₁ -C ₆ alkyl.

Preferably, in certain embodiments of the present invention, in the S6e'', R ₃ is hydrogen; R ₇ is methyl.

Preferably, in certain embodiments of the present invention, the S6'', S6''', S6a'', S6c'' or S6e'' is .

Preferably, in certain embodiments of the present invention, the S is .

More preferably, in certain embodiments of the present invention, the S is or .

More preferably, in certain embodiments of the present invention, the S is .

In certain embodiments of the invention, L is a bond.

In certain embodiments of the present invention, L is -(CH ₂ ) _j -, and one or more methylene groups in -(CH ₂ ) _j - are optionally selected from -NR ^3' -, - O-, -S-, -S(O)-, -S(O)NR ^3' -, -NR ^3' S(O)-, -S(O) ₂ -, -S(O) ₂ NR ^{3 '} -, -NR ^3' S(O) ₂ -, -NR ^4' S(O) ₂ NR ^3' -, -CR ^1' R ^2' -, -C(O)-, -C(O)O -, -OC(O)-, -NR ^3' C(O)O-, -OC(O)NR ^3' -, -C(O)NR ^3' -, -NR ^3' C(O)-, -NR ^4' C(O)NR ^3' -, -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, vinylidene, ethynylene , 3-12-membered cycloalkylene, 3-12-membered heterocycloalkylene containing one or more heteroatoms selected from N, O or S, 6-10-membered arylene or 5-10-membered heteroatom Aryl groups are substituted, and the vinylidene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene groups are each independently optionally replaced by one or more halogen, -OR ^3' , -NR ^3' R ^4' , oxo, nitro, cyano, C1-C6 alkyl, -S (C1-C6 alkyl), C3-C10 cycloalkyl, C3-C10 heterocycloalkyl , 6-10 aryl, 5-10 membered heteroaryl, -C(O)R ^1' , -C(O)OR ^3' , -OC(O)R ^1' , -C(O)NR ^3' , -NR ^3' C(O)R ^1' , -S(O)R ^1' , -S(O)NR ^3' , -S(O) ₂ R ^1' , -S(O) ₂ NR ^3' , -NR ^3' S(O) ₂ R ^1' , -NR ^4' S(O) ₂ NR ^3' , -OC(O)NR ^3' , -NR ^4' Substituents of C(O)NR ^3' Substituted, the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are each independently optionally substituted by 1 or more selected from halogen, -OH, -NR ^3' R ^4' , oxygen generation, nitro, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl Substituent substitution; R ^1' and R ^2' are each independently halogen, -OH, -NR ^3' R ^4' , C ₁ -C ₆ alkyl, chloro C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), -NH(C ₁ -C ₆ alkyl), -NH(C ₁ -C ₆ alkyl) 2, C ₃ -C ₁₀ cycloalkyl, -O(C ₃ -C ₁₀ cycloalkyl), -NH(C ₃ -C ₁₀ cycloalkyl), C ₃ -C ₁₀ heterocycloalkyl, -O(C ₃ -C ₁₀ heterocycloalkyl), -NH(C ₃ -C ₁₀ heterocycloalkyl), 6-10 membered aryl, -O(6-10 membered aryl), -NH(6-10 membered aryl), 5-10 membered heteroaryl , -O (5-10 membered heteroaryl), -NH (5-10 membered heteroaryl), R ^3' and R ^4' are each independently hydrogen, deuterium, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25.

Preferably, in certain embodiments of the present invention, L is -(CH ₂ ) _j -, and one or more methylene groups in -(CH ₂ ) _j - are optionally selected from -NR ^3' -, -O-, -CR ^1' R ^2' -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O) -, -C(O)NR ^3' -, -NR ^3' C(O)-, -S(O) ₂ NR ^3' -, -NR ^3' S(O) ₂ -, vinylidene, ethynylene base, phenyl, 8-10 membered bicyclic arylene group, 3-7 membered saturated or partially unsaturated cycloalkylene group, 5-11 membered saturated or partially unsaturated spirocycloalkylene group, 5-11 membered Saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 4-7 membered with 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms Saturated or partially unsaturated heterocycloalkylene, having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene, having 1-2 5-11 membered saturated or partially unsaturated sub-fused heterocycloalkyl groups independently selected from nitrogen, oxygen or sulfur heteroatoms, 1-2 8-10 independently selected from nitrogen, oxygen or sulfur heteroatoms Membered bicyclic saturated or partially unsaturated heterocycloalkylene, 5-6 membered heteroarylene with 1-4 independently selected from nitrogen, oxygen or sulfur heteroatoms, or 1-5 selected from nitrogen, The 8-10 membered bicyclic heteroaryl group of oxygen or sulfur heteroatom is replaced by the vinylene group, ethynylene group, cycloalkylene group, heterocycloalkylene group, phenyl group, spiroheterocycloalkylene group, The fused heterocycloalkylene group, spirocycloalkylene group, fused cycloalkylene group and heteroarylene group are each independently optionally substituted by one or more selected from halogen, oxo, -NR ^3' R ^4' , -OR ^3' , nitro, -CN, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl substituents, the alkyl, cycloalkyl , Heterocycloalkyl is optionally substituted by one or more substituents selected from halogen, -OH, -NH ₂ , -CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, R ^{1 '} and R ^2' are each independently halogen, -OH, -NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ chloroalkyl, C ₁ -C ₄ hydroxyalkyl, -O(C ₁ - C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), C ₃ -C ₆ cycloalkyl, -O(C ₃ -C ₆ cycloalkyl ), -NH(C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ heterocycloalkyl, -O(C ₃ -C ₆ heterocycloalkyl), -NH(C ₃ -C ₆ cycloalkyl) ); R ^3' and R ^4' are each independently hydrogen, deuterium, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

Preferably, in certain embodiments of the present invention, L is -(CH ₂ ) _j -, and one or more methylene groups in -(CH ₂ ) _j - are optionally selected from -NR ^3' -, -O-, -CR ^1' R ^2' -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O) -, -C(O)NR ^3' -, -NR ^3' C(O)-, -S(O) ₂ NR ^3' -, -NR ^3' S(O) ₂ -, vinylidene, ethynylene base, phenyl, 8-10 membered bicyclic arylene group, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene group, 5-11 membered saturated or partially unsaturated spirocycloalkylene group, 5- 11-membered saturated or partially unsaturated fused cycloalkylene group, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, 5-7 membered cycloalkylene group with 1-2 independently selected from nitrogen or oxygen heteroatoms Saturated or partially unsaturated heterocycloalkylene group, with 1-2 independent 5-11-membered saturated or partially unsaturated spiroheterocycloalkylene group selected from nitrogen or oxygen heteroatoms, with 1-2 independent A 5-11-membered saturated or partially unsaturated subfused heterocycloalkyl group selected from nitrogen or oxygen heteroatoms, an 8-10-membered bicyclic saturated or partially unsaturated heterocycloalkyl group with 1-2 independently selected from nitrogen or oxygen heteroatoms Saturated heterocycloalkylene, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen or oxygen, or 8-10 membered heteroarylene having 1-5 heteroatoms selected from nitrogen or oxygen Bicyclic heteroaryl group substitution, the vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, fused ring Alkyl, spirocycloalkylene, and heteroarylene are each independently optionally substituted by one or more selected from halogen, oxo, -NR ^3' R ^4' , -OR ^3' , nitro, -CN , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl substituents, the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 Or substituted by multiple substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, R ^1' and R ^2' are each independently halogen, -OH, -NH _2. C ₁ -C ₄ alkyl, C ₁ -C ₄ chloroalkyl, C ₁ -C ₄ hydroxyalkyl, -O(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) base), -NH(C ₁ -C ₄ alkyl), C ₃ -C ₆ cycloalkyl, -O(C ₃ -C ₆ cycloalkyl), -NH(C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ heterocycloalkyl, -O(C ₃ -C ₆ heterocycloalkyl), -NH(C ₃ -C ₆ cycloalkyl); R ^3' and R ^4' are each independently hydrogen, Deuterium, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, j is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

Preferably, in certain embodiments of the present invention, L is -(CH ₂ ) _j -, and any of the 1, 2, 3, 4 or 5 methylene groups in -(CH ₂ ) _j - The selected one is selected from -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -CHF-, -CHCF ₃ -, -C(O)-, -C(O)O- , -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC(O)-, -NCH ₃ C(O)-, vinylene, ethynylene, vinylidene Cyclopropyl, cyclobutylene, cyclopentylene, cyclohexylene, oxirylene, oxetanyl, oxolanylene, oxohexylene, aziridine Base, azetidinyl, azopentyl, piperidinyl, piperidinyl, submofulinyl, subgomofulinyl, phenylene, pyrrolylene, thienylene , furylidene, imidazolylene, pyrazolylene, triazoleylidene, tetrazolylene, ethazolenylene, isothiazolylene, thiazolenylene, isothiazolylene, pyridylene, pyrimidine base, pyridine base, pyridine base, , , , , , , , , , , , , is replaced by a group, and the replacement group is optionally substituted by one or more substituents selected from halogen, oxo, -NR ^3' R ^4' , -OR ^3' , C1-C4 alkyl, The alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH ₂ , R ^3' and R ^4' are each independently hydrogen, deuterium, C1-C4 alkyl, j is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

Preferably, in certain embodiments of the present invention, L is -(CH ₂ ) _j -, and any of the 1, 2, 3, 4 or 5 methylene groups in -(CH ₂ ) _j - The selected one is selected from -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -CHF-, -CHCF ₃ -, -C(O)-, -C(O)O- , -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC(O)-, -NCH ₃ C(O)-, cyclopropylene, cyclobutylene , cyclopentylene, cyclohexylene, oxirylene, oxetanyl, oxetanyl, oxanyl, aziridyl, aziridinyl , Azocyclopentyl, piperidinyl, piperidinyl, submofulinyl, subgomofulinyl, , , , , , , , , , , , , The replacement group is optionally replaced by one or more groups selected from F, Cl, oxo, -NR ^3' R ^4' , -OR ^3' , C ₁ -C ₄ alkyl Substituted by substituents, the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH ₂ , R ^3' and R ^4' are each independently hydrogen, deuterium, methyl, ethyl group, propyl group, j is 3, 4, 5, 6, 7, 8, 9 or 10.

Preferably, in certain embodiments of the present invention, L is -(CH ₂ ) _j -, and any of the 1, 2, 3, 4 or 5 methylene groups in -(CH ₂ ) _j - The selected one is selected from -O-, -NH-, -NCH ₃ -, -C(O)-, -C(O)NH-, -NHC(O)-, -NCH ₃ C(O)-, - C(O)NCH ₃ -, cyclohexylene, aziridine, azitidine, azidine, piperidinyl, piperidylene, , , , , , , or group substitution, j is 4, 5, 6, 7, 8, 9 or 10.

Preferably, in certain embodiments of the present invention, L is selected from -(CH ₂ ) _j-1 -C(O)-, and the methylene group in -(CH ₂ ) _j-1 -C(O)- As defined in L above, optionally replaced by one or more groups, j is as defined in L above.

Preferably, in certain embodiments of the present invention, L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In some embodiments of the present invention, the L is any of the following structures: , , , , , , , , , , , , , , , , , .

Preferably, in certain embodiments of the present invention, L is LA, LA wherein: Ring A is a bond, C ₃ -C ₁₂ cycloalkylene (for example , , , where the a end is connected to S and the b end is connected to , , or , where the a end is connected to S and the b _end is connected to -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent; Ring B is a bond, C ₃ -C ₁₂ cycloalkylene (e.g. , , where the c-terminus _is connected to , or , where the c _- terminal is connected to ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent substitution; Ring C is C ₃ -C ₁₂ substituent Cycloalkyl (e.g. , , , where the e end is connected to L ₃ and the f end is connected to X'') or a 3-12 membered heterocycloalkylene group containing 1-2 selected from N, O or S heteroatoms (for example , , , , or , where the e end is connected to L ₃ and the f end is connected to X''), the cycloalkylene and heterocycloalkylene groups are optionally selected from halogen, oxo, cyano, amine, hydroxyl, _C -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent substitution; X'' is a bond, -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -S-, -C=C-, -C≡C-, -CHF-, -CHCF ₃ -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC( O)-, -NCH ₃ C(O)- or -C(O)CH ₂ O-; L ₃ is -(CH ₂ ) _k , and one or two methylene groups in L ₃ are optionally substituted Selected from -O-, -NH-, -C≡C-, -N(C ₁ -C ₆ alkyl)-, -N(C ₁ -C ₆ haloalkyl)-, -C(O)-, - N(C ₁ -C ₆ hydroxyalkyl)-or -N(C ₃ -C ₈ cycloalkyl)-replacement, k is 0, 1, 2, 3, 4, 5, 6 or 7; X''' is a bond, -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -S-, -C=C-, -C≡C-, -CHF-, -CHCF ₃ -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O) NCH ₃ -, -CH ₂ NCH ₃ -, -NHC(O)- or -NCH ₃ C(O)-.

In some embodiments, in the LA: Ring A is a bond, a C ₃ -C ₁₂ cycloalkylene group, or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O, or S , the cycloalkylene and heterocycloalkylene groups are optionally selected from halogen, oxo, cyano, amine, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent substitution; Ring B is a bond, C ₃ -C ₁₂ cycloalkylene or contains 1-2 selected from N, O or S 3-12 membered heterocycloalkylene group of heteroatom, the cycloalkylene group and heterocycloalkylene group are optionally selected from halogen, oxo, cyano, amine, hydroxyl, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent; Ring C is C ₃ -C ₁₂ cycloalkylene or contains 1 -2 3-12 membered heterocycloalkylene groups selected from N, O or S heteroatoms, the cycloalkylene and heterocycloalkylene groups are optionally selected from halogen, oxo, cyano, and amine groups , hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent substitution; X'' is a bond , -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -S-, -C=C-, -C≡C-, -CHF-, -CHCF ₃ -, -C (O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC(O)- or -NCH ₃ C(O)-; L ₃ is -(CH ₂ ) _k , and one or two methylene groups in L ₃ are optionally selected from -O- , -NH-, -N(C ₁ -C ₆ alkyl)-, -N(C ₁ -C ₆ haloalkyl)-, -N(C ₁ -C ₆ hydroxyalkyl)- or -N(C ₃ -C ₈ cycloalkyl) - substitution, k is 0, 1, 2, 3 or 4; X''' is a bond, -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ - , -S-, -C=C-, -C≡C-, -CHF-, -CHCF ₃ -, -C(O)-, -S(O)-, -S(O) ₂ -, -C (O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC(O)- or -NCH ₃ C(O)-.

In certain embodiments of the present invention, in the LA, L ₃ is -(CH ₂ ) _k , and one or two methylene groups in the L ₃ are optionally selected from -O-, -NH-, -C≡C-, -N(C ₁ -C ₆ alkyl)-, -N(C ₁ -C ₆ haloalkyl)-, -N(C ₁ -C ₆ hydroxyalkyl)- or -N(C ₃ -C ₈ cycloalkyl) - substitution, k is 0, 1, 2, 3, 4, 5, 6 or 7.

Preferably, in certain embodiments of the present invention, in the LA, ring A is a bond.

Preferably, in certain embodiments of the present invention, in the LA, ring A is a 3-7-membered saturated or partially unsaturated cycloalkylene group, or a 4-11-membered saturated or partially unsaturated spirocycloalkylene group. , 4-11 membered saturated or partially unsaturated fused cycloalkylene group, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, with 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 4-7 membered saturated or partially unsaturated heterocycloalkylene group, 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms , having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms, 4-11 yuan saturated or partially unsaturated sub-fused heterocycloalkyl, having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group.

Preferably, in certain embodiments of the present invention, in the LA, ring A is a 3-6-membered saturated cycloalkylene group or a 4-7-membered saturated cycloalkylene group with 1 or 2 independently selected from nitrogen heteroatoms. Monocyclic heterocycloalkylene.

Preferably, in certain embodiments of the present invention, in the LA, ring A is a cyclohexylene group (such as cyclohexan-1,4-diyl, such as trans cyclohexan-1,4-diyl), cyclohexylene group Piperidinyl (eg piperidin-1,4-diyl) or piperidinyl (eg piperidin-1,4-diyl).

In certain embodiments of the present invention, in the LA, ring A is , , , , , or , where the a end is connected to S and the b end is connected to X'''.

In certain embodiments of the present invention, in the LA, ring A is , or , where the a end is connected to S and the b end is connected to X'''.

In certain embodiments of the present invention, in the LA, Ring A is , where the a end is connected to S and the b end is connected to X'''.

Preferably, in certain embodiments of the present invention, in the LA, ring B is a bond.

Preferably, in certain embodiments of the present invention, in the LA, ring B is a 3-7-membered saturated or partially unsaturated cycloalkylene group, or a 4-11-membered saturated or partially unsaturated spirocycloalkylene group. , 4-11 membered saturated or partially unsaturated fused cycloalkylene group, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, with 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 4-7 membered saturated or partially unsaturated heterocycloalkylene group, 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms , having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms, 4-11 yuan saturated or partially unsaturated sub-fused heterocycloalkyl, having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group.

Preferably, in certain embodiments of the present invention, in the LA, ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, Heteroatom 7-11 membered spiroheterocycloalkyl or fused heterocycloalkyl.

Preferably, in certain embodiments of the present invention, in the LA, ring B is a piperidylene group (such as piperidin-1,4-diyl) or a piperidylene group (such as piperidine-1,4-diyl). base).

In certain embodiments of the present invention, in the LA, ring B is , , , or , where the c end is connected to X'''' and the d end is connected to L ₃ .

Preferably, in certain embodiments of the present invention, ring B is , or , where the c end is connected to X'''' and the d end is connected to L ₃ .

Preferably, in certain embodiments of the present invention, in the LA, ring C is a 3-7-membered saturated or partially unsaturated cycloalkylene group, or a 4-11-membered saturated or partially unsaturated spirocycloalkylene group. , 4-11 membered saturated or partially unsaturated fused cycloalkylene group, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, with 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 4-7 membered saturated or partially unsaturated heterocycloalkylene group, 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms , having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms, 4-11 yuan saturated or partially unsaturated sub-fused heterocycloalkyl, having 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group.

Preferably, in certain embodiments of the present invention, in the LA, ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, Heteroatom 7-11 membered spiroheterocycloalkyl or fused heterocycloalkyl.

Preferably, in certain embodiments of the present invention, in the LA, ring C is piperidylene (such as piperidin-1,4-diyl), piperidylene (such as piperidin-1,4-diyl). base), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )or (For example ).

In certain embodiments of the present invention, in the LA, ring C is , , , , , , , or , where the e end is connected to L ₃ and the f end is connected to X''.

In certain embodiments of the present invention, in the LA, Ring C is , , , , or , where the e end is connected to L ₃ and the f end is connected to X''.

Preferably, in certain embodiments of the present invention, ring A in the LA is a 3-6 membered saturated cycloalkylene group; ring B is a 4-7 membered saturated monocyclic heteroalkylene group containing 1 or 2 nitrogen heteroatoms. Cycloalkyl; Ring C is a 4-7-membered saturated monocyclic heterocycloalkylene containing 1 or 2 nitrogen heteroatoms, and a 7-11-membered spiroheterocyclic ring containing 1 or 2 nitrogen heteroatoms. _{Alkyl or} fused heterocycloalkyl _; , 2, 3 or 4).

Preferably, in certain embodiments of the present invention, in the LA, X'' is a bond or -C(O)-.

Preferably, in certain embodiments of the present invention, in the LA, X'' is a bond.

Preferably, in certain embodiments of the present invention, in the LA, X'' is -C(O)-.

Preferably, in certain embodiments of the present invention, in the LA, X'' is -C(O)CH ₂ O-.

Preferably, in certain embodiments of the present invention, in the LA, X''' is a bond or -C(O)-.

Preferably, in certain embodiments of the present invention, in the LA, X'''' is a bond.

Preferably, in certain embodiments of the present invention, in the LA, X''' is -C(O)-.

Preferably, in certain embodiments of the present invention, in the LA, k is 1, 2, 3, 4 or 5.

Preferably, in certain embodiments of the present invention, in the LA, L ₃ is -(CH ₂ ) _k , and k is 1, 2, 3, 4 or 5.

Preferably, in certain embodiments of the present invention, in the LA, L ₃ is -(CH ₂ ) _k , and one or two methylene groups in L ₃ are optionally replaced by -O-, -NH- , -C≡C- or -N(C ₁ -C ₆ alkyl)- (for example -N(CH ₃ )-) substitution, k is 1, 2, 3, 4 or 5.

Preferably, in certain embodiments of the present invention, in the LA, k is 1, 2, 3 or 4. Preferably, in certain embodiments of the present invention, in the LA, L ₃ is -(CH ₂ ) _k -, wherein one or two CH ₂ contained in the L ₃ are each independently optionally substituted by -O -, -NH- or -N(C ₁ -C ₆ alkyl)- (for example -N(CH ₃ )-), or a -CH ₂ CH ₂ - contained in the L ₃ is optionally replaced by - C≡C-substitution; k is 1, 2, 3 or 4.

Preferably, in certain embodiments of the present invention, in the LA, L ₃ is -(CH ₂ ) _k -, and one methylene group in the L ₃ is optionally replaced by -O-, -NH- or - Substitution of N(C ₁ -C ₆ alkyl)- (eg -N(CH ₃ )-); k is 1, 2, 3 or 4.

Preferably, in certain embodiments of the present invention, the LA is LA-1: LA-1 wherein said Ring A, Ring B, Ring C, L ₃ , X'' are as defined and described in LA.

In certain embodiments of the present invention, the LA is LA-2: LA-2 Among them, ring A is , , , , or , where the a end is connected to S and the b end is connected to X'''; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally replaced by F; X''' is -C(O)- ; Ring B is , , , or , where the c end is connected to X'''', and the d end is connected to L ₃ ; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally replaced by F; L ₃ is -(CH ₂ ) _k - , wherein one or two CH ₂ contained in said L ₃ are each independently optionally replaced by -O-, -NH- or -N(C ₁ -C ₆ alkyl)- (for example -N(CH ₃ ) -) substitution, or one -CH ₂ CH ₂ - contained in the L ₃ is optionally replaced by -C≡C-; k is 1, 2, 3 or 4; Ring C is , , , or , where the e end is connected to L ₃ and the f end is connected to X''; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F; X'' is -C(O)-.

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-2, ring A is , or , where the a end is connected to S and the b end is connected to X'''.

Preferably, in certain embodiments of the present invention, Ring B is , or , where the c end is connected to X'''' and the d end is connected to L ₃ .

In certain embodiments of the present invention, in the LA, LA-1 and LA-2, L ₃ is -(CH ₂ ) _k -, wherein one or two CH ₂ contained in the L ₃ are independently any The selected one is replaced by -O-, -NH- or -N(CH ₃ )-; k is 1, 2, 3 or 4.

In certain embodiments of the present invention, in the LA, LA-1 and LA-2, L ₃ is -(CH ₂ ) _k -, wherein one or two CH ₂ contained in the L ₃ are independently any The chosen one is replaced by -O-; k is 1, 2, 3 or 4.

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-2, k is 3 or 4, preferably 4.

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-2, L ₃ is -(CH ₂ ) _k -, wherein one CH ₂ contained in the L ₃ is optionally -O- substitution; k is 4.

In certain embodiments of the present invention, in the LA, LA-1 and LA-2, L ₃ can be -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) _4- , , , , , , or , where the k'' end is connected to ring B, and the k' end is connected to ring C.

Preferably, in certain embodiments of the present invention, among the LA, LA-1 and LA-2, L ₃ can be -(CH ₂ ) ₄ -, or .

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-2, Ring C is , or , where the e end is connected to L ₃ and the f end is connected to X''.

In certain embodiments of the present invention, the LA-2 has any of the following structures: , , , , , , , , , , , , , , .

Preferably, in certain embodiments of the present invention, the LA-2 has any of the following structures: , , , , , , .

In certain embodiments of the present invention, the LA is LA-3: LA-3 Among them, ring A is , , , , or , where the a end is connected to S and the b end is connected to X'''; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally replaced by F; X''' is -C(O)- ; Ring B is , , , or , where the c end is connected to X'''', and the d end is connected to L ₃ ; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally replaced by F; L ₃ is -(CH ₂ ) _k - , wherein one CH ₂ contained in L ₃ is optionally replaced by -O-, -NH- or -N(C ₁ -C ₆ alkyl)- (such as -N(CH ₃ )-); k is 1 or 2; Ring C is , , or , where the e end is connected to L ₃ and the f end is connected to X''; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F; X'' is -C(O)-.

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-3, ring A is , or , preferably or ;The a end is connected to S, and the b end is connected to X'''.

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-3, Ring B is , or , where the c end is connected to X'''' and the d end is connected to L ₃ .

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-3, L ₃ is -(CH ₂ ) _k -, and k is 1 or 2.

Preferably, in certain embodiments of the present invention, in the LA, LA-1 and LA-3, Ring C is , or , where the c end is connected to X'''' and the d end is connected to L ₃ .

In some embodiments of the present invention, the LA-3 has any of the following structures: , , , , , , , .

Preferably, in certain embodiments of the present invention, the LA-3 has any of the following structures: , , , , , .

In certain embodiments of the present invention, the LA is LA-4: LA-4 Among them, ring A is , , , , , , , where the a end is connected to S, and the b end is connected to X'''; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally replaced by F; X''' is a bond, -C(O )NH- or -C(O)NCH ₃ -; Ring B is a bond; L ₃ is -(CH ₂ ) _k , and one or two methylene groups in L ₃ are optionally replaced by -O-, - NH-, -C(O)-, -C≡C- or -N(C ₁ -C ₆ alkyl)-substitution, k is 0, 1, 2, 3, 4, 5, 6 or 7; Ring C for , , , , , , , or , where the e end is connected to L ₃ and the f end is connected to X''; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F; X'' is -C(O)-.

In certain embodiments of the present invention, in the LA-4, ring A is , or , where the a end is connected to S and the b end is connected to X'''.

In certain embodiments of the present invention, in the LA-4, L ₃ is -CH ₂ -, , or , where the k'' end is connected to ring B, and the k' end is connected to ring C.

In certain embodiments of the present invention, in the LA-4, ring C is or , where the e end is connected to L ₃ and the f end is connected to X''.

In some embodiments of the present invention, the LA-4 has any of the following structures: , , , , .

Preferably, in certain embodiments of the present invention, the LA-4 has any of the following structures: , .

In certain embodiments of the present invention, the LA is LA-5: LA-5 Among them, ring A, X''', ring B, L ₃ and ring C are as defined in LA-2 or LA-3; X'' is -C(O)CH ₂ O-, in X'' The -C(O)- is connected to ring C.

In certain embodiments of the present invention, in the LA-5, Ring A is , where the a end is connected to S and the b end is connected to X'''.

In certain embodiments of the present invention, in the LA-5, Ring B is , where the c end is connected to X'''' and the d end is connected to L ₃ .

In certain embodiments of the present invention, in the LA-5, L ₃ is -(CH ₂ ) _k , k is 1 or 2, preferably 1.

In certain embodiments of the present invention, in the LA-5, ring C is , where the e end is connected to L ₃ and the f end is connected to X''.

Preferably, in certain embodiments of the present invention, the LA-5 is .

Preferably, in certain embodiments of the present invention, the LA is , , , , , , , , , , , , , , , , , , , , , , , , , , or .

Preferably, in certain embodiments of the present invention, the E is CRBN, VHL, XAIP or MDM2 E3 ubiquitin ligase small molecule ligand.

Preferably, in certain embodiments of the present invention, the E is E1, E1a, E1b or E1c , , E1 E1a or , E1b E1c wherein E1, E1a, E1b or E1c: Each R ¹ is independently halogen, optionally substituted hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted Alkynyl, optionally substituted carbocyclic ring, optionally substituted heterocyclic ring, optionally substituted aryl group, optionally substituted heteroaryl group, -CN or -O(CH ₂ ) _X R ^1A ; and there is at least one R ¹ is -O(CH ₂ ) _x R ^1A ; R ⁶ is unsubstituted isopropyl, -(CH ₂ )C(O)OMe, or -(CH ₂ ) ₂ OH; R ^6A is substituted alkyl; R ⁷ is hydrogen, optionally substituted acyl group, optionally substituted alkyl group or nitrogen protecting group; R ^1A is hydrogen, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted carbocyclic ring, optionally substituted heterocyclic ring, optionally substituted aryl group, optionally substituted heteroaryl group, -OR ^A , -N( ^RB ) ₂ , or -SR ^A ; each ^RA is independently is hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, and is an oxygen protecting group when connected to O and a sulfur protecting group when connected to S; each R ^B is independently hydrogen, optionally Substituted acyl group, optionally substituted alkyl, nitrogen protecting group; n is 1, 2, 3 or 4; and x is 0, 1, 2, 3, 4, 5 or 6, and when R ⁶ is isopropyl group, R ^6A is methyl, R ⁷ is hydrogen, when n is 1, R ¹ is not methyl or hydroxymethyl.

Preferably, in certain embodiments of the present invention, the E is E2 E2 wherein in E2: X ₁₀₁ is a bond, -CH ₂ -, -CHCF ₃ -, -S(O) ₂ -, -S(O)-, -P(O)R ₁₀₀ -, -P(O )OR ₁₀₀ -, -P(O)N(R ₁₀₀ ) ₂ , -C(O)-, -C(S)-, or _{; X 201 is C or Si ;} Halogen, -CN, -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -P(O)(OR ₁₀₀ ) ₂ , - P(O)[N(R ₁₀₀ ) ₂ ](OR ₁₀₀ ), -P(O)[N(R ₁₀₀ ) ₂ ] ₂ , -Si(OH) ₂ (R ₁₀₀ )-, -Si(OH)( R ₁₀₀ ) ₂ -, -Si(R ₁₀₀ ) ₃ -, or optionally substituted C ₁ -C ₄ alkyl; R ₂₀₁ is selected from hydrogen, -R ₆₀₁ , halogen, -CN, -NO ₂ , -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -S(O) ₂ N(R ₁₀₀ ) ₂ , -C(O)R ₁₀₀ , -C(O)OR ₁₀₀ , -C(O)N(R ₁₀₀₎₂ , -OC(O)R ₁₀₀ , -OC(O)N(R ₁₀₀ ) ₂ , -NR ₁₀₀ C(O)OR ₁₀₀ , -NR ₁₀₀ C(O)R ₁₀₀ , -NR ₁₀₀ C(O)N(R ₁₀₀ ) ₂ , -OP(O)(R ₁₀₀ ) ₂ , -OP(O)(OR ₁₀₀ ) ₂ , -OP (O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -OP(O)[N(R ₁₀₀ ) ₂ ], -NP(O)(R ₁₀₀ ) ₂ , -NR ₁₀₀ P(O)(OR ₁₀₀ ) ₂ , -N(R ₁₀₀ ) P(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -N(R ₁₀₀ ) P(O) [N(R ₁₀₀ ) ₂ ] ₂ , or -NR ₁₀₀ S(O) ₂ R ₁₀₀ ; L ₁₀₁ is a bond or a C ₁ -C ₄ alkylene group, and 1 or 2 methylene groups in the C ₁ -C ₄ alkylene group are optionally selected from -O-, -C(O)-, -C(S)-, -C(R ₁₀₀ ) ₂ -, -CH(R ₁₀₀ )-, -C(F) ₂ -, -N(R ₁₀₀ )-, -S- , -S(O) ₂ -or -CH=CH substitution; Ring A is bicyclic or tricyclic, selected from or ; Among them: Ring B is a 6-membered heteroaryl group containing 1-2 N atoms, phenyl group, a 5-7-membered saturated or partially unsaturated cycloalkyl group, containing 1-2 members selected from N, O, S 5-7 membered saturated or partially unsaturated heterocycloalkyl group of heteroatoms, or 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, O, S; R ₃₀₁ is selected from hydrogen, halogen, -OR ₁₀₀ , -SR ₁₀₀ or -N(R ₁₀₀ ) ₂ ; R ₄₀₁ is hydrogen, -R ₆₀₁ , -halogen, -CN, nitro, -OR ₁₀₀ , -SR ₁₀₀ , -N(R ₁₀₀ ) ₂ , -S (O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -S(O) ₂ N(R ₁₀₀ ) ₂ , -C(O)R ₁₀₀ , -C(O)OR ₁₀₀ , -C(O)N(R ₁₀₀₎₂ , -OC(O)R ₁₀₀ , -OC(O)N(R ₁₀₀ ) ₂ , -NR ₁₀₀ C(O)OR ₁₀₀ , -NR ₁₀₀ C(O )R ₁₀₀ , -NR ₁₀₀ C(O)N(R ₁₀₀ ) ₂ or -NR ₁₀₀ S(O) ₂ R ₁₀₀ ; R ₅₀₁ is hydrogen, -CN or C ₁ -C ₄ alkyl; R ₆₀₁ is optional Substituted C ₁ -C ₆ alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 selected from N, O or S heteroatoms, containing 1-4 selected 5-6 membered heteroaryl from N, O or S heteroatoms; R ₁₀₀ is selected from hydrogen, optionally substituted C ₁ -C ₆ alkyl, phenyl, containing 1-2 selected from N, O or 4-7 membered saturated or partially unsaturated heterocycloalkyl group containing S heteroatom, 5-6 membered heteroaryl group containing 1-4 selected from N, O or S heteroatoms, or two R ₁₀₀ and its The connected N atoms together form a saturated or partially unsaturated 4-7-membered heteroaryl group that in addition to the connected N atoms also contains 0-3 heteroatoms selected from N, O or S; m'' is 0, 1, 2, 3 or 4.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E3: _{E3 Where : _ _ 100} -, -P(O)N(R ₁₀₀ ) ₂ , -C(O)-, -C(S)-, or ; X ₂₀₁ is C, N, or Si; X ₃₀₁ is -CH ₂ -, -O-, -S-, -C( _{R 100} ) ₂ - or -Si(R ₁₀₀ ) ₂ -; Deuterium, halogen, -CN, -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -P(O)(OR ₁₀₀ ) ₂ , -P(O)[N(R ₁₀₀ ) ₂ ](OR ₁₀₀ ), -P(O)[N(R ₁₀₀ ) ₂ ] ₂ , -Si(OH) ₂ (R ₁₀₀ )-, -Si(OH )(R ₁₀₀ ) ₂ -, -Si(R ₁₀₀ ) ₃ -, or an optionally substituted C ₁ -C ₄ alkyl group; L ₁₀₁ is a bond or a C ₁ -C ₄ alkylene group, and the C ₁ - One or two methylene groups in the C ₄ alkylene group are optionally selected from -O-, -C(O)-, -C(S)-, -C(R ₁₀₀ ) ₂ -, -CH(R ₁₀₀ )-, -C(F) ₂ -, -N(R ₁₀₀ )-, -S-, -S(O) ₂ -or -CH=CH substitution; Ring A does not exist or is monocyclic or bicyclic, selected from : or ; R ₂₀₁ is selected from hydrogen, -R ₆₀₁ , halogen, -CN, -NO ₂ , -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -S(O) ₂ NR ₁₀₀ , -C(O)R ₁₀₀ , -C(O)OR ₁₀₀ , -C(O)N(R ₁₀₀₎₂ , -OC(O)R ₁₀₀ , -OC (O)N(R ₁₀₀ ) ₂ , -NR ₁₀₀ C(O)OR ₁₀₀ , -NR ₁₀₀ C(O)R ₁₀₀ , -NR ₁₀₀ C(O)N(R ₁₀₀ ) ₂ , -OP(O)( R ₁₀₀ ) ₂ , -OP(O)(OR ₁₀₀ ) ₂ , -OP(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -OP(O)[N(R ₁₀₀ ) ₂ ], -NP (O)(R ₁₀₀ ) ₂ , -NR ₁₀₀ P(O)(OR ₁₀₀ ) ₂ , -N(R ₁₀₀ ) P(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -N(R ₁₀₀ )P(O)[N(R ₁₀₀ ) ₂ ] ₂ , or -NR ₁₀₀ S(O) ₂ R ₁₀₀ ; Ring B is a 6-membered heteroaryl, phenyl, 5- 7-membered saturated or partially unsaturated cycloalkyl, 5-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S, or 1-3 selected from 5-membered heteroaryl group with N, O, S heteroatoms; R ₃₀₁ and R ₄₀₁ are each independently hydrogen, -R ₆₀₁ , halogen, -CN, -NO ₂ , -OR ₁₀₀ , -SR ₁₀₀ , -S(O )R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -S(O) ₂ NR ₁₀₀ , -C(O)R ₁₀₀ , -C(O)OR ₁₀₀ , -C(O )N(R ₁₀₀₎₂ , -OC(O)R ₁₀₀ , -OC(O)N(R ₁₀₀ ) ₂ , -NR ₁₀₀ C(O)OR ₁₀₀ , -NR ₁₀₀ C(O)R ₁₀₀ , -NR ₁₀₀ C(O)N(R ₁₀₀ ) ₂ or -NR ₁₀₀ S(O) ₂ R ₁₀₀ ; R ₅₀₁ is hydrogen, -CN or C ₁ -C ₄ alkyl; R ₆₀₁ is optionally substituted C ₁ -C ₆ Alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, containing 1-4 heteroatoms selected from N, O or S 5-6 membered heteroaryl of heteroatoms; R ₁₀₀ is selected from hydrogen, optionally substituted C ₁ -C ₆ alkyl, phenyl, 4-containing 1-2 heteroatoms selected from N, O or S 7-membered saturated or partially unsaturated heterocycloalkyl, 5-6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or two R ₁₀₀ together with the N atom to which they are connected In addition to connecting N atoms, the formation also contains 0-3 heteroatoms selected from N, O or S; P'' is 0 or 1; m'' is 0, 1 or 2; n'' is 0, 1, 2, 3 or 4.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E4: E4 wherein in E4: X ₁₀₁ is a bond, -CH ₂ -, -CHCF ₃ -, -S(O) ₂ -, -S(O)-, -P(O)R ₁₀₀ -, -P(O )OR ₁₀₀ -, -P(O)N(R ₁₀₀ ) ₂ , -C(O)-, -C(S)-, or ; X ₂₀₁ is C, N, or Si; X ₃₀₁ is -CH ₂ -, -O-, -S-, -C( _{R 100} ) ₂ - or -Si(R ₁₀₀ ) ₂ -; Deuterium, halogen, -CN, -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -P(O)(OR ₁₀₀ ) ₂ , -P(O)[N(R ₁₀₀ ) ₂ ](OR ₁₀₀ ), -P(O)[N(R ₁₀₀ ) ₂ ] ₂ , -Si(OH) ₂ (R ₁₀₀ )-, -Si(OH )(R ₁₀₀ ) ₂ -, -Si(R ₁₀₀ ) ₃ -, or an optionally substituted C ₁ -C ₄ alkyl group; L ₁₀₁ is a bond or a C ₁ -C ₄ alkylene group, and the C ₁ - One or two methylene groups in the C ₄ alkylene group are optionally selected from -O-, -C(O)-, -C(S)-, -C(R ₁₀₀ ) ₂ -, -CH(R ₁₀₀ )-, -C(F) ₂ -, -N(R ₁₀₀ )-, -S-, -S(O) ₂ - or -CH=CH substitution; R ₂₀₁ is selected from hydrogen, -R ₆₀₁ , halogen, - CN, -NO ₂ , -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -S(O) ₂ NR ₁₀₀ , -C (O)R ₁₀₀ , -C(O)OR ₁₀₀ , -C(O)N(R ₁₀₀₎₂ , -OC(O)R ₁₀₀ , -OC(O)N(R ₁₀₀ ) ₂ , -NR ₁₀₀ C (O)OR ₁₀₀ , -NR ₁₀₀ C(O)R ₁₀₀ , -NR ₁₀₀ C(O)N(R ₁₀₀ ) ₂ , -OP(O)(R ₁₀₀ ) ₂ , -OP(O)(OR ₁₀₀ ) ₂ , -OP(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -OP(O)[N(R ₁₀₀ ) ₂ ], -NP(O)(R ₁₀₀ ) ₂ , -NR ₁₀₀ P( O)(OR ₁₀₀ ) ₂ , -N(R ₁₀₀ ) P(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -N(R ₁₀₀ ) P(O) [N(R ₁₀₀ ) ₂ ] ₂ , or -NR ₁₀₀ S(O) ₂ R ₁₀₀ ; R ₆₀₁ is optionally substituted C ₁ -C ₆ alkyl, phenyl, 4-7 yuan containing 1-2 heteroatoms selected from N, O or S Saturated or partially unsaturated heterocycloalkyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; R ₁₀₀ is selected from hydrogen, optionally substituted C ₁ -C ₆ Alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, containing 1-4 heteroatoms selected from N, O or S A 5-6 membered heteroaryl group of heteroatoms, or the two R _100s together with the N atoms connected to them form a ring that in addition to the connected N atoms also contains 0-3 heteroatoms selected from N, O or S; Ring E , Ring F and Ring G are each independently a 6-membered heteroaryl group containing 1-2 N atoms, phenyl, a 5-7-membered saturated or partially unsaturated cycloalkyl group, containing 1-2 N atoms selected from , 5-7 membered saturated or partially unsaturated heterocycloalkyl group with O and S heteroatoms, or 5-membered heteroaryl group containing 1-3 selected from N, O, S heteroatoms; m'' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E5: E5 wherein in E5: ring M is selected from , , , , , , , , or _{; Each X 101 , X 601} and , -P(O)OR ₁₀₀ -, -P(O)N(R ₁₀₀ ) ₂ , -C(O)-, -C(S)-, or ; Each X ₃₀₁ and X ₅₀₁ is independently a bond _, -C(R ₁₀₀ ) ₂ -, -NR ₁₀₀ -, -O-, -S-, or -Si(R ₁₀₀ ) ₂ -; , , , , , or ; Each R ₁₀₀ is independently selected from hydrogen, optionally substituted C ₁ -C ₆ alkyl, phenyl, 4-7 yuan saturated or containing 1-2 heteroatoms selected from N, O or S. Partially unsaturated heterocycloalkyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or two R _100s formed together with the N atom to which they are connected in addition to the N atom to which they are connected. In addition, it also contains 0-3 heteroatoms selected from N, O or S; each R _301a is independently hydrogen, deuterium, -R ₆₀₁ , halogen, -CN, -NO ₂ , -OR ₁₀₀ , -SR ₁₀₀ , -N(R ₁₀₀ ) ₂ , -Si(R ₁₀₀ ) ₃ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -S(O) ₂ N(R ₁₀₀ ) ₂ , -C (O)R ₁₀₀ , -C(O)OR ₁₀₀ , -C(O)N(R ₁₀₀ ) ₂ , -C(O)N(R ₁₀₀ )OR ₁₀₀ , -C(R ₁₀₀ ) ₂ N (R ₁₀₀ )C(O)R ₁₀₀ , -C(R ₁₀₀ ) ₂ N (R ₁₀₀ )C(O) N(R ₁₀₀ ) ₂ , -OC(O)R ₁₀₀ , -OC(O)N(R ₁₀₀ ) ₂ , -NR ₁₀₀ C(O)OR ₁₀₀ , -NR ₁₀₀ C(O)R ₁₀₀ , -NR ₁₀₀ C(O)N(R ₁₀₀ ) ₂ , -OP(O)(R ₁₀₀ ) ₂ , -OP(O )(OR ₁₀₀ ) ₂ , -OP(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -OP(O)[N(R ₁₀₀ ) ₂ ], -NP(O)(R ₁₀₀ ) ₂ , -NR ₁₀₀ P(O)(OR ₁₀₀ ) ₂ , -N(R ₁₀₀ ) P(O)(OR ₁₀₀ )[N(R ₁₀₀ ) ₂ ], -N(R ₁₀₀ ) P(O) [N(R ₁₀₀ ) ₂ ] ₂ , or -NR ₁₀₀ S(O) ₂ R ₁₀₀ ; Each R ₆₀₁ is independently an optionally substituted C ₁ -C ₆ alkyl group, phenyl group, containing 1-2 selected from N, 4-7 membered saturated or partially unsaturated heterocycloalkyl with O or S heteroatoms, 5-6 membered heteroaryl containing 1-4 selected from N, O or S heteroatoms; each R ₇₀₁ is individually Independently, hydrogen, deuterium, halogen, -CN, -OR ₁₀₀ , -SR ₁₀₀ , -S(O)R ₁₀₀ , -S(O) ₂ R ₁₀₀ , -N(R ₁₀₀ ) ₂ , -P(O) (OR ₁₀₀ ) ₂ , -P(O)[N(R ₁₀₀ ) ₂ ](OR ₁₀₀ ) , -P(O)[N(R ₁₀₀ ) ₂ ] ₂ , -Si(OH) ₂ (R ₁₀₀ )- , -Si(OH)(R ₁₀₀ ) ₂ -, -Si(R ₁₀₀ ) ₃ -, or optionally substituted C1-C4 alkyl; or R ₇₀₁ and X ₁₀₁ or X ₃₀₁ together with the atom to which they are connected. 5-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si or S; or two R ₇₀₁ on the same carbon and the atoms to which they are connected Together they form a 3-6 membered ring or a 4-7 membered heterocyclic ring containing 1-2 heteroatoms selected from boron, N, O, Si or S; or two R ₇₀₁ on adjacent carbons together with the atoms they are connected to form A 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring containing 1-3 heteroatoms selected from boron, N, O, Si or S, or a saturated or partially unsaturated carbocyclic ring containing 1-3 heteroatoms. 7-13-membered bridged heterocycle or spiroheterocycle selected from boron, N, O, Si or S heteroatoms; Ring D is each independently a 6-membered 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, O or S Heteroaryl, phenyl, 5-7-membered saturated or partially unsaturated cycloalkyl, 5-7-membered saturated or partially unsaturated heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S , or a 5-membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S; L ₁₀₁ is a bond or a C ₁ -C ₄ alkylene group, and 1 of the C ₁ -C ₄ alkylene groups Or 2 methylene is optionally selected from -O-, -C(O)-, -C(S)-, -C(R ₁₀₀ ) ₂ -, -CH(R ₁₀₀ )-, -C(F) ₂ -, -N(R ₁₀₀ )-, -S-, -S(O) ₂ - or -CH=CH- group substitution; n'' is 0, 1, 2, 3 or 4; q'' is 0, 1, 2, 3 or 4.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E6, E6a, E6b, E6c, E6d, E6e, E6f, E6g, E6h or E6i: E6 E6a E6b E6c E6d E6e E6f E6g or E6h E6i Wherein E6, E6a, E6b, E6c, E6d, E6e, E6f, E6g, E6h or E6i: for or ; Y is a bond, Y ₁ , O, NH, NR ₂ , C(O)O, C(O)NR ₂ ', Y ₁ -O, Y ₁ -NH, Y ₁ -NR ₂ , Y ₁ -C( O), Y1-C(O)O, Y ₁ -OC(O), Y ₁ -C(O)NR ₂ ' or Y ₁ -NR ₂ 'C(O), where Y ₁ is C ₁ -C ₆ Alkylene, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; X is C(O) or C(R ₃ ) ₂ ; X ₁ -X ₂ is C(R ₃ )=N or C (R ₃ ) ₂ -C(R ₃ ) ₂ ; Each R ₁ is independently halogen, nitro, NH ₂ , OH, C(O)OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl Oxygen group; R ₂ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl or C(O)-3-8 membered hetero Cycloalkyl, and R ₂ may optionally be replaced by one or more halogens, N(R _a ) ₂ , NHC(O)R _a , NHC(O)OR _a , OR _b , C ₃ -C ₈ cycloalkyl , 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, wherein C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl may be optionally substituted by one or more halogen, NH ₂ , CN, nitro, OH, C(O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy substituted; R ₂ ' is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ Cycloalkyl or 3-8-membered heteroheterocycloalkyl, and when R ₂ ' is not H, it can optionally be replaced by one or more halogens, N(R _a ) ₂ , NHC(O)R _a , NHC (O) OR _a , OR _b , C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl substituted, wherein C ₃ -C _8- cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl may optionally be replaced by another or more halogens, NH ₂ , CN, nitro, OH, C(O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy substituted; each R ₃ is independently H or C ₁ -C ₃ alkyl, the C ₁ -C ₃ alkyl is optionally substituted by C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; each R ₃ ' is independently C ₁ -C ₃ alkyl; each R ₄ is independently H or C ₁ -C ₃ alkyl; or two R ₄ together with the carbon atoms to which they are attached form C(O), C ₃ -C ₆ cycloalkyl or contains 1 or 2 4-, 5- or 6-membered heterocycloalkyl groups of heteroatoms selected from N and O; R ₅ is H, C ₁ -C ₃ alkyl, F or Cl; each R _a is independently H or C ₁ -C ₆ alkyl; R _b is H or toluene sulfonyl group; t is 0 or 1; m is 0, 1, 2 or 3; n is 0, 1 or 2. _{Rings A , _ _ _ _ _ _} Incorporated into this article by reference.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E7, E7b, E7c, E7d or E7e: E7 E7b E7c or E7d E7e wherein in E7, E7b, E7c, E7d and E7e: W is CH ₂ , CR _a R _b , C(S), C(O) or SO ₂ ; X is H ₂ , CH ₂ , O or S ; Y is NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocycloalkyl, O or S; Z is H ₂ , CH ₂ , O or S, And in E7c, Z cannot be H ₂ at the same time; G and G′ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, OH, -CH ₂ -heterocycloalkyl optionally substituted by R ^′ , optional -CH ₂ -phenyl substituted by R ^′ ; Q ₁ , Q ₂ , Q ₃ , Q ₄ are each independently carbon, nitrogen or nitrogen oxide; A is hydrogen, C ₁ -C ₆ alkyl, cycloalkyl Or halogen; R, R _a and R _b are each independently selected from hydrogen, hydroxyl, halogen, -NH ₂ , -N(C ₁ -C ₆ alkyl) _1-2 , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -CONR _′ R _′′ , -OR _′ , -NR _′ R _′′ , -SR _′ , -SO ₂ R _′ , -SO ₂ NR _′ R _{′ ′} , -CR _′ R _′′ , -CR _′ NR _′ R _′′ , aryl, heteroaryl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR _′ )R _′′ , -P(O)R _′ R _′′ , -OP(O)(OR _′ )R _′′ , -Cl, -F, -Br, -I, -CF ₃ , -CN, - NR _′ SO ₂ NR _′ R _′′ , -NR _′ C(O)NR _′ R _′′ , -C(O)NR _′ C(O)R _′′ , -NR _′ C(=N-CN)NR _′ R _′′ , - C(=N-CN)NR _′ R _′′ , -NR _′ C(=N-CN)R _′′ , -NR _′ C(=C-NO ₂ )NR _′ R _′′ , - SO ₂ NR _′ COR _′′ , -NO ₂ , -COR _′ , -C(C=N-OR _′ )R _′′ , -CR _′ =CR _′ R _′′ , -CCR _′ , -S(C=O )(C=NR _′ )R _′′ , -SF ₅ or -OCF ₃ ; R _′ and R _′′ are each independently selected from bond, hydrogen, C ₁ -C ₆ alkyl, cycloalkyl, aryl, hetero Aryl or heterocycloalkyl; n ^′′ is an integer from 1 to 4; ----- is a bond, which can be R stereoisomer, S stereoisomer or non-stereoisomer.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is: .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E8, E8a, E8b, E8c, E8d, E8e, E8f, E8g, E8h, E8i, E8j, E8k, E8l, E8m, E8n, E8o, E8p, E8q, E8s, E8t, E8u , E8v, E8w, E8x, E8y, E8z, E8aa, E8bb or E8cc: E8 E8a E8b E8c E8d E8e E8f E8g E8h E8i E8k E8l E8m E8n E8o E8p E8q E8s E8t E8v E8w E8x E8y E8z E8aa or E8bb E8cc wherein said E8, E8a, E8b, E8c, E8d, E8e, E8f, E8g, E8h, E8i, E8j, E8k, E8l, E8m, E8n, E8o, E8p, E8q, E8s, E8t, E8u, E8v, E8w , E8x, E8y, E8z, E8aa, E8bb or E8cc: W is independently selected from CH ₂ , CHR, C(O) or SO ₂ ; Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ are each independently selected is carbon, N, or N substituted by R', or nitrogen oxide; R ¹ is absent, or is hydrogen, hydroxyl, cyano, C ₁ -C ₃ alkyl or C(O); R ² is absent, Or hydrogen, hydroxyl, cyano, C ₁ -C ₃ alkyl, CHF ₂ , CF ₃ , CHO or C(O)NH ₂ ; R ³ is selected from hydrogen, alkyl (such as: C ₁ -C ₆ alkyl Or C ₁ -C ₃ alkyl), optionally substituted alkyl (such as: C ₁ -C ₆ alkyl or C ₁ -C ₃ alkyl), alkoxy (such as: C ₁ -C ₆ alkoxy group or C ₁ -C ₃ alkoxy group), optionally substituted alkoxy group (such as: C ₁ -C ₆ alkoxy group or C ₁ -C ₃ alkoxy group); R ⁴ is selected from hydrogen, alkyl group Or an optionally substituted alkyl group; R ⁵ or R ⁶ are each independently selected from hydrogen, halogen, C(O)R', cyano, hydroxyl, CF ₃ ; X is carbon, nitrogen or C(O); X ₁ is carbon, nitrogen or C(O); R' is selected from hydrogen, halogen, amine, alkyl (such as: C ₁ -C ₃ alkyl), optionally substituted alkyl (such as: C ₁ -C ₃ alkyl group), alkoxy group (such as: C ₁ -C ₃ alkoxy group), optionally substituted alkoxy group (such as: C ₁ -C ₃ alkoxy group), NR ² R ³ , C(O)OR ² , optionally substituted phenyl; R is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl; n is 0, 1, 2, 3 or 4 ; Be a single bond or a double bond.

In a preferred embodiment of the compound of formula I of the present invention, and/or its stereoisomer, hydrate, solvate, prodrug and/or its pharmaceutically acceptable salt, E is E9a, E9b, E9c, E9d, E9e, E9f, E9g, E9h, E9i, E9j, E9k, E9l, E9m, E9n, E9o, E9p, E9q, E9r or E9s: , , E9a E9b , , E9c E9d E9e , , , E9f E9g E9h , , E9i E9j E9k , , , E9l E9m E9n , , E9o E9p , E9s E9r E9q wherein said E9a, E9b, E9c, E9d, E9e, E9f, E9g, E9h, E9i, E9j, E9k, E9l, E9m, E9n, E9o, E9p, E9q, E9r or E9s: W is independently selected from CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl; R ¹ is selected from H, CN, C ₁ -C ₃ alkyl; R ² is H or C ₁ -C ₃ alkyl; R ⁴ is methyl or ethyl; R ⁵ is H or halogen; R ⁶ is H or halogen; R is H; R' is H; Q ₁ and Q ₂ are each independently selected from H or C ₁ -C ₃ Alkyl groups substituted with C or N; Is it a single bond or a double bond.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E10, E10a or E10b: E10 E10a E10b wherein in E10, E10a or E10b: X ^A is C(O) or C(R ^3A ) ₂ ; Z is NR ^3A or CR ^3A ; each R ^1A is independently halogen, hydroxyl, -C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; each R ^3A is independently hydrogen or C ₁ -C ₃ alkyl; R ^3' is each independently C ₁ -C ₃ alkyl; each Each R ^4A is independently hydrogen or C ₁ -C ₃ alkyl, or two R ^4A together with the carbon atom to which it is connected form a C(O), C3-C6 cycloalkyl group, or together they form a group containing 1 or 2 A 3-membered, 4-membered, 5-membered or 6-membered heterocycloalkyl group selected from N or O heteroatoms; R ^5A is selected from hydrogen, C ₁ -C ₃ alkyl or halogen; Each R ^6A is independently hydrogen Or C ₁ -C ₃ alkyl, or two R ^6A and the carbon atom to which it is connected together form C(O), C ₃ -C ₆ cycloalkyl, or together form a group containing 1 or 2 selected from N or O 3-, 4-, 5- or 6-membered heterocycloalkyl group of heteroatom; m is 0, 1, 2 or 3; n is 0, 1 or 2; a1 is 0 or 1.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E11: E11 wherein in E11: -X ₁ -X ₂ - is -C(R ^3A )=N- or -C(R ^3A ) ₂ -C(R ^3A ) ₂ -; each R ^1A is independently halogen , hydroxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ^3A is hydrogen or C ₁ -C ₃ alkyl; R ^3' is each independently C ₁ -C ₃ alkyl; R ^4A is hydrogen, or C ₁ -C ₃ alkyl; or two R ^4A together with the carbon atom to which they are connected form C(O), C ₃ -C ₆ cycloalkyl, or together form a group containing 1 or 2 selected from 4-membered, 5-membered or 6-membered heterocycloalkyl group with N or O heteroatom; m is 0, 1, 2 or 3; n is 0, 1 or 2; a1 is 0 or 1.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E12: E12 wherein in E12: each R ^2' is independently halogen, hydroxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; each R ^4' is independently halogen, hydroxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; each R ^5' is independently halogen, hydroxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; n1 is 0 , 1, 2, 3, 4, 5 or 6; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1 or 2.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E13: E13 wherein in E13: R ^3A is hydrogen or C1-C3 alkyl; each R ^3' is C ₁ -C ₃ alkyl; each R ^6' is independently halogen, hydroxyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; n1 is 0, 1, 2, 3, 4 or 5; m1 is 0, 1, 2, 3, 4 or 5.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E14, E14a, E14b, E14c, E14d or E14e: E14 E14a E14b E14c or , E14d E14e wherein among E14, E14a, E14b, E14c, E14d and E14e, Ar is an aryl group, cycloalkyl group, heterocycloalkyl group or heteroaryl group; L does not exist or is -SO ₂ , -SO ₂ R ' , SO ₂ R'R'' , -SO ₂ NR'R'' , -SO ₂ NR'R'' C(=O) , -NR' SO ₂ R'' , - R' SO ₂ NR' R ''', -C(=O);, -C(=O)R', -OC(=O)R', -C(=O)NR'R'', - NR' C(=O) R'', - NR' C(=O), R'' C(=O), -OR';, -NR'R'',-SR', -N ₃ -C(=O)OR', -O(CR'R'') _r C(=O)R', -O(CR'R'') _r NR''C(=O)R',-O(CR'R'') _r NR ''SO ₂ R', -OC(=O) NR'R', - NR' C(=O) O R'' or optionally substituted C ₁ -C ₆ alkyl; R', R'', R ''' are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ether group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle Alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or Unsubstituted alkylated acyl aryl, or substituted or unsubstituted amine; r is an integer from 1 to 6; R ¹ , R ² , R ³ are each independently selected from H, halogen, hydroxyl, azide, Alkoxy group, mercapto group, imine group, amine group, phosphonate, phosphate, carbonyl group, carboxyl group, cyano group, silyl group, ether, alkylthio group, sulfonyl group, sulfonamide group, ketone, aldehyde, Substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, mofolinyl, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl , substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocycloalkyl, or combinations thereof; or R ¹ and R ² combine to form a 5-7 membered heterocycle, and when R ¹ and R ² combine to form a 5-7 membered heterocycle, Ar and 5-7 The heterocyclic ring does not form a union, but is a substituent of a 5- to 7-membered heterocyclic ring; R ⁴ and R ⁵ are hydrogen, halogen, hydroxyl, azide, ether, alkoxy, mercapto, alkylthio, and sulfonyl , sulfonamide, ketone, aldehyde, ester, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted ketene group, unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl or combinations thereof; R ⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or Unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl Aryl or combination thereof; is a single or double bond; x is 0, 1 or 2; y is an integer from 1 to 6.

In some embodiments, in the E14, E14a, E14b, E14c, E14d and E14e, Ar, R ¹ , R ² , R 3 , R ⁴ , R ⁵ , R ⁶ , R ^{7 ,} R ⁸ , A, L , x, y and As defined and described in WO2017/161119, the entire text of which is incorporated herein by reference.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E15, E15a, E15b, E15c, E15d, E15e, E15f, E15g or E15h: E15 E15a E15c E15d E15e E15f or , E15g E15h wherein among E15, E15a, E15b, E15c, E15d, E15e, E15f, E15g and E15h: Ring B is aryl, heteroaryl, cycloalkyl, heterocycloalkyl; L ₁₀₁ is a bond or C ₁ -C ₆ alkyl; A is C, S, substituted or unsubstituted C ₁ -C ₈ alkyl, or a combination thereof; G ₁₀₀ is C, S, N, substituted or substituted C ₁ -C ₈ alkyl Or a combination thereof; R ₁₀₁ , R ₂₀₁ and R ₃₀₁ are respectively selected from hydrogen, halogen, hydroxyl, azide, alkoxy, thiol, imine, amide, phosphonate, phosphinate, carbonyl, Carboxyl group, cyano group, silyl group, ether group, alkylthio group, sulfonyl group, sulfonamide group, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, ? Folin, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyne base, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl; substituted or unsubstituted heterocycloalkyl; substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylheteroaryl, and combinations thereof; or wherein R ₁₀₁ and R ₂₀₁ combine to form 5- 7-membered heterocycloalkyl; wherein when R ₁₀₁ and R ₂₀₁ combine to form a 5-7-membered heterocycle, Ring B is optionally not fused with the 5-7-membered heterocycle, but is a substituent of the 5-7-membered heterocycle ; R ₄₀₁ and R ₅₀₁ are respectively selected from hydrogen, halogen, hydroxyl, azide, ether, alkoxy, mercapto, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, substituted or unsubstituted Alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocycle Alkyl and combinations thereof; R ₆₀₁ and R ₇₀₁ are each independently oxo, hydrogen, C ₁ -C ₈ alkyl, or R ₆₀₁ and R ₇₀₁ are combined together to form oxo; R ₈₀₁ is selected from hydrogen, substituted or unsubstituted Alkyl, substituted or unsubstituted alkyl halide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocycle Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkaryl, and combinations thereof; x'', y'' are each independently 0, 1 or 2; Is a single bond or a double bond; the compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or In a preferred embodiment of its pharmaceutically acceptable salt, E is E16, E16a or E16b: E16 E16a E16b wherein in E16, E16a and E16b: W ₁₀₁ is CR ₆₀₁ R ₇₀₁ , C(O), C(S), C=CH ₂ , SO ₂ , S(O), P(O)O alkane group, P(O)NH alkyl, P(O)N(alkyl) ₂ , P(O) alkyl, P(O)OH, P(O)NH ₂ ; W ₂₀₁ is CR ₈₀₁ R ₉₀₁ , C (O), C(S), C=CH ₂ , SO ₂ , S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl) ₂ , P (O)alkyl, P(O)OH, P(O)NH ₂ ; X ₁₀₀ is independently selected from NH, NR ₃₀₁ , CH ₂ , CHR ₃₀₁ , C(R ₃₀₁ ) ₂ , O or S; n'' is 0, 1, 2 or 3; is a single bond or a double bond; where When it is a single bond, n'' is 0, 1, 2 or 3; when When it is a double bond, n'' is 0, 1 or 2; R ₁₀₁ is selected from: or R _101* ; R ₂₀₁ is alkyl, hydrogen, heteroalkyl, aryl, heteroaryl or heterocycloalkyl; or R ₁₀₁ and R ₂₀₁ combine to form 4, 5, 6, 7, 8, 9 or 10 One-membered heterocycloalkyl or heteroaryl, the heterocycloalkyl or heteroaryl is optionally substituted by one or more substituents selected from R _{501 and} R ₁₂₀ ; R _101* is selected from: R ₃₀₁ is selected from: alkyl, -C(O)H, C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, alkynyl, aryl, heteroaryl Or heteroalkyl; R ₄₀₁ is selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amine, cyano, -NH (alkyl), -N (alkyl) ₂ , -NHS(O) ₂ (alkyl), -N(alkyl)SO ₂ alkyl, -NHSO ₂ (aryl, heteroaryl or heterocycloalkyl), -N(alkyl)SO ₂ (aryl base, heteroaryl or heterocycloalkyl), -NHSO ₂ (alkenyl), -N(alkyl)SO ₂ (alkenyl), -NHSO ₂ (alkynyl), -N(alkyl)SO ₂ ( Alkynyl) or haloalkyl, aryl, heteroaryl, heteroalkyl and cycloalkyl; or two R ₄₀₁ together with the carbon atoms to which they are connected form a 3, 4, 5 or 6-membered ring; R ₅₀₁ and R ₁₄₀ Each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azido, amine, cyano, -NH (alkyl), -N (alkyl) ₂ , - NHS(O) ₂ (alkyl), -N(alkyl)SO ₂ (alkyl), -NHSO ₂ (aryl, heteroaryl or heterocycloalkyl), -N(alkyl)SO ₂ (aryl base, heteroaryl or heterocycloalkyl), -NHSO ₂ (alkenyl), -N(alkyl)SO ₂ (alkenyl), -NHSO ₂ (alkynyl), -N(alkyl)SO ₂ ( Alkynyl) or haloalkyl, aryl, heteroaryl, heteroalkyl and cycloalkyl; or R ₅₀₁ is independently selected from C(O)R ₄₀₁ , cyano, aryl, aryloxy, heterocycloalkyl group, heteroaryl, arylalkyl, alkoxy, hydroxyl, O-aralkyl or cycloalkyl; R ₆₀₁ , R ₇₀₁ , R ₈₀₁ , R ₉₀₁ , R ₁₀₀₁ , or R ₁₁₀ are independently selected from hydrogen , alkyl, heteroalkyl, hydroxyl, alkoxy, amine, -NH (alkyl) and -N (alkyl) ₂ ; or R ₆₀₁ and R ₇₀₁ together with the carbon atoms to which they are attached form 3, 4, 5 Or a 6-membered spirocarbocycle, or form a 4, 5, or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O; or R ₈₀₁ and R ₉₀₁ together with the carbon atoms to which they are connected form 3 , 4, 5 or 6-membered spirocarbocycle; or form a 4, 5 or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N, O; or the carbons to which R ₁₀₀₁ and R ₁₁₀ are connected The atoms together form a 3, 4, 5 or 6-membered spirocarbocyclic ring; or form a 4, 5 or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O; or R ₆₀₁ and R ₈₀₁ together Form 1 or 2 carbon bridged rings; or R ₆₀₁ and R ₁₀₀₁ together form 1 or 2 carbon bridged rings; or R ₈₀₁ and R ₁₀₀₁ together form 1 or 2 carbon bridged rings; or R ₆₀₁ and R ₁₄₀ together form 3, 4, 5 or 6 carbon fused rings; or R ₁₄₀ and R ₁₀₀₁ together form 3, 4, 5 or 6 carbon fused rings; or R ₈₀₁ and R ₁₄₀ together form 1 or 2 carbon bridged rings; Or R ₄₀₁ and R ₁₄₀ together form a 3, 4, 5 or 6 carbon fused ring, wherein the R ₅₀₁ is located on the R ₁₄₀ α carbon, or together form a 1, 2, 3 or 4 carbon bridged ring, wherein the Said R ₅₀₁ is not located on the alpha carbon of R ₁₄₀ ; R ₁₂₀ is L ₁₀₀ ; R ₁₇₀ is selected from: ; Y ₁₀₀ is selected from N, CH or CR ₁₀₁ ; wherein 0, 1, 2 or 3 Y ₁₀₀ is N; R ₁₀₁ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, Hydroxy, aryl, heteroaryl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -C(O)Oalkyl, -C (O)OH, NO ₂ , F, Cl, Br, I, CF ₃ , NH ₂ , NH(alkyl), N(alkyl) ₂ , or heteroalkyl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E17, E17a, E17b or E17c: E17 E17a or E17b E17c wherein in E17, E17a, E17b and E17c: W ₁ is CR ₆ R ₇ , C=O, C= S, C = CH ₂ , SO ₂ , S(O), P(O)O alkyl , P(O)NH alkyl, P(O)N(alkyl) ₂ , P(O)alkyl, P(O)OH or P(O)H ₂ ; W ₂ is CR ₈ R ₉ , C= O, C= S, C = CH ₂ , SO ₂ , S(O) , P(O)O alkyl, P( O)NH alkyl, P(O)N(alkyl) ₂ , P(O) Alkyl, P(O)OH or P(O)H ₂ ; X and X ₁ are each independently selected from NH, NR ³ , CH ₂ , CHR ³ , C(R ³ ) ₂ , O or S; n'' is 0, 1, 2 or 3; is a single bond or a double bond; and when When it is a single bond, n'' is 0, 1, 2 or 3; When it is a double bond, n'' is 0, 1 or 2; R ₁ is Or R _1* , where X is O or N, and when X is O oxygen, R ₂ does not exist; Ring A is phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl or 4- 6-membered heterocycloalkyl, the phenyl, 5-6-membered heteroaryl, 3-6-membered cycloalkyl or 4-6-membered heterocycloalkyl is optionally substituted by R ¹² ; Ring B is absent, benzene base or 5-6 membered heteroaryl, the phenyl or 5-6 membered heteroaryl is optionally substituted by R ₅ or R ₁₂ ; R ₂ is alkyl, H, aliphatic, heteroaliphatic, aryl, Heteroaryl or heterocycloalkyl; R _1* is optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, ester, sulfonyl or amide group ; R ₃ is alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl or alkynyl; R ₄ is alkyl, Alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amine, -NH alkyl, -N (alkyl) ₂ , -NHSO ₂ alkyl, -N (alkyl)SO ₂ alkyl , _{-NHSO 2aryl} , -N(alkyl)SO 2aryl, -NHSO _2alkenyl , -N(alkyl)SO _2alkenyl , -NHSO 2alkynyl, -N ₍ alkyl)SO _2alkyne base or haloalkane; or 2 R ₄ together with the C atoms to which they are connected form a 3-membered, 4-membered, 5-membered or 6-membered ring; R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ independently Selected from hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxyl, alkoxy, amine, -NH (aliphatic, including alkyl) and -N (aliphatic, including alkyl) ₂ ; or R ₆ , R ₇ together with the carbon atoms to which they are bonded form a 3, 4, 5 or 6-membered spirocarbocyclic ring, or a 4, 5 or 6-membered spirocyclic heterocyclic ring, and the heteroatoms are 1 or 2 N or O; or R _8. R ₉ together with the carbon atoms to which they are bonded form a 3, 4, 5 or 6-membered spirocarbocyclic ring, or a 4, 5 or 6-membered spirocyclic heterocyclic ring, and the heteroatoms are 1 or 2 N or O ; Or R ₁₀ and R ₁₁ together with the carbon atoms to which they are bonded form a 3, 4, 5 or 6-membered spirocarbocyclic ring, or a 4, 5 or 6-membered spirocyclic heterocyclic ring, and the heteroatoms are 1 or 2 N or O; or R ₆ and R ₈ form 1 or 2 carbon bridged rings; or R ₆ and R ₁₀ form 1 or 2 carbon bridged rings; or R ₈ and R ₁₀ form 1 or 2 carbon bridged rings; or R ₁₄ and R ₆ form 3, 4, 5 or 6 carbon fused rings; or R ₁₄ and R ₁₀ form 3, 4, 5 or 6 carbon fused rings; or R ₁₄ and R ₈ form 1 or 2 carbon Bridged ring; or R ₁₄ and R ₄ form a 3, 4, 5 or 6 carbon fused ring, and R ₄ is on the carbon α connecting R ₁₄ ; or form a 1, 2, 3 or 4 carbon bridged ring, and R ₄ is not Connected to carbon α of R ₁₄ ; R ₁₂ is a chain connected to the target ligand; R ₅ and R ₁₄ are respectively selected from hydrogen, alkyl, alkenes, alkynes, halogen, hydroxyl, alkoxy, azide, and amine groups , cyano group, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl) ₂ , -NHSO ₂ (aliphatic, including alkyl), -N (aliphatic, including alkyl)SO _2Alkyl , -NHSO ₂ (aryl, heteroaryl or heterocycle), C(O)R ₄ , -N(alkyl)SO ₂ (aryl, heteroaryl or heterocycle), -NHSO _2ene Base, -N(alkyl)SO ₂ alkenyl, -NHSO ₂ alkynyl, -N(alkyl)SO ₂ alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclic rings; wherein each R ₅ may optionally be replaced by one or more selected from the group consisting of alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azido, amine, -NH alkyl, -N (Alkyl) ₂ , aryl, heterocycloalkyl, heteroaryl, haloalkyl and cycloalkyl; R ₁₆ is , , , , , , , , or .

In some embodiments, in the E17, E17a, E17b and E17c, R ₁ , R ₄ , R ₁₀ , R ₁₁ , R ₁₄ , R ₁₆ , W ₁ , W ₂ , X, and n'' are as defined in WO2018/237026, the entire contents of which are incorporated herein by reference.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E18, E18a, E18b, E18c, E18d, E18e, E18f, E18g, E18h, E18i, E18g, E18k, E18l or E18m: E18 E18a E18b E18c E18d E18e E18f E18g E18h E18i E18j E18k or E18l E18m Among the E18, E18a, E18b, E18c, E18d, E18e, E18f, E18g, E18h, E18i, E18g, E18k, E18l and E18m: X ¹ is -C(R) ₂ , -O-, -NR -, -CF ₂ -, , -C(O)-, -C(S)-or ; X ² and X ³ are each independently -CH ₂ -, -C(O)-, -C(S)-, -C(R) ₂ C(O)- or ; Z ¹ and Z ² are each independently a carbon atom or a nitrogen atom; Ring ^A Heterocycloalkyl group with O or S heteroatom, 5-6 membered heteroaryl group containing 1-4 selected from N, O or S heteroatom; L ^x is a bond or C ₁ -C ₃ alkylene group, the 1-2 methylene groups in the alkylene group are optionally selected from -O-, -S-, -C(O)-, -C(S)-, -C(R) ₂ -, -CRF , -CF ₂ -, -NR-, -S(O) ₂ -, -CH=CH- or alkynylene group; R ^x is selected from hydrogen, deuterium, -R ^z , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O)R, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -CF(R) ₂ -, -CF ₂ R -, -CF ₃ -, -C(R) ₂ (OR)-, -C(R) ₂ [N(R) ₂ ]-, -C(O)R, -C(O )OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)N(R) ₂ , -C(S)NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -C(R) ₂ N (R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OP(O)(R) ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)[N (R) ₂ ], -OP(O)[N(R) ₂ ], -NP(O)(R) ₂ , -NRP(O)(OR) ₂ , -N(R) P(O)(OR )[N(R) ₂ ], -N(R) P(O) [N(R) ₂ ] ₂ , -Si(OR)R ₂ or -SiR ₃ ; or two R ^x together with the atom to which they are connected Forming an optionally substituted 5-8 membered partially unsaturated or aryl-fused heterocycloalkyl group containing 0-2 heteroatoms selected from N, O or S; each R is independently hydrogen, or Optionally substituted selected from C ₁ -C ₆ alkyl, phenyl, 4-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 5 -6-membered heteroaryl ring containing 1-4 heteroatoms selected from N, O or S; or two R on the same carbon atom or on the same nitrogen atom together with the atom to which they are connected form an optionally substituted 4 -7-membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl, or forming a heteroaryl group containing 1-4 heteroatoms selected from N, O or S; R ^y is selected from hydrogen or ; Ring ^B -6-membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, the ring B ^x is further optionally substituted by 1-2 oxo groups; each R ^w is independently selected from hydrogen , Deuterated, R _z , Halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -S(O)R, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -CF(R) ₂ -, -CF ₂ R -, -CF ₃ -, -C(R) ₂ (OR)-, -C(R) ₂ [N(R) ₂ ]- , -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)N (R) ₂ , -C(S)NR ₂ , -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R, -C(R ) ₂ N (R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OP(O)(R) ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)[N(R) ₂ ], -OP(O)[N(R) ₂ ], -NP(O)(R) ₂ , -NRP(O)(OR) ₂ , -N(R) P(O)(OR)[N(R) ₂ ], -N(R) P(O) [N(R) ₂ ] ₂ , -Si(OR)R ₂ or -SiR ₃ ; Each R _z is independently a C ₁ -C ₆ alkyl group, a phenyl group, a 4-7-membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S , 5-6 membered heteroaryl ring containing 1-4 heteroatoms selected from N, O or S; x is 0, 1, 2, 3 or 4; y is 0, 1 or 2; w is 0, 1 , 2, 3 or 4.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h or E19i: E19 E19a E19b E19c E19d E19e E19f E19g E19h or , E19i wherein in E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h and E19i: A ¹ is -C(R ^16a )= or -N=; A ² is -C(R ^16b ) = or -N=; A ³ is -C(R ^16c )= or -N=; G is -C(R ^16d )= or -N=; Z is -CH ₂ or -C(=O)-; R ⁵ is H, methyl or F; R ^16a , R ^16b , R ^16c and R ^16d are each independently selected from H, halogen or C ₁ -C ₄ alkyl.

In some embodiments, in E19, E19a, E19b, E19c, E19d, E19e, E19f, E19g, E19h and E19i, A ¹ , A ² , A ³ , Z, G and R ⁵ are as in WO2017/176958 (which (the entire text of which is incorporated herein by reference).

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E is E20, E20a, E20b, E20c, E20d, E20e or E20f: E20 E20a E20b E20c E20d E20e E20f wherein among the E20, E20a, E20b, E20c, E20d, E20e and E20f: L ¹ is selected from: bond, , , , , , , , , , , , , , , , , , or ; X ¹ , X ² , ^{X 3 and X 4} are ^each independently selected from nitrogen or CR ⁴ , and at most two ^of X ¹ , -CH ₂ -or -C(O)- and at least one of Z ¹ and Z ² is selected from -C(O)-; o is selected from 0, 1, 2, 3 or 4; each R ⁴ is independent Selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl; each R ⁵ is independently selected from hydrogen, C ₁ -C ₆ alkyl group or -C(O)-alkyl; each R ⁸ is independently selected from hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or two R ⁸ are together with the atom to which they are connected. Cyclopropyl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E21: _{E21 wherein in E21 : _} N; R ₃ '' are each independently hydrogen, deuterium, hydroxyl, amine, cyano, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl ( e.g. morpholinki, e.g. ), 6-10-membered aryl, 5-10-membered heteroaryl, -O(C ₁ -C ₆ alkyl), -O-(C ₃ -C ₈ cycloalkyl), -O-(3-8 membered heterocycloalkyl), N(C ₁ -C ₆ alkyl) _1-2 , NH (C ₃ -C ₈ cycloalkyl), NH (3-8 membered heterocycloalkyl), -O-(6 -10 aryl), -O-(5-10 membered heteroaryl); the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally selected from 1 to 3 independently Substituted from hydroxyl, halogen, cyano, amine groups; m'' is 1, 2 or 3; R ₁ '' is each independently hydrogen, deuterium, hydroxyl, amine, cyano, halogen, C ₁ - C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -O(C ₁ -C ₆ alkyl), The alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are optionally substituted by 1-3 independent groups selected from hydroxyl, halogen, cyano and amino groups; R ₂ '' is hydrogen, deuterium, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, the C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl are optionally replaced by 1-3 independent Substituted with a group selected from hydroxyl, halogen, cyano, and amine.

In some embodiments of the present invention, one or two of Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Q ₅ in E21 are N, and the others are each independently CR ₃ ″.

In some embodiments of the present invention, Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ in E21 are each independently CR ₃ ″.

In some embodiments of the present invention, X'' in E21 is N.

In some embodiments of the present invention, X'' in E21 is C.

In some embodiments of the present invention, Y'' in E21 is N.

In certain embodiments of the present invention, R ₁ '' in E21 is each independently hydrogen, deuterium, -F, -Cl, or C ₁ -C ₆ alkyl, and the alkyl is optionally replaced by 1-3 halogen substitution; preferably R ₁ '' is hydrogen.

In certain embodiments of the present invention, R ₂ '' in E21 is hydrogen or C ₁ -C ₆ alkyl, and the alkyl is optionally substituted by 1 to 3 halogens; preferably R ₂ '' is hydrogen.

In certain embodiments of the present invention, each of R ₃ '' in E21 is independently hydrogen, deuterium, halogen, -O(C ₁ -C ₆ alkyl), or C ₁ -C ₆ alkyl, and the The alkyl group is optionally substituted by 1-3 halogens; preferably R ₃ '' is each independently hydrogen, deuterium, F, Cl, methyl, methoxy, ethoxy, trifluoromethoxy, 2-hydroxypropyl -2-yl or trifluoromethyl.

In some embodiments of the present invention, m in E21 is 2.

In some embodiments of the present invention, the E21 has the following structure: E21-1a wherein Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '', and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1b wherein R ₁ '', R ₂ '', R ₃ '' and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1c wherein R ₁ '', R ₂ '' and R ₃ '' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1d wherein R ₃ '' is as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1e wherein Q ₁ , Q ₂ , Q ₃ , Q ₅ , R ₁ '', R ₂ '' and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1f wherein R ₁ '', R ₂ '', R ₃ '' and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1g wherein R ₁ '', R ₂ '' and R ₃ '' are as defined in E21-1 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1h wherein R ₃ '' is as defined in E21 above.

In some embodiments of the present invention, the E21 has the following formula structure: E21-1i wherein R ₃ '' is as defined in E21 above.

In some embodiments of the present invention, the E21 has the following formula structure: E21-1j wherein R ₃ '' is as defined in E21 above.

In certain embodiments of the present invention, in E21 and E21-1a to 1j, R ₃ '' is hydrogen, halogen (such as F or Cl), C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ Alkyl) (eg -OCH ₃ ), the C ₁ -C ₆ alkyl and -O (C ₁ -C ₆ alkyl) are optionally substituted by 1 to 3 halogens (eg F).

In certain embodiments of the present invention, in E21 and E21-1a to 1j, R ₃ ″ is hydrogen, F, Cl, CF ₃ , -OCF ₃ , or -OCH ₃ .

In certain preferred embodiments of the present invention, E21-1h, R ₃ ″ is halogen (such as F or Cl) or -O(C ₁ -C ₆ alkyl) (such as -OCH ₃ ).

In some embodiments of the present invention, the E21-1h is any of the following structures: , , , , .

In some preferred embodiments of the present invention, the E21-1h is any of the following structures: , , .

In some embodiments of the present invention, the E21-1i has the following structure: .

In some embodiments of the present invention, the E21-1j is any of the following structures: , .

In certain embodiments of the present invention, the E21 is selected from or .

In certain embodiments of the present invention, the E21 is selected from , or .

In some preferred embodiments of the present invention, the E21 has the following formula: .

In some preferred embodiments of the present invention, the E21 has the following formula: .

In some preferred embodiments of the present invention, the E21 has the following formula structure: .

In some preferred embodiments of the present invention, the E21 has the following formula structure: .

In some preferred embodiments of the present invention, the E21 has the following formula structure: .

In some embodiments of the present invention, the E21 has the following structure: E21-1aa wherein Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '', and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1bb wherein R ₁ '', R ₂ '', R ₃ '' and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1cc wherein R ₁ '', R ₂ '' and R ₃ '' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1dd wherein R ₃ '' is as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1ee wherein Q ₁ , Q ₂ , Q ₃ , Q ₅ , R ₁ '', R ₂ '' and m'' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1ff wherein R ₁ '', R ₂ '', R ₃ '' and m'' are as defined in E21-1 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1gg wherein R ₁ '', R ₂ '' and R ₃ '' are as defined in E21 above.

In some embodiments of the present invention, the E21 has the following structure: E21-1hh wherein R ₃ '' is as defined in E21 above.

In certain embodiments of the present invention, the E21 is selected from or .

In certain embodiments of the present invention, the E21 is selected from or .

Preferably, in certain embodiments of the present invention, the E21 is any one of the following structures: , , , , .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E22: E22 or a pharmaceutically acceptable salt thereof, wherein in E22: R ^{1 '} is optionally substituted C ₁ -C ₆ alkyl, optionally substituted -(CH ₂ ) _n OH, optionally substituted -(CH ₂ ) _n SH, optionally substituted -(CH ₂ ) _n -O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n -WC(O)CW -(C0-C6 alkyl), where each W is independently hydrogen or C1-C3 alkyl, optionally substituted -(CH ₂ ) _n C(O)OH, optionally substituted -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted-(CH ₂ ) _n NHC(O)-R ₁ , optionally substituted-(CH ₂ ) _n C( O)-NR ₁ R ₂ , optionally substituted-(CH ₂ ) _n OC(O)-NR ₁ R ₂ ,-(CH ₂ O) _n H, optionally substituted-(CH ₂ ) _n OC (O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n C(O)OH, optionally substituted -(OCH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted-(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted-(CH ₂ O) _n C(O)-NR ₁ R ₂ , -(CH ₂ CH ₂ O) _n H, optionally substituted -(CH ₂ CH ₂ O) _n COOH, optionally substituted -(OCH ₂ CH ₂ ) _n O-(C ₁ - C ₆ alkyl), optionally substituted -(OCH ₂ CH ₂ ) _n C(O)-NR ₁ R ₂ , optionally substituted -S(O) ₂ R _s , optionally substituted S( O) R _s , nitro, cyano, or halogen (F, Cl, Br or I, preferably F or Cl); R ₁ and R ₂ are each independently hydrogen or C ₁ -C ₆ alkyl, the alkyl The radical is optionally substituted by 1 or 2 hydroxyl groups or by 1, 2 or 3 halogens (preferably F); R _s is C ₁ -C ₆ alkyl, optionally substituted aryl, heteroaryl , or heterocycloalkyl or -(CH ₂ ) _m NR ₁ R ₂ ; X and X' are each independently C(O), C(S), S(O), S(O) ₂ (preferably X and X' is all C(O)); R ^2' is optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl, optionally substituted - (CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycloalkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N , optionally substituted -NR ¹ - (CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ )nC(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -aryl-heteroaryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -Heteroaryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w - Heterocycloalkyl, optionally substituted -X ^R2' -alkyl, optionally substituted -X ^R2' -aryl, optionally substituted -X ^R2' -heteroaryl, optionally substituted -X ^R2' -Heterocycloalkyl; R ^3' is optionally substituted alkyl, optionally substituted -(CH ₂ ) _n (O) _u (NR ₁ )v(SO ₂ ) _w -alkyl , optionally substituted -(CH ₂ ) _n C(O) _u (NR ₁ )v(SO ₂ ) _w -NR _1N R _2N , optionally substituted -(CH ₂ ) _n C(O) _u ( NR ₁ ) _v (SO ₂ ) _w -C(O)NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, any Selected substituted -(CH ₂ ) _n C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocyclic aryl, optionally substituted -NR ¹ -(CH ₂ )nC(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted - NR ¹ -(CH ₂ )nC(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aromatic group, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl group, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -Heterocycloalkyl, optionally substituted -O-(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -O-(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w - NR _1N R _2N , optionally substituted -O-( CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w - NR ₁ C(O)R _1N , optionally substituted -O-(CH ₂ ) _n -C(O) _u ( NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -O-(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted Substituted -O-(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycloalkyl, -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -alkyl, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -aryl, optionally substituted -( CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heteroaryl, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heterocycloalkyl, optionally substituted -(CH ₂ ) _n -N(R _1' )[C(O)] _m' -(V) _n' -alkyl, optional Substituted -(CH ₂ ) _n -N(R _1' )[C(O)] _m' -(V) _n' -aryl, optionally substituted -(CH ₂ ) _n -N(R _{1 '} )[C(O)] _m' -(V) _n' -Heteroaryl, optionally substituted -(CH ₂ ) _n -N(R _1' )[C(O)] _m' -(V ) _n' -heterocycloalkyl, optionally substituted-X ^R3' -alkyl, optionally substituted-X ^R3' -aryl, optionally substituted-X ^R3' -heteroaryl, any Selected substituted -X ^R3' -heterocycloalkyl; R _1N and R _2N are each independently hydrogen, optionally substituted -(CH ₂ ) _n -aryl, optionally substituted -(CH ₂ ) _n -heteroaryl, optionally substituted -(CH ₂ ) _n -heterocycloalkyl, C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is optionally substituted by 1 or 2 Hydroxy is substituted or optionally substituted by 1, 2 or 3 halogens; V is O, S or NR ₁ ; R ¹ and R ^1' are each independently hydrogen or C ₁ -C ₃ alkyl; X ^R2' or X ^R3' is each independently optionally substituted -(CH ₂ ) _n -, -(CH ₂ ) _n -CH(X _v )=CH(X _v )-(cis or trans), -(CH ₂ ) _n -C CH-, -(CH ₂ CH ₂ O)- or C ₃ -C ₆ cycloalkyl, the X _v is hydrogen, halogen or optionally substituted C ₁ -C ₃ alkyl; m is each independently 0 , 1, 2, 3, 4, 5 or 6; m' is each independently 1 or; n is each independently 0, 1, 2, 3, 4, 5 or 6; n' is each independently 0 or 1 ; u is 0 or 1 independently; v is 1 or 1 independently; w is 0 or 1 independently.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E is E23, E23a, E23b, E23c, E23d or E23e: E23 E23a E23b E23c E23d E23e wherein in E23, E23a, E23b, E23c, E23d and E23e: R ^1' , R ^2' , R ^3' , and X are defined as described in E22; R ₅ and R ₆ are independently selected from OH, SH or an optionally substituted alkyl group; or R ₅ and R ₆ and the carbon atoms to which they are connected form C=O; R ₇ is H or an optionally substituted alkyl group; E is a bond, C=O or C=S; G is a bond, optionally substituted alkyl, -COOH or C=J; J is O or NR ₈ ; R ₈ is H, CN, optionally substituted alkyl or optionally substituted alkoxy; M is aryl, heteroaryl base, heterocyclyl or ; The aryl group, heteroaryl group and heterocyclic group can be optionally substituted; R ₉ and R ₁₀ are independently selected from H, alkyl, cycloalkyl, hydroxyalkyl, thioalkyl, disulfide connected to ULM bond, heteroaryl or haloalkyl, the alkyl, cycloalkyl, hydroxyalkyl, thioalkyl, disulfide bond connecting ULM, heteroaryl or haloalkyl may be optionally substituted; or R ₉ , R ₁₀ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl group; R ₁₁ is heterocycloalkyl, alkoxy, heteroaryl, aryl or , the heterocycloalkyl group, alkoxy group, heteroaryl group, and aryl group may be optionally substituted; R ₁₂ is H or an optionally substituted alkyl group; R ₁₃ is H, alkyl, alkyl-C=O, ( Cycloalkyl)alkyl-C=O, aralkyl-C=O, aryl-C=O, (heterocycloalkyl)-C=O, aralkyl or alkoxy-C=O, so The alkyl group, alkyl-C=O, (cycloalkyl)alkyl-C=O, aralkyl-C=O, aryl-C=O, (heterocycloalkyl)-C=O, aromatic Alkyl or alkoxy-C=O may be optionally substituted; R ₁₄ is H, haloalkyl, cycloalkyl, alkyl or heterocycloalkyl, and the cycloalkyl, alkyl or heterocycloalkyl may be optionally substituted; R ₁₅ is H, heteroaryl, haloalkyl, aryl, alkoxy or heterocycloalkyl, and the heteroaryl, haloalkyl, aryl, alkoxy or heterocycloalkyl can be optionally substituted. Substituted; R ₁₆ is halogen, alkyl, haloalkyl, CN or haloalkoxy, and the alkyl, haloalkyl or haloalkoxy can be optionally substituted; R ₁₇ is H, halogen, cycloalkyl, alkyl, alkenyl group or haloalkyl, the cycloalkyl, alkyl, and alkenyl groups may be optionally substituted; R ₂₃ is H or OH; R ₂₅ is H or substituted alkyl; or 2 R ₂₅ form =O or substituted ring Alkyl; Z ₁ , Z ₂ , Z ₃ and Z ₄ are each independently selected from C or N; X is O or S; Y is H, methyl or ethyl; o is 0, 1, 2, 3 or 4 .

In some embodiments, in the E23, E23a, E23b, E23c, E23d and E23e, R ^1' , R ^2' , R 3', R ⁵ , R ₆ , R ₇ , R ₉ , R ₁₀ , _{R 11} , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₃ , R ₂₅ , E, M, o, X, Y, Z ₁ , Z ₂ , Z ₃ and Z ₄ as defined and described in US 2016/0272639 , the entire contents of which are incorporated herein by reference.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E23a: E23a wherein in E23a: R ^1' is hydroxyl; R ^2' is -NH-CH ₂ -aryl-HET; R ^3' is selected from optionally substituted alkyl, -(CH)R ^CR3' -NH -C(O)-R ^3p1 or -(CH)R ^CR3' -R ^3p2 ; R ^CR3' is optionally substituted C ₁ -C ₄ alkyl; R ^3p1 is optionally substituted C ₁ -C ₆ Alkyl, optionally substituted oxetanyl, -(CH ₂ ) _n OCH ₃ , phenyl optionally substituted by -O(CH ₂ CH ₃ ) or attached to the carbonyl group at position 2 or 3 Folin base, the n is 1 or 2; R ^3p2 is or optionally substituted phenyl; HET is selected from optionally substituted thiazole, ethazole, isoethazole or isothiazole; R ^HET is selected from hydrogen, halogen, cyano, optionally substituted C ₁ -C ₆ alkyl , optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted aryl group.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E23c E23c or a pharmaceutically acceptable salt thereof, wherein in E23c: Each R ₅ and R ₆ are independently -OH, -SH or optionally substituted alkyl, or R ₅ , R ₆ and their respective The attached carbon atoms form a carbonyl group; R ₇ is H or optionally substituted alkyl; E is a bond, C=O or C=S; G is a bond, optionally substituted alkyl, -COOH or C =J; J is O or NR ₈ ; R ₈ is H, CN, optionally substituted alkyl or optionally substituted alkoxy; M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl or ; Each R ₉ and R ₁₀ is independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl radical, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R ₁₁ is any optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or ; R ₁₂ is H or optionally substituted alkyl; R ₁₃ is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) Alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycloalkyl)carbonyl or optionally substituted aralkyl; any Optionally substituted (oxyalkyl)carbamate, each R ₁₄ is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally optionally substituted heterocycloalkyl; R ₁₅ is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy or optionally substituted substituted heterocycloalkyl; each R ₁₆ is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy; each R ₂₅ are independently H or optionally substituted alkyl; or two R ₂₅ groups can together form oxo or optionally substituted cycloalkyl; R ₂₃ is H or OH; Z ₁ , Z ₂ , _Z3 and _Z4 are independently C or N; and o is 0, 1, 2, 3, or 4.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E23d: E23d wherein in E23d: X is O or S; Y is H, methyl or ethyl; R ₁₇ is H, methyl, ethyl, hydroxymethyl or cyclopropyl; M is optionally substituted Heteroaryl, optionally substituted aryl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E23d-1 E23d-1 wherein in E23d-1: Y is H, methyl or ethyl; R ₉ is H; R ₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl; R ₁₁ is optionally substituted amide, optionally substituted isoindolinone, optionally substituted isoethazole, optionally substituted heterocycle;

R ₁₇ is H, methyl, ethyl, hydroxymethyl or cyclopropyl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is the specific compound of Examples 1 to 208 in CN108601764 (the entire text of which is incorporated herein by reference).

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E24: E24 or ^{a pharmaceutically} acceptable salt _thereof ^{, wherein} in E24: X ¹ and ; R ^Y3 and R ^Y4 are each independently hydrogen, C ₁ -C ₆ alkyl optionally substituted by one or more halogens, C ₁ -C ₆ alkoxy optionally substituted by 0-3 R ^p ; R ^p is 0, 1, 2 or 3 selected from hydrogen, halogen, hydroxyl, C ₁ -C ₃ alkyl or C (=O); W ³ is selected from optionally substituted T, optional Substituted -TN(R ^1a R ^1b )X ³ , optionally substituted -TN(R ^1a R ^1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl , optionally substituted-T-bicyclic heteroaryl, optionally substituted-T-heterocycloalkyl, optionally substituted-T-bicyclic heterocycloalkyl, optionally substituted-NR ¹ - T-aryl, optionally substituted-NR ¹ -T-heteroaryl or optionally substituted-NR ¹ -T-heterocycloalkyl; X ³ is C(O), R ¹ , R ^1a or R ^1b ; Each R ¹ , R ^1a or R ^1b is independently selected from hydrogen, C1-C6 alkyl optionally substituted by one or more halogens or hydroxyl groups, R ^Y3 C(O), R ^Y3 C( S), R ^Y3 S(O), R ^Y3 S(O) ₂ , N(R ^Y3 R ^Y4) C(O), N(R ^Y3 R ^Y4) C(S), N(R ^Y3 R ^Y4) S (O) or N(R ^Y3 R ^Y4) S(O) ₂ ; T is selected from optionally substituted alkyl, -(CH ₂ ) _n -, each methylene group is optionally selected from halogen , hydroxyl, optionally substituted amino acid side chain, methyl, optionally substituted alkoxy, optionally substituted C ₁ -C ₆ alkyl by one or more halogens, -C(O)NR ¹ R ^1a or NR ¹ R ^1a is substituted by a substituent; or R ¹ and R ^1a may optionally form an optionally substituted heterocycloalkyl group; n is 0, 1, 2, 3, 4, 5 or 6; W ⁴ is or ; R _14a and R _14b are each independently hydrogen, haloalkyl or optionally substituted alkyl; W ⁵ is optionally substituted phenyl or optionally substituted heteroaryl; R ₁₅ is optionally substituted hydrogen, cyano, halogen, hydroxyl, nitro, NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a CONR _{14b ,} SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted Alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted of heterocycloalkyl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E25 or E25a: or E25 E25a Wherein said E25 and E25: said W ³ is an optionally substituted aryl group, an optionally substituted heteroaryl group or ; R ₉ and R ₁₀ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, Or R ₉ and R ₁₀ together with the carbon atom to which they are connected form an optionally substituted cycloalkyl group; R ₁₁ is selected from the group consisting of optionally substituted heterocycloalkyl, optionally substituted alkoxy, and optionally substituted heteroaryl group, optionally substituted aryl group, , , , or ; R ₁₂ is each independently hydrogen or optionally substituted alkyl; R ₁₃ is each independently hydrogen, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkyl carbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycloalkyl)carbonyl or optionally substituted aralkyl; R _14a and R _14b are each independently hydrogen, Haloalkyl or optionally substituted alkyl; W ⁵ is selected from optionally substituted phenyl or optionally substituted 5-10-membered heteroaryl; R ₁₅ is optionally substituted hydrogen, cyano, halogen, hydroxyl, Nitro, NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a CONR _{14b ,} SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl group, optionally substituted haloalkyl group , optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl; each R ₁₆ Each independently is halogen, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxyl or optionally substituted haloalkyl; o is 0, 1, 2, 3 or 4; R ₁₈ is each independently selected from halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy; p is 0, 1, 2, 3 or 4.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is 26, E26a or E26b, or E26 E26a E26b or a pharmaceutically acceptable salt thereof, wherein in E26, E26a and E26b, R ₁ is hydrogen, methyl, ethyl, isopropyl, third butyl, second butyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl; R _14a is hydrogen, haloalkyl, optionally substituted Alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; X is CH ₂ or C(O); R ₁₅ is selected from hydrogen, halogen, CN, hydroxyl, nitrogen base, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl or optionally substituted Heterocycloalkyl; R ₃ is absent or is an optionally substituted 5-6 membered heteroaryl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E is E27, E27a, E27b, E27c, E27d, E27e, E27f and E27g: E27 E27a E27b E27c E27d E27e or E27f E27g wherein in E27, E27a ^, E27b, E27c, E27d, E27e, E27f and ^E27g , to 6 alkyl; Y and Z are independently carbon or nitrogen; A, A' and A" are independently selected from C, N, O or S, or may form a fused bicyclic ring, or 6, 5 and 5 , one or two atoms of a 5-fused aromatic bicyclic group; R ₁ and R ₂ are independently selected from aryl or heteroaryl, with one or two heteroatoms independently selected from sulfur or nitrogen Heteroaryl, wherein the aryl or heteroaryl may be monocyclic or bicyclic, or unsubstituted or substituted by one to three substituents independently selected from: halogen, -CN, C1 to C6 Alkyl, C3 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, styrene having 1 to 6 carbons, having 1 Ketones with 2 to 6 carbons, ketones with 2 to 6 carbons, amides with 2 to 6 carbons and dialkylamines with 2 to 6 carbons; R ₃ and R ₄ are independently selected from H, methane and C ₁ to C ₆ alkyl; R ₅ is selected from aryl or heteroaryl, heteroaryl having one or two heteroatoms independently selected from sulfur or nitrogen, wherein said aryl or heteroaryl Can be monocyclic or bicyclic, or unsubstituted or substituted by one to three substituents independently selected from: halogen, -CN, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl , -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfonylene having 1 to 6 carbons, styrene having 1 to 6 carbons, having 2 Ketones with 6 to 6 carbons, amides with 2 to 6 carbons, dialkylamines with 2 to 6 carbons, alkyl ethers (C ₂ to C ₆ ), alkyl ketones (C ₃ to C ₆ ) , morpholinyl, alkyl ester (C ₃ to C ₆ ), alkyl cyanide (C ₃ to C ₆ ); R ₆ is H or -C(=O)R ^b , where R ^b is selected from alkyl, Cycloalkyl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperidinyl), 1-piperidinyl, 4-NR ^c - Moflinyl, 4- ^Rc -1-piperidinyl and 3- ^Rc -1-piperidinyl, wherein ^Rc is selected from alkyl, fluorine-substituted alkyl, cyanoalkyl, hydroxy-substituted alkyl base, cycloalkyl, alkoxyalkyl, amide alkyl, alkyl terine, alkyl terine, alkyl amide, aryl, heteroaryl, monosubstituted, disubstituted or trisubstituted aryl or Heteroaryl, CH ₂ CH ₂ R ^d and CH2CH2CH2R ^d , where R ^d is selected from the group consisting of alkoxy, alkyl terine, alkyl terine, N-substituted formamide, -NHC(O)-alkyl, - NH-SO ₂ -alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R ₇ is selected from H, C ₁ to C ₆ alkyl, cycloalkyl, fluorine substituted alkyl, Cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, substituted 5- or 6-membered heteroaryl or aryl; R ₈ is selected from -R ^e -C(O)-R ^f , -R ^e -Alkoxy, -R ^e -aryl, -R ^e -heteroaryl, and -R ^e -C(O)-R ^f -C(O)-R ^g , where: R ^e has 1 to 6 Carbon alkylene or bond; R ^f is a substituted 4 to 7 membered heterocycle; R ^g is selected from aryl, heteroaryl, substituted aryl or heteroaryl, and 4 to 7 membered heterocycle; R ₉ Selected from monosubstituted, disubstituted or trisubstituted groups on the fused bicyclic aromatic ring, wherein the substituents are independently selected from halogen, alkenes, alkynes, alkyl, unsubstituted or substituted by Cl or F; R ₁₀ is selected from aryl or heteroaryl, wherein the heteroaryl may contain one or two heteroatoms such as sulfur or nitrogen, the aryl or heteroaryl may be monocyclic or bicyclic, the aryl or heteroaryl may Aryl groups may be unsubstituted or substituted with one to three substituents, including halogen, F, Cl, -CN, alkenes, alkynes, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, -OH , alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, styrene having 1 to 6 carbons, styrene having 1 to 6 carbons, styrene having 2 to 6 carbons Ketones of carbon; R ₁₁ is -C(O)-N(R ^h )(R ⁱ ), wherein R ^h and R ⁱ are selected from the following: H, C ₁ to C ₆ alkyl, alkoxy-substituted alkyl Base, trisubstituted alkyl, aryl, heteroaryl, mono-, di- or tri-substituted aryl or heteroaryl, alkylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, fluorine-substituted Alkyl carboxylic acid, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl; wherein R ^h and R ⁱ are independently selected from H, linked to form a ring, 4-hydroxycyclohexane; monohydroxy and dihydroxy substituted alkyl (C ₃ to C ₆ ); 3-hydroxycyclobutane; phenyl-4-carboxylic acid and substituted phenyl-4-carboxylic acid; R ₁₂ and R ₁₃ are independently selected from H , lower alkyl (C ₁ to C ₆ ), lower alkenyl (C ₂ to C ₆ ), lower alkynyl (C ₂ to C ₆ ), cycloalkyl (4, 5 and 6-membered rings), substituted ring Alkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl and heteroaryl, R ₁₂ and R ₁₃ can be connected to form a 5- and 6-membered ring with or without substitution on the ring; R ₁₄ Selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted Cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R ₁₅ is CN; R ₁₆ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl in which one or more hydrogens are replaced by fluorine, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, in which one CH ₂ is replaced by S(=O), -S or -S(=O) ₂ alkyl Or cycloalkyl, in which the terminal CH ₃ is replaced by S(=O) ₂ N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S (=O) ₂ (alkyl), -C (=O) 2 (alkyl), -O (alkyl) alkyl or cycloalkyl, in which hydrogen is replaced by a hydroxyl C1-6 alkyl or alkyl group - Cycloalkyl, 3 to 7-membered cycloalkyl or heterocycloalkyl, optionally containing a -(C=O)- group, or 5 to 6-membered aryl or heteroaryl, the heterocycloalkyl or A heteroaryl group may contain one to three heteroatoms independently selected from O, N, or S, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be unsubstituted or independently selected from Halogen, C ₁ -C ₆ alkyl, hydroxylated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl containing thioether, ether, sulfur, styrene, fluorine substituted ether or one to three cyano groups Substituted with substituents; R ₁₇ is selected from (CH ₂ ) _n C(O)NR ^k R ^l , where R ^k and R ^l are independently selected from H, C ₁ -C ₆ alkyl, hydroxylated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyalkyl, C ₁ -C ₆ alkyl in which one or more hydrogens are replaced by fluorine, one of the carbons is replaced by S(O), S(O)(O) C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyalkyl in which one or more hydrogens are replaced by fluorine, C ₁ -C ₆ alkyl in which one or more hydrogens are replaced by cyano, 5 and 6-membered aryl or heteroaryl, alkylaryl wherein the alkyl group contains 1 to 6 carbons, and alkylheteroaryl wherein the alkyl group contains 1 to 6 carbons, wherein the aryl or heteroaryl The group may be further substituted; and n is an integer from 0 to 6; R ₁₈ is selected from substituted aryl, heteroaryl, alkyl, cycloalkyl, and the substitution is preferably -N(C ₁ -C ₄ Alkyl)(cycloalkyl), -N(C ₁ -C ₄ alkyl)alkyl-cycloalkyl, and -N(C ₁ -C ₄ alkyl)[(alkyl)-(heterocycle substituted )-cycloalkyl; R ₁₉ is selected from aryl, heteroaryl, bicyclic heteroaryl, and these aryl or heteroaryl can be replaced by halogen, C1-6 alkyl, C1-6 cycloalkyl, CF ₃ , F, CN, alkyne, alkyl sulfide substitution, the halogen substitution can be mono-substituted or tri-substituted; R ₂₀ and R ₂₁ are independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl , C ₁ -C ₆ alkoxy, hydroxylated C ₁ -C ₆ alkoxy and fluorine substituted C ₁ -C ₆ alkoxy, where R ₂₀ and R ₂₁ can also be connected to form 5, 6 and 7 A membered ring or heterocyclic ring, which may be further substituted; R ₂₂ is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide , sulfonamide, reverse sulfonamide, N-acyl urea, nitrogen-containing 5-membered heterocycle, the 5-membered heterocycle can be further substituted by C ₁ -C ₆ alkyl, alkoxy, fluorine-substituted alkyl substituted by alkyl, CN and alkyl group; R ₂₃ is selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkyl-cycloalkyl, - NH-alkyl, -NH-alkyl-cycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(alkyl) -Heteroaryl, the aryl or heteroaryl may be substituted by halogen, C ₁ -C ₆ alkyl, hydroxylated C ₁ -C ₆ alkyl, cycloalkyl, fluorine substituted C ₁ -C ₆ alkyl , CN, alkoxy, alkylphenol, amide and sulfonamide substitution; R ₂₄ is selected from -CH ₂ -(C ₁ -C ₆ alkyl), -CH ₂ -cycloalkyl, -CH ₂ -aryl radical, CH ₂ -heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl may be substituted by halogen, alkoxy, hydroxylated alkyl, cyano alkyl, cycloalkyl and substituted Cycloalkyl substitution; R ₂₅ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, Substituted aryl or heteroaryl, 5, 6 and 7-membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocycles, and these saturated heterocycles can be C1- 6 alkyl, fluorine-substituted C ₁ -C ₆ alkyl, alkoxy, aryl and heteroaryl substitution; R ₂₆ is selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, the Alkyl or cycloalkyl may be -OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH ₂ , -NH-alkyl, NH-C(O)alkyl, -NH- S(O) ₂ -alkyl and -S(O) ₂ -alkyl substituted; R ₂₇ is selected from aryl, heteroaryl, bicyclic heteroaryl, wherein the aryl or heteroaryl can be C ₁ - C ₆ alkyl, alkoxy, NH ₂ , NH-alkyl, halogen or -CN substituted, and the substitution can be independently mono-substituted, disubstituted and tri-substituted; R ₂₈ is selected from aryl, 5 and 6 Yuanheteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidone, tetrahydropyran, N-acyl-piperidine, wherein the cycloalkyl, saturated heterocycle, aromatic The radical or heteroaryl group may be further substituted by -OH, alkoxy, mono-, di- or tri-substituted groups including halogen, -CN, alkyl terine and fluorine-substituted alkyl; and R _1″ is selected from alkyl, Aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E28, E28a, E28b, E28c, E28d, E28e, E28f, E28g, E28h or E28i, (MDM2) E28 E28a E28b E28c E28d E28e E28f E28g or , E28h E28i wherein in E28, E28a, E28b, E28c, E28d, E28e, E28f, E28g, E28h and E28i: R _1' and R _2' are each independently F, Cl, Br, I, ethynyl, cyanide base, nitro or CF ₃ ; R _3' is selected from -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CH ₂ OCH ₃ or -OCH(CH ₃ ) ₂ ; R _4' is selected from From hydrogen, halogen, methyl, -CF ₃ , -OCH ₃ , -C(CH ₃ ) ₃ , -CH(CH ₃ ) ₂ , -cyclopropyl, cyano, -C(CH ₃ ) ₂ OH, - C(CH ₃ ) ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ OCH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₂ OH , -C(CH ₃ ) ₂ CN, -C(CH ₃ ) ₂ C(O)CH ₃ , -C(CH ₃ ) ₂ C(O)NHCH ₃ , -C(CH ₃ ) ₂ C(O)N (CH ₃ ) ₂ , -SCH ₃ , -SCH ₂ CH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , -NHC(CH ₃ ) _{3 ,} -NC(CH ₃ ) _2. Pyrrolidinyl or morpholinyl; R _5' is selected from halogen, cyclopropyl, -S(O) ₂ CH _{3 ,} -S(O) ₂ CH ₂ CH ₃ , pyrrolidinyl, -NH ₂ , -N(CH ₃ ) ₂ or -NHC(CH ₃ ) ₃ ; R _6' is selected from hydrogen, , , , , , , , , , , , , , , , , , , , , , , , , , , , , or _; ^wherein _{the _} , F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, hydroxyl, Other C ₁ -C ₆ alkyl, other C ₁ -C ₆ alkenyl, other C ₁ -C ₆ alkynyl; R _9' is optionally substituted alkyl, optionally substituted alkenyl, optional Substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl; Z is hydrogen, -OCH ₃ , -OCH ₂ CH ₃ or halogen; R _10' and _R11' Each independently is hydrogen, (CH ₂ ) _n -R', (CH ₂ ) _n -NR'R'', (CH ₂ ) _n -NR'C(O)R'', (CH ₂ ) _n -NR'S (O) ₂ R'', (CH ₂ ) _n -C(O)OH, (CH ₂ ) _n -C(O)OR', (CH ₂ ) _n -C(O)NR'R'', ( CH ₂ ) _n -OR', (CH ₂ ) _n -SR', (CH ₂ ) _n -SOR', (CH ₂ ) _n -CH(OH)-R', (CH ₂ ) _n -C(O) R', (CH ₂ ) _n -S(O) ₂ R', (CH ₂ ) _n -S(O)NR'R'', (CH ₂ ) _n -S(O) ₂ NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -R', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OH, (CH ₂ CH ₂ O) _m -(CH ₂ ) _n - OR', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'C(O)R'', ( CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O) ₂ NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)OH, (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)OR', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O)OR', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)R', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O)NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O) ₂ NR'R'', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n R', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OH, -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OR', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'R'', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'C(O)R'', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'S(O) ₂ R'', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)OH, -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)OR', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)NR'R'', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O) ₂ R', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -C(O)R', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O)NR'R'', -(CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -S(O) ₂ NR'R'', aryl-(CH ₂ ) _n -C(O)OH or heteroaryl-alkyl-C(O)-alkyl-NR'R'' , the alkyl group is optionally substituted by OR'; or R ^10' and R ^11' are each independently a heteroaryl-(CH2)n-heterocycloalkyl group, the heterocycloalkyl group is optionally an alkyl group, Hydroxy, C(O)OR' or C(O)R'substitution; the R' and R'' are each independently selected from hydrogen, optionally selected from halogen, hydroxyl, NH ₂ , NH (alkyl), NH (alkyl) _1-2 , oxo, carboxyl, cycloalkyl or heteroaryl; m, n and p are each independently 0, 1, 2, 3, 4, 5 or 6; R _12' are each independently are -O-alkyl, -O-alkyl-alkoxy, -C(O)-alkyl, -C(OH)-alkyl-alkoxy, -C(O)-NH-alkyl , -C(O)-N-(alkyl) _1-2 , -S(O)-alkyl, S(O) ₂ -alkyl, -C(O)-cyclic amine, -O-aryl- Alkyl, -O-aryl-alkoxy; R ^1'' is selected from hydrogen, alkyl optionally substituted by aryl or alkoxy, cycloalkyl optionally substituted by aryl or alkoxy.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E29: E29 R ₁ is independently selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl or C ₃ -C ₁₀ -cycloalkyl, which is not Substituted or substituted; R ₂ is independently selected from H, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl or C ₃ -C ₁₀ -cycloalkyl , which is unsubstituted or substituted; R ₃ is independently selected from H, -CF ₃ , -C ₂ H ₅ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ - C ₄ -Alkynyl, -CH ₂ -Z or any R ₂ and R ₃ together form a heterocycle; each Z is independently selected from H, -OH, F, Cl, -CH ₃ , -CF ₃ , -CH ₂ Cl, -CH ₂ F or -CH ₂ OH; R ₄ is independently selected from C ₁ -C ₁₆ linear or branched alkyl, C ₁ -C ₁₆ -alkenyl, C ₁ -C ₁₆ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, -(CH ₂ ) _0-6 -Z ₁ , -(CH ₂ ) _0-6 -aryl and -(CH ₂ ) _0-6 -het, where alkyl, cyclo Alkyl and phenyl are unsubstituted or substituted; R ₅ is independently selected from H, C _1-10 -alkyl, aryl, phenyl, C _3-7 -cycloalkyl, -(CH ₂ ) _{1- 6} -C _3-7 -cycloalkyl, -C _1-10 -alkyl-aryl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl-(CH ₂ ) _0-6 -benzene Base, -(CH ₂ ) _0-4 -CH[(CH ₂ ) _1-4 -phenyl] ₂ , indanyl, -C(O)-C _1-10 -alkyl, -C(O)- (CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(O)-(CH ₂ ) _0-6 -phenyl, -(CH ₂ ) _0-6 -C(O)-phenyl , -(CH ₂ ) _0-6 -het, -C(O)-(CH ₂ ) _1-6 -het or R ₅ is selected from the residues of amino acids, wherein alkyl, cycloalkyl, phenyl and Aryl substituents are unsubstituted or substituted; Z ₁ is independently selected from -N(R ₁₀ )-C(O)-C _1-10 -alkyl, -N(R ₁₀ )-C(O)-( CH ₂ ) _0-6 -C _3-7 -Cycloalkyl, -N(R ₁₀ )-C(O)-(CH ₂ ) _0-6 -phenyl, -N(R ₁₀ )-C(O) (CH ₂ ) _1-6 -het, -C(O)-N(R ₁₁ )(R ₁₂ ), -C(O)-OC _1-10 -alkyl, -C(O)-O-(CH ₂ ) _1-6 -C _3-7 -Cycloalkyl, -C(O)-O-(CH ₂ ) _0-6 -phenyl, -C(O)-O-(CH ₂ ) _1-6 - het, -OC(O)-C _1-10 -alkyl, -OC(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -OC(O)-(CH ₂ ) _{0 -6} -phenyl, -OC(O)-(CH ₂ ) _1-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; het is independently selected from the group consisting of 1-4 5-7 membered heterocyclic ring or 8-12 membered fused ring system containing heteroatoms from N, O and S, which includes at least one 5-7 membered heterocyclic ring system containing 1, 2 or 3 heteroatoms selected from N, O and S. 7-membered heterocyclic ring, the heterocyclic ring or fused ring system is unsubstituted or substituted on the carbon or nitrogen atom; R ₁₀ is selected from H, -CH ₃ , -CF ₃ , -CH ₂ OH or -CH ₂ Cl ; R ₁₁ and R ₁₂ are independently selected from H, C _1-4 -alkyl, C _3-7 -cycloalkyl, -(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, (CH ₂ ) _0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R ₁₁ and R ₁₂ together with nitrogen form het, and U is independently: where _: each n is _{independently} selected from _0-5 ; One or more carbon atoms of are optionally replaced with heteroatoms selected from O, S or N, and wherein each alkyl group is independently unsubstituted or substituted; R _d is selected from Re-Q-(R _f ) _p (R _g ) _q and Ar ₁ -D-Ar ₂ ; R _c is selected from H or any R _c and R _d together form cycloalkyl or het; where if R _c and R _d form cycloalkyl or het, then R _is attached to the formed ring at a C or N atom; p and q are independently selected from 0 or 1; R _is selected from C _1-8 -alkyl and alkylene, and each _R is unsubstituted or Substituted; Q is selected from N, O, S, S(O) and S(O) ₂ ; Ar ₁ and Ar ₂ are independently selected from substituted or unsubstituted aryl and het; R _f and R _g are independently selected is selected from H, -C ₁ - ₁₀ -alkyl, C _1-10 -alkylaryl, -OH, -OC _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 - Cycloalkyl, -O-(CH ₂ ) _0-6 -aryl, phenyl, aryl, phenyl-phenyl, -(CH ₂ ) _1-6 -het, -O-(CH ₂ ) _{1- 6} -het, -OR ₁₃ , -C(0)-R ₁₃ , -C(O)-N(R ₁₃ )(R ₁₄ ), -N(R ₁₃ )(R ₁₄ ), -SR ₁₃ , -S (O)-R ₁₃ , -S(O) ₂ -R ₁₃ , -S(O) ₂ -NR ₁₃ R ₁₄ , -NR ₁₃ -S(O) ₂ -R ₁₄ , -SC _t-10 -alkyl , aryl-C _1-4 -alkyl or het-C _1-4 -alkyl, wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted, -SO ₂ -C _1-2 - Alkyl, -SO ₂ -C _1-2 -alkylphenyl, -OC _1-4 -alkyl or any R _g and R _f together form a ring selected from het or aryl; D is selected from -CO- , -C(O)-C _1-7 -alkylene or arylene, -CF ₂ -, -O-, -S(O) _r , where r is 0-2, 1,3-dioxa Cyclopentane or C _1-7 -alkyl-OH; where alkyl, alkylene or arylene is unsubstituted or substituted by one or more halogens, OH, -OC _1-6 -alkyl, -SC _{1 -6} -alkyl or -CF ₃ substituted; or each D is independently selected from N(R _h ); R _h is selected from H, unsubstituted or substituted C _1-7 -alkyl, aryl, unsubstituted Substituted or substituted -O-(C _1-7 -cycloalkyl), -C(O)-C _1-10 -alkyl, -C(O)-C _0-10 -alkyl-aryl , -COC _01-10 -alkyl, -COC _0-10 -alkyl-aryl, -SO ₂ -C _1-10 -alkyl or -SO ₂ -(C _0-10 -alkylaryl); R ₆ , R ₇ , R ₈ and R ₉ are independently selected from H, -C _1-10 -alkyl, -C _1-10 -alkoxy, aryl-C _1-10 -alkoxy, -OH , -OC _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -O-(CH ₂ ) _0-6 -aryl, phenyl, -(CH ₂ ) _1-6 -het, -O-(CH ₂ ) _1-6 -het, -OR ₁₃ , -C(O)-R ₁₃ , -C(O)-N(R ₁₃ )(R ₁₄ ), -N (R ₁₃ )(R ₁₄ ), -SR ₁₃ , -S(O)-R ₁₃ , -S(O) ₂ -R ₁₃ , -S(O) ₂ -NR ₁₃ R ₁₄ or -NR ₁₃ -S( O) ₂ -R ₁₄ ; wherein each alkyl, cycloalkyl and aryl group is unsubstituted or substituted; and any R ₆ , R ₇ , R ₈ and R ₉ optionally together form a ring system; R ₁₃ and R ₁₄ is independently selected from H, C _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -(CH ₂ ) _0-6 -(CH) _0-1 - (Aryl) _1-2 , -C(O)-C _1-10 -alkyl, -C(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(O) -O-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0-6 -O-fluorenyl, -C(O)-NH-(CH ₂ ) _0-6 -aryl Base, -C(O)-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0-6 -het, -C(S)-C _1-10 -alkyl, - C(S)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(S)-O-(CH ₂ ) _0-6 -aryl, -C(S)-(CH ₂ ) _0-6 -O-fluorenyl, -C(S)-NH-(CH ₂ ) _0-6 -aryl, -C(S)-(CH ₂ ) _0-6 -aryl or -C(S )-(CH ₂ ) _1-6 -het, wherein each alkyl, cycloalkyl and aryl group is unsubstituted or substituted; or either R ₁₃ and R ₁₄ together with the nitrogen atom form het; R ₁₃ and R The alkyl substituents of ₁₄ are unsubstituted or substituted, and when substituted, are substituted with one or more substituents selected from C _1-10 -alkyl, halogen, OH, -OC _{1- 6} -alkyl, -SC _1-6 -alkyl and -CF ₃ ; and the substituted phenyl or aryl groups of R ₁₃ and R ₁₄ are substituted by one or more substituents selected from halogen, hydroxyl , C _1-4 -alkyl, C _1-4 -alkoxy, nitro, -CN, -OC(O)-C _1-4 -alkyl and -C(O)-OC _1-4 -aryl base; or its pharmaceutically acceptable salt or hydrate.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment of E is E30, E30a, E30b, E30c or E30d: E30 E30a E30b E30c or , E30d wherein among E30, E30a, E30b, E30c and E30d: R ¹ is selected from hydrogen or alkyl; R ² is selected from hydrogen or alkyl; R ³ is selected from hydrogen, alkyl, cycloalkyl or heterocycloalkyl; R ⁵ and R ⁶ are each independently selected from hydrogen, alkyl, cycloalkyl or heterocycloalkyl; or R ⁵ and R ⁶ together with the atoms to which they are connected form a pyrrolidinyl or piperidine ring and are optionally combined with 1 - 2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings are fused, and each ring is further optionally chelated to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring Aryl ring; or R ⁵ and R ³ together with the atoms to which they are connected form a 5-8 membered ring and are optionally combined with 1 or 2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings ; R ⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, ethylcycloalkylalkyl, aryl or bicyclic aryl, arylalkyl, heteroaryl or bicyclic heteroaryl or heteroarylalkyl, and further optionally substituted by 1 to 3 alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, zylcycloalkylalkyl, aryl or bicyclic aryl, aromatic Alkyl, heteroaryl or bicyclic heteroaryl, heteroarylalkyl substituents.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E31 E31 wherein in E31: A1 and A2 are each independently selected from optionally substituted monocyclic rings, fused rings, aryl groups and heteroaryl groups; R is selected from H or Me.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E32, E32 wherein in E32: R ¹ is selected from alkyl, cycloalkyl and heterocycloalkyl, and most preferably is selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl; R ² is selected from –OPh or H.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E33, E33 Wherein, in E33: R ¹ is selected from H, -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ ; X is selected from S or CH ₂ ; n is 1, 2 or 3; R ² is selected from: , , or ; R ³ and R ⁴ are independently selected from H or Me.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E34, E34 wherein in E34: R ¹ is selected from H or Me; R ² is selected from H or .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E35, E35 Wherein E35: R ¹ is selected from: , or ; R ² is selected from: , or .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E36, E36 wherein in E36: n is 0, 1 or 2, preferably 2; Z does not exist or is O; R ¹ is selected from: , , , ; where R ¹⁰ is selected from hydrogen, alkyl or aryl; X is selected from CH ₂ and O; and Is a nitrogen-containing heteroaryl group.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E37, E37 wherein in E37: Z is absent or O; R ³ and R ⁴ are independently selected from H or Me; R ¹ is selected from: , , , ; R ¹⁰ in is selected from H, alkyl or aryl; X in is selected from CH ₂ and O; and , middle Is a nitrogen-containing heteroaryl group.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E38, E38 wherein in E38: Z does not exist or is O; R ¹ is selected from: , , , ; R ¹⁰ in is selected from H, alkyl or aryl; X in is selected from CH ₂ and O; and , middle is a nitrogen-containing heteroaryl group; and R ² is selected from H, alkyl, or acyl.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E39, E39 wherein in E39: R ² is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably, it is selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably Self-ringing base; is a 5- or 6-membered nitrogen-containing heteroaryl group; more preferably a 5-membered nitrogen-containing heteroaryl group and most preferably a thiazole; and Ar is an aryl or heteroaryl group.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E40, E40 wherein in E40: R ¹ is selected from halogen (for example, fluorine), cyano, , , , ; X is selected from O or CH ₂ .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E41, E41 wherein in E41: R is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halogen (in variable substitution positions).

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E42, E42 wherein said E36, It is a 6-membered nitrogen-containing heteroaryl group.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E43, E43 Wherein, in said E43, X is selected from CH ₂ , O, NH or S.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E44, E44a or E44b, E44 E44a E44b wherein in E44, E44a and E44b: n is 1 or 2; R ² , R ³ and R ⁴ are independently selected from H or methyl; X is independently selected from O or S; and R ¹ is selected from: , , , .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E45, E45 wherein in E45: R ³ and R ⁴ are each independently selected from hydrogen or methyl; is a 5-membered heterocycle selected from the following: , , , or .

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is E46 or E46a, E46 E46a where: R ¹ is selected from: , ; R ² is selected from H or methyl n is selected from 0, 1 or 2.

The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts In a preferred embodiment, E is: CRBN: VHL: MDMA: IAP: ; or .

Preferably, in certain embodiments of the present invention, the compound of formula I is: .

Preferably, in certain embodiments of the present invention, the compound of formula I is: .

In certain embodiments, the deuterated compound is ring A, ring B, L in a compound structure (e.g., L, e.g., LA, LA-1, LA-2, LA-3, LA-4, LA-5 _3. A structure formed by replacing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 H's in ring C) with deuterium.

In certain embodiments, the deuterated LA structure is , , or .

In certain embodiments, the deuterated compound has any of the following structures: .

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its Methods for the preparation of pharmaceutically acceptable salts.

The invention provides a pharmaceutical composition, including a therapeutically effective amount of a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, Metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients.

The invention provides a method for degrading SOS1 protein, which includes making the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites A drug, prodrug and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is contacted with the SOS1 protein.

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for the treatment or prevention of SOS1-mediated diseases or conditions.

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament for the treatment or prevention of diseases or conditions (cancer) caused by the interaction of SOS1 with Ras (e.g. KRAS) or SOS1 with Rac (e.g. KRAS) .

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its Use of a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment or prevention of SOS1-mediated diseases or conditions (eg, cancer).

The invention provides compounds of formula I, and/or their stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or their pharmaceuticals. Use of the above acceptable salts, or pharmaceutical compositions thereof, in the preparation of drugs for the treatment or prevention of diseases or conditions (such as cancer) caused by the interaction of SOS1 and Ras (such as KRAS) or SOS1 and Rac (such as KRAS).

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its Use of pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of drugs for the treatment or prevention of cancer.

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its Pharmaceutically acceptable salts, or pharmaceutical compositions thereof, for use in the treatment or prevention of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovary Cancer, prostate cancer, glioblastoma, renal cancer and sarcoma drug applications.

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its Pharmaceutically acceptable salts, or pharmaceutical compositions thereof for the preparation of treatments or prevention of neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with freckles (NSML), capillary malformations - Application of drugs in arteriovenous malformation syndrome (CM-AVM), congenital varicella syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Legers syndrome and hereditary gingival fibromatosis.

The present invention provides a method for treating or preventing diseases or conditions mediated by SOS1, comprising administering to a patient in need a therapeutically effective amount of a compound of formula I, and/or its stereoisomers, enantiomers, non-enantiomers, and Enantiomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

The present invention provides a method of treating or preventing a disease or disorder (eg, cancer) regulated by the interaction of SOS1 and Ras (eg, KRAS) or SOS1 and Rac (eg, KRAS), comprising administering to a patient in need thereof a therapeutically effective amount of Formula I compound, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its pharmaceutically acceptable salts, or pharmaceutical compositions thereof.

In some embodiments of the present invention, the cancer can be selected from: Heart: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma group; Lung: Bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, interstitial carcinoma skin tumors; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, Carcinoid tumors, vasoactive intestinal peptide tumors), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, Carcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary system: kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (spermatogonia) tumor, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, cholangiocarcinoma; Bone: Osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, enchondroma (osteochondral exostoses), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytoma, medulloblastoma, glioma, ventricle) Angiomangiomas, germinal cell tumors (pineal tumors), glioblastoma multiforme, oligodendroglioblastoma, schwannomas, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, Glioma, sarcoma); Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, agerminoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: Hematology (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's disease Lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland: Neuroblastoma.

In certain embodiments of the present invention, the cancer can be selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, Prostate cancer, glioblastoma, renal cancer and sarcoma.

The present invention also provides the aforementioned compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or its Use of a pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of KRAS-mediated diseases or conditions.

The present invention also provides a method for treating and/or preventing KRAS-mediated diseases or disorders, comprising administering a therapeutically effective amount of a compound of formula I, and/or its stereoisomers and enantiomers to a patient in need. , diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

In certain embodiments of the present invention, the KRAS may be mutant KRAS. The mutant KRAS is preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D and KRAS G12V.

The invention provides a compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and/or its Preparation method of pharmaceutically acceptable salt: When S is S6c , L is LA , and when ring B contains an NH group, the preparation method is: INT-A and INT-B undergo a reductive amination reaction to obtain the target compound; the reducing reagents for the reductive amination include but are not limited to Pd/C, sodium borohydride, sodium cyanoborohydride, borane, and triacetyl oxide. Sodium borohydride. stated therein Refers to ring B containing an NH group; R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ are as defined and described in S6b; refers to L ₃ containing an aldehyde group; ring A, ring B, ring C, and X'' are as defined in LA; E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21- 1bb, E21-1cc, E21-1dd, E21-1ee, E21-1ff, E21-1gg or E21-1hh. When S is S6c , L is LA , and ring C contains an NH group, and when X'' is C(O), the preparation method is: INT-C and INT-D undergo a substitution reaction under alkaline conditions to obtain the target compound; the bases include but are not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate. . in Refers to ring C containing NH group; P ₁₀₀ is pentafluorophenyl or p-nitrophenyl; R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ are as defined and described in S6b; Ring A , Ring B, Ring C, L ₃ are as defined in LA; E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21- 1ee, E21-1ff, E21-1gg or E21-1hh. When S is S6d , L is LA , and ring C contains an NH group, and when X'' is C(O), the preparation method is: INT-E and INT-D undergo a substitution reaction under alkaline conditions to obtain the target compound; the bases include but are not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium bicarbonate. . in Refers to ring C containing an NH group; P ₁₀₀ is pentafluorophenyl or p-nitrophenyl; R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ are as defined and described in S6d; Ring A , Ring B, Ring C, L ₃ are as defined in LA; E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21- 1ee, E21-1ff, E21-1gg or E21-1hh.

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

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched alkyl; C ₁ -C ₈ alkyl refers to an alkyl group containing 1-8 carbon atoms, such as methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2 , 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2 -Trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl Butyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl , 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethyl Pentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2, 2-Dimethylhexyl, 3, 3-dimethylhexyl, 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2- Ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof; preferably C ₁ -C ₆ alkyl; more preferably C ₁ -C ₄ alkyl. The alkyl group may be substituted or unsubstituted. In some embodiments, the alkyl group is C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ alkyl.

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C ₃ -C ₁₁ cycloalkyl" refers to a cycloalkyl group including 3 to 11 carbon atoms; "C ₃ - "C ₈ -membered cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms; "C ₅ -C ₁₀ -membered cycloalkyl" refers to a cycloalkyl group including 5 to 10 carbon atoms; Monocyclic cycloalkyl Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C ₃ -C ₈ -membered cycloalkyl; more preferably C ₃ -C ₆ -membered cycloalkyl.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups that share one carbon atom (called a spiro atom) between single rings. They may contain one or more double bonds, but no ring has a fully conjugated π electron system. According to the number of shared spiro atoms between rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, preferably 7-12 membered spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include: .

"Condensed cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings may contain one or more double bonds, but No ring has a fully conjugated pi electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, with bicyclic fused cycloalkyl groups being preferred. Non-limiting examples of fused cycloalkyl groups include: .

"Bridged cycloalkyl" refers to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected. They may contain one or more double bonds, but no ring has a fully conjugated π electron system. , according to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include: The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted.

In some embodiments, the cycloalkyl is C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ monocyclic or polycyclic (e.g., spirocyclic , fused ring or bridged ring) cycloalkyl.

"Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (e.g., 2, 3, 4, or 5) ring atoms are selected from nitrogen, oxygen, or S ( O) _r (where r is an integer 0, 1 or 2), but does not contain the ring part -OO-, -OS- or -SS- and the remaining ring atoms are carbon. "3-11 membered heterocycloalkyl" refers to a ring group containing 3 to 11 ring atoms, "5-10 membered heterocycloalkyl" refers to a ring group containing 5 to 10 ring atoms, "3-8 membered heterocycloalkyl""Cycloalkyl" refers to a ring group containing 3 to 8 ring atoms, preferably containing 1-2 "3-11 membered heterocycloalkyl" selected from N, O or S heteroatoms, more preferably containing 1 or 2 3-11 membered heterocycloalkyl group with N atoms.

The monocyclic heterocycloalkyl group is preferably a 3-8 membered monocyclic heterocycloalkyl group containing 1-2 N heteroatoms; non-limiting examples of the monocyclic heterocycloalkyl group include pyrrolidinyl, piperidinyl, piperidyl, 𠯤 group, mofulinyl group, thiomorpholinyl group, homopiperidinyl group, etc., with piperidinyl group and piperidinyl group being preferred.

Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. "Spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group that shares one atom (called a spiro atom) between single rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _r (where r are integers 0, 1, 2), and the remaining ring atoms are carbon. They can contain one or more double bonds, but no ring has a fully conjugated π-electron system. According to the number of shared spiro atoms between rings, spirocycloalkyl groups are divided into single spiroheterocycloalkyl groups, double spiroheterocycloalkyl groups or polyspiroheterocycloalkyl groups, preferably containing 1-2 spiroheterocycloalkyl groups selected from N, O Or a saturated "3-11 membered bispiroheterocycloalkyl" containing S heteroatom; more preferably a saturated "7-11 membered bispiroheterocycloalkyl" containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyl include: .

"Condensed heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but No ring has a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S(O) _r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, preferably "3-11 membered bicyclic fused heterocycloalkyl" containing 1-3 heteroatoms selected from N, O or S. group"; more preferably a saturated "3-11 membered bicyclic fused heterocycloalkyl group" containing 1 or 2 N atoms. Non-limiting examples of fused heterocycloalkyl groups include: .

"Bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected. They may contain one or more double bonds, but no ring has fully conjugated π electrons. Systems in which one or more ring atoms are selected from nitrogen, oxygen, or S(O) _r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged heterocycloalkyl groups include: .

The heterocycloalkyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocycloalkyl. Non-limiting examples include: , the heterocycloalkyl group may be optionally substituted or unsubstituted.

In some embodiments, the heterocycloalkyl group is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered monocyclic or polycyclic (such as spiro, fused or bridged) heterocyclic ring. Cycloalkyl, in which the number of heteroatoms can be 1, 2, 3, 4 or 5, each heteroatom is independently nitrogen, oxygen or S(O) _r (where r is an integer 0, 1 or 2) .

"Aryl" refers to an all-carbon monocyclic or fused polycyclic group (that is, a ring sharing adjacent pairs of carbon atoms) and a polycyclic group with a conjugated π electron system. "6-10 membered aryl" refers to a polycyclic group containing 6 - All-carbon aryl radicals of 10 carbon atoms, such as phenyl and naphthyl; preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples include: , the aryl group may be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6-10 membered aryl group.

"Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, or S(O) _r (where r is an integer 0, 1, 2), 5-6 membered Aryl refers to a heteroaromatic system containing 5-6 ring atoms, and 5-10-membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, preferably 5-6-membered heteroaryl; more preferably containing 1 5-6 membered heteroaryl with one or two N atoms; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl, pyrazole, imidazole base, triazolyl, tetrazolyl, etc.; pyridinyl is preferred. The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. Non-limiting examples include: , the heteroaryl group may be optionally substituted or unsubstituted. In some embodiments, the heteroaryl group is a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group, in which the number of heteroatoms can be 1, 2, 3, 4 or 5, and each heteroaryl group The atoms are independently nitrogen, oxygen, or S.

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and "C ₂ - ₈ alkenyl" refers to a straight or branched chain containing 2 to 8 carbons. Alkenyl, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or ₃ -butenyl, etc., preferably "C _2-6 alkenyl", more preferably "C _{2-4 alkenyl} "base". The alkenyl group may be substituted or unsubstituted. In some embodiments, the alkenyl group is _C2 , _C3 , _C4 , _C5 , _C6 , _C7 , _C8 alkenyl.

"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and "C ₂ - ₈ alkynyl" refers to a straight or branched chain alkynyl group containing 2 to 8 carbons. , including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C ₂ - ₆ alkynyl", more preferably "C ₂ - ₄ alkynyl"base". The alkynyl group may be substituted or unsubstituted. In some embodiments, the alkynyl group is C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ alkynyl.

"Yylene" refers to a divalent group, such as alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, and Heterocycloalkyl refers to a divalent heterocycloalkyl group, arylene refers to a divalent aryl group, and heteroarylene refers to a divalent heteroaryl group. The alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups The radicals, aryl groups and heteroaryl groups are as defined above, and the subunits may be optionally substituted or unsubstituted.

"Haloalkyl" refers to an alkyl group optionally substituted by one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkyl group is as defined above, non-limiting examples include difluoromethyl, dichloromethyl , dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

"Hydroxyalkyl" refers to an alkyl group optionally substituted by one or more -OH, wherein the alkyl group is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl base.

"Alkoxy" refers to -O-alkyl, wherein alkyl is as defined above, non-limiting examples include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

"Cycloalkoxy" refers to -O-cycloalkyl, wherein said cycloalkyl is as defined above, non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexane Oxygen etc.

"Heterocycloalkoxy" refers to -O-heterocycloalkyl, wherein said heterocycloalkyl is as defined above, non-limiting examples include azetidinyloxy, azetidinyloxy, pipera Alkylinyloxy, piperayloxy, oxanyloxy, oxanyloxy, etc.

"-C(O)C ₁ -C ₃ alkyl" refers to -C(O)-CH ₃ , -C(O)-CH ₂ CH ₃ and the like.

"Cyano" refers to -CN.

"Hydroxy" refers to -OH.

"Sulfonyl" refers to -S(O) _2- .

"Carboxy" or "carboxylic acid" refers to -COOH.

"Oxo" refers to the =O group.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Pd(PPh ₃ ) ₂ Cl ₂ " means (bis(triphenylphosphorus)palladium dichloride).

"TEA" refers to triethylamine.

"EA or EtOAc" refers to ethyl acetate.

"THF" refers to tetrahydrofuran.

"NaBH ₄ " refers to sodium borohydride.

"DCM" refers to dichloromethane.

"Tf ₂ O" refers to trifluoromethanesulfonic anhydride.

"(Bpin) ₂ " refers to bispinacol diboronate.

"Pd(dppf) ₂ Cl ₂ " refers to 1,1'-bisdiphenylphosphine ferrocene palladium dichloride.

"KOAc" refers to potassium acetate.

"DMF" refers to N,N-dimethylformamide.

"NBS" refers to N-bromosuccinimide.

"EtOH" refers to ethanol.

"MeOH" methanol.

"Pd/C" refers to palladium/carbon.

"Pd(OH) ₂ /C" refers to palladium hydroxide/carbon.

"DMSO" refers to dimethylsulfoxide.

"HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"TFA" refers to trifluoroacetic acid.

"NMP" refers to N-methylpyrrolidone.

"IBX" refers to 2-iodobenzoic acid.

"DIEA" refers to N,N-diisopropylethylamine.

"STAB" refers to sodium triacetyloxyborohydride.

"T ₃ P" refers to 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide.

"NaOH" refers to sodium hydroxide.

"DMAP" refers to 4-dimethylaminopyridine.

"TPSCl" refers to 2,4,6-triisopropylbenzenesulfonyl chloride.

"DPBS" refers to Dulbecco's Phosphate Buffered Saline.

"Dess-Martin" refers to Dess-Martin reagent.

"PBS" refers to phosphate buffered saline.

"SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

"PVDF" refers to polyvinylidene fluoride.

"PE" refers to petroleum ether.

"NaHCO ₃ " refers to sodium bicarbonate.

"Na ₂ SO ₄ " refers to sodium sulfate.

"NH ₄ Cl" refers to ammonium chloride.

"AcOH" refers to acetic acid.

"HCl" refers to hydrochloric acid.

"DCC" refers to N,N'-dicyclohexylcarbodiimide.

"Ti(OEt) ₄ " refers to tetraethyl titanate.

"L-Selectride" refers to lithium triisobutylborohydride.

“BOP” refers to benzotriazole-1-oxytris(dimethylamino)phosphorus hexafluorophosphate

“DBU” refers to 1,8-diazacyclo[5,4,0]undecene-7

"LiOH.H ₂ O" refers to lithium hydroxide monohydrate

"EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

"NIS" N-iodosuccinimide.

"Ac ₂ O" refers to acetic anhydride.

"HOAc" refers to acetic acid.

"Hantzsch-ester" refers to diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

"DMA" refers to dimethylacetamide.

"NiBr ₂ (dtbpy)" refers to 4,4-di-tert-butylbipyridyl nickel dibromide.

"K ₂ CO ₃ " refers to potassium carbonate.

"9-BBN" refers to 9-borobicyclo[3.3.1]nonane.

"MTBE" refers to methyl tert-butyl ether.

"LiOH" refers to lithium hydroxide.

"DCE" refers to dichloroethane.

" _NaBH3CN " refers to sodium cyanoborohydride.

"CBr ₄ " refers to carbon tetrabromide.

" _PPh3 " refers to triphenylphosphine.

" n -BuLi" refers to n-butyllithium.

"NaH" refers to sodium hydrogen.

" i -PrOH" refers to isopropyl alcohol.

"ACN" refers to acetonitrile.

"NH ₄ HCO ₃ " refers to ammonium bicarbonate.

" m -CPBA" refers to m-chloroperoxybenzoic acid.

"KI" refers to potassium iodide.

"IPA" refers to isophthalic acid

"N ₂ H ₄ -H ₂ O" refers to hydrazine hydrate.

"NMI" refers to N-methylimidazole.

“TCFH” refers to tetramethylchlorourea hexafluorophosphonate

"Ruphos Pd G2" refers to chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl) Phen-2-yl)palladium(II).

"K ₃ PO ₄ " refers to potassium phosphate.

"(Boc) ₂ O" refers to di-tert-butyl dicarbonate.

"Prep-HPLC" refers to preparative high performance liquid chromatography.

"sat." refers to a saturated solution.

"aq" refers to aqueous solution.

In the chemical structure of this article, "-" as a connecting bond represents a single bond, and "=" represents a double bond (if the configuration is not limited, it can be trans or cis).

"Optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances in which the event or circumstance does or does not occur. For example, "heterocycloalkyl group optionally substituted by alkyl" means that alkyl groups may but need not be present, and this description includes the case where the heterocycloalkyl group is substituted by an alkyl group and the heterocycloalkyl group is not substituted by an alkyl group. replacement situation.

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and that a person of ordinary skill in the art to which this invention belongs can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

Unless otherwise stated, the term "optionally substituted" as used herein may be unsubstituted or substituted; when substituted, the substituents may be one or more (eg, 2, 3, 4, 5, or 6) independently Selected from alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, amine, aminoalkyl, cyano, halogen, oxo, cycloalkyl, heterocycloalkyl, aromatic and heteroaryl, the alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, amine, aminoalkyl groups are optionally replaced by one or more (such as 2, 3, 4, 5 or 6) cycloalkyl, heterocycloalkyl, aryl and heteroaryl substituted; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more selected from Alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, haloalkyl, alkoxy, amine, aminoalkyl, cyano, halogen, oxo group substitutions.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms, facilitate the absorption of active ingredients, and thereby exert biological activity.

The present invention also provides pharmaceutically acceptable salts of compounds of formula (I). The term "pharmaceutically acceptable salts" refers to relatively non-toxic acid or base addition salts of the compounds of the present invention. The acid addition salt is a salt formed by the compound of formula (I) of the present invention and a suitable inorganic acid or organic acid. These salts can be prepared during the final separation and purification process of the compound, or the purified compound of formula (I) can be used. The free base form is prepared by reacting with a suitable organic or inorganic acid. Representative acid addition salts include hydrobromide, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, and silicic acid Salt, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, Benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobiate and lauryl sulfonate, etc. The base addition salt is a salt formed by a compound of formula (I) and a suitable inorganic base or organic base, including, for example, salts formed with alkali metals, alkaline earth metals, and quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, Calcium salt, magnesium salt, tetramethyl quaternary ammonium salt, tetraethyl quaternary ammonium salt, etc.; amine salts include salts formed with ammonia (NH ₃ ), primary amines, secondary amines or tertiary amines, such as methylamine salts, Dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically (powder, ointment or drops). , or intratumoral administration.

The dosage of the compound of the present invention may be approximately 0.05-300 mg/kg body weight/day, preferably 10-300 mg/kg body weight/day, and more preferably 10-200 mg/kg body weight/day.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compound of formula (I) of the present invention is mixed as the active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (1) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.; (2) Binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, etc. ; (3) Moisturizing agents, such as glycerin, etc.; (4) Disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates and sodium carbonate, etc.; (5) Retarder, Such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents such as cetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents, such as kaolin, etc.; and (9) lubrication Agents, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Buffering agents may also be included in capsules, tablets and pills.

The solid dosage forms such as tablets, dragees, capsules, pills and granules may be coated or microencapsulated using coating and shell materials such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active ingredient can also be in the form of microcapsules with one or more of the above-mentioned excipients.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into liquid dosage forms for oral administration, including but not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art such as water and other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol , ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, etc. or these Mixtures of substances, etc. In addition to these inert diluents, the liquid dosage forms of the present invention may also contain conventional auxiliaries, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and perfumes, and the like.

The suspending agent includes, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated for parenteral injection in dosage forms including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and for reconstitution into Sterile powder for injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention or pharmaceutically acceptable salts thereof may also be formulated for topical administration in dosage forms including ointments, powders, suppositories, drops, sprays, inhalants, and the like. The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and optional preservatives, buffers, or propellants that may be required if necessary. .

The present invention also provides pharmaceutical compositions, which contain the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent. When preparing pharmaceutical compositions, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is usually mixed with a pharmaceutically acceptable carrier, excipient or diluent.

The composition of the present invention can be formulated into conventional pharmaceutical preparations according to conventional preparation methods. For example, tablets, pills, capsules, powders, granules, emulsions, floating agents, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, sprays, etc.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be administered alone or, if necessary, in combination with other pharmaceutically acceptable therapeutic agents, such as other anti-tumor drugs. The ingredients to be combined can be administered simultaneously or sequentially, in a single formulation or in different formulations. The combination may include not only a combination of a compound of the invention and one other active agent, but also a combination of a compound of the invention and two or more other active agents.

In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) can be: EGFR and/or its mutant inhibitors, ErbB2 (Her2) and/or its mutants Inhibitors, ALK and/or its mutant inhibitors, MEK and/or its mutant inhibitors, Kras and/or its mutant inhibitors, BCR-ABL and/or its mutant inhibitors, FGFR1/FGFR2/FGFR3 and/or its mutant inhibitors, ROS1 and/or its mutant inhibitors, c-MET and/or its mutant inhibitors, AXL and/or its mutant inhibitors, NTRK1 and/or its mutant inhibitors , RET and/or its mutant inhibitors, taxanes, platinum-containing compounds, antimetabolites, mitotic kinase inhibitors, immunotherapeutics, anti-angiogenic drugs, topoisomerase inhibitors, A-Raf/B- Raf/C-RAf and/or its mutant inhibitors, ERK and/or its mutant inhibitors, apoptosis inhibitors, mTOR inhibitors, epigenetic regulators, IGF1/2 and/or IGF1-R inhibitors , Ras GEF and/or its mutant inhibitors, PI3K and/or its mutant inhibitors.

In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) can be: afatinib, erlotinib, gefitinib (gefitinib), lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816, trastuzumab, Pertuzumab, crizotinib, alectinib, entrectinib, brigatinib, trametinib, cobimetinib cobimetinib, binimetinib, selumetinib, refametinib, imatinib, dasatinib, nilotinib ), nintedanib, crizotinib, lorlatinib, ceritinib, merestinib, paclitaxel, nab-paclitaxel, docetaxel docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, floxuridine, cytarabine, Combination of gemcitabine, trifluridine and tipiracil (=TAS102), palbociclib, ribociclib, abemaciclib, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab ), pidilizumab, PDR-001 (=spartalizumab), bevacizumab, irinotecan, liposomal irinotecan, toprol topotecan, ulixertinib, rapamycin, temsirolimus, everolimus, ridaforolimus, JQ-1, GSK 525762, OTX 015 (=MK8628), CPI 0610, TEN-010 (=RO6870810), xentuzumab (antibody 60833 in WO 2010/066868) or MEDI-573 (=dusigitumab) ).

The present invention proves through SOS1 kinase activity test experiments that the compound of formula I of the present invention can effectively bind to the SOS1 target protein or produce an inhibitory effect, and proves through Western-Blot that the compound of formula I of the present invention can effectively and specifically degrade NCI- SOS1 protein in H358 cells. The compound of formula I of the present invention, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or its pharmaceutical properties Acceptable salts can effectively degrade SOS1 protein, thereby achieving the effect of preventing or treating diseases or conditions related to SOS1 or caused by the interaction between SOS1 and Ras or SOS1 and Rac.

The present invention will be further described in detail and completely with reference to the examples below, but in no way limits the present invention, nor is the present invention limited only to the contents of the examples. The starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be adopted or synthesized according to methods known in the art. Unless otherwise specified, experimental methods without specifying specific conditions in the examples of the present invention usually follow conventional conditions or conditions recommended by raw material or product manufacturers.

Ⅰ Compound Preparation Example

Intermediate 1: Preparation step 1 of ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride: 1-(3-nitro-5 Preparation of -(trifluoromethyl)phenyl)ethyl-1-one Under nitrogen protection, 1-bromo-3-nitro-5-(trifluoromethyl)benzene (18 g, 66.7 mmol), tributyl (1-ethoxyvinyl) stannane (31 g, 86.7 mmol) ), the reaction mixture of Pd(PPh ₃ ) ₂ Cl ₂ (4.7 g, 6.67 mmol) and TEA (13.5g, 133 mmol) in 1,4-dioxane (200 mL) was stirred at 80 ° C overnight. . The reaction solution was quenched with potassium fluoride (saturated aqueous solution, 300 mL), and extracted with EA (200 mL×3). The organic layer was collected and concentrated under reduced pressure. The concentrate was dissolved in THF (180 mL), hydrochloric acid (100 mL, 6 M) was added, and the mixture was stirred at room temperature for 3 h. The mixture was then quenched with water (300 mL) and extracted with EA (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-one. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (t, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.54 (d, J = 0.5 Hz, 1H), 2.76 (s, 3H). Step 2: Preparation of ( R , E )-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethylene)propyl-2-sulfinamide 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-one (10.6 g, 45.5 mmol), ( R )-2-methylpropyl-2-sulfinamide (8.3 g, 68.2 mmol) and tetraethyl titanate (25.9 g, 114 mmol) in THF (200 mL) were stirred for 2 h at 60 °C. The reaction mixture was quenched with water (300 mL) and the solution was extracted with EA (200 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target product ( R , E )-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethylene)propyl- 2-Sulfinamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.87 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 2.90 (s, 3H), 1.37 (s, 9H). Step 3 : Preparation of ( R )-2-methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl-2-sulfinamide To ( R , E )-2-methyl- N -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylene)propyl-2-sulfinamide (10 g , 30.7 mmol) To a mixture of THF (100 mL) and water (20 mL) solution was added NaBH ₄ (1.28 g, 33.7 mmol). The reaction mixture was stirred at -10°C for 1 minute, then quenched with water (300 mL), and the solution was extracted with EA (200 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target product ( R )-2-methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl Base-2-sulfinamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 – 8.42 (m, 2H), 7.96 (s, 1H), 4.76 – 4.68 (m, 1H), 3.56 (d, J = 4.2 Hz, 1H), 1.62 ( d, J = 6.7 Hz, 3H), 1.26 (s, 9H). Step 4: ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine salt Preparation of acid salts ( R )-2-methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl-2-sulfinamide (5.5 g, 16.3 mmol) was placed in hydrochloric acid (80 mL, 4M) dihexane solution, and the reaction was stirred at 25 °C for 2 h. The crude product was filtered and washed with petroleum ether (100 mL) to obtain the target product ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride. LC-MS: (ESI, m/z ): [M+H] ⁺ = 235.2.

Intermediate 2: ethyl 4-(4,4,5,5-tetramethyl-1,3,2-diethylboropentan-2-yl)cyclohex-3-ene-1-carboxylate step 1 : Preparation of 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylic acid ethyl ester To stir 4-oxocyclohexane-1-carboxylic acid ethyl ester (5 g, 32.0 mmol) and 2,6-dimethylpyridine (4.6 g, 42.9 mmol) in DCM (60 mL) at 0 °C. ) was added dropwise to the mixture in Tf ₂ O (9 g, 32.0 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was then stirred at 25 °C for 15 min, and Tf ₂ O (7 g, 25.6 mmol) was added. The reaction mixture was then stirred at 25°C overnight. The reaction mixture was concentrated, quenched with water (300 mL), and extracted with EA (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-carboxylate. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.90 (d, J = 3.9 Hz, 1H), 4.14 – 4.02 (m, 2H), 2.68 – 2.60 (m, 1H), 2.47 – 2.27 (m, 4H ), 2.08 – 1.98 (m, 1H), 1.88 – 1.76 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H). Step 2: 4-(4,4,5,5-tetramethyl- Preparation of ethyl 1,3,2-bisborane-2-yl)cyclohex-3-ene-1-carboxylate 4-(((Trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylic acid ethyl ester (4.7 g, 16.8 mmol), (Bpin) ₂ (6.4 g, 25.2 mmol), A mixture of Pd(dppf) ₂ Cl ₂ (1.2 g, 1.68 mmol) and KOAc (4.9 g, 50.4 mmol) in 1,4-dioxane (80 mL) was stirred and reacted at 90 °C overnight. The reaction was quenched with water (300 mL) and extracted with EA (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 4-(4,4,5,5-tetramethyl-1,3,2-dimethylboropentan-2-yl)cyclohex-3-ene-1-carboxylic acid Ethyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.42 (d, J = 2.2 Hz, 1H), 4.11 - 4.02 (m, 2H), 2.33 - 1.95 (m, 4H), 1.93 - 1.83 (m, 1H ), 1.53 - 1.38 (m, 1H), 1.21 - 1.14 (m, 16H).

Intermediate 3: ((1 R ,4 R )-4-(4-((( R )-1-(3-amino)-5-(trifluoromethyl)phenyl)ethyl)amino) -7-Methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone Step 1: 2-Amino-5-bromo-4-methoxybenzene Preparation of formic acid To a stirred solution of 2-amino-4-methoxybenzoic acid (30 g, 179 mmol) in DMF (600 mL) was added NBS (35 g, 197 mmol) at 0 °C, and the reaction mixture was incubated at 25 °C. Stir the reaction for 1 h. The reaction solution was quenched with sodium thiosulfate (saturated aqueous solution, 500 mL), and extracted with EA (500 mL×3). The organic layer was collected, washed with sodium chloride (saturated aqueous solution, 500 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product of 2-amino-5-bromo-4-methoxybenzoic acid, crude product It was used directly in the next step without further purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 246.0. Step 2: 6-Bromo-7-methoxy-2-methylquinazolin-4(3 H )-one Preparation To a stirred solution of 2-amino-5-bromo-4-methoxybenzoic acid (17.0 g, 69.1 mmol) in methanol (170 mL) was added ammonium acetate (53.2 g, 691 mmol) and trimethyl orthoacetate (83.0 g, 691 mmol). The resulting reaction mixture was stirred in a closed container at 120 °C for 24 h. The reaction mixture was poured into water (1 L) and the solid product was filtered. The crude product was washed with EA (1 L) to obtain the target product 6-bromo-7-methoxy-2-methylquinazolin-4( 3H )-one. The crude product can be used directly in the next reaction without purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 268.9. Step 3: Preparation of 6-bromo-4-chloro-7-methoxy-2-methylquinazoline A mixture of 6-bromo-7-methoxy-2-methylquinazolin-4 (3 H )-one (10 g, 37.2 mmol) in a solution of phosphorus oxychloride (200 mL) was stirred at 105 °C. Stay overnight. The reaction mixture was concentrated, quenched with sodium bicarbonate (saturated aqueous solution, 500 mL), and extracted with EA (300 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the target product 6-bromo-4-chloro-7-methoxy-2-methylquinazoline. LC-MS: (ESI, m/z ): [M+H] ⁺ = 287.0. Step 4: ( R )-6-bromo-7-methoxy-2-methyl- N -(1-(3 - Preparation of nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine To a mixture of 6-bromo-4-chloro-7-methoxy-2-methylquinazoline (1.8 g, 6.27 mmol) in EtOH (12 mL) was added ( R )-1-(3-nitrogen Trifluoromethyl)phenyl)ethyl-1-amine hydrochloride (1.7 g, 7.52 mmol) and DIEA (1.6 g, 12.5 mmol). The reaction mixture was stirred in the microwave at 100 °C for 5 h. The reaction was quenched with water (300 mL) and extracted with EA (300 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain ( R )-6-bromo-7-methoxy-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)benzene) as a yellow oil ethyl)quinazolin-4-amine. LC-MS: (ESI, m/z ): [M+H] ⁺ = 484.9. Step 5: 4-(7-methoxy-2-methyl-4-((( R )-1-(3 - Preparation of ethyl nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohex-3-ene-1-carboxylate ( R )-6-bromo-7-methoxy-2-methyl- N -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazoline-4 -Amine (2 g, 4.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)cyclohex-3-ene-1- Ethyl carboxylate (2.31 g, 8.24 mmol), sodium carbonate (873 mg, 8.24 mmol) and Pd(dppf) ₂ Cl ₂ (300 mg, 0.41 mmol) in DMF (24 mL) and water (3 mL) The reaction mixture was stirred at 110°C overnight. The reaction was quenched with water (300 mL). The solution was extracted with EA (300 mL×3), washed with sodium chloride (saturated aqueous solution, 500 mL×3), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) Base)amino)quinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 559.7. Step 6: ( R )-4-(4-((1-(3-amino-5-(trifluoromethyl) Preparation of )phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-1-carboxylic acid ethyl ester To 4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazole To a mixture of ethyl cyclohex-3-ene-1-carboxylate (1.7 g, 3.04 mmol) in MeOH (60 mL) was added Pd/C (1.02 g, 0.6 w/w) . The reaction mixture was stirred at 50°C for 4 days under a hydrogen atmosphere. The crude product was filtered to obtain ( R )-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2 -Ethyl methylquinazolin-6-yl)cyclohexan-1-carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 531.2. Step 7: (1 R ,4 R )-4-(4-((( R )-1-(3-amino) Preparation of -5-(trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid To ( R )-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole To a mixture of ethyl pholin-6-yl)cyclohexane-1-carboxylate (1.5 g, 2.82 mmol) in methanol (8 mL), THF (8 mL), and water (16 mL) was added lithium hydroxide ( 203 mg, 8.46 mmol). The reaction mixture was stirred at 60°C overnight. The crude product was purified by preparative HPLC to obtain (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ =503.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.69 (s, 1H), 5.56 (dd, J = 13.6, 5.8 Hz, 3H), 3.88 (s, 3H ), 2.92 (t, J = 11.7 Hz, 1H), 2.35 (s, 3H), 2.24 (t, J = 11.8 Hz, 1H), 2.05 (d, J = 10.8 Hz, 2H), 1.87 (d, J = 11.8 Hz, 2H), 1.66 – 1.40 (m, 7H). Step 8: 4-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5) -(Trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)pipiperidine-1-carboxylic acid 3rd butyl ester To (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy To a mixture of (2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (220 mg, 0.44 mmol) in EA (12 mL) was added tert-butylpiperidine-1-carboxylate. ester (163 mg, 0.88 mmol), DIEA (169 mg, 1.31 mmol) and T ₃ P (209 mg, 0.66 mmol). The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with water (100 mL) and extracted with EA (100 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Base) amino)-7) methoxy-2-methylquinazolin-6-yl) cyclohexane-1-carbonyl) piperazine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =671.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 – 8.07 (m, 2H), 6.99 (s, 1H), 6.86 (d, J = 10.5 Hz, 2H), 6.70 (s, 1H), 5.56 (dd, J = 16.7, 9.3 Hz, 3H), 3.89 (s, 3H), 3.47 (m, 4H), 3.32 (m , 4H), 2.95 (s, 1H), 2.67 (s, 1H), 2.36 (s, 3H), 1.83 (d, J = 14.5 Hz, 4H), 1.59 (t, J = 22.3 Hz, 7H), 1.41 (s, 9H). Step 9: ((1 R ,4 R )-4-(4-((( R )-1-(3-amino)-5-(trifluoromethyl)phenyl)ethyl Preparation of (base)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone 4-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7 )Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.33 mmol) in ethyl acetate hydrochloride (3M , 10 mL) solution was stirred and reacted for 2 h at 25 °C. The reaction was concentrated to obtain ((1 R ,4 R )-4-(4-((( R )-1-(3-amino)-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone, the crude product can be used in the next reaction without further purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 571.2.

Intermediate 4: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4 -yl)acetaldehyde step 1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione To a solution of 4-fluorophthalic acid (5.52 g, 0.03 mol) in acetic acid (50 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (5.0 g, 0.03 mol) and potassium acetate (8.8 g, 0.09 mol), the reaction mixture was stirred at 120°C overnight, the reaction mixture was concentrated under reduced pressure, the concentrate was diluted with water (100 mL), stirred at room temperature for 30 minutes, filtered, and the solid was treated with water (50 mL×2 ) washing. Drying under reduced pressure gave the product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 277.1 Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2- Preparation of hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol), 2-(piperidin-4-yl) ) A mixture of ethyl-1-ol (280 mg, 2.17 mmol)) and DIEA (701 mg, 5.43 mmol) in NMP (5 mL) was reacted in a microwave reactor at 140 °C for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phase was collected and washed with water (100 mL×2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified on a silica gel column to obtain the product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 386.1. Step 3: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1 , Preparation of 3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione( A mixture of 300 mg, 0.78 mmol) and IBX (436 mg, 1.56 mmol) in acetonitrile (6 mL) was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×2). The organic phase was collected and washed with water (50 mL×2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 384.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H), 9.69 (t, J = 1.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.6, 2.2 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.03 (dd, J = 10.3, 2.9 Hz, 2H), 3.04 – 2.82 (m, 3H), 2.65 – 2.52 (m, 2H), 2.41 (dd, J = 6.7, 1.6 Hz, 2H) , 2.17 – 1.97 (m, 2H), 1.73 (d, J = 11.1 Hz, 2H), 1.2-1.18 (m, 2H).

Intermediate 5: 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5] Undecyl-9-yl)acetaldehyde Step 1: Preparation of 4-chloro-3-(2,4-dioxoectohydropyrimidin-1(2H)-yl)benzoic acid 3-Amino-4-chlorobenzoic acid (5.0 g, 2.93 mmol) was suspended in acrylic acid (8.05 mL, 117 mmol), and the reaction was stirred at 100 °C for 3 h, and then the reaction solution was stirred and cooled to room temperature. Acetic acid (33 ml) was added, and the stirred suspension was heated at 100°C for 10 minutes. Urea (11.00 g, 183 mmol) was added, and the reaction solution was stirred and reacted at 120°C overnight. The reaction solution was added to a mixture of ice water and concentrated hydrochloric acid (37%), stirred, and the resulting suspension was stored in a refrigerator at 5°C overnight, then filtered, and the solid was washed with water and dried to obtain a solid. The solid was ground in hydrochloric acid solution (0.05 M), filtered, washed with methyl tert-butyl ether, and dried under reduced pressure at 40°C to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =269.0 Step 2: 4-chloro-3-(2,4-dioxoectohydropyrimidine-1(2 H )-yl) Preparation of pentafluorophenyl benzoate 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoic acid (2.0 g, 7.58 mmol), 2,3,4,5,6-pentafluorophenol (1.67 g, 9.09 mmol) and N , N '-dicyclohexylcarbodiimide (1.87 g, 9.09 mmol) in a solution of N, N -dimethylformamide (20 mL) at room temperature. Stir the reaction for 3 h. The reaction solution was poured into water (200 mL) and stirred for 0.5 h. The solution was extracted with ethyl acetate (200 mL×3). The organic phase was collected, washed with water (500 mL×2) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =435.0 Step 3: Preparation of 2-(3-aza[5.5]undecan-9-yl)ethan-1-ol To a mixture of 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (1.0 g, 3 mmol) in EA (10 mL) was added Pd (OH) ₂ /C (200 mg), the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain the target product. Step 4: 1-(2-chloro-5-(9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( Preparation of 1 H ,3 H )-diketone To a mixture of 2-(3-azaspiro[5.5]undecan-9-yl)ethan-1-ol (500 mg, 2.5 mmol) in DMSO (5 mL) was added 4-chloro-3- Pentafluorophenyl (2,4-dioxoectoine-1(2 H )-yl)benzoate (1.0 g, 2.5 mmol) and DIEA (0.5 mL). The reaction was quenched with water (30 mL) and extracted with EA (10 mL×3). The organic layer was collected and washed with water (10 mL×2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to obtain the target compound. LC-MS: (ESI, m/z ): [M+ H] ⁺ = 448.1 Step 5: 2-(3-(4-chloro-3-(2,4-dioxoectohydropyrimidine-1(2 Preparation of H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde To 1-(2-chloro-5-(9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H To a mixture of , 3H )-diketone (700 mg, 1.56 mmol) in THF (12 mL) was added IBX (873 mg, 3.1 mmol). The reaction mixture was stirred at 80°C for 2 h. The reaction was quenched with water (30 mL) and the solution was extracted with EA (10 mL×3). The organic layer was collected and washed with water (10 mL×2) and saturated salt brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to obtain the target compound. LC-MS: (ESI, m/z ): [M+ H] ⁺ = 446.1

Intermediate 6: 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1 -acetaldehyde step 1: Preparation of tert-butyl ester of 4-(2,2-dimethoxyethyl)pipiperidine-1-carboxylate To a mixture of tert-butylpiperzoate-1-carboxylate (2.0 g, 10.75 mmol), potassium carbonate (4.45 g, 32.26 mmol), and potassium iodide (892 mg, 5.38 mmol) in acetone (20 mL) was added 2-bromo -1,1-Dimethoxyethane (3.63 g, 21.51 mmol). The reaction was stirred at 80°C overnight. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (50 mL), and washed with water (50 mL×2) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 275.0. Step 2: Preparation of 1-(2,2-dimethoxyethyl)piperdine Mixture chamber of tert-butyl 4-(2,2-dimethoxyethyl)piperidine-1-carboxylate (2.2 g, 8.03 mmol) in hydrochloric acid/dioxane (4M, 10 mL) Stir overnight at warm temperature. Concentrate under reduced pressure to obtain the target product (1.5g, crude product). The crude product was used directly in the next step. Step 3: 5-(4-(2,2-dimethoxyethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline Preparation of -1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.48 g, 5.36 mmol), 1-(2,2-dimethyl A mixture of a solution of oxyethyl piperazine (1.4 g, 8.05 mmol) and DIEA (4.15 g, 36.16 mmol) in NMP (10 mL) was reacted in a microwave reactor at 140 °C for 5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phase was collected and washed with water (100 mL×2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 431.1. Step 4: 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1 , Preparation of 3-dioxoisoindolin-5-yl)piperidine-1-yl)acetaldehyde 5-(4-(2,2-Dimethoxyethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, A mixture of 3-diketone (1.8 g, 4.19 mmol) in trifluoroacetic acid/dichloromethane (5 mL/5 mL) solution was stirred at room temperature for 60 h. The mixture was concentrated under reduced pressure, water was added, and the pH was adjusted to 8 with sodium bicarbonate (aq). The mixture was extracted with ethyl acetate (100 mL×2). The organic phase was collected, washed with water (100 mL×2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified on a silica gel column to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =385.0.

Intermediate 7: 2-(9-(4-chloro-3-(2,4-dioxoectohydropyrimidin-1(2 H )-yl)benzoyl)-3,9-diaza Spiro[5.5]undecan-3-yl)acetaldehyde Step 1: 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl) Preparation of tert-butyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To 3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoic acid (1.0 g, 3.78 mmol) at room temperature under nitrogen , HATU (1.66 g, 4.37 mmol), 3,9-diazaspiro[5.5]undecyl-3-carboxylic acid tert-butyl ester ( 0.96 g, 3.78 mmol) and N-methylmorpholine (0.8 g, 7.92 mmol). After stirring for 2 h, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was collected, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 505.2 Step 2: 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecyl-3 Preparation of -carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 9-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3,9-diazaspiro[5.5]undecane The reaction solution of -3-carboxylic acid tert-butyl ester (1.56 g, 3.1 mmol) in trifluoroacetic acid/dichloromethane (2.5 mL/5 mL) solution was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to obtain a crude product of the target compound. The crude product was used directly in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 405.1 Step 3: 1-(2-chloro-5-(9-(2,2-dimethoxyethyl)-3, Preparation of 9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione To 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-bis To a mixture of ketone (200 mg, 0.25 mmol), potassium carbonate (155 mg, 1.25 mmol) and potassium iodide (19 mg, 0.11 mmol) in acetone (4 mL) was added 2-bromo-1,1-dimethoxy ethane (46 mg, 0.3 mmol). The reaction solution was stirred at 80 °C for 3 h, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the target compound. LC-MS: (ESI, m/z ): [M+H] ⁺ = 493.3. Step 4: 2-(9-(4-chloro-3-(2,4-dioxoectoine-1) Preparation of (2 H )-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetaldehyde 1-(2-Chloro-5-(9-(2,2-dimethoxyethyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydro A mixture of pyrimidine-2,4 (1 H ,3 H )-dione (121 mg, 0.246 mmol) in trifluoroacetic acid/dichloromethane (1 mL/2 mL) solution was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the target compound. LC-MS: (ESI, m/z ): [M+H] ⁺ =447.1.

Intermediate 8: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4 -yl)propionaldehyde step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline Preparation of -1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol), 3-(piperidin-4-yl) ) A mixture of propyl-1-ol (310 mg, 2.17 mmol)) and DIEA (701 mg, 5.43 mmol) in NMP (5 mL) was reacted in a microwave reactor at 140 °C for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phase was collected and washed with water (100 mL×2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified on a silica gel column to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 400.2. Step 2: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1 , Preparation of 3-dioxoisoindolin-5-yl)piperidin-4-yl)propionaldehyde 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione (310 mg, 0.78 mmol) and IBX (436 mg, 1.56 mmol) in acetonitrile (6 mL) were stirred and reacted at 80 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×2). The organic phase was collected and washed with water (50 mL×2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 398.2.

Intermediate 9: ( R ) -N- (1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidine -4-yl)quinazolin-4-amine Step 1: Preparation of 2-amino-5-bromo-4-methoxybenzoic acid To a stirred solution of 2-amino-4-methoxybenzoic acid (16.7 g, 100.0 mmol) in DMF (300 mL) at 0 °C was added NBS (19.6 g, 110.0 mmol). The reaction mixture was stirred at 25°C for 1 h, quenched with water (300 mL), extracted with EA (300 mL×3), collected the organic layer, and washed with sodium chloride (saturated aqueous solution, 300 mL×3) , dried with anhydrous ammonium sulfate and concentrated to obtain the target crude product. The crude product was used directly in the next reaction without purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 247.4. Step 2: Preparation of 6-bromo-7-methoxy-2-methylquinazolin-4-ol To a mixture of 2-amino-5-bromo-4-methoxybenzoic acid (19.5 g, 79.3 mmol) in MeOH (195 mL) was added ammonium acetate (61.0 g, 793 mmol) and trimethylorthoacetate Ester (95.1g, 793 mmol). The reaction mixture was stirred in a closed container at 120°C for 24 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered. The crude product was washed with EA to obtain the target crude product, which was directly used in the next reaction without purification. LC-MS: (ESI, m/z ): [M+H] ⁺ =271.0. Step 3: 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)- Preparation of tert-butyl 3,6-dihydropyridine-1(2 H )-carboxylate To a mixture of 6-bromo-7-methoxy-2-methylquinazolin-4-ol (1.5 g, 3.09 mmol) in DMF (30 mL) and water (4 mL) was added 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylic acid tert-butyl (1.73 g, 6.18 mmol), sodium carbonate (982 mg, 9.27 mmol) and Pd (dppf) ₂ Cl ₂ (226 mg, 0.319 mmol). The reaction mixture was stirred at 110°C overnight. The reaction mixture was quenched with water (300 mL) and extracted with EA (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 372.2. Step 4: 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piper Preparation of tert-butyl ester of 1-carboxylic acid To 4-(4-hydroxy-7-methoxyquinazolin-6-yl)-3,6-dihydropyridine-1(2 H )-carboxylic acid tert-butyl ester (500 mg, 0.894 mmol) Pd/C (300 mg) was added to MeOH (20 mL) solution. The reaction mixture was stirred at 50 °C under _H2 atmosphere for 2 days. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the target product 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester. The crude product was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 374.2. Step 5: 4-(7-methoxy-2-methyl-4-(((2,4,6-tri Preparation of tert-butyl ester of isopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)piperidine-1-carboxylate To tert-butyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carboxylate (250.0 mg, 0.76 mmol), TPSCl (295.0 mg, 1.0 mmol), DMAP (13.0 mg, 0.1 mmol) in DCM (5.0 mL) was added with TEA (0.3 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction solution was diluted with DCM and washed with saturated NaHCO _solution . _The organic phase was dried over _Na2SO4 , filtered and concentrated. The crude product obtained was purified by column chromatography (the eluent system was EA/PE) to obtain the product 4-(7-methoxy-2-methyl-4-((2,4,6-triisopropylphenyl) )Sulfonyl)oxy)quinazolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 640.0. Step 6: ( R )-4-(7-methoxy-2-methyl-4-((1-(3 - Preparation of tert-butyl nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylate To 4-(7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)piperidine -To a solution of tert-butyl 1-carboxylate (400 mg, 0.03 mmol) in DMSO (8 mL) was added ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl- 1-amine hydrochloride (203 mg, 0.75 mmol) and TEA (0.8 mL). The reaction mixture was stirred at 90°C overnight. The reaction was quenched with water and extracted with EA. _The organic phase was dried over _Na2SO4 , filtered and concentrated. The obtained crude product was purified by forward column to obtain the target product ( R )-4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) )ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 590.3. Step 7: ( R )-7-methoxy-2-methyl- N -(1-(3-nitro- Preparation of 5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)quinazolin-4-amine To ( R )-4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazole To a solution of tert-butylpholin-6-yl)piperidine-1-carboxylate (220 mg, 0.328 mmol) in DCM was added TFA. The reaction mixture was stirred at 25 °C for 2 h. Concentrate to obtain the target product ( R )-7-methoxy-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidine) -4-yl)quinazolin-4-amine. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 490.2 Step 8: ( R )- N -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl Preparation of methyl)-7-methoxy-2-methyl-6-(piperidin-4-yl)quinazolin-4-amine To ( R )-7-methoxy-2-methyl- N -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidine-4- To a solution of quinazolin-4-amine (124 mg, 0.25 mmol) in EtOH/H ₂ O (3 mL/1 ml), NH ₄ Cl (135.6 mg, 2.5 mmol) and Fe powder (141.5 mg, 2.5 mmol). The reaction mixture was stirred at 70 °C under _N2 atmosphere for 2 h. The reaction solution was filtered and concentrated to obtain crude product. The crude product was purified by preparative HPLC to obtain the target product ( R ) -N- (1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6 -(Piperidin-4-yl)quinazolin-4-amine. LC-MS: (ESI, m/z ): [M+H] ⁺ = 460.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.32 (s, 1H), 8.09 (s, 1H), 7.03 ( s, 1H), 6.88 (d, J = 11.1 Hz, 1H), 6.70 (s, 1H), 5.57 (d, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.39 – 3.25 (m, 2H ), 3.22 – 3.13 (m, 1H), 3.07 – 2.95 (m, 2H), 2.36 (s, 3H), 2.03 – 1.85 (m, 4H), 1.56 (d, J = 7.0 Hz, 3H).

Intermediate 10: ( R ) -N- (1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidine -4-Oxy)quinazolin-4-amine Step 1: 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.0 g, 49.7 mmol) and TEA (15.0 g, 149.1 mmol) in DCM (100 mL) was added dropwise at 0 °C. Methanesulfonyl chloride (7.4 g, 64.9 mmol) in DCM (20.0 mL). The reaction mixture was stirred at room temperature overnight, then water (200 mL) was added, extracted with DCM (200 mL×2), the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the concentrate was passed through a column The target product was obtained through chromatography purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 280.1. Step 2: Preparation of 6,7-dimethoxy-2-methylquinazolin-4-ol To a mixture of 2-amino-4,5-dimethoxybenzoic acid (20.0 g, 0.1 mol) in 2-methoxyethanol (120.0 mL) was added acetamidine hydrochloride (19.0 g, 0.2 mol) and sodium acetate (16.4 g, 0.2 mol). The reaction mixture was stirred at 140°C overnight. The reaction mixture was poured into water (250 mL) and stirred at room temperature for 10 min. The mixture was then filtered, the filter cake was washed with water, and the solid was vacuum dried to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 221.2. Step 3: Preparation of 7-methoxy-2-methylquinazoline-4,6-diol 6,7-Dimethoxy-2-methylquinazolin-4-ol (9.1 g, 41.4 mmol) and DL-methionine (10.5 g, 70.4 mmol) were dissolved in methanesulfonic acid (50 mL) The reaction mixture was stirred at 80 °C overnight. The reaction was quenched with ice water and basified with sodium hydroxide (2 N) solution. The precipitate was filtered off to obtain the target crude product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 207.2. Step 4: 4-((4-hydroxy-7-methoxy-2-methylquinazolin-6-yl) Preparation of tert-butyloxy)piperidine-1-carboxylate 7-Methoxy-2-methylquinazoline-4,6-diol (1.4 g, 6.8 mmol), 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid was added The reaction mixture of butyl ester (2.2 g, 8.2 mmol) and potassium carbonate (1.8 g, 13.6 mmol) in NMP (10.0 mL) solution was stirred at 100 °C overnight. Then water (50.0 mL) was added, and extracted with EA (50 mL×3). The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by reverse-phase column chromatography (acetonitrile:water = 0-100%) to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 390.2. Step 5: 4-((7-methoxy-2-methyl-4-(((2,4,6- Preparation of tert-butyl triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)oxy)piperidine-1-carboxylate 4-((4-Hydroxy-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (800.0 mg, 2.0 mmol), 2 The reaction mixture of 4,6-triisopropylbenzenesulfonyl chloride (748.0 mg, 2.4 mmol), DMAP (125.0 mg, 0.4 mmol) and TEA (623.0 mg, 6.0 mmol) in DCM (10.0 mL) was The reaction was stirred at room temperature overnight. The reaction mixture was concentrated, and the concentrate was purified by column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+Na] ⁺ = 678.1. Step 6: ( R )-4-((7-methoxy-2-methyl-4-((1-( Preparation of 3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester 4-((7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)oxy (R)-1-(3-nitro-5- ( trifluoromethyl)phenyl)ethyl-1-amine salt (0.8 g, 1.2 mmol), tert-butyl piperidine-1-carboxylate The reaction mixture of acid salt (0.43 g, 1.8 mmol) and TEA (1.1 g, 10.8 mmol) in DMSO (15.0 mL) was stirred at 90 °C overnight. Then water (50.0 mL) was added, and extracted with EA (50 mL×3). The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrate was purified by reverse-phase column chromatography (acetonitrile-water = 0 -100%) to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 606.0. Step 7: ( R )-7-methoxy-2-methyl- N -(1-(3-nitro- Preparation of 5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-oxy)quinazolin-4-amine ( R )-4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quino A mixture of tert-butyl oxazolin-6-yl)oxy)piperidine-1-carboxylate (140 mg, 0.23 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 2.0 h. The reaction product was concentrated under reduced pressure to obtain ( R )-7-methoxy-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6- (Piperidin-4-oxy)quinazolin-4-amine. LC-MS: (ESI, m/z ): [M+H] ⁺ = 506.1. Step 8: ( R )- N -(1-(3-amino-5-(trifluoromethyl)phenyl) Preparation of ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine ( R )-7-methoxy-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidine-4- The reaction mixture of quinazolin-4-amine (100.0 mg, 0.19 mmol) and Pd/C (20.0 mg) in methanol (5.0 mL) was stirred at room temperature under hydrogen atmosphere overnight. The reaction solution was filtered, the filtrate was concentrated, and the concentrate was purified by preparative HPLC to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =476.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.91 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.04 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.69 (s, 1H), 5.66 - 5.46 (m, 3H), 4.54 - 5.48 (m, 1H), 3.87 (s, 3H), 3.01 - 2.93 (m, 2H), 2.64 - 2.53 (m, 2H), 2.35 (s, 3H), 1.93 - 1.89 (m, 2H), 1.58 - 1.44 (m, 5H).

Intermediate 11: 4-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester Step 1: 4-((2-carboxyethyl)amino)benzene Preparation of formic acid Add acrylic acid (23.62 g, 328.1 mmol) to a solution of 4-aminobenzoic acid (15.0 g, 109.4 mmol) in AcOH/H ₂ O (40 ml/200 mL), stir at 110°C for 12 hours, cool the reaction solution, and filter , the target product 4-((2-carboxyethyl)amino)benzoic acid was obtained. LC-MS: (ESI, m/z ): [M+H] ⁺ = 210.0. Step 2: 4-(2,4-Dioxoectoine-1(2 H )-yl)benzoic acid Preparation Urea (114.83 g, 1913.8mmol) was added to a solution of 4-((2-carboxyethyl)amino)benzoic acid (20.0 g, 95.69 mmol) in AcOH (240 mL), and stirred at 110°C for 24 h. The reaction solution After cooling, add HCl solution, adjust the pH value to 1-2, precipitate solid, and filter to obtain the target product 4-(2,4-dioxoectoine-1(2 H )-yl)benzoic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ = 233.1. Step 3: 4-(2,4-Dioxoectoine-1(2 H )-yl)benzoic acid penta Preparation of fluorophenyl ester Pentafluorophenol (12.97 g, 70.51 mmol) and DCC (14.52 g, 70.51 mmol) were added to 4-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoic acid (15.0 g, 64.1 mmol) in DMF (200 mL), stirred at room temperature overnight, extracted with ethyl acetate (100 mL×3), washed the organic phase with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate, and the crude product is purified by column chromatography (EA:PE=3:7) to obtain the target product 4-(2,4-dioxoectoine-1( 2H )-yl)benzoic acid pentafluorophenyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 8.20 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 3.94 (t, J = 6.6 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H).

Intermediate 12: ( R )-(3-(1-Aminoethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester Step 1: 1-(3-nitro-5 Preparation of -(trifluoromethyl)phenyl)ethane-1-one 1-Bromo-3-nitro-5-(trifluoromethyl)benzene (50.0 g, 185.1 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (12.9 g, 18.5 mmol), TEA (37.4 g, 370.2 mmol) ) and tributyl(1-ethoxyvinyl)stannane (86.6 g, 240.6 mmol) in dihexane (300 mL) was stirred at 80 °C for 16 h. Water (900 mL) was added to the reaction solution to quench the reaction, and EA (500 mL×3) was added. The organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was stirred in a mixed solution of 6N HCl (200 mL) and THF (200 mL) for 30 min, then water (500 mL) and EA (500 mL×2) were added, the organic phases were combined, washed with saturated brine and anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The crude product was purified using column chromatography (EA:PE=0~1:9) to obtain 1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-one. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 2.75 (s, 3H). Step 2: 1-(3-Amino- Preparation of 5-(trifluoromethyl)phenyl)ethane-1-one A mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one (1.5 g, 6.4 mmol) and Pd/C (400 mg) in THF (30 mL) Stir at 60°C for 16 h. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(3-amino-5-(trifluoromethyl)phenyl)ethane-1-one. The obtained product was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 203.0. Step 3: (3-Acetyl-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester Preparation 1-(3-Amino-5-(trifluoromethyl)phenyl)ethane-1-one (1.1 g, 5.4 mmol) and (Boc) ₂ O (5.9 g, 27.0 mmol) were dissolved in dioxane (20 mL) was stirred at 80 °C for 16 h. The reaction solution was directly concentrated under reduced pressure, and the obtained crude product was purified by chromatography column (EA:PE=0~3:17) to obtain (3-acetyl-5-(trifluoromethyl)phenyl)carbamic acid third butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =303.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.26 (s, 1H), 8.18 (d, J = 6.5 Hz, 1H), 8.05 (s, 1H), 2.67 (d, J = 11.4 Hz, 3H), 1.41 (d, J = 11.7 Hz, 9H). Step 4: ( S , E )-(3-(1-( Preparation of tert-butyl (tert-butylthionyl)imino)ethyl)-5-(trifluoromethyl)phenyl)carbamate Add tert-butyl (3-acetyl-5-(trifluoromethyl)phenyl)carbamate (1.0 g, 3.3 mmol), Ti(OEt) ₄ (1.8 g, 6.6 mmol), diethylene di A mixture of alcohol dimethyl ether (2.3 g, 17.5 mmol) and ( S )-propane-2-sulfinamide (1.2 g, 9.9 mmol) in THF (10 mL) was stirred at 70 °C for 12 h. Water (50 mL) was added to the reaction solution, extracted with EA (30 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (EA:PE=0~1:4) to obtain ( S , E )-(3-(1-((tert-butylsulfonyl)imino)ethyl)-5 -(Trifluoromethyl)phenyl)carbamic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 407.0. Step 5: (3-(( R )- Preparation of tert-butyl 1-((( S )-tert-butylthionyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate At -78 ℃, to ( S , E )-(3-(1-((tert-butylthionyl<sulfinyl>)imino)ethyl)-5-(trifluoromethyl) L-Selectride (1.0 mol/L /THF, 3.6 mL) was added to a solution of tert-butyl phenyl)carbamate (1.0 g, 2.4 mmol) in THF (20 mL), and the reaction solution was stirred at -78 °C for 50 min. . Water (50 mL) was added to the reaction solution to quench the reaction, and then extracted with EA (50 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (EA:PE=0~1:1) to obtain (3-(( R )-1-((( S )-tert-butylsulfonyl)amino)ethyl)- 5-(Trifluoromethyl)phenyl)carbamic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 409.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.71 (s, 1H), 7.74 (d, J = 5.1 Hz, 2H), 7.39 (s, 1H), 4.15 (q, J = 6.7 Hz, 1H), 1.48 (s, 15H), 1.31 (d, J = 6.7 Hz, 3H), 1.11 (d, J = 2.1 Hz, 3H). Step 6: Preparation of ( R )-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (3-(( R )-1-((( S )-tert-butylsulfinyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid at 0°C The tert-butyl ester (1.0 g, 2.4 mmol) was stirred in 1N HCl/EtOAc (20 mL) for 3 h. The reaction solution was quickly filtered through a chromatography column, washed first with EtOAc, and then with DCM/MeOH (5/1) mixed solvent. The filtrate was alkalized with 7N NH ₃ /MeOH, and the organic phase was washed with water and dried over anhydrous Na ₂ SO ₄ . Filter and concentrate to obtain ( R )-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =305.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 7.71 (s, 1H), 7.69 ( s, 1H), 7.35 (s, 1H), 4.02 – 3.99 (m, 1H), 1.48 (s, 9H), 1.23 (d, J = 6.6 Hz, 3H).

Intermediate 13: (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl)benzene (ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester Add (1 R ,4 R )-4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (330 mg) with stirring. , 1.0 mmol) in DMF (5 mL), add BOP (574 mg, 1.3 mmol) and DBU (380 mg, 2.5 mmol), stir for 15 min, then add ( R )-(3-(1-amino) Ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester hydrochloride (396 mg, 1.3 mmol), the reaction solution was continued to stir at 70 °C for 12 h. Water (10 mL) was added to the reaction solution to quench the reaction, and then extracted with EA (30 mL×3). The organic phase was dried over _{anhydrous Na2SO4} and concentrated under reduced pressure. The crude product obtained was purified by chromatography column (EA:PE=0~1) to obtain (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)) Amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester . LC-MS: (ESI, m/z ): [M+H] ⁺ = 617.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.69 (s, 1H), 8.12 (s, 1H), 7.77 ( d, J = 25.2 Hz, 2H), 7.41 (s, 1H), 7.01 (s, 1H), 5.71 – 5.55 (m, 1H), 3.90 (s, 3H), 3.62 (s, 3H), 2.96 (d , J = 11.8 Hz, 1H), 2.39 (d, J = 10.4 Hz, 4H), 2.06 (d, J = 12.0 Hz, 2H), 1.89 (d, J = 14.0 Hz, 2H), 1.64 – 1.50 (m , 7H), 1.46 (s, 9H).

Intermediate 14: (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl)benzene (yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid To (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl (methyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (250 mg, 0.4 mmol) in THF/H ₂ O (10 mL /5 mL), LiOH.H ₂ O (48 mg, 1.2 mmol) was added, and the reaction solution was stirred at 40 °C overnight. The reaction solution was adjusted to pH with 10% citric acid, and then extracted with EtOAc (30 mL×3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain (1 R , 4 R )-4-(4- ((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2- Methylquinazolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ = 603.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.67 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H), 8.07 (s, 1H), 7.77 (d, J = 24.0 Hz, 2H), 7.41 (s, 1H), 7.00 (s, 1H), 5.68 – 5.52 (m, 1H), 3.89 (s, 3H ), 2.95 (d, J = 11.3 Hz, 1H), 2.40 – 2.23 (m, 4H), 2.06 (d, J = 12.0 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.67 – 1.41 (m, 16H).

Intermediate 15: (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)) Phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid Step 1: (1 R ,4 R )-4-(7-methoxy-2-methyl- 4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl Preparation of esters Add (1 R ,4 R )-4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (500 mg) with stirring. , 1.52 mmol) in DMF (10 mL), add BOP (871 mg, 1.97 mmol) and DBU (577 mg, 3.80 mmol), continue stirring for 15 min, then add ( R )-1-(3-nitro -5-(Trifluoromethyl)phenyl)ethane-1-amine (461 mg, 1.97 mmol). The reaction solution was then stirred at 70°C overnight. Water (50 mL) was added to the reaction solution, and extracted with EA (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (EA:PE=0~1) to obtain (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3) -Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =547.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.62 (s, 1H), 8.34 (d, J = 6.0 Hz, 3H), 8.04 (s, 1H), 7.01 (s, 1H), 5.68 (p, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.64 (s, 3H), 2.94 (t, J = 11.4 Hz, 1H), 2.48 – 2.37 (m, 1H), 2.34 (s, 3H), 2.08 (d, J = 12.0 Hz, 2H), 1.97 – 1.86 (m, 2H), 1.69 (d, J = 7.1 Hz , 3H), 1.65 – 1.47 (m, 4H). Step 2: (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3 - Preparation of -nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) To a solution of ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (300 mg, 0.55 mmol) in THF/H ₂ O (15 mL, 1:2) was added LiOH. H ₂ O (240 mg, 8.0 mmol). The reaction solution was then stirred at 50°C overnight. Water (50 mL) was added to the reaction solution to quench the reaction, and extracted with EA (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain (1 R , 4 R )-4-(7-methoxy-2-methyl-4 -((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ =533.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (s, 1H), 8.89 (s, 1H), 8.63 ( s, 1H), 8.36 (d, J = 10.6 Hz, 2H), 8.14 (s, 1H), 7.02 (s, 1H), 5.89 – 5.64 (m, 1H), 3.92 (s, 3H), 2.95 (t , J = 11.6 Hz, 1H), 2.41 (s, 3H), 2.37 – 2.26 (m, 1H), 2.08 (d, J = 10.7 Hz, 2H), 1.96 – 1.85 (m, 2H), 1.72 (d, J = 7.1 Hz, 3H), 1.68 – 1.44 (m, 4H).

Intermediate 16: (1 R ,4 R )-4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2- Methylquinazolin-6-yl)cyclohexane-1-carboxylic acid Step 1: 1-(1,3-dicarbonylisoindolin-2-yl) 4-methyl(1 R ,4 R )-Preparation of cyclohexane-1,4-dicarboxylate To (1 R ,4 R )-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (20 g, 107.4 mmol) and 2-hydroxyisoindoline-1,3-dione (20 g , 107.4 mmol) in DCM (300 mL), EDCI (34.7 g, 118.2 mmol) and DMAP (1.3 g, 10.7 mmol) were added. The reaction solution was then stirred at room temperature for 2 h. Add brine and DCM to the reaction solution. _The organic layer was separated, dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The crude product was purified by chromatography column (DCM) to obtain 1-(1,3-dicarbonylisoindolin-2-yl) 4-methyl(1 R ,4 R )-cyclohexane-1,4-di Carboxylic acid esters. LC-MS: (ESI, m/z ): [M+Na] ⁺ =354.1. Step 2: Preparation of 2-amino-5-iodo-4-methoxybenzonitrile To a solution of 2-amino-4-methoxybenzonitrile (86.3 g, 582 mmol) in DMF (1000 mL) was added NIS (133 g, 613 mmol). The reaction solution was then stirred at room temperature for 2 h. Add brine and DCM to the reaction solution. The organic layer was separated, dried and filtered over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain 2-amino-5-iodo-4-methoxybenzonitrile. LC-MS: (ESI, m/z ): [M+Na] ⁺ = 296.9. Step 3: Preparation of N -(2-cyano-4-iodo-5-methoxyphenyl)acetamide To a solution of 2-amino-5-iodo-4-methoxybenzonitrile (160 g, 580 mmol) in HOAc (1600 mL) was added Ac ₂ O (71.3 g, 700 mmol). The reaction was then stirred at room temperature overnight. The reaction solution was filtered and concentrated to obtain N- (2-cyano-4-iodo-5-methoxyphenyl)acetamide. LC-MS: (ESI, m/z ): [M+H] ⁺ = 317.0. Step 4: (1 R ,4 R )-4-(4-acetamide-5-cyano-2-methyl Preparation of methyl oxyphenyl)cyclohexane-1-carboxylate To N -(2-cyano-4-iodo-5-methoxyphenyl)acetamide (15.0 g, 47.45 mmol), 1-(1,3-dicarbonylisoindolin-2-yl) DMA (237 mL , 0.2 M ) solution, add NiBr ₂ (dtbpy) (2.31 g, 4.75 mmol). The reaction solution _was blown with N for 5 minutes and irradiated with two Kessil PR160-purple LED lamps (30 W High Luminous DEX 2100 LED, λ max = 390 nm) for 16 h. The reaction temperature is controlled at 30-40°C. After the reaction was completed, the reaction solution was poured into water (1 L), and then extracted with EtOAc (150 mLx3). The organic phases were combined and washed with saturated brine (400 mLx3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product obtained was purified by chromatography column (MeOH:DCM=1:99). Collect the eluate containing the product and concentrate it to 80 mL, filter, and concentrate the filtrate to obtain a mixture with a cis-to-trans ratio of 1:1, and the filter cake is a mixture with a cis-to-trans ratio of 15:1. The mixture with a cis-to-trans ratio of 15:1 was dissolved in DMA (85 mL), and then 0.5MK ₂ CO ₃ aqueous solution (200 mL) was added. The resulting mixture was stirred at room temperature for 2 hours, and filtered to obtain a mixture with a cis-to-trans ratio of 20:1. The mixture was recrystallized with acetonitrile (180 mL) to obtain the target product (cis-to-trans ratio 97:2) LC-MS: (ESI, m/z ): [M+H] ⁺ = 331.1. ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.55 (s, 1H), 7.29 (s, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 2.90-2.84 (m, 1H) , 2.35-2.26 (m, 1H), 2.25 (s, 3H), 2.11-2.08 (m, 2H), 1.92-1.89 (m, 2H), 1.63-1.56 (m, 2H), 1.39-1.33 (m, 2H). Step 5: (1 R ,4 R )-4-(7-methoxy-2-methyl-4-carbonyl-3,4-dihydroquinazolin-6-yl)cyclohexane- Preparation of 1-carboxylic acid methyl ester (1 R ,4 R )-4-(4-acetamide-5-cyano-2-methoxyphenyl)cyclohexane-1-carboxylic acid methyl ester (3 g, 9.08 mmol) was added i -PrOH (80 mL), and then pass HCl gas at room temperature for 1 h. The reaction solution was filtered and dried to obtain (1 R ,4 R )-4-(7-methoxy-2-methyl-4-carbonyl-3,4-dihydroquinazolin-6-yl)cyclohexane -1-Carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 331.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (s, 1H), 7.23 (s, 1H), 3.95 ( s, 3H), 3.61 (s, 3H), 2.98-2.87 (m, 1H), 2.58 (s, 3H), 2.47-2.39 (m, 1H), 2.06-1.98 (m, 2H), 1.88-1.80 ( m, 2H), 1.59-1.42 (m, 4H). Step 6: ( R , Z ) -N- (1-(4-bromothiophen-2-yl)ethylene)-2-methylpropane-2 -Preparation of sulfenamides 1-(4-Bromothiophen-2-yl)ethane-1-one (10.0 g, 48.80 mmol), ( R )-2-methylpropane-2-sulfinamide (8.90 g, 73.20 mmol) The reaction solution of Ti(OEt) ₄ (27.8 g, 122.00 mmol) in THF (70 mL) was stirred at 80 °C for 3 h. The reaction solution was quenched by adding water (200 mL), and then extracted with EA (100 mLx3). The organic phases were combined, dried over anhydrous _Na2SO4 , filtered, and concentrated _under reduced pressure. The crude product obtained was purified by chromatography column (DCM:MeOH=100:1) to obtain ( R , Z ) -N- (1-(4-bromothiophen-2-yl)ethylene)-2-methylpropane-2 -Sulfinamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.96 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 1.2 Hz, 1H), 2.68 (s, 3H), 1.19 (s, 9H) . Step 7: Preparation of ( R ) -N -(( R )-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide To ( R , Z )- N -(1-(4-bromothiophen-2-yl)ethylene)-2-methylpropane-2-sulfinamide (7.0 g, 22.7 mmol) in THF (10 mL) solution, add 9-BBN/THF (0.5 M, 200 mL). The reaction solution was stirred at 25 °C for 0.5 h. MeOH (10 mL) was added to the reaction solution to quench the reaction, then water (100 mL) was added, and then extracted with EA (100 mLx3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by chromatography column (DCM:MeOH=100:1) to obtain ( R ) -N -(( R )-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane- 2-Sulfinamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 (d, J = 1.2 Hz, 1H), 7.08 (s, 1H), 5.93 (d, J = 7.2 Hz, 1H), 4.64-4.58 (m, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H). Step 8: ( R )-1-(4-bromothiophen-2-yl)ethane-1-amine hydrochloride Preparation To ( R )- N -(( R )-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (6.0 g, 19.34 mmol) To a solution of 4-dioxane (60 mL) was added HCl (12 M, 454 mmol). The reaction solution was then stirred at 25 °C for 2 h. The reaction solution was directly concentrated. The obtained crude product was stirred in MTBE (100 mL) solution, filtered, and dried to obtain ( R )-1-(4-bromothiophen-2-yl)ethane-1-amine hydrochloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.62 (s, 3H), 7.71 (s, 1H), 7.32 (s, 1H), 4.71-4.67 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H). Step 9: (1 R ,4 R )-4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy Preparation of methyl-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-carbonyl-3,4-dihydroquinazolin-6-yl)cyclohexane-1- at room temperature Add DBU (3.45 g, 22.67 mmol) to a solution of methyl carboxylate (3.00 g, 9.07 mmol) and BOP (5.21 g, 11.79 mmol) in DMF (35 mL). After stirring for 15 minutes, add ( R )-1 dropwise -(4-bromothiophen-2-yl)ethane-1-amine hydrochloride (2.86 g, 11.79 mmol) in DMF (35 mL), then the reaction solution was stirred at room temperature for 20 minutes, and then heated to 70 °C and stirred for 8 hours. The reaction solution was purified by reverse phase column to obtain (1 R ,4 R )-4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy Methyl-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 518.0, 520.0. Step 10: (1 R ,4 R )-4-(4-((( R )-1-(4- Preparation of bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid To (1 R ,4 R )-4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquin To a solution of oxazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (2.00 g, 3.86 mmol) in THF/H ₂ O (20.0 mL/20.0 mL) was added LiOH (0.81 g, 19.30 mmol). The reaction solution was stirred at 25 °C for 16 h. The reaction solution was acidified with 2N HCl solution, and a precipitate formed. Filter and dry the filter cake under vacuum to obtain (1 R ,4 R )-4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ = 504.0, 506.0.

Intermediate 17: 4-(2,6-dioxopiperidin-3-yl)benzoate pentafluorophenyl ester Step 1: 4-(4-cyano-1-methoxy-1-oxobutane Preparation of -2-yl)benzoic acid methyl ester Benzyltrimethylammonium hydroxide (6.03 g, 36.057 mmol) and acrylonitrile (5.727 g, 79.32 mmol) were added to 4-(2-methoxy-2-oxyethane) methyl benzoate (15.0 g, 72.12 mmol) in toluene solution (200 mL), stirred at 30°C for 16 h, extracted with ethyl acetate (100 mL×5), washed the organic phase with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure, and the crude product is purified by column chromatography (EA:PE=3:7) to obtain the target product 4-(4-cyano-1-methoxy-1-oxobutan-2-yl)benzoic acid methyl ester. . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.95 (d, J = 4.0 Hz, 2H), 7.46 (d, J = 6.0 Hz, 2H), 3.90-3.80 (m, 4H), 3.62 (s, 3H), 2.48-2.38 (m, 2H), 2.36-2.26 (m, 1H), 2.10-1.96 (m, 1H). Step 2: 4-(2,6-dioxopiperidin-3-yl)benzene Preparation of formic acid Dissolve 4-(4-cyano-1-methoxy-1-oxobutan-2-yl)benzoic acid methyl ester (8.5 g, 32.56 mmol) in acetic acid (30 mL), add sulfuric acid (15 mL ), stir at 110°C for 12 h, extract with dichloromethane/methanol (10/1, 150 ml×3), wash the organic phase with saturated brine (500 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product Purification using column chromatography (MeOH:DCM=1:10) gave 4-(2,6-dioxopiperidin-3-yl). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.89 (s, 1H), 10.89 (s, 1H), 7.91 (d, J = 4.0 Hz, 2H), 7.36 (d, J = 4.0 Hz, 2H) , 4.02-3.92 (m, 1H), 2.72-2.63 (m, 1H), 2.56-2.45 (m, 1H), 2.30-2.20 (m, 1H), 2.10-2.00 (m, 1H). Step 3: 4 Preparation of -(2,6-dioxopiperidin-3-yl)benzoate pentafluorophenyl ester Dissolve 4-(2,6-dioxopiperidin-3-yl)benzoic acid (1.3 g, 5.579 mmol) with DMF (100 mL), add pentafluorophenol (1.129 g, 6.14 mmol) and DCC (1.265 g , 6.14 mmol), stirred at room temperature overnight, extracted with ethyl acetate (100 mL×3), washed the organic phase with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography. (EA:PE=3:7) was purified to obtain 4-(2,6-dioxopiperidin-3-yl)benzoic acid pentafluorophenyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (s, 1H), 8.17 (d, J = 4.0 Hz, 2H), 7.56 (d, J = 4.0 Hz, 2H), 4.14-4.08 (m, 1H), 2.79-2.69 (m, 1H), 2.66-2.55 (m, 1H), 2.30-2.23 (m, 1H), 2.15-2.05 (m, 1H).

Intermediate 18: 3-(2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoic acid pentafluorophenyl ester Step 1: 3-(2,4-di Preparation of oxoectoine-1(2 H )-yl)-4-methoxybenzoic acid 3-Amino-4-methoxybenzoic acid (5.0 g, 2.93 mmol) was suspended in acrylic acid (8.05 mL, 117 mmol), and the reaction was stirred at 100 ° C for 3 h, and then the reaction solution was stirred and cooled to room temperature. Warm. Acetic acid (33 ml) was added, the stirred suspension was heated at 100°C for 10 minutes, urea (11.00 g, 183 mmol) was added, and the reaction solution was stirred at 120°C overnight. The reaction solution was added to a mixture of ice water and concentrated hydrochloric acid (37%), stirred, and the resulting suspension was stored in a refrigerator at 5°C overnight, then filtered, and the solid was washed with water and dried to obtain a solid. The solid was ground in hydrochloric acid solution (0.05 M), filtered, washed with methyl tert-butyl ether, and dried under reduced pressure at 40°C to obtain the target product. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.70 (s, 1H), 10.34 (s, 1H), 7.92 (dd, J = 8.6, 2.2 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 3.94 - 3.82 (m, 3H), 3.60 (t, J = 6.7 Hz, 2H), 2.69 (s, 2H). Step 2: 3-(2 , Preparation of 4-dioxoectoine-1(2 H )-yl)-4-methoxybenzoic acid pentafluorophenyl ester 3-(2,4-Dioxoectoine-1(2 H )-yl)-4-methoxybenzoic acid (2.0 g, 7.58 mmol), 2,3,4,5,6-penta A mixture of fluorophenol (1.67 g, 9.09 mmol) and N , N' -dicyclohexylcarbodiimide (1.87 g, 9.09 mmol) in a solution of N , N -dimethylformamide (20 mL) was placed in the chamber. The reaction was stirred at room temperature for 3 h. The reaction solution was poured into water (200 mL) and stirred for 0.5 h. The solution was extracted with ethyl acetate (200 mL×3). The organic phase was collected, washed with water (500 mL×2) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to obtain the target product 3-(2,4-dioxoectoine-1(2 H )-yl)-4-methoxybenzoic acid pentafluorophenyl ester. LC-MS: (ESI, m/z ):[M+H] ⁺ =431.1.

Intermediate 19: 3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-fluorobenzoic acid pentafluorophenyl ester Prepare according to the method of intermediate 18. LC-MS: (ESI, m/z ):[M+H] ⁺ =419.0.

Intermediate 20: 3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester Prepare according to the method of intermediate 18. LC-MS: (ESI, m/z ):[M+H] ⁺ =401.0.

Intermediate 21: (1 R ,4 R )-4-(4-((( R )-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl) Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester Step 1: (1 R ,4 R )-4-(4 -((( R )-1-(4-(2-formylphenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- Preparation of cyclohexane-1-carboxylic acid methyl ester To (1 R ,4 R )-4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquin To a solution of oxazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (250 mg, 0.48 mmol) in 1,4-dioxane/H ₂ O (1.5 mL/0.5 mL) was added K ₃ PO ₄ (255 mg, 1.2 mmol), (PPh ₃ ) ₂ PdCl ₂ (34 mg, 0.048 mmol) and (2-formylphenyl)boronic acid (87 mg, 0.58 mmol). The reaction solution was stirred at 100°C overnight. The reaction solution was concentrated and then purified through a chromatography column (PE/EA= 2/1~1/2) to obtain (1 R ,4 R )-4-(4-((( R )-1-(4-(2 -Formylphenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =544.1. Step 2: (1 R ,4 R )-4-(4-((( R )-1-(4-(2 -((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1 -Preparation of methyl carboxylate To (1 R ,4 R )-4-(4-((( R )-1-(4-(2-formylphenyl)thiophen-2-yl)ethyl)amino)-7-methyl To the mixture of methyl oxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (200 mg, 0.36 mmol) and dimethylamine hydrochloride (60 mg, 0.74 mmol) was added MeOH ( 3 mL), DCE (3 mL) and AcOH (5 drops). After the above solution was stirred at room temperature for 1 h, NaBH ₃ CN (46 mg, 0.74 mmol) was added, and the reaction solution was continued to stir at room temperature for 3 h. DCM and water were added to the reaction solution, and the organic phase was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by Prep-HPLC to obtain (1 R ,4 R )-4-(4-((( R )-1-(4-(2-(dimethylamino)methyl)phenyl)thiophene- 2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =573.3 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.34 (m, 3H), 7.33-7.28 (m, 4H), 7.12 (s, 1H), 6.11-6.02 (m, 1H), 5.69-5.60 (m, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 3.38 (s, 2H), 3.04-2.98 (m , 1H), 2.63 (s, 3H), 2.44-2.33 (m, 1H), 2.24-2.18 (m, 6H), 2.16-2.07 (m, 2H), 2.05-1.95 (m, 2H), 1.82-1.79 (d, J = 6.8 Hz, 3H), 1.67-1.60 (m, 4H).

Intermediate 22: 4-(3-Bromoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester Step 1: 4-(2,2-dibromovinyl)piperidine-1 -Preparation of tert-butyl carboxylate To a solution of CBr ₄ (14.0 g, 42.24 mmol) in DCM (200 mL) was added PPh ₃ (22.13 g, 84.48 mmol) with stirring at 0 °C, and stirring was continued for 30 min at 0 °C, and then 4-aldehyde was added piperidine-1-carboxylic acid tert-butyl ester (6.0 g, 28.16 mmol), and the reaction solution was stirred at room temperature overnight. The reaction solution was diluted with EA (200 mL) and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was passed through flash column (EA:PE=0~3:7) to obtain 4-(2,2-dibromovinyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M-tBu] ⁺ =313.9. Step 2: 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl Preparation of esters To a solution of tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (4.0 g, 10.86 mmol) in THF (60 mL) at -78 °C was added n -BuLi (13.6 mL, 1.6 M/hexane). After the mixture was stirred at -78 °C for 1 h, paraformaldehyde (977 mg, 32.60 mmol) was added. The reaction was stirred at room temperature overnight. NH ₄ Cl (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with EA (100 mL×3). The organic phases were combined and washed with saturated brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained crude product was purified by flash column (EA:PE=0~4:1) to obtain 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M-Boc] ⁺ =140.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.04 (t, J = 5.9 Hz, 1H), 4.04 (dd, J = 5.8, 2.0 Hz, 2H), 3.65 – 3.55 (m, 2H), 3.04 (t, J = 10.1 Hz, 2H), 2.60 (ddd, J = 8.8, 7.0, 3.5 Hz, 1H), 1.77 – 1.64 (m, 2H), 1.43 – 1.31 (m, 11H). Step 3: Preparation of tert-butyl 4-(3-bromoprop-1-yn-1-yl)piperidine-1-carboxylate At 0°C, add 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester (700 mg, 2.92 mmol) and PPh ₃ (1.94 g, 5.83 To a solution of mmol) in DCM (10 mL) was added CBr ₄ (1.94 g, 5.83 mmol). The reaction was stirred at room temperature overnight. The reaction solution was diluted by adding EA (10 mL), and then filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by flash column (EA:PE=0~3:7) to obtain 4-(3-bromoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M-tBu] ⁺ =246.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.24 (d, J = 2.0 Hz, 2H), 3.64 – 3.54 ( m, 2H), 3.13 – 3.00 (m, 2H), 2.75 – 2.65 (m, 1H), 1.78 – 1.68 (m, 2H), 1.44 – 1.33 (m, 11H).

Intermediate 23: 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester Step 1: 4-(2-(pyridin-4-ylmethoxy) Preparation of tert-butyl)ethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1.0 g, 4.36 mmol) in THF (20 mL) at 0 °C was added NaH (60%, 1.2 g, 30.58 mmol) and stirred at 0°C for 20 minutes. After rising to room temperature, 4-(bromomethyl)pyridine hydrogen bromide (1.3 g, 5.13 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, and the mixture was extracted with EA (30 mL×3). The organic phases were combined and washed with brine (30 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The concentrate was purified by flash column (EA:PE=0~4:1) to obtain the target product 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 321.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 5.9 Hz, 2H), 7.24 (d, J = 5.7 Hz, 2H), 4.51 (s, 2H), 4.09 (d, J = 15.9 Hz, 2H), 3.55 (t, J = 6.1 Hz, 2H), 2.70 (t, J = 12.2 Hz, 2H), 1.66 (d, J = 13.9 Hz, 2H), 1.58 (m, 2H), 1.45 (s, 9H), 1.26 (m, 1H), 1.13 (d, J = 8.4 Hz, 2H). Step 2: 4-( Preparation of tert-butyl 2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 5.9 mmol) and Pd/C (570 mg) were dissolved in i-PrOH/ The mixture in H ₂ O (30 mL/35 mL) was stirred at 75 °C overnight. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the target product 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. The obtained product did not require purification and was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 327.2.

Intermediate 24: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4 -yl)acetaldehyde step 1: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline Preparation of -1,3-dione To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.0 g, 3.6 mmol) in DMF (10 mL) was added 2-(piperidin-4-yl)ethan-1-ol (467 mg, 3.6 mmol) and DIEA (1.4 g, 10.8 mmol). The reaction solution was stirred at 100°C overnight. Water (100 mL) was added to the reaction solution to quench the reaction. Then extract with EA (20 mL×3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (EA:PE=0~1:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-hydroxyethyl)piper (ridin-1-yl)isoindoline-1,3-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =386.1. Step 2: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1 , Preparation of 3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde While stirring, add 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3 -To a solution of dione (1.1 g, 3.0 mmol) in ACN (20 mL), add IBX (1.7 g, 6.0 mmol). The reaction solution was stirred at 80 °C for 2 h. The reaction solution was filtered and the filtrate was concentrated. The crude product obtained was purified by flash column (EA:PE=0~1:1) to obtain 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-4-yl)piperidin-4-yl)acetaldehyde. LC-MS: (ESI, m/z ): [M+H] ⁺ =384.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.72 (s, 1H), 7.77 – 7.58 (m, 1H), 7.34 (dd, J = 7.7, 4.9 Hz, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 3.68 (d, J = 11.8 Hz, 2H), 2.97-2.82 (m, 3H), 2.64 – 2.53 (m, 2H), 2.45 (d, J = 6.6 Hz, 2H), 2.13 – 1.99 (m, 3H), 1.82-1.72 (m, 2H), 1.50-1.30 (m , 2H).

Intermediate 25: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4 -yl)propanal Step 1: Preparation of 3-(piperidin-4-yl)propan-1-ol To tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (930.0 mg, 3,8 mmol) in DCM (8.00 mL) was added TFA (4.0 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was directly concentrated to obtain 3-(piperidin-4-yl)propan-1-ol. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ =144.2. Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3 Preparation of -Hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione To a solution of 3-(piperidin-4-yl)propan-1-ol (730 mg, TFA salt, 3.8 mmol) in DMF (10 mL) was added 2-(2,6-dioxopiperidine) with stirring. (ridin-3-yl)-4-fluoroisoindoline-1,3-dione (1.0 g, 3.8 mmol) and DIEA (1.5 g, 11.4 mmol). The reaction solution was stirred at 100°C overnight. Water (100 mL) was added to the reaction solution to quench the reaction. Then extract with EA (20 mL×3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The crude product obtained was purified by flash column (EA:PE=0~1:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piper (ridin-1-yl)isoindoline-1,3-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =400.0. Step 3: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1 , Preparation of 3-dioxoisoindolin-4-yl)piperidin-4-yl)propionaldehyde While stirring, add 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3 -To a solution of dione (700 mg, 1.7 mmol) in ACN (20 mL), add IBX (982 mg, 3.5 mmol). The reaction solution was stirred at 80 °C for 2 h. The reaction solution was filtered and the filtrate was concentrated. The crude product obtained was purified by flash column (EA:PE=0~1:1) to obtain 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-4-yl)piperidin-4-yl)propionaldehyde. LC-MS: (ESI, m/z ): [M+H] ⁺ =398.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.71 (t, J = 1.4 Hz, 1H), 7.74 – 7.60 (m, 1H), 7.33 (dd, J = 7.7, 3.4 Hz, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 3.69 (d, J = 11.9 Hz, 2H ), 2.93-2.79 (m, 3H), 2.64 – 2.46 (m, 4H), 2.07 – 2.00 (m, 1H), 1.80-1.72 (m, 2H), 1.54 (dd, J = 14.0, 7.1 Hz, 2H ), 1.40-1.27 (m, 3H).

Intermediate 26: 9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester Step 1: 9-((4-(((9 H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxy Preparation of tert-butyl acid 9-Aldehyde-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.0 g, 3.56 mmol) and (9 H -Fluoren-9-yl)methyl piperazine-1-carboxylate (1.35 g, 3.91 mmol) was dissolved in THF (20 mL), added STAB (2.26 g, 10.68 mmol), and stirred at room temperature overnight , add water (100 mL), extract with ethyl acetate (100 mLx3), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (EA/PE= 3:2) was purified to obtain 9-((4-((( 9H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5] Monoalkyl-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =574.2. Step 2: (9 H -fluoren-9-yl)methyl 4-((3-azaspiro[5.5]eleven Preparation of alkyl-9-yl)methyl)piperamide-1-carboxylate 9-(((4-(((9 H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3- Dissolve tert-butyl carboxylate (1.1 g, 1.92 mmol) in DCM (10 mL), add TFA (2 mL), stir at room temperature for 1 h, and concentrate under reduced pressure to obtain (9 H -fluoren-9-yl) Methyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide-1-carboxylate was used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ =474.1. Step 3: 9-((4-(((9 H -fluoren-9-yl)methoxy)carbonyl)piperaniline Preparation of -1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (9 H -Fluoren-9-yl)methyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carboxylate (1.1 g, 2.33 mmol ) was dissolved in ACN (20 mL), add NaHCO ₃ saturated solution (20 mL), add CbzCl (0.60 g, 3.50 mmol) with stirring, and react at room temperature overnight. Concentrate under reduced pressure to remove acetonitrile, add water (50 mL), extract with ethyl acetate (100 mLx3), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use column chromatography for the crude product (EA/PE=11:9) was purified to obtain 9-((4-(((9 H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-aza Spiro[5.5]undecane-3-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =608.1. Step 4: 9-(piperidine-1-ylmethyl)-3-azaspiro[5.5]undecane-3 -Preparation of benzyl carboxylate 9-(((4-(((9 H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3- Benzyl carboxylate (0.97 g, 1.60 mmol) was dissolved in CAN (10 Ml), piperidine (2 mL) was added, and the mixture was stirred at room temperature for 3 h. Concentrate under reduced pressure to remove the solvent, add water (50 mL), extract with ethyl acetate (100 mLx3), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use column chromatography for the crude product (MeOH/DCM=3:17) was purified to obtain 9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =386.1.

Intermediate 27: 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester Step 1: 4-((( Preparation of trifluoromethoxy)sulfonyl)oxy)cyclohex-3-ene-1-carboxylic acid methyl ester 2,6-Dimethyl-1λ ² -piperamide (51.4 g, 480.37 mmol) and Tf ₂ O (90.38 g, 320.50 mmol) were added to 4-oxocyclohexane-1-carboxylic acid methyl ester (50.0 g, 320.51 mmol) in dichloromethane (500 ml), stir at 0°C for 1 h, then add Tf ₂ O (72.3 g, 256.38 mmol), stir at room temperature overnight, wash with water, dry over anhydrous sodium sulfate, and reduce pressure After concentration, the crude product was subjected to column chromatography (PE:EA=5:1) to obtain 4-(((trifluoromethoxy)sulfonyl)oxy)cyclohex-3-ene-1-carboxylic acid methyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.90 (s, 1H), 3.63 (s, 3H), 2.70 – 2.60 (m, 1H), 2.47 – 2.28 (m, 4H), 2.11 – 1.98 (m , 1H), 1.81 (tt, J = 8.9, 6.0 Hz, 1H). Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2- Preparation of cyclohex-3-ene-1-carboxylic acid methyl ester (Bpin) ₂ (39.1 g, 153.94 mmol), Pd(dppf) ₂ Cl ₂ (7.5 g, 10.24 mmol) and potassium acetate (30.4 g, 310.2 mmol) were added to 4-((trifluoromethoxy) Sulfonyl)oxy)cyclohex-3-ene-1-carboxylic acid methyl ester (30.0 g, 104.17 mmol) was dissolved in dihexane (500 ml) and stirred at 90°C overnight. The reaction solution was diluted with water (2 L). Extract with ethyl acetate (500 mL×3), wash with saturated brine (500 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (PE:EA=0:100) to obtain 4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.53 (s, 1H), 3.71 – 3.64 (m, 3H), 2.61 – 2.46 (m, 1H), 2.42 – 1.95 (m, 6H), 1.28 – 1.19 (m , 12H). Step 3: Preparation of 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (25.0 g, 93.98 mmol), Pd(dppf) ₂ Cl ₂ (5.3 g, 7.24 mmol) and Na ₂ CO ₃ (15.3 g, 144.34 mmol) were added to 6-bromo-7-methoxy-2-methylquinazoline-4 -Alcohol (19.4 g, 72.12 mmol) in DMF/H ₂ O (300 ml /30 ml), stirred at 110°C overnight, diluted the reaction solution with water (1 L), extracted with ethyl acetate (500 mL×3), and saturated The organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=0:100) to obtain the crude product 4-(4-hydroxy-7-methyl). Oxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =329.0.

Intermediate 28: (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(4-(2-((methylamino)methyl)methyl) Base)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (1 R ,4 R )-4-(4-((( R )-1-(4-(2-aldehylphenyl)thiophen-2-yl)ethyl)amino)-7-methoxy Methyl-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (180 mg, 0.33 mmol) and methylamine solution (0.33 ml, 0.66 mmol, 2M in THF) were added to MeOH/ To DCE (2 mL/2 mL), add a few more drops of AcOH (4 drops). After the mixed solution was stirred at room temperature for 1 h, NaBH ₃ CN (42 mg, 0.66 mmol) was added and the stirring reaction was continued for 3 h. DCM and water were added to the reaction solution, the organic phase was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(4-(2-((methylamine) Base)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =559.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.39 (m, 1H), 7.35-7.26 (m, 5H), 7.24-7.20 (m, 1H), 7.10 (s, 1H), 6.08-6.01 (m, 1H), 5.65-5.60 (m, 1H), 3.92 (s, 3H), 3.73-3.69 (m, 5H), 3.04-2.98 (m, 1H), 2.63 (s, 3H), 2.44-2.36 (m, 4H), 2.14-1.99 (m, 4H), 1.80 (d, J = 6.8 Hz, 3H), 1.70-1.53 ( m, 4H).

Example 1: 1-(5-(9-(2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl) -3-Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy methyl-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone (50 mg, 0.09 mmol), 2-(3-(4-chloro-3-(2, 4-Dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde (39 mg, 0.09 mmol) and A mixture of STAB (55 mg, 0.27 mmol) in THF (2 mL) solution was stirred and reacted at 25 °C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EA (50 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (acetonitrile/0.08% ammonium bicarbonate in water, 5% to 95%) to give 1-(5-(9-(2-(4-((1 R ,4 R ))-4 -(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline- 6-yl)cyclohexane-1-carbonyl)piperidin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1000.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.14 – 8.03 (m, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.00 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.62 – 5.49 (m, 3H), 3.89 (s, 3H), 3.80 – 3.70 (m, 1H), 3.67 – 3.42 (m, 7H), 3.31 – 3.23 (m, 2H), 2.99 – 2.88 (m, 1H), 2.78 – 2.59 (m, 3H), 2.40 – 2.25 (m, 9H), 1.94 – 1.76 (m, 4H), 1.74 – 1.20 (m, 18H ), 1.16 – 0.98 (m, 4H).

Example 2: 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 9-((4-(( 1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl Preparation of esters ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy methyl-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone (140.0 mg, 0.2 mmol) and 9-formyl-3-azaspiro[5.5] To a mixture of tert-butyl monoalkane-3-carboxylate (100.0 mg, 0.36 mmol) in THF (6.0 mL) was slowly added STAB (107 mg, 0.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (20.0 mL) and extracted with EA (20.0 mL×2). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product. The crude product can be used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ =836.2. Step 2: (4-(((3-azaspiro[5.5]undecan-9-yl)methyl)piper 𠯤-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amine base)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]eleven A mixture of tert-butyl alkane-3-carboxylate (140 mg, 0.2 mmol) in TFA/DCM (3.0 mL, 1:5) was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to obtain the target product. The crude product was used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ = 736.2. Step 3: 1-(5-(9-((4-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( Preparation of 1 H ,3 H )-diketone To (4-(((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl) To a mixture of methanone (100 mg, 0.14 mmol) in DMSO (5.0 mL) was added DIEA (54.2 mg, 0.42 mmol) and 4-chloro-3-(2,4-dioxoectoine-1) (2 H )-yl)pentafluorophenyl benzoate (73.0 mg, 0.17 mmol), the reaction mixture was stirred at room temperature for 5.0 hours. Water (15.0 mL) was added to quench the reaction, and EA (20 mL×3) was added Extract, collect the organic layer, wash with saturated brine (20.0 mL), and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and the concentrate is purified by preparative HPLC to obtain the target product. LC-MS: (ESI, m/z) : [M+H] ⁺ =986.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.16 – 8.02 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H) , 7.54 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.65- 5.47 (m, 3H), 3.88 (s, 3H), 3.79-3.71 (m, 1H), 3.67-3.54 (m, 3H), 3.51-3.42 (m, 4H), 2.97-2.90 (m, 1H), 2.78-2.72 (m, 2H), 2.67-2.61 (m, 1H), 2.39-2.23 (m, 7H), 2.15-2.05 (m, 2H), 1.87-1.78 (m, 4H), 1.73 – 1.21 (m , 17H), 1.17-0.98 (m, 4H).

Example 3: 1-(5-(9-(2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl) -3,9-diazaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Prepare according to the method of Example 2. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1001.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.09-8.06 (m, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H ), 6.70 (s, 1H), 5.65 – 5.47 (m, 3H), 3.89 (s, 3H), 3.82 – 3.40 (m, 9H), 3.02 – 2.90 (m, 1H), 2.82 – 2.71 (m, 2H ), 2.70 – 2.60 (m, 1H), 2.46 – 2.24 (m, 15H), 1.94 – 1.75 (m, 4H), 1.73 – 1.26 (m, 16H).

Example 4: ( R )-1-(5-(9-((4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl))ethyl) Amino)Amino)-7-methoxy-2-methylquinazolin-6-yl)piperidin-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5 ]Undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(7-methoxy-2-methyl- 4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)-3,6-dihydropyridine-1(2 H )-carboxylic acid Preparation of tert-butyl ester To tert-butyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carboxylate (200 mg, 0.539 mmol) in DCM (10 mL) To the mixture in solution were added TPSCl (245 mg, 0.809 mmol), DMAP (35 mg, 0.269 mmol) and TEA (163 mg, 1.617 mmol). The reaction mixture was stirred overnight at 25°C. The reaction mixture was diluted with DCM and washed with sodium bicarbonate (saturated aqueous solution). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =638.2. Step 2: ( R )-4-(7-methoxy-2-methyl-4-((1-(3 -Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)-3,6-dihydropyridine-1(2 H )-carboxylic acid tert-butyl ester Preparation To 4-(7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)-3 , To a mixture of tert-butyl 6-dihydropyridine-1(2 H )-carboxylate (220 mg, 0.345 mmol) in DCM (5 mL) was added ( R )-1-(3-nitro- 5-(trifluoromethyl)phenyl)ethyl-1-amine (150 mg, 0.414 mmol) and TEA (105 mg, 1.035 mmol). The reaction mixture was stirred at 90°C overnight. The reaction mixture was quenched with water and extracted with EA. The organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound. LC-MS: (ESI, m/z ): [M+H] ⁺ =588.2. Step 3: ( R )-7-methoxy-2-methyl- N -(1-(3-nitro- Preparation of 5-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine To ( R )-4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazole To a mixture of tert-butylolin-6-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (200 mg, 0.340 mmol) in DCM (4 mL) was added trifluoroacetic acid ( 2 mL). The reaction mixture was stirred at 25°C for 1.0 hours. The reaction mixture was quenched with aqueous sodium hydroxide (40%) solution and extracted with DCM (50 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =488.2. Step 4: ( R )-4-(4-(7-methoxy-2-methyl-4-((1 -(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)piper Preparation of tert-butylpyridine-1-carboxylate ( R )-7-methoxy-2-methyl- N -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(1,2,3, 6-Tetrahydropyridin-4-yl)quinazolin-4-amine (10 mg, 0.017 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9 mg, 0.034 mmol), The reaction mixture of HATU (10 mg, 0.025 mmol), DIEA (7 mg, 0.051 mmol) in DMF (1.0 mL) was stirred at 25 °C overnight. The reaction solution was concentrated under reduced pressure, and the target product was purified by column chromatography. The crude product was used in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ = 699.4. Step 5: ( R )-(4-(7-methoxy-2-methyl-4-((1-( 3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)-3,6-dihydropyridin-1(2 H )-yl)(piperidine Preparation of -4-yl)methanone To ( R )-4-(4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amine) )quinazolin-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.340 mmol) in DCM (4 mL) Trifluoroacetic acid (2 mL) was added to the mixture, and the reaction mixture was stirred at 25 °C for 1.0 h. The reaction was quenched with NaOH (40%) aqueous solution, and extracted with DCM (50 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =599.3. Step 6: ( R )-9-((4-(4-(7-methoxy-2-methyl-4) -((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)-1,2,3,6-tetrahydropyridine-1 Preparation of -carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester To ( R )-(4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quino Zozolin-6-yl)-3,6-dihydropyridin-1(2 H )-yl)(piperidin-4-yl)methanone (140.0 mg, 0.2 mmol) and 9-methanoyl-3- To a mixture of azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (100.0 mg, 0.36 mmol) in THF (6.0 mL) was slowly added STAB (107 mg, 0.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (20.0 mL) and the solution was extracted with EA (20.0 mL×2). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target crude product. The crude product was used in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ =864.5. Step 7: ( R )-9-((4-(4-(4-((1-(3-amino- 5-(Trifluoromethyl)phenyl)ethyl)amino)amino)-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carbonyl)piperidine-1 Preparation of tert-butyl -methyl)-3-azaspiro[5.5]undecane-3-carboxylate ( R )-9-((4-(4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethyl )Amino)quinazolin-6-yl)-1,2,3,6-tetrahydropyridin-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]eleven A mixture of tert-butyl alkyl-3-carboxylate (100.0 mg, 0.19 mmol) and Pd/C (20.0 mg) in MeOH (5.0 mL) was stirred and reacted overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain the target crude product. The crude product was used directly in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 836.7. Step 8: ( R )-(1-((3-azaspiro[5.5]undecan-9-yl) Methyl)piperidin-4-yl)(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- Preparation of 2-methylquinazolin-6-yl)piperidin-1-yl)methanone ( R )-9-((4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)piperidin-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid The reaction mixture of tributyl ester (140 mg, 0.2 mmol) in TFA/DCM (3.0 mL, 1:5) mixed solution was stirred at room temperature for 2.0 hours. Concentrate under reduced pressure to obtain the target crude product. The crude product was used in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ = 736.7. Step 9: ( R )-1-(5-(9-((4-(4-(4-((1- (3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)amino)-7-methoxy-2-methylquinazolin-6-yl)piperidine-1- Carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H ) -Preparation of diketones To ( R )-(1-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)(4-(4-((1-(3- Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)piperidin-1-yl)methanone (100.0 mg, 0.14 mmol) in DMSO (5.0 mL) was added DIEA (54.2 mg, 0.42 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H ) -(yl)pentafluorophenyl benzoate (73.0 mg, 0.17 mmol), the reaction mixture was stirred at room temperature for 3.0 h. Water (15 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL×2). The organic layer was collected, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The concentrate was purified by preparative HPLC to obtain the target product. LC-MS: (ESI, m/z): [M+H] ⁺ =986.4 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.14 (d, J = 7.3 Hz, 1H ), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.87 (s , 1H), 6.84 (s, 1H), 6.69 (s, 1H), 5.62-5.44 (m, 3H), 4.69-4.59 (m, 1H), 4.12-4.01 (m, 1H), 3.90 (s, 3H ), 3.82-3.71 (m, 1H), 3.66-3.52 (m, 3H), 3.27-3.10 (m, 3H), 2.86-2.65 (m, 4H), 2.71-2.51 (m, 2H), 2.36 (s , 3H), 2.19-2.04 (m, 2H), 1.93-1.83 (m, 2H), 1.85-7.72 (m, 2H), 1.69-1.42 (m, 16H), 1.41-1.21 (m, 2H), 1.17 -0.97 (m, 4H).

Example 5: ( R )-1-(5-(9-((4-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl))ethyl) )Amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidine-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[ 5.5]Undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: ( R )-4-(4-((7- Methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidine Preparation of -1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester ( R )-1-(5-(9-((4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl))ethyl)amino) Amino)-7-methoxy-2-methylquinazolin-6-yl)piperidin-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]eleven Alk-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3 H )-dione (140 mg, 0.277 mmol), 1-(tert-butoxycarbonyl)piperidine- A mixture of 4-formic acid (70 mg, 0.305 mmol), HATU (126 mg, 0.332 mmol) and DIEA (107 mg, 0.831 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL), stirred and filtered. Dry the filter cake to obtain the target product. The crude product was used directly in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ =717.5. Step 2: ( R )-(4-((7-methoxy-2-methyl-4-((1- (3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)(piperidin-4-yl)methyl Preparation of ketones ( R )-4-(4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amine) (170 mg, crude) in TFA/DCM (4 mL, 1:3) The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain the target product. The crude product was used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ = 617.3. Step 3: ( R )-9-((4-(4-((7-methoxy-2-methyl- 4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidine-1-carbonyl)piperidine- 1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ( R )-(4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) Quinazolin-6-yl)oxy)piperidin-1-yl)(piperidin-4-yl)methanone (180 mg, crude), 9-formyl-3-azaspiro[5.5] The reaction mixture of tert-butyl monoalkane-3-carboxylate (70 mg, 0.249 mmol) and STAB (240 mg, 1.13 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with EA (50 mL×3). The organic layer was collected, washed with water (100 mL×2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ = 882.5. Step 4: ( R )-(1-((3-azaspiro[5.5]undecan-9-yl) Methyl)piperidin-4-yl)(4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethyl) Preparation of base)amino)quinazolin-6-yl)oxy)piperidin-1-yl)methanone ( R )-9-((4-(4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)) Ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxy The reaction mixture of tert-butyl acid ester (182 mg, 0.206 mmol) in DCM (4 mL) and TFA (1 mL) was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =782.50. Step 5: ( R )-1-(2-chloro-5-(9-((4-(4-((7 -Methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl))phenyl)ethyl)amino)quinazolin-6-yl)oxy )piperidin-1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 Preparation of H )-diketone To ( R )-(1-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)(4-((7-methoxy-2- Methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl) To a mixture of methanone (145 mg, 0.19 mmol) in DMSO (4.0 mL) was added DIEA (0.1 mL) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)pentafluorophenyl benzoate (9.0 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EA. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target product. LC-MS: (ESI, m/z ): [M-18+H] ⁺ =1031.43. Step 6: ( R )-1-(5-(9-((4-(4-((4-() (1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidine -1-carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone To ( R )-1-(2-chloro-5-(9-((4-(4-((7-methoxy-2-methyl-4-((1-(3-nitro-5) -(Trifluoromethyl))phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-carbonyl)piperidin-1-yl)methyl)-3-aza Spiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (160 mg, 0.16 mmol) in ethanol/water (3 mL/1 mL) Ammonium chloride (83.0 mg, 1.55 mmol) and iron powder (86.6 mg, 1.55 mmol) were added to the mixture in the solution. The reaction mixture was stirred at 70°C for 2 hours under a nitrogen atmosphere. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the concentrate was purified by preparative HPLC to obtain the target product. LC-MS: (ESI, m/z ): [M+H] ⁺ =1002.5 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H ), 7.85 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), 7.06 (s , 1H), 6.87 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 5.64 – 5.35 (m, 3H), 4.72 – 4.64 (m, 1H), 3.87 (s, 3H), 3.81 – 3.69 (m, 3H), 3.66 – 3.54 (m, 3H), 3.47 – 3.39 (m, 2H), 2.89 – 2.68 (m, 4H), 2.63 – 2.53 (m, 1H), 2.35 (s, 3H ), 2.15 – 2.03 (m, 2H), 2.00 – 1.81 (m, 4H), 1.76 – 1.19 (m, 20H), 1.16 – 0.92 (m, 4H).

Example 6: ( R )-1-(5-(9-((4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl))ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl) -2-Chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: ( R )-9-((4-((7-methoxy-2-methyl-4- ((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3 - Preparation of azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ( R )-7-methoxy-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidine-4- oxy)quinazolin-4-amine (100 mg, 0.198 mmol), 9-carboxaldehyde-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (83 mg, 0.297 mmol) and A mixture of STAB (210 mg, 0.99 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with EA (50 mL×3). The organic phase was washed with water (100 mL×2) and saturated brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The obtained crude product was purified by flash column to obtain the target product ( R )-9-((4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)) Base)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid Tributyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 771.5. Step 2: ( R )-6-((1-((3-azaspiro[5.5]undecane-9- (yl)methyl)piperidin-4-yl)oxy)-7-methoxy-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) Preparation of quinazolin-4-amine ( R )-9-((4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)) Amino)quinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (130 mg, 0.169 mmol) in TFA/DCM (4 mL, 1:3) was stirred at room temperature for 1 h. The reaction solution was concentrated. Obtain the target product ( R )-6-((1-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)oxy)-7-methoxy -2-Methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine. The crude product was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 671.3. Step 3: ( R )-1-(2-chloro-5-(9-((4-((7-methoxy) Base-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidine- Preparation of 1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione ( R )-6-((1-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)oxy)-7-methoxy-2 -Methyl- N -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (130 mg, crude), 4-chloro-3-( 2,4-Dioxoectoine-1(2 H )-yl)pentafluorophenyl benzoate (75 mg, 0.170 mmol) and DIEA (110 mg, 0.85 mmol) in DMSO (5 mL) The reaction was stirred at room temperature overnight. Pour the reaction solution into water (50 mL), stir and filter. The filter cake was vacuum dried to obtain the target product ( R )-1-(2-chloro-5-(9-((4-((7-methoxy-2-methyl-4-((1-(3-nitrogen)) Base-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3-azaspiro[5.5]ten Alk-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. The crude product was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 921.4. Step 4: ( R )-1-(5-(9-((4-((4-((1-(3) -Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl) Preparation of methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Put ( R )-1-(2-chloro-5-(9-((4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(tri)) Fluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl )phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (120 mg, 0.130 mmol), Fe powder (73 mg, 1.30 mmol) and NH ₄ Cl (70 mg, 1.30 mmol) in The reaction solution in EtOH/H ₂ O (8 mL, 3:1) was stirred at room temperature for 1 h. The reaction solution was filtered and concentrated, and the crude product obtained was purified by preparative HPLC to obtain the target product ( R )-1-(5-(9-((4-((4-((1-(3-amino-5-(tri)) Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)methyl)-3-aza Spiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 891.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.04 ( s, 1H), 6.87 (s, 1H), 6.83 (s, 1H), 6.69 (s, 1H), 5.61 – 5.50 (m, 3H), 4.450 – 4.42 (m, 1H), 3.86 (s, 3H) , 3.80 – 3.70 (m, 1H), 3.67 – 3.52 (m, 3H), 2.78 – 2.61 (m, 4H), 2.35 (s, 3H), 2.30 – 2.10 (m, 4H), 1.99 – 1.90 (m, 2H), 1.75 – 1.65 (m, 4H), 1.60 – 0.94 (m, 16H).

Example 7: 1-(5-(9-((1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3 ,9-diazaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione step 1: 9-((1 Preparation of -((benzyloxy)carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester To 3,9-diazaspiro[5.5]undecane-3-carboxylate (300.0 mg, 1.2 mmol) and phenyl 4-carboxaldehyde piperidine-1-carboxylic acid tert-butyl ester (346.0 mg, 1.4 STAB (770.0 mg, 3.6 mmol) was slowly added to a solution of mmol) in THF (5 mL), and the reaction solution was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and extracted with EA (50 mL×2). The organic phase was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EtOAc-PE, 0-30%) to obtain the target product 9-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-3,9- Diazaspiro[5.5]Undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 486.4. Step 2: 9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]eleven Preparation of tert-butyl alkane-3-carboxylate 9-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ( The reaction of 300.0 mg, 0.6 mmol) and 10% Pd/C (60.0 mg) in EtOAc (5 mL) was stirred overnight at 70 °C under an atmosphere of H ₂ (60 psi). The reaction solution was filtered through celite and concentrated to obtain the target product 9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ = 352.4. Step 3: 9-((1-((1 R ,4 R )-4-(7-methoxy-2- Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1- Preparation of tert-butyl carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)cyclohexyl-1-carboxylic acid (140.0 mg, 0.2 mmol), 9-(piperidin-4-ylmethyl)-3,9-diazaspiro [5.5]Undecane-3-carboxylic acid tert-butyl ester (84.0 mg, 0.24 mmol) and HATU (114 mg, 0.3 mmol) in DMF (2.0 mL) solution, DIEA (78.0 mg, 0.6 mmol) was slowly added dropwise . The reaction solution was stirred at room temperature for 2 h. The reaction solution was quenched with ice water (20 mL), filtered, and the filter cake was dried under vacuum to obtain the target product 9-((1-((1 R ,4 R )-4-(7-methoxy-2-methyl) -4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl) Piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ = 866.5. Step 4: 9-((1-((1 R ,4 R )-4-(4-((( R )- 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- Preparation of tert-butyl carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 9-((1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5-(tri Fluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5 ] Reaction of tert-butyl undecane-3-carboxylate (130.0 mg, 0.15 mmol) and 10% Pd/C (30.0 mg) in MeOH (10.0 mL) at 70 °C H ₂ (90 psi) Stir overnight under ambient conditions. The reaction solution was filtered through celite and concentrated to obtain the target product 9-((1-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl) -3,9-Diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 836.5. Step 5: (4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl )piperidin-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Preparation of amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone 9-((1-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amine base)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5 The reaction solution of tert-butyl undecane-3-carboxylate (90.0 mg, 0.1 mmol) in TFA/DCM (1.0 mL/3.0 mL) was stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain the target product (4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)((1 R ,4 R )- 4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline -6-yl)cyclohexane)methanone. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 736.4. Step 6: 1-(5-(9-((1-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2 ,4(1 H ,3 H )-diketone To (4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)((1 R ,4 R )-4-(4-( (( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring To a solution of hexane)methanone (100.0 mg, 0.12 mmol) in DMSO (5.0 mL) was added DIEA (54.20 mg, 0.42 mmol) and 4-chloro-3-(2,4-dioxoectoine-1 (2 H )-yl)pentafluorophenyl benzoate (73.0 mg, 0.17 mmol), the reaction solution was stirred at room temperature for 2 h. Water (15.0 mL) was added to the reaction solution, and extracted with EA (20 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(5-(9-((1-((1 R ,4 R ))-4-(4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 986.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.16-8.02 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 ( s , 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H ), 6.70 (s, 1H), 5.65-5.47 (m, 3H), 4.41-4.38 (m, 1H), 3.89-3.75 (m, 4H), 3.79-3.71 (m, 1H), 3.67-3.54 (m , 3H), 3.31-2.90 (m, 2H), 2.78-2.72 (m, 2H), 2.70-2.60 (m, 1H), 2.55-2.51 (m, 1H), 2.45-2.20 (m, 7H), 2.15 -2.05 (m, 2H), 1.95-1.29 (m, 24H), 1.17-0.98 (m, 2H).

Example 8: 1-(5-(9-((1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 9-(hydroxy(pyridine-4) Preparation of -(yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester To a solution of n -BuLi (2.3 mL, 2.5 M/n-hexane, 5.7 mmol) in anhydrous THF (15 mL) was added dropwise 4-bromopyridine (1.0 g, 6.3 mmol) in anhydrous THF (5.0 mL) at -78 °C. ) solution, stir for 15 min at -78°C, then slowly add 9-carbaldehyde-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.5 g, 5.3 mmol) dropwise THF solution. The reaction solution was continued to stir at -78°C for 45 min. The reaction was quenched with water (20 mL) at -70 °C and extracted with EA (20 mL×2). _The organic phase was washed with saturated brine, dried over _Na2SO4 , filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EtOAc-PE, 0-30%) to obtain the target product 9-(hydroxy(pyridin-4-yl)methyl)-3-azaspiro[5.5]undecane-3- tert-butyl carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 361.1. Step 2: 9-(acetyloxy(pyridin-4-yl)methyl)-3-azaspiro[5.5] Preparation of tert-butyl undecane-3-carboxylate 9-(Hydroxy(pyridin-4-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol), Ac ₂ O (0.4 g , 4.0 mol) and TEA (0.2 ml) in DCE (10.0 mL) was stirred at 70 °C for 5 h. The reaction solution was concentrated, then extracted with chloroform, and the organic phase was concentrated. The obtained crude product was purified by silica gel column chromatography to obtain the target product 9-(acetyloxy(pyridin-4-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 403.2. Step 3: 9-(pyridin-4-ylmethyl)-3-azaspiro[5.5]undecane-3- Preparation of tert-butyl carboxylate 9-(Acetyloxy(pyridin-4-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (600.0 mg, 1.5 mmol), 10% Pd /C (150.0 mg) and ammonium formate (472.0 mg, 7.5 mmol) in MeOH (10.0 mL) was stirred at 80 °C overnight. The reaction solution was filtered through celite and concentrated to obtain the target product 9-(pyridin-4-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 345.2. Step 4: 9-(piperidin-4-ylmethyl)-3-azaspiro[5.5]undecane-3 -Preparation of tert-butyl carboxylate 9-(Pyridin-4-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (450.0 mg, 1.3 mmol), 10% Pd/C (80.0 mg) The reaction in i -PrOH (10.0 mL) and H ₂ O (5.0 mL) was stirred overnight at 70 °C under an atmosphere of H ₂ (90 psi). The reaction solution was filtered through celite and concentrated to obtain the target product 9-(piperidin-4-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 351.1. Step 5: 9-((1-((1 R ,4 R )-4-(7-methoxy-2- Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1- Preparation of tert-butyl carbonyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecane 3-carboxylate To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)cyclohexyl-1-carboxylic acid (140.0 mg, 0.2 mmol), 9-(piperidin-4-ylmethyl)-3-azaspiro[5.5] To a solution of tert-butyl undecane-3-carboxylate (84.0 mg, 0.24 mmol) and HATU (114 mg, 0.3 mmol) in DMF (2.0 mL), DIEA (78.0 mg, 0.6 mmol) was slowly added dropwise, and then reacted The solution was stirred at room temperature for 2 h. The reaction was quenched with ice water (20 mL), filtered, and the filter cake was dried under vacuum to obtain the target product 9-((1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4) -((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine -4-yl)methyl)-3-azaspiro[5.5]undecane 3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 865.4. Step 6: 9-((1-((1 R ,4 R )-4-(4-((( R )- 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- Preparation of tert-butyl carbonyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecane 3-carboxylate 9-((1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5-(tri Fluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]eleven The reaction of tert-butyl alkane 3-carboxylate (130.0 mg, 0.15 mmol) and 10% Pd/C (30.0 mg) in MeOH (10.0 mL) was stirred overnight at 70 °C under an atmosphere of H ₂ (90 psi). . The reaction solution was filtered through celite and concentrated to obtain the target product 9-((1-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl) -3-Azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 835.5. Step 7: (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine -1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino) Preparation of -7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone 9-((1-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amine base)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]eleven The reaction solution of tert-butyl alkane 3-carboxylate (130.0 mg, 0.15 mmol) in TFA/DCM (3.0 mL, 1:5) was stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain the product (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-1-yl)((1 R ,4 R )-4-(4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )cyclohexane)methanone. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 736.4. Step 8: 1-(5-(9-((1-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1 H ,3 H )-diketone To (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane) To a solution of methanone (100.0 mg, 0.14 mmol) in DMSO (5.0 mL) was added DIEA (54.20 mg, 0.42 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)pentafluorophenyl benzoate (73.0 mg, 0.17 mmol), the reaction solution was stirred at room temperature for 2 h. The reaction was quenched by adding water (15 mL), extracted with EA (20 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ , concentrated, and the crude product was analyzed by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) was purified to obtain the target product 1-(5-(9-((1-((1 R ,4 R ))-4-(4-((( R )-1-( 3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piper (Din-4-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione . LC-MS: (ESI, m/z ): [M+H] ⁺ = 985.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.16-8.02 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 ( s , 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H ), 6.70 (s, 1H), 5.65-5.47 (m, 3H), 4.41-4.38 (m, 1H), 3.89-3.75 (m, 4H), 3.79-3.71 (m, 1H), 3.67-3.54 (m , 3H), 3.31-2.90 (m, 2H), 2.78-2.72 (m, 2H), 2.70-2.60 (m, 1H), 2.38-2.35 (s, 3H), 1.86-1.75 (m, 4H), 1.73 -1.28 (m, 22H), 1.20-0.95 (m, 8H).

Example 9: (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)- N -((3-(4-chloro-3-(2,4-dioxoectoine-1(2 H ))- (yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl) -N -methylcyclohexane-1-methamide step 1: 9-((benzyl) Preparation of (methyl)amino)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester To 9-carbaldehyde-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (300.0 mg, 1.1 mmol) and N-methyl-1-benzylamine (130.0 mg, 1.1 mmol) STAB (680.0 mg, 3.3 mmol) was added to THF (10.0 mL) solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was poured into NaHCO ₃ (20 mL) aqueous solution, extracted with EA (20 mL×2), the organic phase was washed with water and saturated brine, dried over Na ₂ SO ₄ , filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EtOAc-PE, 0-30%) to obtain the target product 9-((phenylmethyl(methyl)amino)methyl)-3-azaspiro[5.5]undecane. -Tertiary butyl 3-carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 387.2. Step 2: 9-((methylamino)methyl)-3-azaspiro[5.5]undecane-3 -Preparation of tert-butyl carboxylate 9-((Benzyl(methyl)amino)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (240.0 mg, 0.6 mmol) and 10% Pd The reaction of /C (50.0 mg) in MeOH (10.0 mL) was stirred overnight at 50 °C under an atmosphere of H ₂ (60 psi). The reaction solution was filtered through celite and concentrated to obtain the target product 9-((methylamino)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 297.2. Step 3: 9-(((1 R ,4 R )-4-(7-methoxy-2-methyl- 4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)- N -methylcyclohexane- Preparation of 1-amide)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)cyclohexyl-1-carboxylic acid (120.0 mg, 0.2 mmol), 9-((methylamine)methyl)-3-azaspiro[5.5]eleven To a solution of tert-butyl alkane-3-carboxylate (65.0 mg, 0.22 mmol) and HATU (98.8 mg, 0.26 mmol) in DMF (2.0 mL), DIEA (78.0 mg, 0.6 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 h. The reaction was quenched with ice water (20 mL), stirred and filtered. The filter cake was vacuum dried to obtain the target product 9-(((1 R ,4 R )-4-(7-methoxy-2-methyl-4-(( R )-1-(3-nitro-5) -(Trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)- N -methylcyclohexane-1-amide)methyl)-3-azaspiro[5.5 ] Undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 811.5. Step 4: 9-(((1 R ,4 R )-4-(4-((( R )-1-( 3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)- N -methylcyclohexane- Preparation of 1-amide)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester 9-(((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5-(trifluoromethyl) )phenyl)ethyl)amino)quinazolin-6-yl)- N -methylcyclohexane-1-amide)methyl)-3-azaspiro[5.5]undecane-3 -The reaction of tert-butyl carboxylate (130.0 mg, 0.15 mmol) and 10% Pd/C (30.0 mg) in MeOH (10.0 mL) was stirred overnight at 70 °C under an atmosphere of H ₂ (90 psi). The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the target product 9-(((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl) (base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) -N -methylcyclohexane-1-amide)methyl)-3 -Azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 781.5. Step 5: (1 R ,4 R )- N -((3-azaspiro[5.5]undecane-9- methyl)-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2 Preparation of -methylquinazolin-6-yl) -N- methylcyclohexane-1-methamide 9-(((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-methoxy-2-methylquinazolin-6-yl)- N -methylcyclohexane-1-amide)methyl)-3-azaspiro[5.5]undecane-3 -The reaction solution of tert-butyl carboxylate (100.0 mg, 0.1 mmol) in TFA/DCM (1.0 mL/3.0 mL) was stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain the target product (1 R ,4 R ) -N -((3-azaspiro[5.5]undecan-9-yl)methyl)-4-(4-((( R )- 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) -N -methylcyclo Hexane-1-methamide. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 681.3. Step 6: (1 R ,4 R )-4-(4-((( R )-1-(3-amino) -5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)- N -((3-(4-chloro-3 -(2,4-Dioxoectoine-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)- N -methane Preparation of cyclohexane-1-methamide To (1 R ,4 R )- N -((3-azaspiro[5.5]undecan-9-yl)methyl)-4-((( R )-1-(3-amine Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) -N -methylcyclohexane-1-methyl To a solution of amide (90.0 mg, 0.13 mmol) in DMSO (5.0 mL) was added DIEA (54.2 mg, 0.42 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)pentafluorophenyl benzoate (63.0 mg, 0.17 mmol), the reaction solution was stirred at room temperature for 2 h. The reaction was quenched with water (15 mL), extracted with EA (30 mL×2), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%), and then purified by preparative TLC (5.0% MeOH/DCM) to obtain the target product (1 R , 4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base) -N -((3-(4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)benzoyl)-3-azaspiro[5.5] Undecan-9-yl)methyl) -N -methylcyclohexane-1-methamide. LC-MS: (ESI, m/z ): [M+H] ⁺ = 931.6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 11.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.65 – 5.47 (m, 3H), 3.89 (s, 3H), 3.80 – 3.70 (m, 1H), 3.65 – 3.51 (m, 3H), 3.25 –3.15 (s, 2H), 3.02 (s, 2H), 2.94 (d, J = 10.9 Hz, 1H), 2.80 (s, 1H), 2.76 – 2.69 (m, 2H ), 2.68 – 2.62 (m, 1H), 2.36 (s, 3H), 1.92 – 1.82 (m, 3H), 1.76 – 1.51 (m, 11H), 1.45 – 1.33 (m, 4H), 1.32 – 1.20 (m , 4H), 1.15 – 1.02 (s, 4H).

Example 10: 1-(2-chloro-5-(9-((4-((1 R ,4 R ))-4-(4-((( R ))-1-(1,1-dioxo -2,3-Dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl )Piper-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1 : Preparation of 4-bromobenzo[b]thiophene 1,1-dioxo m-CPBA (4.8 g, 28.4 mmol) was added to a solution of 4-bromobenzo[b]thiophene (3.0 g, 14.2 mmol) in DCM (60.0 ml), and the reaction solution was stirred at 25 °C overnight. The reaction was quenched with ice water (150 mL), extracted with EA (80 mL×3), the organic phases were combined, washed with brine (30 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EA/PE =60/40) to obtain the target product 4-bromobenzo[b]thiophene 1,1-dioxo. LC-MS: (ESI, m/z ): [M+H] ⁺ = 245.1. Step 2: Preparation of 4-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxo To a solution of 4-bromobenzo[b]thiophene 1,1-dioxo (4.0 g, 16.3 mmol) in MeOH (40.0 ml) at 0 °C, NaBH ₄ (465.3 mg, 12.2 mmol) was added, and the reaction solution was heated at 25 The reaction was stirred at ℃ for 4.0 h. The reaction was quenched with water (100 mL), extracted with EA (80 mL×3), the organic phases were combined, washed with brine (30 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EA/PE =70/30) to obtain the target product 4-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxo. LC-MS: (ESI, m/z ): [M+H] ⁺ = 247.1. Step 3: 1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene-4- Preparation of ethanol 4-Bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxo (4.0 g, 16.3 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (117.7 mg, 1.6 mmol), TEA ( The reaction solution of 4.9 g, 48.9 mmol) and tributyl(1-ethoxyethylene)stannane (8.8 g, 24.4 mmol) in 1,4-dioxane (80.0 mL) was replaced with N ₃ times. The reaction solution was stirred for 16.0 h under _N2 atmosphere at 80°C. The reaction was quenched with ice water (200 mL), extracted with EA (80 mL×3), the organic phases were combined, washed with brine (50 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was stirred in 6N HCl (10 mL) at room temperature for 2 h, and then concentrated. The crude product was purified by column chromatography (EA/PE =30/70) to obtain the target product 1-(1,1-dioxo-2, 3-Dihydrobenzo[b]thiophen-4-yl)ethanone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 210.1. Step 4: ( E )- N -(1-(1,1-dioxo-2,3-dihydrobenzo Preparation of [b]thiophen-4-yl)ethylene)-2-methylpropane-2-sulfinamide 1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethanone (2.0 g, 9.5 mmol), Ti(OEt) ₄ (5.4 g, 1.6 mmol) ) and ( R )-propane-2-sulfinamide (1.7 g, 14.2 mmol) in THF (40.0 mL) was stirred and reacted at 70 °C for 4.0 h. The reaction was quenched with ice water (100 mL), extracted with EA (80 mL×3), the organic phases were combined, washed with brine (30 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EA/PE =50/50) to obtain the target product ( E ) -N- (1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene-4 -Ethylidene)-2-methylpropane-2-sulfinamide. LC-MS: (ESI, m/z ): [M+H] ⁺ = 314.2. Step 5: N -(( R )-1-(1,1-dioxo-2,3-dihydrobenzo Preparation of [b]thiophen-4-yl)ethyl)-2-methylpropane-2-sulfinamide To ( E )- N -(1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethylene)-2-methylpropane- To a solution of 2-sulfinamide (2.0 g, 6.3 mmol) in THF/H ₂ O (20.0 mL/4.0 mL) was added NaBH ₄ (0.5 g, 12.6 mmol). The reaction solution was stirred at 0°C for 5.0 min. The reaction was quenched with ice water (100 mL), extracted with EA (80 mL×3), the organic phases were combined, washed with brine (40 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EA/PE =50/50) to obtain the target product N -(( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene-4 -ethyl)-2-methylpropane-2-sulfinamide. LC-MS: (ESI, m/z ): [M+H] ⁺ = 316.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 4.76 – 4.66 (m, 1H), 3.59 – 3.47 (m, 3H), 3.43 – 3.28 (m, 2H), 1.54 (d, J = 6.6 Hz, 3H), 1.24 (s, 9H). Step 6: ( R )-4-(1-aminoethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxo Preparation of hydrochloride salt N -(( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)-2-methylpropane-2-sulfen A solution of amide in dimethane hydrochloride (4N, 20.0 mL) was stirred at 25°C for 2.0 h. The reaction solution was concentrated. The residue was washed with PE (20 mL×2), and the solid was dried to obtain the target product ( R )-4-(1-aminoethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxo hydrochloride. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 211.2. ¹ HNMR (400 MHz, DMSO- d ₆ ) δ 8.56 (s, 2H), 7.94 (d, J = 7.6 Hz, 1H ), 7.77 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 4.65 – 4.49 (m, 1H), 3.69 – 3.56 (m, 2H), 3.55-3.42 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H). Step 7: (1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2, 3-Dihydrobenzo[b]thiophen-4-yl)ethyl)amine)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester Preparation ( R )-4-(1-Aminoethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxo (0.7 g, 3.3 mmol), DIEA (928.8 mg, 7.2 mmol) and (1 R ,4 R )-4-(4-chloro-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (835.2 mg, 2.4 mmol ) in dihexane (10.0 mL) and stirred at 110°C for 20.0 h. The reaction was quenched with water (50 mL), extracted with EA (30.0 mL×3), the organic phases were combined, washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by preparative HPLC (acetonitrile/0.05% HCOOH aqueous solution, 5% to 95%) to obtain the target product (1 R , 4 R )-4-(4-((( R )-1-(1,1-dioxo) Generation-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- Methyl carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 524.5. Step 8: (1 R ,4 R )-4-(4-((( R )-1-(1,1- Dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- Preparation of 1-carboxylic acid To (1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (100.0 mg, 0.2 mmol) in THF/H ₂ O (2.0 mL/ 1.0 mL) solution was added LiOH (24 mg, 1.0 mmol). The reaction solution was stirred at 50°C for 12.0 h. The pH of the reaction solution was adjusted to 4-5 with 1N HCl, and then concentrated to obtain the target product (1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2, 3-Dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 510.1. Step 9: 4-((1 R ,4 R )-4-(4-((( R )-1-(1 ,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclic Preparation of tert-butyl hexane-1-carbonyl)piperidine-1-carboxylate To (1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (110.0 mg, 0.2 mmol), tert-butyl piperazine-1-carboxylate (45.0 mg, 0.22 mmol) and DIEA (85.0 mg, 0.6 mmol) in DMF (2.0 mL) was added with HATU (124.0 mg, 0.24 mmol). The reaction solution was stirred at room temperature for 2.0 h. The reaction was quenched with ice water (40 mL), then the precipitate was filtered, and the filter cake was dried under vacuum to obtain the target product 4-((1 R ,4 R )-4-(4-((( R ))-1-(1 ,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclic Hexane-1-carbonyl) piperazine-1-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 678.1. Step 10: ((1 R ,4 R )-4-(4-((( R )-1-(1,1 -Dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl) Preparation of (piperidin-1-yl)methanone 4-((1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl )Ethyl)Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)pipiperidine-1-carboxylic acid tert-butyl ester (110.0 mg, 0.1 mmol) TFA/DCM (1.0 mL/3.0 mL) reaction solution was stirred at room temperature for 1 h. The reaction solution was concentrated to obtain the target product ((1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene- 4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 578.2. Step 11: 9-((4-((1 R ,4 R )-4-(4-((( R )- 1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 Preparation of tert-butyl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate To ((1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl) (yl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone (60.0 mg, 0.1 mmol) and 9-carbaldehyde-3 -To a solution of azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (35.0 mg, 0.12 mmol) in THF (5.0 mL) was added STAB (64.0 mg, 0.3 mmol). The reaction solution was stirred at room temperature for 2.0 h. The reaction was quenched with ice water (10 mL), extracted with EA (30.0 mL × 3), the combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by column chromatography (MeOH/DCM, 0-10%) to obtain the target product 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(1, 1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan Alk-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 843.3. Step 12: (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide -1-yl)((1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene-4 Preparation of -ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene -4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -The reaction solution of azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (70.0 mg, 0.08 mmol) in TFA/DCM (1.0 mL/3.0 mL) was stirred at room temperature for 1.0 h. The reaction solution was concentrated to obtain the target product (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide-1-yl)((1 R ,4 R )-4-(4 -((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2- Methylquinazolin-6-yl)cyclohexyl)methanone. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 743.3. Step 13: 1-(2-chloro-5-(9-((4-((1 R ,4 R ))-4 -(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl ) Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione To (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazoline DIEA (31.20 mg, 0.24 mmol) and 4-chloro-3-(2,4-dioxo) were added to a solution of -6-yl)cyclohexyl)methanone (60.0 mg, 0.08 mmol) in DMSO (1.0 mL). Tetrahydropyrimidine-1(2 H )-yl)benzoate pentafluorophenyl ester (43.4 mg, 0.1 mmol). The reaction solution was stirred at room temperature for 2.0 h. The reaction was quenched with water, extracted with EA, and the combined organic phases were washed with brine, dried anhydrously, and concentrated. The crude product was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(2-chloro-5-(9-((4-((1 R ,4 R )- 4-(4-((( R )-1-(1,1-dioxo-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy methyl-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)benzene base)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 993.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.29 (d, J = 7.0 Hz, 1H), 8.06 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.70-7.50 (m, 4H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 6.98 (s, 1H ), 5.65-5.55 (m, 1H), 3.87 (s, 3H), 3.81-3.70 (m, 2H), 3.68-3.52 (m, 4H), 3.54-3.42 (m, 5H), 2.98-2.91 (m , 1H), 2.7-2.71 (m, 2H), 2.70-2.62 (m, 1H), 2.39-2.22 (m, 7H), 2.18-2.10 (m, 2H), 1.91-1.77 (m, 4H), 1.75 -1.18 (m, 19H), 1.13-1.00 (m, 4H).

Example 11: 1-(5-(4-(3-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)propyl) Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(3-(1-(tert-butoxycarbonyl)piperdine Preparation of benzyl pyridin-4-yl)propyl)piperidine-1-carboxylate 4-(3-(Toluenesulfonyloxy)propyl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.3 mmol), piperidine-1-carboxylic acid benzyl ester (1.0 g, 2.7 mmol) ), K ₂ CO ₃ (1.5 g, 11.3 mmol) and KI (450.0 mg, 2.7 mmol) in DMF (10.0 mL) were stirred and reacted overnight at 70 °C. The reaction was quenched with ice water (100 mL), extracted with EA (30 mL×3), the combined organic phases were washed with brine (15 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by column chromatography (EA/PE =0-30%) to obtain the target product 4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic Benzyl acid ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 446.5. Step 2: 4-(3-(Piperidine-1-yl)propyl)piperidine-1-carboxylic acid tert-butyl Preparation of esters 4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic acid benzyl ester (400.0 mg, 0.6 mmol) and Pd(OH) ₂ /C (10%, 100.0 mg) in EtOAc (20.0 mL) was stirred at 70 °C under H ₂ (60 psi) for 12.0 h. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with EA (10 mL×2). The filtrate was combined and concentrated to obtain the target product 4-(3-(piperidine-1-yl)propyl)piperidine-1-carboxylic acid. 3rd butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ = 312.2. Step 3: 4-(3-(4-((1 R ,4 R ))-4-(7-methoxy- 2-Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane- Preparation of 1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carboxylic acid tert-butyl ester To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)cyclohexyl-1-carboxylic acid (85.0 mg, 0.2 mmol), 4-(3-(piperidine-1-yl)propyl)piperidine-1- To a solution of tert-butyl carboxylate (68.0 mg, 0.22 mmol) and DIEA (59.0 mg, 0.6 mmol) in DMF (2.0 mL) was added HATU (91.0 mg, 0.24 mmol). The reaction solution was stirred at room temperature for 2.0 h. The reaction was quenched with ice water (20 mL), the precipitate was collected by filtration, washed with water (10 mL×2), and dried to obtain the target product 4-(3-(4-((1 R ,4 R )-4-(7) -Methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl )Cyclohexane-1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 826.5. Step 4: 4-(3-(4-((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- Preparation of 1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(4-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5- (Trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexyl-1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carboxylic acid tert-butyl The reaction solution of ester (130.0 mg, 0.18 mmol) and 10% Pd/C (30.0 mg) in MeOH (10.0 mL) was stirred overnight at 60 °C under H ₂ (90 psi). The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the target product 4-(3-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5) -(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl) Propyl)piperidine-1-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ = 796.5. Step 5: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine) Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidine) Preparation of -4-yl)propyl)piperidine-1-yl)methanone 4-(3-(4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl))ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl-1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carboxylic acid tert-butyl The reaction solution of ester (100.0 mg, 0.1 mmol) in TFA/DCM (1.0 mL/3.0 mL) was stirred at room temperature for 1 h. The reaction solution was concentrated to obtain the target product ((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ = 696.3. Step 6: 1-(5-(4-(3-(4-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base)cyclohexane-1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones To ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)methanone (100 mg, 0.14 mmol ) in DMSO (5.0 mL), DIEA (103 mg, 0.8 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)benzoic acid pentafluoroate were added Phenyl ester (73 mg, 0.17 mmol), the reaction solution was stirred at room temperature for 2.0 h. The reaction was quenched with water (15 mL), extracted with EA (30.0 mL×3), the organic phases were combined, washed with brine (15 mL), dried over anhydrous Na ₂ SO ₄ , and the reaction solution was concentrated. The crude product was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(5-(4-(3-(4-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidine-1-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone. LC-MS: (ESI, m/z): [M+H] ⁺ = 946.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.13 (d, J = 5.5 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.63 – 5.50 (m, 3H), 4.44 (s, 1H), 3.89 (s, 3H), 3.79-3.74 (m, 1H), 3.64 – 3.59 (m, 1H), 3.48-3.41 (m, 4H), 3.18-2.90 (m, 2H), 2.78 – 2.62 (m, 4H), 2.38-2.21 (m, 9H) , 1.90 – 1.43 (m, 17H), 1.24-1.19 (m, 2H), 1.10-1.08 (m, 2H).

Example 12: 1-(5-(4-(2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl) Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(2-(1-(tert-butoxycarbonyl)piperdine Preparation of benzyl ethyl)piperidine-1-carboxylate 4-(2-(Toluenesulfonyloxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (500.0 mg, 2.3 mmol), piperidine-1-carboxylic acid benzyl ester (1.0 g, 2.7 mmol) ), the reaction solution of K ₂ CO ₃ (1.5 g, 11.3 mmol) and KI (450.0 mg, 2.7 mmol) in DMF (10.0 mL) was stirred at 70 ° C overnight. The reaction was quenched with ice water (100 mL), extracted with EA (30.0 mL×3), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by column chromatography (EA/PE =0-30%) to obtain the target product 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic Benzyl acid ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 432.7. Step 2: 4-(2-(Piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl Preparation of esters 4-(2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester (400.0 mg, 0.6 mmol) and 10% Pd(OH) ₂ /C (100 mg) in EtOAc (20 mL) was stirred at 70 °C under H ₂ (60 psi) for 12 h. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with EA (10 mL×2), and the filtrate was concentrated to obtain the target product 4-(2-(piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tertiary acid butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 298.2. Step 3: 4-(2-(4-((1 R ,4 R )-4-(7-methoxy- 2-Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane- Preparation of 1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid (85.0 mg, 0.2 mmol), 4-(2-(piperidin-1-yl)ethyl)piperidine-1 -To a solution of tert-butyl carboxylate (68.0 mg, 0.22 mmol) and DIEA (59.0 mg, 0.6 mmol) in DMF (2.0 mL) was added HATU (91.0 mg, 0.24 mmol). The reaction solution was stirred at room temperature for 2 h. The reaction was quenched with ice water (20.0 mL), the precipitate was collected by filtration, washed with water (10 mL×2), and dried under vacuum to obtain the target product 4-(2-(4-((1 R ,4 R )-4- (7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -(yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 812.5. Step 4: 4-(2-(4-((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- Preparation of 1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester 4-(2-(4-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5- (Trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tertiary The reaction of butyl ester (130 mg, 0.18 mmol) and 10% Pd/C (30 mg) in MeOH (10 mL) was stirred overnight at 60 °C under H ₂ (90 psi). The reaction solution was filtered through celite, the filter cake was washed with methanol (5 mL×2), the filtrate was combined and concentrated to obtain the target product 4-(2-(4-((1 R ,4 R )-4-(4-() (( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 782.5. Step 5: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine) Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidine) Preparation of -4-yl)ethyl)piperidine-1-yl)methanone 4-(2-(4-((1 R ,4 R )-4-(4-(( R )-1-(3-amino-5-(trifluoromethyl)phenyl))ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carboxylic acid tertiary The reaction solution of butyl ester (100 mg, 0.1 mmol) in TFA/DCM (1 mL/3 mL) was stirred at room temperature for 1.0 h. The reaction solution was concentrated to obtain the target product ((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidin-4-yl)ethyl)piperidin-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ = 682.2. Step 6: 1-(5-(4-(2-(4-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base)cyclohexane-1-carbonyl)piperidin-1-yl)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones To ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidin-4-yl)ethyl)piperidin-1-yl)methanone (100 mg, 0.14 mmol ) in DMSO (5.0 mL), DIEA (103 mg, 0.8 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)benzoic acid pentafluoroate were added Phenyl ester (73 mg, 0.17 mmol), the reaction solution was stirred at room temperature for 2.0 h. The reaction solution was quenched with water (15 mL), extracted with EA (30 mL×3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(5-(4-(2-(4-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone. LC-MS: (ESI, m/z): [M+H] ⁺ = 932.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.06 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.88 ( s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.65-5.50 (m, 3H), 4.50-4.40 (m, 1H), 3.88 (s, 3H), 3.78-3.72 (m, 1H), 3.68-3.61 (m, 1H), 3.52-3.41 (m, 4H), 3.07-2.91 (m, 2H), 2.77-2.60 (m, 3H), 2.38-2.30 (m, 9H), 1.88- 1.52 (m, 16H), 1.45-1.35 (m, 2H), 1.28-1.01 (m, 2H).

Example 13: 1-(5-(4-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)piperidine -1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-((1-(tert-butoxycarbonyl)piperidine-4- Preparation of benzyl)methyl)piperidine-1-carboxylate To benzyl piperidine-1-carboxylate (500.0 mg, 2.27 mmol) and 4-carboxaldehyde piperidine-1-carboxylic acid tert-butyl ester (726.5.0 mg, 3.4 mmol) in THF (10.0 mL) were slowly added STAB (1.2 g, 5.5 mmol), the reaction solution was stirred at room temperature overnight. The reaction was quenched with water (20 mL), extracted with EA (20 mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA/PE =10/90) to obtain the target product 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidine-1-carboxylic acid benzyl ester . LC-MS: (ESI, m/z): [M+H] ⁺ = 418.1. Step 2: Preparation of tert-butyl 4-(piperidine-1-ylmethyl)piperidine-1-carboxylate To benzyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidine-1-carboxylate in EtOAc (15.0 mL) was added Pd(OH) ₂ /C ( 300.0 mg, 0.36 mmol), the reaction solution was stirred and reacted overnight at 80°C in a H ₂ atmosphere. The reaction solution was filtered and concentrated to obtain the target product 4-(piperidine-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ = 284.1. Step 3: (1 R ,4 R )-4-(7-methoxy-2-methyl-4-(( Preparation of ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid To (1R,4r)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )Amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (100.0 mg, 0.2 mmol) was added to a solution of THF/H ₂ O (1:1) LiOH (9.60 mg, 0.4 mmol) ), the reaction solution was stirred at room temperature for 16 h. The pH of the reaction solution was adjusted to 4-5 with 1N HCl, and then extracted with a mixed solvent of MeOH/CH ₂ Cl ₂ (1/10, 10.0 mL×2). The organic phase was dried over Na ₂ SO ₄ and concentrated to obtain the target product (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro) -5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ = 533.1. Step 4: 4-((4-((1 R ,4 R )-4-(7-methoxy-2- Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1- Preparation of tert-butyl carbonyl)piperidine-1-yl)methyl)piperidine-1-carboxylate To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) To a solution of ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid (90.00 mg, 0.17 mmol) in DMF (5.0 mL) was added DIEA (65.20 mg, 0.52 mmol), HATU (197.6 mg, 0.52 mmol) and tert-butyl 4-(piperidine-1-ylmethyl)piperidine-1-carboxylate (57.6 mg, 0.2 mmol). The reaction solution was stirred at room temperature for 5 h. The reaction solution was diluted with water (40 mL) and extracted with EA (20 mL×3). The organic phase was dried _{over Na2SO4} and concentrated. The obtained crude product was purified by column chromatography (EA/PE =50/50) to obtain the target product 4-((4-((1 R ,4 R )-4-(7-methoxy-2-methyl-4- ((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piper𠯤- 1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 798.2. Step 5: 4-((4-((1 R ,4 R )-4-(4-((( R )- 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- Preparation of tert-butyl carbonyl)piperidine-1-yl)methyl)piperidine-1-carboxylate To 4-((4-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5-(tri Fluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.05 mmol) in EA (15.0 mL) was added Pd/C (15.0 mg). The reaction solution was stirred for 16 h under _H2 atmosphere at 80°C. The reaction solution was filtered, and the filter cake was washed with EA (10 mL×2). The organic phase was concentrated to obtain the target product 4-((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl) )ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)piperidine-1-carboxy tert-butyl acid. The crude product obtained was directly used in the next step. LC-MS: (ESI, m/z): [M+H] ⁺ = 768.3. Step 6: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine) Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(piperidine-4- Preparation of methyl)piperidine-1-yl)methanone 4-((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amine (yl)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol) in TFA/DCM (3.0 mL, 1:5) was stirred at room temperature for 2 h. The reaction solution was concentrated to obtain the target product ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino) )-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(piperidin-4-ylmethyl)piperidin-1-yl)methanone. The crude product obtained was directly used in the next step. LC-MS: (ESI, m/z): [M+H] ⁺ = 668.3. Step 7: 1-(5-(4-((4-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidine-1-yl)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Preparation ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(piperidin-4-ylmethyl)piperidin-1-yl)methanone (25.0 mg, 0.037 mmol) in DMSO ( 5.0 mL), DIEA (14.50 mg, 0.112 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)benzoate pentafluorophenyl ester (19.30 mg, 0.044 mmol). The reaction solution was stirred at room temperature for 5 h. The reaction solution was diluted with water (50 mL), extracted with EtOAc (25 mL × 3), the organic phases were combined, washed with brine (10 mL), dried over Na ₂ SO ₄ , and concentrated. The crude product was subjected to preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(5-(4-((4-((1 R ,4 R ))-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidine-1-yl)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ = 918.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.20-8.04 (m, 2H), 7.64 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.99 (s, 1H), 6.93-6.83 (m, 2H), 6.70 (s, 1H), 5.60-5.45 (m, 3H), 4.54-4.44 (m, 1H), 3.98-3.80 (m, 4H), 3.80-3.67 (m, 2H), 3.05-2.90 (m, 2H), 2.84-2.60 (m, 5H), 2.45- 2.10 (m, 10H), 1.92-1.40 (m, 16H), 1.15-0.98 (m, 2H).

Example 14: 1-(5-(4-(3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl) Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: 4-(3-(piperidin-4-yl)propyl)piperidine Preparation of -1-carboxylic acid benzyl ester Dissolve 1,3-bis(piperidin-4-yl)propane (6.0 g, 28.6 mmol) in acetonitrile/water (1:1, 720 mL), add NaHCO ₃ (12.21 g, 71.5 mmol) and CbzCl ( 4.88 g, 28.6 mmol), stirred at room temperature overnight, concentrated under reduced pressure, extracted with MeOH/DCM (1/10, 200 mL×5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography (20 % MeOH/DCM, 0.1% ammonia water) was purified to obtain the target product 4-(3-(piperidin-4-yl)propyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 345.2. Step 2: 4-(3-(1-((1 R ,4 R )-4-(7-methoxy- 2-Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyll)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane Preparation of -1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic acid benzyl ester To (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) To a solution of ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid (120 mg, 0.225 mmol) in DMF (10 mL) was added 4-(3-(piperidine-4- Benzyl)propyl)piperidine-1-carboxylate (116 mg, 0.337 mmol), HATU (110 mg, 0.292 mmol) and DIEA (87 mg, 0.675 mmol), stir at room temperature for 2 hours, add water (100 mL ) and stir for 10 min, extract with ethyl acetate (100 mL×3), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (100% EA /PE) to purify the target product 4-(3-(1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-(( R )-1-(3) -nitro-5-(trifluoromethyll)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine -1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 859.5. Step 3: 4-(3-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyll)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane Preparation of -1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic acid benzyl ester To 4-(3-(1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5- (Trifluoromethyll)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic acid benzyl To a solution of ester (110 mg, 0.13 mmol) in EtOH (10 mL), Raney nickel (0.2 mL) and N ₂ H ₄ -H ₂ O (0.2 mL) were added, stirred at room temperature for 0.5 h, filtered, and concentrated under reduced pressure. The product 4-(3-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl 1)phenyl)) Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic acid Benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 829.4. Step 4: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine) Base-5-(trifluoromethyll)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperate) Preparation of pyridin-4-yl)propyl)piperidin-1-yl)methanone To 4-(3-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl 1)phenyl))ethyl base)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carboxylic acid benzyl Pd(OH) ₂ /C (10 mg) was added to the ethyl acetate solution (10 mL) of the ester (85 mg, 0.1 mmol), stirred at 75 ° C under a hydrogen atmosphere for 8 h, filtered, and concentrated under reduced pressure to obtain (( 1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyll)phenyl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ = 695.4. Step 5: 1-(5-(4-(3-(1-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyll)phenyl)ethyl)amino)-7- Methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)methanone (60 mg, 0.09 mmol) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (41 mg, 0.095 mmol) were dissolved in DMSO (5 mL) , DIEA (35 mg, 0.27 mmol) was added, and then the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, stirred for 2 minutes, filtered, and the solid was purified by column chromatography (10% MeOH/DCM). Afterwards, the target product 1-(5-(4-(3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amine) is purified by p-TLC Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-4 -(yl)propyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ = 945.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.20-8.04 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H ), 6.85 (s, 1H), 6.70 (s, 1H), 5.65 – 5.44 (m, 3H), 4.55-4.40 (m, 2H), 3.98-3.84 (m, 4H), 3.80-3.70 (m, 1H ), 3.66-3.48 (m, 2H), 3.30-3.20 (m, 1H), 3.10-2.90 (m, 3H), 2.78-2.60 (m, 4H), 2.48-2.40 (m, 2H), 2.39-2.30 (m, 2H), 1.90-1.42 (m, 14H), 1.24-0.83 (m, 12H).

Example 15: 1-(5-(4-(2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl) Piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 1,2-di(piperidin-4-yl)ethane Preparation Pd/C (1.2 g, 11.32 mmol) was added to a solution of 1,2-bis(pyridin-4-yl)ethane (4.0 g, 21.74 mmol) in IPA/H ₂ O (120 mL/140 mL). In an autoclave filled with _H2 , stir at 75°C for 72 h, filter, rinse with dichloromethane (100 mL×4), and concentrate under reduced pressure to obtain the target product 1,2-bis(piperidin-4-yl)ethane. alkyl. LC-MS: (ESI, m/z): [M+H] ⁺ = 197.2. Step 2: 4-(2-(piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester Preparation NaHCO ₃ (1.0 g, 11.9 mmol) and CbzCl (0.872 g, 5.10 mmol) were added to 1,2-bis(piperidin-4-yl)ethane (1.0 g, 5.10 mmol) in ACN/H ₂ O ( 60 mL/60 mL), stir at room temperature overnight, add water (200 mL) and stir for 10 min, extract with ethyl acetate (100 mL×3), wash the organic phase with saturated brine (150 mL), and dry over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the crude product was purified using column chromatography (30% ACN/H ₂ O) to obtain the target product 4-(2-(piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester. . LC-MS: (ESI, m/z): [M+H] ⁺ = 331.4. Step 3: 4-(2-(1-((1 R ,4 R )-4-(7-methoxy- 2-Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane- Preparation of 1-carbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester To a solution of benzyl 4-(2-(piperidin-4-yl)ethyl)piperidine-1-carboxylate (160 mg, 0.477 mmol) in DMF (20 mL) was added (1 R ,4 R ) -4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazole Phin-6-yl)cyclohexane-1-carboxylic acid (170 mg, 0.319 mmol), HATU (182.14 mg, 0.479 mmol) and DIEA (123.66 mg, 0.9586 mmol), stir at room temperature overnight, add water (200 mL) Stir for 10 min, extract with ethyl acetate (100 mL×3), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (20% EA/ PE) was purified to obtain the target product 4-(2-(1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-(( R )-1-(3-) Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)piperidine-1 -Benzyl carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ = 845.7. Step 4: 4-(2-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- Preparation of 1-carbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester 4-(2-(1-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5- (Trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester (200 mg, 0.236 mmol) was dissolved in ethanol (30 mL), Raney nickel (1 mL) and N ₂ H ₄ -H ₂ O (1 mL) were added, stirred at room temperature for 1 h, filtered, concentrated and dried to obtain the target Product 4-(2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl))ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester . LC-MS: (ESI, m/z): [M+H] ⁺ = 815.4. Step 5: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidine) Preparation of -4-yl)ethyl)piperidin-1-yl)methanone 4-(2-(1-((1 R ,4 R )-4-(4-(( R )-1-(3-amino-5-(trifluoromethyl)phenyl))ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)piperidine-1-carboxylic acid benzyl ester (160 mg, 0.196 mmol) was dissolved in ethyl acetate (20 mL), added Pd(OH) ₂ (32 mg, 20%), stirred at 60 °C for 2 h, filtered, concentrated and dried to obtain the target product ((1 R , 4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexyl)(4-(2-(piperidin-4-yl)ethyl)piperidin-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ = 681.2. Step 6: 1-(5-(4-(2-(1-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidin-4-yl)ethyl)piperidin-1-yl)methanone (120 mg, 0.176 mmol ) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (84.25 mg, 0.194 mmol) were dissolved in DMSO (5 mL). DIEA (68.30 mg, 0.529 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, stirred for 2 minutes, filtered, and the solid was purified through reversed phase preparation to obtain the target product 1-(5-( 4-(2-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)piperidine-1-carbonyl)-2- Chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ = 931.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.20-8.03 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.41 – 7.34 (m, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s , 1H), 6.70 (s, 1H), 5.65 – 5.49 (m, 3H), 4.54-4.34 (m, 2H), 3.98-3.85 (m, 4H), 3.80-3.70 (m, 1H), 3.67-3.53 (m, 2H), 3.10-2.86 (m, 3H), 2.80-2.60 (m, 4H), 2.36 (s, 3H), 1.90 – 1.36 (m, 17H), 1.35-1.18 (m, 5H), 1.16 -0.86 (m, 4H).

Example 16: 1-(2-chloro-5-(9-((4-((1 R ,4 R ))-4-(4-((( R ))-1-(2-fluoro-3-( Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl )-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 1-(2-fluoro-3- Preparation of (trifluoromethyl)phenyl)ethane-1-one 1-Bromo-2-fluoro-3-(trifluoromethyl)benzene (4.0 g, 16.4 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (1.1 g, 1.6 mmol), TEA (4.9 g, 48.9 mmol) The reaction solution of tributyl(1-ethoxyvinyl)stanane (8.8 g, 24.4 mmol) in dihexane (80.0 mL) was stirred at 80 °C for 16.0 h. The reaction was quenched with ice water (200 mL), extracted with EA (80 mL×3), the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was stirred in 6N HCl (20 mL), the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (EA/PE, 0-40%) to obtain the target product 1-(2-fluoro-3-(trifluoromethyl) )phenyl)ethane-1-one. Step 2: Preparation of ( S , E ) -N- (1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide 1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethane-1-one (2.0 g, 9.7 mmol), Ti(OEt) ₄ (5.5 g, 24.2 mmol) and ( S )-propane The reaction mixture of -2-sulfinamide (1.7 g, 14.5 mmol) in THF (40.0 mL) was stirred at 60 °C for 2 h. The reaction was quenched with water (100 mL) and the solution was extracted with EA (80 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target product ( S , E ) -N- (1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2- Sulfenamide. LC-MS: (ESI, m/z): [M+H] ⁺ = 310.2. Step 3: ( S )- N -(( R )-1-(2-fluoro-3-(trifluoromethyl)) Preparation of phenyl)ethyl)-2-methylpropane-2-sulfinamide To ( S , E )- N -(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfenamide at -78 °C L-Selectride (1.0 mol/L/THF, 7.1 mL) was added to a solution of THF (20.0 mL) (2.0 g, 6.4 mmol), and the reaction mixture was stirred at -78 °C for 50 min. The reaction was quenched with ice water (100 mL), and the solution was extracted with EA (80 mL×3). The organic layer was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA/PE, 0-60%) to obtain the target product ( S ) -N -(( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl base)-2-methylpropane-2-sulfinamide. LC-MS: (ESI, m/z): [M+H] ⁺ = 312.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.27-7.22 (m, 1H), 4.91 – 4.81 (m, 1H), 3.55 (d, J = 5.2 Hz, 1H), 1.56 (d, J = 6.7 Hz, 3H), 1.23 (s, 9H). Step 4: Preparation of ( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride ( S ) -N -(( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (2.0 g, The reaction mixture was stirred at 25 °C for 1.0 h. The reaction solution was concentrated under reduced pressure. The concentrate was washed with PE (20 mL×3) to obtain the target product ( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride. LC-MS: (ESI, m/z): [M+H] ⁺ = 208.1. Step 5: (1 R ,4 R )-4-(4-((( R )-1-(2-fluoro- Preparation of methyl 3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate Combine ( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine (0.7 g, 3.3 mmol), DIEA (928.8 mg, 7.2 mmol) and (1 R , 4 R )-4-(4-Chloro-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl-1-carboxylic acid methyl ester (835 mg, 2.4 mmol) in dimethane ( The reaction mixture in 10.0 mL) was stirred at 110 °C for 20.0 h. The reaction was quenched by adding water (50 mL), extracted with EA (30.0 mL×2), the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The concentrate was purified by preparative HPLC (acetonitrile/0.05% HCOOH aqueous solution, 5% to 95%) to obtain the target product (1 R , 4 R )-4-(4-((( R )-1-(2-fluoro-3) -(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 520.3. Step 6: (1 R ,4 R )-4-(4-((( R )-1-(2-fluoro- Preparation of 3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy Methyl -2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (100 mg, 0.2 mmol), LiOH (48 mg, 2.0 mmol) in THF/H ₂ O (2.0 mL/1.0 mL) and stirred at 50°C for 12.0 h. The reaction solution was adjusted to pH 4-5 with 1N HCl, and concentrated under reduced pressure to obtain the target product (1 R , 4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl) (yl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ = 506.4. Step 7: 4-((1 R ,4 R )-4-(4-((( R )-1-(2 -Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine- Preparation of tert-butyl 1-carboxylate To (1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (110 mg, 0.2 mmol), tert-butyl piperazine-1-carboxylate (45 mg, 0.22 mmol) and DIEA ( HATU (124 mg, 0.24 mmol) was added to a solution of DMF (2 mL) (85 mg, 0.6 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with ice water (20 mL), the precipitate was collected by filtration, and then dried under vacuum to obtain the target product 4-((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro) -3-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1- tert-butyl carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ = 674.5. Step 8: ((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro) -3-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone Preparation 4-((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7- Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.1 mmol) in TFA/DCM (1 mL/ The reaction mixture in 3 mL) was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure to obtain the target product ((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amine (yl)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ = 574.2. Step 9: 9-((4-((1 R ,4 R )-4-(4-((( R )- 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl ) Preparation of tert-butyl piperazine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate To ((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy methyl-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone (60 mg, 0.1 mmol) and 9-carbaldehyde-3-azaspiro[5.5]undecane STAB (64 mg, 0.3 mmol) was added to a solution of tert-butyl-3-carboxylate (35 mg, 0.12 mmol) in THF (5.0 mL), and the reaction mixture was stirred at room temperature for 2.0 h. Add ice water (10 mL) to quench the reaction, extract with EA (30.0 mL×2), combine the organic phases and wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was purified by column chromatography (MeOH/DCM, 0-10%) to obtain the target product 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(2 -Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl-1-carbonyl)piperidine-1 -(yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 839.4. Step 10: (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide -1-yl)((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)- Preparation of 7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone 9-((4-((1 R ,4 R )-4-(4-(( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane The reaction mixture of -3-tert-butylcarboxylate (70 mg, 0.08 mmol) in TFA/DCM (1 mL/3 mL) was stirred at room temperature for 1.0 h. The reaction solution was directly concentrated to obtain the target product (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide-1-yl)((1 R ,4 R )-4-( 4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )cyclohexyl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ = 739.5. Step 11: 1-(2-chloro-5-(9-((4-((1 R ,4 R ))-4 -(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone To (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone (60 mg, 0.08 mmol) in DMSO (1.0 mL) was added DIEA (31 mg, 0.24 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )- base) pentafluorophenyl benzoate (43 mg, 0.1 mmol), and then the reaction mixture was stirred at room temperature for 2.0 h. The reaction was quenched with water (15 mL), extracted with EA (30 mL×2), the organic phases were combined, washed with brine, dried, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(2-chloro-5-(9-((4-((1 R ,4 R ) -4-(4-((( R )-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline -6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4 (1 H ,3 H )-diketone. LC-MS: (ESI, m/z): [M+H] ⁺ = 989.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.26 (s, 1H), 8.10 ( s, 1H), 7.80 (s, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.55 (s, 1H), 7.42 – 7.34 (m, 2H), 6.99 (s, 1H), 5.77 (s , 1H), 3.88 (s, 3H), 3.82-3.72 (m, 1H), 3.68-3.42 (m, 7H), 3.02-2.92 (m, 1H), 2.78-2.70 (m, 2H), 2.70-2.63 (m, 1H), 2.38-2.25 (m, 7H), 2.18-2.10 (m, 2H), 1.90-1.78 (m, 4H), 1.71-1.22 (m, 18H), 1.98-1.00 (m, 4H) .

Example 17: N -(3-(( R )-1-((6-((1 R ,4 R ))-4-(4-((3-(4-chloro-3-(2,4- Dioxotetrahydropyrimidine-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carbonyl)cyclohexyl) -7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)benzene (base)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-aza Spiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (70 mg, 0.07 mmol) in acetic anhydride (3.0 mL) The reaction mixture was stirred at room temperature for 12.0 h. The reaction solution was directly concentrated under reduced pressure. The concentrate was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product N- (3-(( R )-1-((6-((1 R ,4 R ) -4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5 ]Undecyl-9-yl)methyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5- (Trifluoromethyl)phenyl)acetamide. LC-MS: (ESI, m/z): [M+H] ⁺ = 1028.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 10.22 (s, 1H), 8.19 ( d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 5.68 – 5.54 (m, 1H), 3.88 (s, 3H), 3.79-3.72 (m, 1H) , 3.62-3.41 (m, 7H), 2.98-2.91 (m, 1H), 2.78-2.70 (m, 2H), 2.70-2.63 (m, 1H), 2.38-2.22 (m, 7H), 2.18-2.08 ( m, 2H), 2.03 (s, 3H), 1.89-1.78 (m, 4H), 1.74 – 1.22 (m, 18H), 1.18-0.98 (m, 4H).

Example 18: 1-(2-chloro-5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-(isopropylamine) (base)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine- 1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione To 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (70 mg, 0.07 mmol), acetone (40 mg, 0.7 mmol) and AcOH (0.2 mL) in MeOH/THF (1.0 mL/1.0 mL) was added STAB (89 mg, 0.42 mmol). The reaction mixture was then stirred at room temperature for 30 h. The reaction was quenched by adding water, extracted with EA, the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain the target product 1-(2-chloro-5-(9-((4-((1 R ,4 R ) -4-(4-((( R )-1-(3-(isopropylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2 -Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)di Hydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ = 1028.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 10.22 (s, 1H), 8.19 ( d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 5.68 – 5.54 (m, 1H), 3.88 (s, 3H), 3.82-3.56 (m, 8H) , 2.98-2.91 (m, 1H), 2.78-2.70 (m, 2H), 2.70-2.63 (m, 2H), 2.38-2.22 (m, 7H), 2.18-2.08 (m, 2H), 1.95-1.75 ( m, 4H), 1.89-1.48 (m, 15H), 1.42 – 1.25 (m, 6H), 1.18-0.98 (m, 7H).

Example 19: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-() Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy Base)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-((2-(1-(th) Preparation of tributoxycarbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester 4-(2-(Piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 5.81 mmol) and benzyl chloroformate (1.19 mg, 6.97 mmol) The reaction solution of ACN/sat.NaHCO ₃ (30 mL/30 mL) was stirred at room temperature overnight. The reaction solution was quenched with water (50 mL), and then extracted with EA (50 mL×3). The organic phase was washed with saturated brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product was purified by flash column (EA:PE=0~7:3) to obtain the target product 4-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethoxy)methyl) Piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 461.3. Step 2: 4-((2-piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxy Preparation of acid benzyl ester To benzyl 4-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylate (600 mg, 1.3 mmol) in DCM ( TFA (2 mL) was added to the solution. The reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain the target product 4-((2-piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester. The crude product obtained was directly used in the next reaction without purification. LC-MS: (ESI, m/z): [M+H] ⁺ = 361.1. Step 3: (1 R ,4 R )-4-(4-((( R )-1-(3-((( 3-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- Preparation of 1-carboxylic acid (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (21 mg, 0.34 mmol), LiOH (71 mg, 1.70 mmol) The THF/H ₂ O (8 mL/4 mL) reaction was stirred at 50 °C overnight. 10% citric acid aqueous solution (5 mL) was added to the reaction solution, and extracted with EA (20 mL×3). The organic phase was washed with saturated brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target product (1 R , 4 R )-4-(4-((( R )-1-(3- (((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan Alkane-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ = 603.1. Step 4: 4-((2-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-(tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline Preparation of -6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester To ((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl To a solution of methyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (200 mg, 0.33 mmol) in DMF (10 mL) was added 4- ((2-Piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester (155 mg, 0.43 mmol), HATU (190 mg, 0.50 mmol) and DIEA (128 mg, 0.99 mmol). The reaction mixture was stirred at room temperature for 2 h. Water (100 mL) was added to the reaction solution, and extracted with EA (30 mL×3). The organic phase was washed with saturated brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by flash column (EA:PE=0~4:1) to obtain the target product 4-((2-(1 R ,4 R )-4-(4-((( R )-1-(3-) ((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane -1-Carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 945.3. Step 5: (3-(( R )-1-((7-methoxy-2-methyl-6-( (1 R ,4 R )-4-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino Preparation of tert-butyl)ethyl)-5-(trifluoromethyl)phenyl)carbamate To 4-((2-(1 R ,4 R )-4-(4-((( R )-1-(3-(tert-butoxycarbonyl)amino))-5-(trifluoromethyl) Phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl) To a solution of benzyl piperidine-1-carboxylate (230 mg, 0.24 mmol) in EA (20 mL) was added Pd(OH) ₂ /C (100 mg). The reaction mixture was stirred at 70°C overnight. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the target product (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R )-4) -(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(tri Fluoromethyl)phenyl)carbamic acid tert-butyl ester. The obtained product was directly used in the next reaction without purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 811.3. Step 6: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methyl Oxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl) Preparation of tert-butyl phenyl)carbamate (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4-(2-(piperidin-4-yl) Methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (200 mg, 0.24 mmol), 4-chloro-3-(2,4-dioxoectohydropyrimidin-1(2 H )-yl)benzoate (126 mg, 0.29 mmol) and DIEA (93 mg, 0.72 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction solution was diluted with water (50 mL), and then extracted with DCM (20 mL×2). The organic phases were combined, washed with saturated brine, dried, filtered and concentrated under reduced pressure. The obtained crude product was purified by flash column (MeOH:DCM=0~1:9) to obtain the target product (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(2 -((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl (yl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)amine tert-butyl formate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1061.3. Step 7: 1-(5-(4-((2-(1-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone To (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(2-((1-(4-chloro-3-(2,4-dioxo) Substitutetetrahydropyrimidine-1(2 H )-yl)benzyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy- To a solution of tert-butyl 2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate in DCM (3 mL) was added dropwise TFA (1.0 mL). The reaction solution was stirred at room temperature for 2 h. DIEA (5 mL) was added to the reaction solution, then diluted with water (50 mL), and extracted with DCM (30 mL×3). The organic phase was washed with saturated brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5%~95%) to obtain the target product 1-(5-(4-((2-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2, 4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 961.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 9.32 (s, 1H), 8.25 ( s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.37 (dd, J = 8.2, 1.8 Hz, 1H), 7.04 (s, 1H), 6.86 (d, J = 7.3 Hz, 2H), 6.74 (s, 1H), 5.75-5.55 (m, 3H), 4.50-4.30 (m, 2H), 3.98-3.87 (m, 4H), 3.80-3.70 ( m, 1H), 3.68-3.54 (m, 2H), 3.41 (t, J = 6.2 Hz, 2H), 3.23 (d, J = 6.0 Hz, 2H), 3.12-2.90 (m, 3H), 2.82-2.60 (m, 4H), 1.92-1.40 (m, 22H), 1.12-0.92 (m, 5H).

Example 20: 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (4-((3-azaspiro[5.5]undecan-9-yl)methyl)pipero-1-yl)((1 R ,4 R )-4-(4-((( R ) -1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane)methane Ketone (200 mg, 0.12 mmol), 3-(2,4-dioxoectoine-1(2 H )-yl)-4-methoxybenzoate pentafluorophenyl ester (62 mg, 0.15 mmol ) and DIEA (77 mg, 0.60 mmol) in DMSO (5 mL), stirred at room temperature overnight. The reaction solution was diluted with water (50 mL). Then use DCM (20 mL×3). The organic phase was washed with saturated brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by thin layer preparation plate (DCM:MeOH=10:1) to obtain the target product 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 982.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 8.14 – 8.02 (m, 2H), 7.36 (dd, J = 8.4, 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H ), 6.85 (s, 1H), 6.70 (s, 1H), 5.62 – 5.49 (m, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.59 (t, J = 6.7 Hz, 2H) , 3.52-3.42 (m, 6H), 3.02-2.92 (m, 1H), 2.70-2.68 (m, 3H), 2.40-2.24 (m, 7H), 2.16-2.06 (m, 2H), 1.90-1.75 ( m, 4H), 1.78-1.40 (m, 14H), 1.32-1.22 (m, 4H), 1.12-0.92 (m, 4H).

Example 21: 1-(3-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (4-((3-azaspiro[5.5]undecan-9-yl)methyl)pipero-1-yl)((1 R ,4 R )-4-(4-((( R ) -1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone (200 mg, 0.12 mmol), 3-(2,4-dioxoectohydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (60 mg, 0.15 mmol) and DIEA (77 mg, 0.60 mmol) in DMSO (5 mL) and stirred at room temperature overnight. The reaction solution was diluted with water (50 mL). Then extract with DCM (20 mL×3). The organic phase was washed with saturated brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was first purified by column chromatography (MeOH/DCM=0~1:9), and then purified by thin layer preparation plate (DCM:MeOH=10:1) to obtain the target product 1-(3-(9-((4 -((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl) Phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 952.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 8.20-8.04 (m, 2H), 7.47-7.34 (m, 3H), 7.22 (d, J = 7.4 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.63 – 5.48 (m, 3H), 3.88 (s, 3H), 3.82 (t, J = 6.7 Hz, 2H), 3.62-3.50 (m, 2H), 3.50-3.40 (m, 4H), 3.02-2.90 (m , 1H), 2.71 (t, J = 6.6 Hz, 2H), 2.68-2.60 (m, 1H), 2.40-2.30 (m, 5H), 2.20-2.10 (m, 2H), 1.90-1.80 (m, 4H ), 1.68-1.40 (m, 18H), 1.11-0.92 (m, 4H).

Example 22: 1-(4-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (4-((3-Azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methane ketone (80 mg, 0.109 mmol) and 4-(2,4-dioxoectoine-1(2 H )-yl)benzoate pentafluorophenyl ester (44 mg, 0.109 mmol) with DMSO (5 mL ), add DIEA (42 mg, 0.327 mmol), then stir the reaction solution at room temperature for 2 hours, add water (50 mL) to the reaction solution, stir for 2 minutes, filter, and use column chromatography (10% MeOH/DCM) for the solid ), and then purified by p-TLC (MeOH/DCM=1/10) to obtain 1-(4-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-di ketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =952.6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.43 (s, 1H), 8.09 (d, J = 22.5 Hz, 2H), 7.39 (s, 4H), 6.99 (s, 1H), 6.86 (d, J = 10.9 Hz, 2H), 6.70 (s, 1H), 5.64 – 5.48 (m, 3H), 3.88 (s, 3H ), 3.83 (t, J = 6.5 Hz, 2H), 3.60 – 3.53 (m, 2H), 3.50 – 3.40 (m, 5H), 2.94 (s, 1H), 2.77 – 2.59 (m, 4H), 2.31 ( d, J = 37.6 Hz, 8H), 2.12 (s, 2H), 1.91 – 1.75 (m, 4H), 1.75 – 1.60 (s, 4H), 1.60 – 1.40 (m, 11H), 1.15 – 0.95 (m, 4H).

Example 23: 3-(4-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2,6-dione 4-(2,6-Dioxopiperidin-3-yl)benzoate pentafluorophenyl ester (143.12 mg, 0.358 mmol) and (4-((3-azaspiro[5.5]undecane- 9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)) Phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane)methanone (240 mg, 0.326 mmol) was dissolved in DMSO (5 mL) and added DIEA (126.2 mg, 0.978 mmol), then stirred at room temperature for 2 hours, water (50 mL) was added to the reaction solution, stirred for 2 minutes, filtered, and the solid was purified through reversed phase preparation to obtain 3-(4-(9-(( 4-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7- Methoxy-2-methylquinazolin-6-yl)cyclohexyl-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl) Phenyl)piperidine-2,6-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =951.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.86 (s, 1H), 8.20-8.10 (m, 1H), 8.06 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H ), 6.70 (s, 1H), 5.67-5.47 (m, 3H), 3.94 – 3.88 (m, 4H), 3.65-3.42 (m, 8H), 3.00-2.90 (m, 1H), 2.71 – 2.62 (m , 4H), 2.42-2.22 (m, 10H), 2.16 – 2.02 (m, 4H), 1.90-1.76 (m, 6H), 1.74-1.36 (m, 10H), 1.20-0.92 (m, 4H).

Example 24: 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)-2-fluorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (4-((3-Azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methane ketone (100 mg, 0.136 mmol) and 3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-fluorobenzoic acid pentafluorophenyl ester (57 mg, 0.136 mmol). Dissolve DMSO (5 mL), add DIEA (53 mg, 0.41 mmol), stir the reaction solution at room temperature for 2 hours, dilute with water (50 mL), stir for 2 minutes, filter, and use column chromatography for the solid (MeOH:DCM=1: 9) After purification, purify twice with p-TLC (MeOH:DCM=1:10) to obtain 1-(5-(9-((4-((1 R ,4 R ))-4-(4-( (( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-fluorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =970.7. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.52 (s, 1H), 8.14-8.08 (m, 1H), 8.06 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 6.99 (s, 1H), 6.89 (s, 1H), 6.86 (s, 1H ), 6.70 (s, 1H), 5.61 – 5.48 (m, 3H), 3.88 (s, 3H), 3.75 (t, J = 6.6 Hz, 2H), 3.64 – 3.53 (m, 2H), 3.52-3.40 ( m, 5H), 3.02-2.90 (m, 1H), 2.77 – 2.56 (m, 4H), 2.38 – 2.21 (m, 8H), 2.18-2.07 (m, 2H), 1.90 – 1.77 (m, 4H), 1.73-1.40 (m, 15H), 1.13-0.96 (m, 4H).

Example 25: 1-(5-(4-(((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5- (Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl (methyl)amino)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione step 1: 4-(( Preparation of (2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylic acid benzyl ester To 4-(2-(methylamino)ethyl)piperidine-1-carboxylic acid tert-butyl ester (310 mg, 1.28 mmol) and 4-carboxaldehyde piperidine-1-carboxylic acid benzyl ester (316 mg, 1.28 To a solution of mmol) in THF (10 mL) was added STAB (814 mg, 3.84 mmol). The reaction solution was stirred at room temperature for 2 h. Add water (50 mL) to the reaction solution to dilute, EA (50 mL×3). The organic phases were combined and washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was subjected to flash column (MeOH/DCM=0~1:4) to obtain 4-(((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)(methyl)amino) )methyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =474.2. Step 2: 4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl) Preparation of piperidine-1-carboxylic acid benzyl ester 4-(((2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylate (400 mg , 0.85 mmol) in TFA/DCM (10 mL, 1:4) and stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain 4-((methyl(2-(piperidin-4-yl)ethyl)amino)methyl)piperidine-1-carboxylic acid benzyl ester. The crude product was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =374.4. Step 3: 4-(((2-(1-((1 R ,4 R )-4-(4-(( ( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquin Preparation of benzyl oxazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylate To (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.25 mmol) in DMF (10 mL) was added 4-( (Methyl(2-(piperidin-4-yl)ethyl)amino)methyl)piperidine-1-carboxylic acid benzyl ester (139 mg, 0.37 mmol), HATU (142 mg, 0.37 mmol) and DIEA (161 mg, 1.25 mmol). The reaction solution was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL) and extracted with EA (50 mL×3). The organic phases were combined and washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product obtained was purified by chromatography column (MeOH:DCM=0~1:9) to obtain 4-(((2-(1-((1 R ,4 R ))-4-(4-((( R )-1 -(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =958.3. Step 4: (3-(( R )-1-((7-methoxy-2-methyl-6-( (1 R ,4 R )-4-(4-(2-(methyl(piperidin-4-ylmethyl)amino)ethyl)piperidine-1-carbonyl)cyclohexyl)quinazoline-4 Preparation of -tert-butyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate To 4-(((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-((tert-butoxycarbonyl)amino)-5- (Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl To a solution of benzyl(methyl)amino)methyl)piperidine-1-carboxylate (200 mg, 0.21 mmol) in EtOAc (10 mL) was added Pd(OH) ₂ /C (60 mg, 30% ). The reaction solution was stirred at 70 °C under _H2 atmosphere for 4 h. The reaction solution was filtered and concentrated to obtain (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4-(2-(methyl) (piperidin-4-ylmethyl)amino)ethyl)piperidin-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl) phenyl)carboxylic acid tert-butyl ester. The obtained product was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =824.4. Step 5: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(2-(((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl) Methyl)(methyl)amino)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5 Preparation of -(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4-(2-(methyl(piperidine- 4-ylmethyl)amino)ethyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (135 mg, 0.16 mmol), 3-(2,4-dioxoectoine-1(2 H )-yl)-4-methoxybenzoate pentafluorophenyl ester (69 mg , 0.16 mmol) and DIEA (62 mg, 0.48 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction solution was poured into water (50 mL) and stirred for 10 minutes, filtered, and the filter cake was purified by flash column (MeOH:DCM=0~1:4) to obtain (3-(( R )-1-((6-( (1 R ,4 R )-4-(4-(2-(((1-(4-chloro-3-(2,4-dioxoectohydropyrimidin-1(2 H )-yl))benzene Formyl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazoline-4 -tert-butyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =1074.2. Step 6: 1-(5-(4-(((2-(1-((1 R ,4 R ))-4 -(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline- 6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine- Preparation of 2,4(1 H ,3 H )-diketone Put (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(2-(((1-(4-chloro-3-(2,4-di)) Oxoectoine-1(2 H )-yl)benzoyl)piperidin-4-yl)methyl)(methyl)amino)ethyl)piperidin-1-carbonyl)cyclohexyl) -7-Methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (120 mg, 0.11 mmol) The mixture with TFA/DCM (5 mL, 1:4) was stirred at room temperature for 1 h. The reaction solution was concentrated directly, then dissolved in EA (50 mL) and NaHCO ₃ (aq, 30 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by Prep-HPLC to obtain 1-(5-(4-(((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino) -5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-4- Base)ethyl)(methyl)amino)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =974.6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.18 – 7.99 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.63 – 5.47 (m, 3H), 4.49 – 4.38 (m, 1H), 3.95 – 3.85 (m, 4H), 3.79 – 3.69 (m, 1H), 3.67 – 3.50 (m, 2H), 3.09 – 2.87 (m, 3H), 2.78-2.63 (m, 4H), 2.35 (s, 3H), 2.33 – 2.26 (m, 2H), 2.15 – 2.08 (m, 4H ), 1.92–1.48 (m, 20H), 1.40-1.30 (m, 2H), 1.15-0.98 (m, 4H).

Example 26: (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)- N -(2-((3-(1-(4-chloro-3-(2,4-dioxoectoine- 1(2 H )-yl)benzoyl)piperidin-4-yl)prop-2-yn-1-yl)oxo)ethyl)- N -methylcyclohexane-1-methamide Step 1: (3-(( R )-1-((6-((1 R ,4 R ))-4-((2-hydroxyethyl)(methyl)carbonyl)cyclohexyl)-7-methoxy Preparation of tert-butyl-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate To (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.24 mmol) in DMF (5 mL) was added 2-( Methylamino)ethane-1-ol (90 mg, 1.2 mmol), HATU (137 mg, 0.36 mmol) and DIEA (93 mg, 0.72 mmol). The reaction solution was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL) and EA (20 mL×3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated _. The crude product was purified by flash column (MeOH:DCM=0~1:9) to obtain (3-(( R )-1-((6-((1 R ,4 R ))-4-((2-hydroxyethyl) (Methyl)carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tertiary butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =660.2. Step 2: 4-(3-(2-((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline Preparation of tert-butyl ester of -6-yl) -N -methylcyclohexane-1-amide)ethoxy)prop-1-yn-1-yl)piperidine-1-carboxylate (3-(( R )-1-((6-((1 R ,4 R ))-4-((2-hydroxyethyl)(methyl)carbonyl)cyclohexyl)-7-methoxy- 2-Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (150 mg, 0.22 mmol), 4-(3-bromo) A mixture of tert-butyl prop-1-yn-1-yl)piperidine-1-carboxylate (133 mg, 0.44 mmol) and K ₂ CO ₃ (151 mg, 1.1 mmol) in acetonitrile (20 mL) Stir at 70°C overnight. The reaction solution was diluted with water (50 mL), EA (20 mL×3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column (MeOH:DCM=0~1:9) to obtain 4-(3-(2-((1 R ,4 R )-4-(4-((( R ))-1-(3 -(((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)- N -Methylcyclohexane-1-amide)ethoxy)prop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =881.3. Step 3: (1 R ,4 R )-4-(4-((( R )-1-(3-amino) -5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)- N -methyl- N -(2-(( Preparation of 3-(piperidin-4-yl)prop-2-yn-1-yl)oxy)ethyl)cyclohexane-1-methamide To 4-(3-(2-((1 R ,4 R ))-4-(4-((( R )-1-(3-((tertiary butoxycarbonyl)amino))-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) -N -methylcyclohexane-1-amide)ethoxy To a solution of tert-butyl)prop-1-yn-1-yl)piperidine-1-carboxylate (100 mg, 0.11 mmol) in DCM (3 mL) was added TFA (1.0 mL). The reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-methoxy-2-methylquinazolin-6-yl)- N -methyl- N -(2-((3-(piperidin-4-yl)prop-2-yn-1-yl) )oxy)ethyl)cyclohexane-1-methamide. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =681.3. Step 4: (1 R ,4 R )-4-(4-((( R )-1-(3-amino) -5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)- N -(2-((3-(1- (4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)prop-2-yn-1-yl) Preparation of oxo)ethyl) -N -methylcyclohexane-1-methamide (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy methyl-2-methylquinazolin-6-yl) -N -methyl- N- (2-((3-(piperidin-4-yl)prop-2-yn-1-yl)oxy)ethyl yl)cyclohexane-1-carboxamide (100 mg, TFA salt), 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoic acid pentafluoroate The reaction of phenyl ester (60 mg, 0.14 mmol) and DIEA (71 mg, 0.55 mmol) in DMSO (5 mL) was stirred at 25 °C overnight. The reaction solution was diluted with water (50 mL) and filtered. The filtrate is concentrated. The obtained crude product was purified by Prep-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5% to 95%) to obtain (1 R ,4 R )-4-(4-((( R )-1-( 3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)- N -(2-((3 -(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)prop-2-yne- 1-yl)oxo)ethyl) -N -methylcyclohexane-1-methamide. LC-MS: (ESI, m/z): [M+H] ⁺ =931.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 ( d, J = 5.6 Hz, 3H), 6.76 (s, 1H), 6.45 (t, J = 5.9 Hz, 1H), 5.61 (d, J = 7.1 Hz, 1H), 4.84-4.61 (m, 1H), 3.95-3.83 (m, 5H), 3.78-3.70 (m, 1H), 3.61-3.51 (m, 2H), 3.50-3.41 (m, 3H), 3.40-3.33 (m, 2H), 3.08 (s, 1H ), 3.00-2.90 (m, 1H), 2.83 (s, 2H), 2.78-2.60 (m, 2H), 2.67 – 2.54 (m, 3H), 2.34 (s, 3H), 1.94-1.78 (m, 4H ), 1.74-1.49 (m, 10H), 1.45-1.29 (m, 2H).

Example 27: 1-(5-(4-(3-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)propan-1 -Alkyn-1-yl)piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(3-(4-( (1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) Base)Amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)prop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester Preparation ((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5-(trifluoromethyl)phenyl )ethyl)amino)quinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone (300 mg, 0.50 mmol), 4-(3-bromopropan-1-yn-1- The reaction solution of tert-butyl piperidine-1-carboxylate (150 mg, 0.50 mmol) and K ₂ CO ₃ (138 mg, 1.0 mmol) in THF (30 mL) was stirred at 80 °C for 2 h. Water (50 mL) was added to the reaction solution, and extracted with EA (30 mL×3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column (MeOH:DCM=0~1:9) to obtain 4-(3-(4-((1 R ,4 R ))-4-(7-methoxy-2-methyl-4- ((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piper𠯤- 1-yl)prop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =822.3. Step 2: 4-(3-(4-((1 R ,4 R )-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- Preparation of tert-butyl ester of 1-carbonyl)piperidine-1-yl)prop-1-yn-1-yl)piperidine-1-carboxylate To 4-(3-(4-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R ))-1-(3-nitro-5- (Trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)prop-1-yn-1-yl)piperidine -To a solution of tert-butyl-1-carboxylate (170 mg, 0.2 mmol) in EtOH (25 mL) was added Fe (115 mg, 2.0 mmol) and NH ₄ Cl (106 mg, 2.0 mmol). The reaction solution was stirred at 70 °C for 5 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by flash column (MeOH:DCM=0~1:9) to obtain 4-(3-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3- Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine- 1-yl)prop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =792.2. Step 3: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidine) Preparation of -4-yl)prop-2-yn-1-yl)piperidine-1-yl)methanone To 4-(3-(4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl))ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)prop-1-yn-1-yl)piperidine -To a solution of tert-butyl-1-carboxylate (150 mg, 0.19 mmol) in DCM (3 mL) was added TFA (1.0 mL). The reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino) -7-Methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)prop-2-yn-1-yl)piperidin-1 -base) methanone. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =692.2. Step 4: 1-(5-(4-(3-(4-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base) cyclohexane-1-carbonyl) piperazine-1-yl) prop-1-yn-1-yl) piperidine-1-carbonyl)-2-chlorophenyl) dihydropyrimidine-2,4(1 Preparation of H ,3 H )-diketone ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)prop-2-yn-1-yl)piperidin-1-yl)methyl Ketone (200 mg, 0.19 mmol), 4-chloro-3-(2,4-diyloxytetrahydropyrimidin-1(2 H )-yl)benzoate (100 mg, 0.23 mmol) The reaction solution of DIEA (73 mg, 0.57 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction solution was diluted with water (50 mL), extracted with DCM (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was first purified by flash column (MeOH:DCM=0~1:9), and then purified by Prep-TLC (DCM:MeOH=10:1) to obtain 1-(5-(4-(3-(4-( (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)prop-1-yn-1-yl)piperidine-1-carbonyl)-2-chlorobenzene base)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =942.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ10.50 (s, 1H), 8.23-8.10 (m, 1H) , 8.06 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.69 – 5.39 (m, 3H), 3.88 (s, 3H), 3.78-3.71 (m, 1H), 3.63 -3.43 (m, 6H), 3.33-3.20 (m, 4H), 2.94 (t, J = 11.2 Hz, 1H), 2.81 – 2.61 (m, 4H), 2.50-2.40 (m, 2H), 2.40-2.31 (m, 5H), 1.91-1.42 (m, 16H).

Example 28: 1-(5-(4-(3-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)propoxy )Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(3-(piperidine-1-yl)propoxy Preparation of piperidine-1-carboxylic acid benzyl ester To tert-butyl 4-(3-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxo)propyl)piperidine-1-carboxylate (200 mg, 0.43 mmol) TFA (1 mL) was added to the DCM (3 mL) solution, and then stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain benzyl 4-(3-(piperidine-1-yl)propoxy)piperidine-1-carboxylate. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =362.0. Step 2: 4-(3-(4-((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole Preparation of benzyl ester of pholin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)propoxy)piperidine-1-carboxylate To a solution of benzyl 4-(3-(piperidine-1-yl)propoxy)piperidine-1-carboxylate (200 mg, TFA salt) in DMF (6 mL) was added (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.25 mmol), HATU (142 mg, 0.37 mmol) and DIEA (96 mg, 0.74 mmol). The reaction solution was stirred at room temperature for 2 h. The reaction solution was quenched by adding water (60 mL), and extracted with EA (20 mL×3). The organic phases were combined and washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (EA:PE=0~4:1) to obtain 4-(3-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3 -((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidine-1-yl)propoxy)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =946.1. Step 3: (3-(( R )-1-((7-methoxy-2-methyl-6-( (1 R ,4 R )-4-(4-(3-(piperidin-4-yloxy)propyl)piperidin-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl Preparation of tert-butyl)-5-(trifluoromethyl)phenyl)carbamate While stirring, add to 4-(3-(4-((1 R ,4 R ))-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)- 5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl To a solution of benzyl propoxy)piperidine-1-carboxylate (160 mg, 0.17 mmol) in EA (20 mL) was added Pd(OH) ₂ /C (80 mg). The reaction solution was stirred overnight at 70 °C under _H2 atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4- (3-(piperidin-4-yloxy)propyl)piperidin-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl ) tert-butyl carbamate. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =812.2. Step 4: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxo )propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl ) Preparation of tert-butyl carbamate (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4-(3-(piperidin-4-yl) Oxy)propyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (110 mg, 0.13 mmol), 4-chloro-3-(2,4-dioxo-1(2 H )-yl)benzoate pentafluorophenyl ester (71 mg, 0.16 mmol), and DIEA (52 mg, 0.40 mmol) in DMSO (3 mL) was stirred at room temperature overnight. The reaction solution was diluted with water (50 mL), and extracted with DCM (20 mL×3). The organic phases were combined and washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (MeOH:DCM=0~1:9) to obtain (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(3- ((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxo)propyl)piper 𠯤-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid Tributyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =1062.5. Step 5: 1-(5-(4-(3-(4-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- yl)cyclohexane-1-carbonyl)piperidin-1-yl)propoxy)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- Preparation of diketone To (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(3-((1-(4-chloro-3-(2,4-dioxo)) Substituted ectoine-1(2 H )-yl)benzyl)piperidin-4-yl)oxo)propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2- Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (80 mg, 0.07 mmol) in DCM (3 mL) Add TFA (1.0 mL). The reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated, and the obtained crude product was dissolved in a mixed solution of DCM (20 mL) and saturated NaHCO ₃ (20 mL). After the resulting mixture was stirred for 30 min, the organic phase was separated, and the aqueous phase was extracted with DCM (20 mL×2). The organic phases were combined and washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (MeOH:DCM=0~1:9) to obtain 1-(5-(4-(3-(4-((1 R ,4 R ))-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidine-1-yl)propoxy)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =962.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.39-8.17 (m, 1H), 8.09 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H), 7.00 (s, 1H ), 6.88 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.63 – 5.49 (m, 3H), 3.95-3.83 (m, 4H), 3.80-3.70 (m, 1H), 3.68-3.57 (m, 1H), 3.57-3.39 (m, 8H), 3.30-3.18 (m, 2H), 3.00-2.90 (m, 1H), 2.79 – 2.60 (m, 3H), 2.42-2.24 (m , 9H), 1.90-1.77 (m, 6H), 1.72-1.37 (m, 11H).

Example 29: 1-(5-(4-(4-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl) Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(4-carbonylbutyl)piperidine-1-carboxylic acid Preparation of tert-butyl ester To a solution of tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate (1.2 g, 4.67 mmol) in DCM (20 mL) at 0 °C was added Dess-martin (3.96 g, 9.34 mmol) . The reaction solution was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and extracted with DCM (50 mL×3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was first purified by flash column (EA:PE =0~1:4) to obtain 4-(4-carbonylbutyl)piperidine-1-carboxylic acid tert-butyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.66 (t, J = 1.3 Hz, 1H), 3.91 (d, J = 12.0 Hz, 2H), 2.66 (s, 2H), 2.45 – 2.36 (m, 2H), 1.67 – 1.48 (m, 4H), 1.43 – 1.34 (m, 10H), 1.24 – 1.13 (m, 2H), 0.94 (2H). Step 2: 4-(4-(1-(Third D Preparation of oxycarbonyl)piperidin-4-yl)butyl)piperidin-1-carboxylic acid benzyl ester To tert-butyl 4-(4-carbonylbutyl)piperidine-1-carboxylate (390 mg, 1.53 mmol) and benzyl piperidine-1-carboxylate (390 mg, 1.53 mmol) in THF (10 mL) solution was added STAB (973 mg, 4.59 mmol). The reaction solution was stirred at room temperature for 2 h. Water (50 mL) was added to the reaction solution, and extracted with EA (50 mL×3). The organic phases were combined and washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (EA:PE =0~3:2) to obtain 4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butyl)piperidine-1-carboxylic acid acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =460.3. Step 3: 4-(4-(piperidine-1-yl)butyl)piperidine-1-carboxylic acid tert-butyl Preparation of esters Add benzyl 4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butyl)piperidine-1-carboxylate (700 mg, 1.53 mmol) in EtOAc (10 mL) solution was added Pd(OH) ₂ /C (210 mg, 30%). The reaction solution was stirred at 70°C in a _H2 atmosphere for 4 h. The reaction liquid was filtered, and the filtrate was concentrated to obtain tert-butyl 4-(4-(piperidine-1-yl)butyl)piperidine-1-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =326.2. Step 4: 4-(4-(4-((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole Preparation of tert-butyl ester of pholin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carboxylate Add to (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl) with stirring) To a solution of ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (170 mg, 0.28 mmol) in DMF (10 mL) was added 4 -(4-(Piper-1-yl)butyl)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.37 mmol), HATU (140 mg, 0.37 mmol) and DIEA (108 mg, 0.84 mmol ). The reaction solution was stirred at room temperature for 2 h. Water (50 mL) was added to the reaction solution, and extracted with EA (50 mL×3). The organic phases were combined and washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (MeOH:DCM=0~1:9) to obtain 4-(4-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3 -((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =910.3 . Step 5: ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- Preparation of 7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(4-(piperidin-4-yl)butyl)piperidin-1-yl)methanone 4-(4-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3-((tertiary butoxycarbonyl)amino))-5-( Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl ) A solution of tert-butyl piperidine-1-carboxylate (180 mg, 0.20 mmol) in TFA/DCM (5 mL, 1:4) was stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino) -7-Methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(4-(piperidin-4-yl)butyl)piperidin-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ =710.3. Step 6: 1-(5-(4-(4-(4-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(4-(piperidin-4-yl)butyl)piperidin-1-yl)methanone (160 mg, 0.23 mmol )), 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (98 mg, 0.23 mmol ) and DIEA (148 mg, 1.15 mmol) in DMSO (5 mL) and stirred at room temperature overnight. The reaction solution was poured into water (50 mL), stirred for 10 min, filtered, and the filter cake was purified by Prep-HPLC to obtain 1-(5-(4-(4-(4-((1 R ,4 R ))-4 -(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline- 6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H ) -Diketones. LC-MS: (ESI, m/z): [M+H] ⁺ =960.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.15 – 7.98 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H ), 6.86 (s, 1H), 6.70 (s, 1H), 5.64 – 5.48 (m, 3H), 4.50 – 4.35 (m, 1H), 3.88 (s, 3H), 3.80 – 3.70 (m, 1H), 3.65 – 3.55 (m, 1H), 3.51 – 3.41 (m, 4H), 3.00-2.90 (m, 2H), 2.78-2.61 (m, 4H), 2.38 – 2.23 (m, 9H), 1.91-1.76 (m , 4H), 1.76 – 1.37 (m, 13H), 1.35 -1.20 (m, 4H), 1.13 – 1.00 (m, 2H).

Example 30: 1-(5-(4-(2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy )Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(2-ethoxy-2-carbonylethoxy) ) Preparation of piperidine-1-carboxylic acid benzyl ester To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (3.0 g, 12.7 mmol) and NaH (335.0 mg, 13.9 mmol) in THF (30 mL) was added methyl 2-bromoacetate (3.9 g , 25.4 mmol), and the reaction solution was stirred at 25 °C overnight. The reaction was quenched with ice water, EtOAc (30 mL×2). The organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by Flash column (PE:EA=4:1) to obtain 4-(2-ethoxy-2-carbonylethoxy)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =308.1. Step 2: Preparation of 4-(2-hydroxyethoxy)piperidine-1-carboxylic acid benzyl ester Benzyl 4-(2-ethoxy-2-carbonylethoxy)piperidine-1-carboxylate (1.0 g, 3.2 mmol) and LiBH ₄ (0.3 g, 12.8 mmol) were dissolved in THF (15.0 mL) The reaction solution in was stirred at 60 °C for 12 h. The reaction was quenched with ice water, and then extracted with EtOAc (30 mL×2). The organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 4-(2-hydroxyethoxy)piperdine. Benzyl-1-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =280.1. Step 3: 4-(2-(Toluenesulfonyloxy)ethoxy)piperidine-1-carboxylic acid benzyl ester Preparation Benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (700 mg, 2.5 mmol), TsCl (570 mg, 3.0 mmol), TEA (765 mg, 7.5 mmol) and DMAP (24 mg, 0.2 mmol) in DCM (20 mL) was stirred at room temperature for 15 h. The reaction was quenched with ice water, and then extracted with EtOAc (30 mL×2). The organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by flash column (PE:EA=3:1) to obtain 4-(2-(toluenesulfonyloxy)ethoxy)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ = 434.3. Step 4: 4-(2-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxo ) Preparation of tert-butyl ester of piperazine-1-carboxylate 4-(2-(Toluenesulfonyloxy)ethoxy)piperidine-1-carboxylic acid benzyl ester (700 mg, 1.6 mmol), piperidine-1-carboxylic acid tert-butyl ester (241 mg, The reaction solution of K ₂ CO ₃ (662 mg, 4.8 mmol) and KI (318 mg, 1.9 mmol) in DMF (10 mL) was stirred at 70 °C overnight. The reaction was quenched with ice water, and then extracted with EtOAc (30 mL×2). The organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by chromatography column (EtOAc:PE=0~3:7) to obtain 4-(2-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxo)ethyl)piper 𠯤-1-tert-butylcarboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =448.3. Step 5: 4-(2-(Piperidine-1-yl)ethoxy)piperidine-1-carboxylic acid benzyl Preparation of esters 4-(2-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxo)ethyl)piperidine-1-carboxylic acid tert-butyl ester (390 mg, 0.87 mmol) was dissolved in The reaction solution in TFA/DCM (1 mL/3 mL) was stirred at room temperature for 1.0 h. The reaction solution was directly concentrated to obtain benzyl 4-(2-(piperidine-1-yl)ethoxy)piperidine-1-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =348.2. Step 6: 4-(2-(4-((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole Preparation of benzyl ester of pholin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy)piperidine-1-carboxylate To (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl To a solution of methyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (85.0 mg, 0.2 mmol) in DMF (2 mL) was added 4- Benzyl (2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (76.0 mg, 0.22 mmol), HATU (91.0 mg, 0.24 mmol) and DIEA (59.0 mg, 0.6 mmol) . The reaction solution was stirred at room temperature for 2 h. . The reaction was quenched with ice water (20 mL), then filtered, and the resulting filter cake was dried under vacuum to obtain 4-(2-(4-((1 R ,4 R )-4-(4-((( R ))-1 -(3-((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =932.2. Step 7: (3-(( R )-1-((7-methoxy-2-methyl-6-( (1 R ,4 R )-4-(4-(2-(piperidin-4-oxy)ethyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl Preparation of tert-butyl)-5-(trifluoromethyl)phenyl)carbamate 4-(2-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3-((tert-butoxycarbonyl)amino))-5-( Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy Benzyl)piperidine-1-carboxylate (130.0 mg, 0.14 mmol) and 20% Pd(OH) ₂ /C (60.0 mg) in THF (10 mL) at 60 °C H ₂ (90 psi) Stir the atmosphere overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R )-4-( 4-(2-(piperidin-4-oxy)ethyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl) Phenyl)tert-butylcarbamate. LC-MS: (ESI, m/z): [M+H] ⁺ =798.5. Step 8: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxo )Ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl ) Preparation of tert-butyl carbamate To (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4-(2-(piperidine-4-oxo ethyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (90.0 mg, 0.14 mmol) in DMSO (5 mL) were added DIEA (103.2 mg, 0.8 mmol) and 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl) Pentafluorophenyl benzoate (73.0 mg, 0.17 mmol), the reaction solution was stirred at room temperature for 2.0 h. The reaction was quenched by adding water (15 mL), extracted with EtOAc (30 mL×2), the organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by Prep-HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5%~95%) to obtain (3-(( R )-1-((6-((1 R ,4 R )-4- (4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxy Generation)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzene base) tert-butyl carbamate. LC-MS: (ESI, m/z): [M+H] ⁺ =1048.7. Step 9: 1-(5-(4-(2-(4-((1 R ,4 R )-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- yl)cyclohexane-1-carbonyl)piperidin-1-yl)ethoxy)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- Preparation of diketone Put (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(2-((1-(4-chloro-3-(2,4-dioxo) Substituted tetrahydropyrimidine-1(2 H )-yl)benzyl)piperidin-4-yl)oxo)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2- Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (75.0 mg, 0.1 mmol) in TFA/DCM (1.0 mL/ 3.0 mL) solution was stirred at room temperature for 1.0 h. The reaction solution was directly concentrated under reduced pressure, and the residue was alkalized with 8% NaHCO ₃ aqueous solution, then extracted with DCM, separated the organic phase, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain 1-(5-( 4-(2-(4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy)piperidine-1-carbonyl)-2 -Chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =948.6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.13 (d, J = 7.5 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 ( s, 1H), 6.86 (d, J = 10.7 Hz, 2H), 6.70 (s, 1H), 5.64 – 5.46 (m, 3H), 3.95-3.85 (m, 4H), 3.81 – 3.70 (m, 1H) , 3.64 – 3.53 (m, 4H), 3.53-3.42 (m, 4H), 3.32-3.12 (m, 2H), 2.94 (t, J = 11.5 Hz, 1H), 2.80-2.60 (m, 3H), 2.48 -2.30 (m, 7H), 1.94-1.74 (m, 6H), 1.72-1.39 (m, 10H), 1.28-1.11 (m, 2H).

Example 31: 1-(5-(9-((4-((1 R ,4 R ))-4-((4-((( R ))-1-(3-amino-5-(trifluoro Methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo)cyclohexane-1-carbonyl)piperidine-1-yl)methyl (base)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 6,7- Preparation of dimethoxy-2-methylquinazolin-4-ol Add 2-amino-4,5-dimethoxybenzoic acid (20.0g, 101.5 mmol) to acetamidine hydrochloride (19.1 g, 203.19 mmol) in methoxyethanol (120 mL), and stir at 140 °C for 12 h. , add H ₂ O (250 mL), stir for 10 min, filter, and concentrate under reduced pressure to obtain 6,7-dimethoxy-2-methylquinazolin-4-ol. LC-MS: (ESI, m/z): [M+H] ⁺ =221.0. Step 2: Preparation of 7-methoxy-2-methylquinazoline-4,6-diol Methionine (13.16 g, 92.91 mmol) was added to 6,7-dimethoxy-2-methylquinazolin-4-ol (10.0 g, 44.4 mmol) in methylsulfonic acid (60 mL) , stir at 80°C overnight, add ice water (20 mL), make it neutral with saturated NaOH solution, stir in an ice water bath, filter, stir the filter cake in acetonitrile/water (10:1) mixed solution, and filter to obtain 7 -Methoxy-2-methylquinazoline-4,6-diol. LC-MS: (ESI, m/z): [M+H] ⁺ =207.1. Step 3: (1 R ,4 R )-4-((4-hydroxy-7-methoxy-2-methyl Preparation of quinazolin-6-yl)oxo)cyclohexane-1-carboxylic acid methyl ester Methyl (1 S ,4 S )-4-(toluenesulfonyloxo)cyclohexane-1-carboxylate (5.08 g, 16.1 mmol) and K ₂ CO ₃ (3.69 g, 26.8 mmol) were added to A solution of 7-methoxy-2-methylquinazoline-4,6-diol (2.75 g, 13.4 mmol) in NMP (100 mL) was stirred at 30°C overnight, and extracted with ethyl acetate (100 mLx3) , wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is first purified by reverse-phase chromatography (H ₂ O:ACN=3:1), and then chiral separated to obtain ( 1 R ,4 R )-4-((4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)oxo)cyclohexane-1-carboxylic acid methyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.03 (s, 1H), 7.44 (s, 1H), 7.06 (s, 1H), 4.43 – 4.33 (m, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 2.44 – 2.36 (m, 1H), 2.31 (s, 3H), 2.13 – 2.03 (m, 2H), 1.97 (d, J = 13.3 Hz, 2H), 1.57 – 1.42 (m, 4H). Step 4: (1 R ,4 R )-4-((4-((( R )-1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl Preparation of methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo)cyclohexane-1-carboxylate Combine BOP (275.9 mg, 624.2 mmol) and DBU (131.8 mg, 867.1 mmol), ( R )-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamic acid Tributyl ester (137 mg, 0.45 mmol) was added to the (1 R ,4 R )-4-((4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)oxo) ring Hexane-1-carboxylic acid methyl ester (120 mg, 346.8 mmol) in DMF (100 mL), stirred at 70°C overnight, extracted with ethyl acetate (100 mLx3), and washed the organic phase with saturated brine (150 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (H ₂ O:ACN=5:1) to obtain (1 R ,4 R )-4-((4-((( R ) -1-(3-((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline -6-yl)oxo)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =633.1. Step 5: (1 R ,4 R )-4-((4-((( R )-1-(3-( (tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo ) Preparation of cyclohexane-1-carboxylic acid LiOH (320 mg, 7619.05 mmol) was added to (1 R ,4 R )-4-((4-((( R )-1-(3-((tert-butoxycarbonyl)amine))-5 -(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo)cyclohexane-1-carboxylic acid methyl ester (300 mg, 474.7 mmol) in THF/H ₂ O (50 ml/25 ml), stir at 50°C overnight, adjust the pH to neutral with citric acid solution (10%) in an ice bath, and use ethyl acetate (200 ml) Extract, wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain (1 R , 4 R )-4-((4-((( R )-1-(3- (((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy Generation) cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ =619.0. Step 6: 9-((4-((1 R ,4 R )-4-((4-((( R ) -1-(3-((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline Preparation of -6-yl)oxo)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (1 R ,4 R )-4-((4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl (280 mg, 445.86 mmol) in DMF (20 mL) , add 9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (280.3 mg, 728.051 mmol), HATU (276.69 mg, 728.13 mmol) and DIEA (187.8 mg, 1455.8 mmol), stir at room temperature overnight, add water (200 mL) and stir for 10 min, extract with ethyl acetate (100 mL x3), wash the organic phase with saturated brine (150 mL), and filter with anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (EA:PE=1:4) to obtain 9-((4-((1 R ,4 R )-4-((4-((( R ) -1-(3-((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline -6-yl)oxo)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =986.1. Step 7: (3-(( R )-1-((6-(((1 R ,4 R )-4- (4-((3-azaspiro[5.5]undecan-9-yl)methyl)pipiperidine-1-carbonyl)cyclohexyl)oxo)-7-methoxy-2-methylquinazole Preparation of tert-butyl lin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate 9-((4-((1 R ,4 R )-4-((4-((( R ))-1-(3-((tertiary butoxycarbonyl)amino))-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo)cyclohexane-1-carbonyl)piperidine-1-yl) Methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (360 mg, 0.582 mmol) was dissolved in ethyl acetate (20 mL), and Pd(OH) ₂ (72 mg, 20%), stirred at 50°C for 2 h, filtered, concentrated and dried to obtain (3-(( R )-1-((6-(((1 R ,4 R ))-4-(4-((3-aza Spiro[5.5]undecyl-9-yl)methyl)piper-1-carbonyl)cyclohexyl)oxo)-7-methoxy-2-methylquinazolin-4-yl)amino) Ethyl)-tert-butyl 5-(trifluoromethyl)phenyl)carbamate. LC-MS-MC21-1867-57: [M+H] ⁺ =852.2. Step 8: (3-(( R )-1-((6-(((1 R ,4 R ))-4-(4 -((3-(4-chloro-3-(2,4-dicarbonyltetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecane-9- base)methyl)piperidine-1-carbonyl)cyclohexyl)oxo)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl Preparation of tert-butyl)phenyl)carbamate (3-(( R )-1-((6-(((1 R ,4 R ))-4-(4-((3-azaspiro[5.5]undecan-9-yl)methyl) piperazine-1-carbonyl)cyclohexyl)oxo)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl) tert-Butyl carbamate (230 mg, 0.272 mmol) and pentafluorophenyl 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)benzoate (140.7 mg, 0.324 mmol) was dissolved in DMSO (5 mL), DIEA (100 mg, 0.775mmol) was added, and then the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, stirred for 2 minutes, and filtered to obtain Crude product (3-(( R )-1-((6-(((1 R ,4 R ))-4-(4-((3-(4-chloro-3-(2,4-dicarbonyltetrakis) Hydropyrimidin-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carbonyl)cyclohexyl)oxo)-7 -Methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =1102.0. Step 9: 1-(5-(9-((4-((1 R ,4 R )-4-((4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )Oxo)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine- Preparation of 2,4(1 H ,3 H )-diketone (3-(( R )-1-((6-(((1 R ,4 R ))-4-(4-((3-(4-chloro-3-(2,4-dicarbonyltetrahydropyrimidine) -1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carbonyl)cyclohexyl)oxo)-7-methyl Oxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester (250 mg, 0.227 mmol) was treated with dichloro Dissolve methane (20 mL), add trifluoroacetic acid (5 ml), and then stir the reaction solution at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution, adjust the pH to neutral, extract with ethyl acetate, and saturated brine (100 mL) The organic phase was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by reverse phase preparation to obtain 1-(5-(9-((4-((1 R ,4 R ))-4-((4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )Oxo)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z): [M+H] ⁺ =1002.1. ¹ H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.88 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.98 (s, 2H), 6.84 (s, 1H), 5.75 (q , J = 6.8 Hz, 1H), 4.57-4.47(m, 1H), 4.00 (s, 3H), 3.84-3.61 (m, 8H), 3.51-3.49 (m, 2H), 2.93-2.72 (m, 3H ), 2.61-2.42 (m, 7H), 2.34-2.21 (m, 4H), 1.95-1.33 (m, 18H), 1.30-1.03 (m, 4H).

Example 32: 1-(5-(4-((2-(1-(4-(4-(( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)) Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidin-4-yl)ethoxy)methyl) Piperidin-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(2-(piperidin-4-ylmethoxy) ) Preparation of tert-butyl ethyl)piperidine-1-carboxylate Benzyl 4-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylate (300.0 mg, 0.6 mmol) and A mixture of 10% Pd(OH) ₂ /C (150.0 mg) in THF (20 mL) was stirred at 70 °C in an atmosphere of H ₂ (60 psi) for 12 h. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl ester of 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =325.3. Step 2: 4-(2-((1-(3-(2,4-dicarbonyltetrahydropyrimidine-1(2 Preparation of tert-butyl)-yl)-4-methoxybenzoyl ) piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (170 mg, 0.52 mmol) in DMSO (5 mL) was added DIEA (103.2 mg, 0.8 mmol) and 3-(2,4-dicarbonyltetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoic acid pentafluorophenyl ester (247 mg, 0.57 mmol), the reaction solution was Stir at room temperature for 2 h. The reaction was quenched with water, and then extracted with EtOAc (30 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The crude product obtained was purified by Flash (PE:EA=3:1) to obtain 4-(2-((1-(3-(2,4-dicarbonyltetrahydropyrimidin-1(2 H )-yl))-4-methyl Oxybenzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =573.2. Step 3: 1-(2-methoxy-5-(4-((2-(piperidin-4-yl)) Preparation of ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-(2-((1-(3-(2,4-Dicarbonyltetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl A solution of tert-butyloxy)ethyl)piperidine-1-carboxylate (200 mg, 0.42 mmol) in TFA/DCM (1 mL/3 mL) was stirred at room temperature for 1 h. The reaction solution is directly concentrated to obtain 1-(2-methoxy-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydrogen Pyrimidine-2,4(1 H ,3 H )-dione. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ = 473.1. Step 4: 4-(4-((( R )-1-(3-((tert-butoxycarbonyl))amine (base)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid Preparation of methyl ester To 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (200 mg, 0.61 mmol), DBU (228 mg, 1.5 mmol) and BOP (404 mg, 0.91 mmol) in DMF (5 mL), ( R )-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl was added ) tert-butyl carbamate (273 mg, 0.91 mmol). The reaction solution was stirred at 70 °C for 14 h. Water was added to the reaction solution, and then extracted with EtOAc (30 mL×2). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure, and the crude product was purified by Flash column (PE:EA=1:1) to obtain 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amine)) -5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester . LC-MS: (ESI, m/z): [M+H] ⁺ = 615.3. Step 5: 4-(4-((( R )-1-(3-((tert-butoxycarbonyl))amine )-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid Preparation 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7- Methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate (150 mg, 0.24 mmol) and LiOH (110 mg, 4.8 mmol) in THF/H ₂ The mixture in O (4 mL/2 mL) was stirred at 50 °C for 15 h. The reaction solution was concentrated under reduced pressure to obtain 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl)phenyl)ethyl)amino. )-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ = 601.2. Step 6: (3-((1 R )-1-((6-(4-(4-(2-(( 1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoyl)piperidin-4-yl)methoxy)ethyl) Piperidin-1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl Preparation of tert-butyl)phenyl)carbamate 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid (120.0 mg, 0.2 mmol), 1-(2-methoxy-5-(4-(( 2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (104 mg, 0.22 mmol ), a mixture of HATU (91.0 mg, 0.24 mmol) and DIEA (59.0 mg, 0.6 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. Add water to the reaction solution, filter, and the filter cake is purified by Prep-HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5%~95%) to obtain (3-((1 R )-1-((6-(4- (4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-methoxybenzoyl)piperidin-4-yl )methoxy)ethyl)piperidin-1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl )-5-(Trifluoromethyl)phenyl)carbamic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =1056.6. Step 7: 1-(5-(4-((2-(1-(4-(4-((( R ) -1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-3- En-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )- Preparation of diketone (3-((1 R )-1-((6-(4-(4-(2-((1-(3-(2,4-dioxoectoine)-1(2 H )) -yl)-4-methoxybenzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy Tert-butyl-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (100.0 mg, 0.1 mmol) in TFA/DCM (1 mL/3 mL) was stirred at room temperature for 1 h. The reaction solution was concentrated, and the residue was basified with 8% NaHCO ₃ aqueous solution, and then extracted with DCM (20 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-(5-(4 -((2-(1-(4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy yl-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-methyl Oxyphenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ = 955.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 8.29 (s, 1H), 8.08 ( s, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.69 (s, 1H), 5.83 (s, 1H), 5.60-5.50 (m, 3H), 4.47-4.33 (m, 1H), 4.00-3.90 ( m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.61-3.58 (t, J = 6.7 Hz, 2H), 3.45-3.38 (t, J = 6.3 Hz, 2H), 3.33-3.28 (m, 2H), 3.25-3.21 (d, J = 6.3 Hz, 2H), 3.08-2.97 (m, 1H), 2.95-2.82 (m, 2H), 2.70-2.65 (t, J = 6.4 Hz, 2H ), 2.58-2.52 (m, 2H), 2.40-2.32 (m, 5H), 2.25-2.15 (m, 1H), 1.90-1.38 (m, 13H), 1.28-0.92 (m, 5H).

Example 33: 1-(5-(4-((2-(4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-() Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(2-hydroxyethyl)piperidine -Preparation of tert-butyl 1-carboxylate Dissolve tert-butylpiperzoate-1-carboxylate (1.0 g, 5.38 mmol), 2-bromoethan-1-ol (0.67 g, 5.38 mmol) and K ₂ CO ₃ (1.48 g, 10.76 mmol) in DMF (20 mL) was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and then extracted with EA (50 mL×3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by flash column (MeOH:DCM=0~1:9) to obtain tert-butyl ester of 4-(2-hydroxyethyl)piperidine-1-carboxylate. ¹ H NMR (400 MHz, MeOD) δ 3.67 (t, J = 5.9 Hz, 2H), 3.47 – 3.39 (m, 4H), 2.53 (t, J = 5.9 Hz, 2H), 2.50 – 2.42 (m, 4H ), 1.45 (s, 9H). Step 2: Preparation of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (400 mg, 1.74 mmol) in anhydrous THF (10 mL) was added NaH (140 mg, 60%, 3.48 mmol) at 0 °C. ) and stir for 2 h. Then 4-(bromomethyl)pyridine hydrobromide (528 mg, 2.09 mmol) was added, and the reaction solution was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and then extracted with EA (50 mL×3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained crude product was purified by chromatography column (MeOH:DCM=0~1:9) to obtain tert-butyl ester of 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =322.6. Step 3: 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid Preparation of tert-butyl ester Add tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (600 mg, 2.60 mmol) in i -PrOH/H ₂ O (13 mL) with stirring. , 6:7) Pd/C (180 mg) was added to the solution. The reaction solution was then stirred overnight at 75 °C under _H2 atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain tert-butyl ester of 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carboxylate. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =328.2. Step 4: 4-(2-((1-(4-chloro-3-(2,4-dicarbonyltetrahydropyrimidine) Preparation of tert-butyl ester of -1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carboxylate (180 mg, 0.55 mmol) in DMSO (5 mL) was added DIEA (213 mg, 1.65 mmol) and pentafluorophenyl 4-chloro-3-(2,4-dioxoectoine-1(2 H )-yl)benzoate (238 mg, 0.55 mmol). The reaction solution was stirred at room temperature for 2 h. Water (50 mL) was added to the reaction solution, and then extracted with EA (50 mL×3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (MeOH:DCM=0~1:9) to obtain 4-(2-((1-(4-chloro-3-(2,4-dicarbonyltetrahydropyrimidine-1(2 H )) -(yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =578.2. Step 5: 1-(2-chloro-5-(4-((2-(piperidine-1-yl)ethoxy) Preparation of methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methyl A solution of tert-butyloxy)ethyl)piperidine-1-carboxylate (160 mg, 0.28 mmol) in TFA/DCM (5 mL, 1:4) was stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain 1-(2-chloro-5-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone. The crude product obtained was directly used in the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =478.3. Step 6: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(2-((1-(4-chloro-3-(2,4-dioxoectohydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy (yl)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzene Preparation of tert-butyl carbamate 1-(2-Chloro-5-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1 H ,3 H )-diketone (160 mg), (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amine))- 5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.25 mmol ), a mixture of HATU (143 mg, 0.38 mmol) and DIEA (160 mg, 1.25 mmol) in DMF (5 mL) was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and then extracted with EA (50 mL×3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was purified by flash column (MeOH:DCM=0~1:9) to obtain (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(2-() (1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine 𠯤-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid Tributyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =1062.1. Step 7: 1-(5-(4-((2-(4-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone Put (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(2-((1-(4-chloro-3-(2,4-dioxo) Substituted tetrahydropyrimidin-1(2 H )-yl)benzyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2 -Tert-butyl -methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (100 mg, 0.09 mmol) in TFA/DCM (5 mL , 1:4) solution was stirred at room temperature for 1 h. The reaction solution was directly concentrated, and the crude product was purified by Prep-HPLC to obtain 1-(5-(4-((2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-( 3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piper 𠯤-1-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =962.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.20-8.10 (m, 1H), 8.05 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 10.0 Hz, 2H), 6.70 (s, 1H), 5.63 – 5.44 (m, 3H), 4.51 – 4.38 (m, 1H), 3.89 (s, 3H), 3.80 – 3.70 (m, 1H), 3.68 - 3.52 (m, 2H), 3.53-3.40 (m, 6H), 3.27-3.24 (m, 2H), 3.04-2.94 (m, 2H), 2.81-2.61 (m, 5H), 2.45-2.30 (m, 7H ), 1.92-1.45 (m, 15H), 1.20-1.01 (m, 2H).

Example 34: 1-(5-(9-(2-(4-((1 S ,4 S ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl) -3-Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: ( R )-4- (4-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- Preparation of tert-butyl)cyclohexane-1-carbonyl)piperidine-1-carboxylate ( R )-4-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole Phin-6-yl)cyclohexane-1-carboxylic acid (220 mg, 0.44 mmol) was dissolved in ethyl acetate (12 mL) and cooled to 0 °C, N-Boc cyclohexane-1-carboxylic acid (163 mg, 0.88 mmol), DIEA (169 mg, 1.31 mmol) and T ₃ P (209 mg, 0.66 mmol) were added respectively. The reaction solution was stirred at 0 ° C for 3 hours, quenched with water (30 mL), extracted with ethyl acetate (30 mL×3), and organically The phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA=10:1) to obtain ( R )-4-(4-( 4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan Alk-1-carbonyl) piperazine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 671.3. Step 2: ( R )-(4-(4-((1-(3-amino-5-(trifluoromethyl) Preparation of base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone ( R )-4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl Tert-butylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-carboxylate (220 mg, 0.33 mmol) was added to a solution of hydrogen chloride in ethyl acetate (3 M/EA, 10 mL), the reaction solution was stirred at room temperature for 2 hours, and directly concentrated under reduced pressure to obtain ( R )-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl))ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperidine-1-yl)methanone was used directly in the next step without purification. Step 3: 1-(5-(9-(2-(4-((1 S ,4 S ))-4-(4-((( R ))-1-(3-amino-5-(trifluoro Methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)- Preparation of 3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione ( R )-(4-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquin Zozolin-6-yl)cyclohexyl)(piperidin-1-yl)methanone (115 mg, 0.165 mmol) was dissolved in tetrahydrofuran (5 mL), 2-(3-(4-chloro-3-(2, 4-Oxotetrahydropyrimidine-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde (39 mg, 0.09 mmol) and triacetyl Sodium oxyborohydride (55 mg, 0.27 mmol) was added in sequence, and the reaction solution was stirred at room temperature for 2 hours, quenched with water (10 mL), extracted with dichloromethane (30 mL×3), dried over anhydrous sodium sulfate, filtered and reduced to Concentrate under pressure, and the crude product is prepared by reverse phase (first purified with formic acid system, and then purified with ammonium bicarbonate system) to obtain 1-(5-(9-(2-(4-((1 S ,4 S ))-4-( 4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base) cyclohexane-1-carbonyl) piperazine-1-yl) ethyl)-3-azaspiro[5.5] undecane-3-carbonyl)-2-chlorophenyl) dihydropyrimidine-2, 4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1000.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), 6.98 ( s, 1H), 6.88 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 5.66 – 5.42 (m, 3H), 3.87 (s, 3H), 3.75-3.50 (m, 5H) , 3.50-3.40 (m, 5H), 3.00-2.70 (m, 5H), 2.39-2.23 (m, 7H), 2.00-1.84 (m, 4H), 1.75-1.63 (m, 6H), 1.59-1.18 ( m, 13H), 1.13-0.96 (m, 4H).

Example 35: 1-(2-chloro-5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-(ethylamino)) -5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1- methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione To 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)benzene (base)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-aza Spiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (70 mg, 0.071 mmol) in THF (3 ml) Acetaldehyde (40% aqueous solution, 16 mg, 0.142 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then sodium triacetyloxyborohydride (75 mg, 0.355 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (15 mL), extracted with DCM (20×3ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain 1-(2-chloro-5-(9- ((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amine base)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]eleven Alk-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1014.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.52 (s, 1H), 8.13 (s, 1H), 8.07 ( s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J = 6.5 Hz, 2H), 6.64 (s, 1H), 6.05 (s, 1H), 5.60 (t, J = 6.4 Hz, 1H), 3.89 (s, 3H), 3.75-3.40 (m, 8H), 3.11 – 3.00 (m, 2H), 3.00-2.90 (m, 1H), 2.87-2.70 (m, 2H), 2.70-2.60 (m, 1H), 2.40-2.25 (m, 7H), 2.18-2.07 (m, 2H) , 1.90-1.75 (m, 4H), 1.75-1.20 (m, 18H), 1.18-0.96 (m, 7H).

Example 36: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-() Trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethyl Oxy)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 5-amino-2-chloro Preparation of pyridine-4-methamide Dissolve 5-amino-2-chloropyridine-4-carboxylic acid (14.0 g, 81.13 mmol) with DCM (200 mL), add HOBt (13.2 g, 97.67 mmol) and EDCI (18.7 g, 97.67 mmol), and keep at room temperature Stir for 1 h, add NH ₃ ·H ₂ O (200 mL), stir for 2 h, filter, and concentrate under reduced pressure to obtain crude 5-amino-2-chloropyridine-4-methamide. LC-MS: (ESI, m/z ): [M+H] ⁺ =172.0. Step 2: 4-(5-amino-4-aminomethylpyridin-2-yl)cyclohex-3-ene Preparation of -1-carboxylic acid methyl ester 5-Amino-2-chloropyridin-4-carboxamide (5.0 g, 29.24 mmol) was dissolved with Dioxane/H ₂ O (200 mL/20 ml), Cs ₂ CO ₃ (47.51 g, 146.18 mmol), Pd(dppf)Cl ₂ (2.67 g, 3.65 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohexan-3- En-1-carboxylic acid methyl ester (10.1 g, 38.1 mmol) was added respectively, and the reaction solution was heated to 100 °C under nitrogen protection and stirred overnight, diluted with water (500 ml), extracted with ethyl acetate (600 ml), and anhydrous sulfuric acid Dry over sodium and concentrate under reduced pressure. The crude product is purified by column chromatography (PE:EA=1:3) to obtain 4-(5-amino-4-aminopicopyridin-2-yl)cyclohex-3-ene. -1-Carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =276.0. Step 3: 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl) Preparation of cyclohex-3-ene-1-carboxylic acid methyl ester Methyl 4-(5-amino-4-aminomethylpyridin-2-yl)cyclohex-3-ene-1-carboxylate (4.0 g, 14.55 mmol) was added to trimethyl orthoacetate (17.46 g, 145.5 mmol) in methanol (100 ml), stirred overnight at 120°C using a stuffy jar, cooled and concentrated under reduced pressure to obtain the crude product 4-(4-hydroxy-2-methylpyrido[3,4-d ]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =300.0. Step 4: (1 R ,4 R )-4-(4-hydroxy-2-methylpyrido[3,4- d] Preparation of pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester 4-(4-Hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (800 mg, 3.33 mmol) and Pd( OH) ₂ (320 mg) was added to the methanol (50 mL) solution. The reaction solution was replaced with hydrogen three times, heated to 70°C and stirred overnight, filtered, and concentrated under reduced pressure. The crude product was dissolved in methanol (40 mL), and sodium methoxide ( 1 mL, 5.4 mmol/L) was added, stirred at 70°C overnight, adjusted pH to 3-4 with H ₂ SO ₄ , stirred at 50°C overnight, concentrated under reduced pressure, and purified by reverse-phase preparation to obtain (1 R , 4 R )-4 -(4-Hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =302.1. Step 5: (1 R ,4 R )-4-(2-methyl-4-(((2,4,6 - Preparation of methyl triisopropylphenyl)sulfonyl)oxy)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate 2,4,6-Triisopropylphenylsulfonate chloride (1.0 g, 3.3 mmol) and DMAP (20.3 mg, 0.165 mmol), TEA (503 mg, 4.98 mmol) were added to (1 R ,4 R ) -Methyl 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate (500 mg, 1.66 mmol) in dichloromethane (30 ml) solution, stirred at room temperature overnight, washed the organic phase with water (50 ml) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through column chromatography (PE:EA=1:3 ) was purified to obtain (1 R ,4 R )-4-(2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)pyrido[3,4- d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =568.2. Step 6: (1 R ,4 R )-4-(2-methyl-4-((1-(3-nitrogen) Preparation of methyl-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate (1 R ,4 R )-4-(2-methyl-4-((2,4,6-triisopropylphenyl)sulfonyl)oxy)pyrido[3,4-d] Methyl pyrimidin-6-yl)cyclohexane-1-carboxylate (800 mg, 1.41 mmol) and TEA (546.1 mg, 4.23 mmol) were added to 1-(3-nitro-5-(trifluoromethyl) Phenyl)ethyl-1-amine (462 mg, 1.97 mmol) was dissolved in DMSO (20 mL) and stirred at room temperature overnight. The crude product was purified by reversed-phase column chromatography (ACN/H ₂ O=2/1). (1 R ,4 R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3, 4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =518.4. Step 7: (1 R ,4 R )-4-(2-methyl-4-((1-(3-nitrogen) Preparation of base-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid (1 R ,4 R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3 ,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester (400 mg, 0.774 mmol) was dissolved in THF/H ₂ O (40 ml/10 ml) solution, and LiOH (93 mg , 3.87 mmol), the reaction solution was heated to 50°C and stirred overnight, adjusted the pH to neutral with HCl (1 M), added water (50 ml) to dissolve, extracted with ethyl acetate (100 ml), and concentrated under reduced pressure to obtain crude product ( 1 R ,4 R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4 -d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ =504.2. Step 8: 1-(2-methoxy-5-(4-((2-(1-((1 R , 4 R )-4-(2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3, 4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4( Preparation of 1 H ,3 H )-diketone (1 R ,4 R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3 ,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid (180 mg, 0.357 mmol), HATU (203.5 mg, 0.536 mmol) and DIEA (138.2 mg, 1.07 mmol) were added to 1-(2 -Methoxy-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H , 3 H )-diketone in DMF (6 ml), stir at room temperature overnight, add water (50 ml) to dissolve, extract with dichloromethane (30 ml × 3), concentrate under reduced pressure, and use reversed-phase column chromatography for the crude product (ACN/H ₂ O=1/2) purification gave 1-(2-methoxy-5-(4-((2-(1-((1 R ,4 R ))-4-(2-methyl) -4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl) ring Hexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 958.5. Step 9: 1-(5-(4-((2-(1-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine- 6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4( Preparation of 1 H ,3 H )-diketone 1-(2-methoxy-5-(4-((2-(1-((1 R ,4 R ))-4-(2-methyl-4-((( R )-1-( 3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-4- Base)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (300 mg, 0.313 mmol) dissolved in ethanol (20 ml) , Raney nickel (aq., 1mL), hydrazine hydrate (0.5 mL) were added, the reaction solution was stirred at room temperature for 1 hour, filtered, and concentrated under reduced pressure. The crude product was purified using reverse phase preparation to obtain 1-(5-(4-(( 2-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)- 2-Methoxyphenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =928.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 8.91 (s, 1H), 8.58 ( d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.36 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 5.57 – 5.51 (m, 3H), 4.45-4.33 (m, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.2 Hz, 2H), 3.24 (d, J = 6.2 Hz, 2H), 3.05-2.95 ( m, 2H), 2.83-2.70 (m, 2H), 2.70-2.65 (m, 3H), 2.43 (s, 3H), 2.05-1.96 (m, 2H), 1.88-1.40 (m, 20H), 1.23- 0.89 (m, 4H).

Example 37: 1-(5-(2-(4-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-() Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl )piperidin-1-yl)-2-oxoethoxy)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(piperidine- Preparation of tert-butyl 4-ylmethyl)piperidine-1-carboxylate 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.20 mmol) and Pd/C (100 mg ) in MeOH (10 mL) was stirred at room temperature under _H2 atmosphere for 2.0 h. The reaction solution was filtered and concentrated under reduced pressure to obtain tert-butyl ester of 4-(piperidin-4-ylmethyl)piperidin-1-carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =284.1. Step 2: 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydro) Preparation of tert-butyl pyrimidine-1( 2H )-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperidin-1-carboxylate 2-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)phenoxy)acetic acid (240 mg, 0.805 mmol), 4-(piperidine-4 A mixture of tert-butyl-methyl)piperidine-1-carboxylate (251 mg, 0.886 mmol), HATU (612 mg, 1.61 mmol) and DIEA (312 mg, 2.42 mmol) in DMF (5 mL) Stir at room temperature for 3 h. The reaction was quenched by adding water (20 mL), extracted with DCM (20 mL×2), separated the organic phase, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by chromatography column (MeOH:DCM=0-1:24)) to obtain 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2) H )-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 564.2. Step 3: 1-(2-chloro-5-(2-oxo-2-(4-(piperamide-1- Preparation of methyl)piperidin-1-yl)ethoxy)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)phenoxy)acetyl)piperidine-4- A mixture of tert-butyl)methyl)piperidine-1-carboxylate (350 mg, 0.622 mmol) in TFA/DCM (10 mL/3 mL) was stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain 1-(2-chloro-5-(2-oxo-2-(4-(piperidin-1-ylmethyl)piperidin-1-yl)ethoxy)phenyl)di Hydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 464.2. Step 4: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)phenoxy)acetyl)piperidin-4-yl )Methyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl ) Preparation of tert-butyl carboxylate To 1-(2-chloro-5-(2-oxo-2-(4-(piperidin-1-ylmethyl)piperidin-1-yl)ethoxy)phenyl)dihydropyrimidine-2 To a solution of 4(1 H ,3 H )-diketone (260 mg, 0.562 mmol), HATU (426 mg, 1.12 mmol) and DIEA (217 mg, 3.36 mmol) in DMF (3 mL) was added (1 R , 4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (405.6 mg, 0.674 mmol). The reaction solution was then stirred at room temperature for 1 h. Water (20 mL) was added to the reaction solution to quench the reaction, and DCM (20 mL×2) was extracted. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH:DCM=0-2:23)) to obtain (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-((1 -(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piper 𠯤-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tertiary butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1048.6. Step 5: 1-(5-(2-(4-((4-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-chlorophenyl)dihydropyrimidine-2, Preparation of 4(1 H ,3 H )-diketone Put (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-((1-(2-(4-chloro-3-(2,4-dioxo) Substituted ectoine-1(2 H )-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2- Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (140 mg, 0.13 mmol) in DCM/TFA (3 mL/1 mL) solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure, and the crude product obtained was purified by Prep-HPLC (acetonitrile/0.05% NH ₄ HCO ₃ aqueous solution, 5%~95%) to obtain 1-(5-(2-(4-((4-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2 -Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-chlorobenzene base)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 948.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.47 (s, 1H), 8.24-7.87 (m, 2H), 7.45 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 6.99 (s, 1H), 6.93 (dd, J = 9.0, 3.0 Hz, 1H), 6.86 (d, J = 10.9 Hz, 2H), 6.70 (s, 1H), 5.67-5.40 (m, 3H), 4.93 – 4.63 (m, 2H), 4.40-4.24 (m, 1H), 3.89 (s, 3H), 3.82- 3.65 (m, 2H), 3.63-3.42 (m, 4H), 3.09-2.89 (m, 2H), 2.77-2.55 (m, 5H), 2.41-2.25 (m, 7H), 2.12 (d, J = 6.5 Hz, 2H), 1.9-1.48 (m, 14H), 1.15-0.88 (m, 2H).

Example 38: 1-(5-((4-((3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5- (Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propanyl (Methyl)amino)piperidin-1-yl)methyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 1-(2 Preparation of -Chloro-5-(hydroxymethyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (2.0 g, 4.61 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), nitrogen The temperature was lowered to -60°C under protection, and a solution of lithium aluminum hydride in tetrahydrofuran (9.22 mL, 1.0 mmol/L) was added dropwise to the above solution while stirring. After the addition, stir at -60°C for 1 hour, add saturated aqueous ammonium chloride solution (20 mL) dropwise to the reaction solution, filter, and extract the mother liquor with ethyl acetate (30 mLx3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (methanol:dichloromethane=1:9) to obtain 1-(2-chloro-5-(hydroxymethyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )- diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 255.0 Step 2: 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzene Preparation of formaldehyde 1-(2-Chloro-5-(hydroxymethyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione (450 mg, 1.76 mmol) was dissolved in acetonitrile (20 mL) and added IBX (988mg, 3.53mmol) was heated to 80°C and stirred for 1 hour. The reaction solution was filtered, the filter cake was washed with methanol (20 mLx3), the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (methanol:dichloromethane=1:9) to obtain 4-chloro-3-(2,4-dioxo). Substituted ectoine-1( 2H )-yl)benzaldehyde. LC-MS: (ESI, m/z ): [M+H] ⁺ = 253.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 10.01 (s, 1H), 8.06 ( d, J = 1.8 Hz, 1H), 7.93 (dd, J = 8.2, 1.9 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 3.80 (dd, J = 16.6, 9.3 Hz, 1H), 3.64 (dt, J = 12.1, 6.1 Hz, 1H), 2.77 (dd, J = 12.5, 6.4 Hz, 2H). Step 3: 4-(3-oxopropyl)piperidine-1-carboxylic acid tertiary Preparation of butyl ester Dissolve tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (500 mg, 2.05 mmol) in acetonitrile (20 mL), add IBX (1.15g, 4.11mmol) and heat to 70 °C and stir for 1 hour. The reaction solution was filtered, the filter cake was washed with methanol (20 mLx3), the filtrate was concentrated under reduced pressure, and the crude product was purified using column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 4-(3-oxopropyl)piperidine. -1-tert-butylcarboxylate. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.68 (t, J = 1.5 Hz, 1H), 3.91 (d, J = 12.0 Hz, 2H), 2.65 (m, 2H), 2.46 (td, J = 7.5, 1.5 Hz, 2H), 1.61 (d, J = 13.0 Hz, 2H), 1.46 (2H), 1.42 – 1.33 (m, 10H), 0.94 (2H). Step 4: 4-((3-(1 Preparation of -(tert-butoxycarbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester 4-(3-Oxopropyl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.2 mmol) and 4-(methylamino)piperidine-1-carboxylic acid benzyl ester (308 mg, 1.2 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium triacetoxyborohydride (1.2 g, 6.0 mmol) was added with stirring. After stirring at room temperature for 2 hours, add water (50 mL), extract with dichloromethane (30 mLx3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Use a column for the crude product. Chromatography (methanol:dichloromethane=1:9) purified to obtain 4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine -1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 474.3. Step 5: 4-(3-(Methyl(piperidin-4-yl)amino)propyl)piperidine-1 -Preparation of tert-butyl carboxylate 4-((3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester (400 mg, 0.84 mmol) dissolved To EA (20 mL), Pd(OH) ₂ /C (200 mg, 0.28 mmol) was added, and the temperature was raised to 70 °C under a hydrogen atmosphere and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(3-(methyl(piperidin-4-yl)amino)propyl)piperidine-1-carboxylate. The crude product was used directly in the next reaction without purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 340.3. Step 6: 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydro) Preparation of tert-butyl pyrimidine-1(2 H )-yl)phenyl)piperidin-4-yl)(methyl)amino)propyl)piperidine-1-carboxylate 4-(3-(Methyl(piperidin-4-yl)amino)propyl)piperidine-1-carboxylic acid tert-butyl ester (280 mg, 0.82 mmol) and 4-chloro-3-(2, 4-Dioxotetrahydropyrimidine-1(2 H )-yl)benzaldehyde (311 mg, 1.23 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium triacetyloxyborohydride (869 mg, 4.1 mmol) was added . The reaction solution was heated to 50°C and stirred for 2 hours, diluted with water (50 mL), extracted with dichloromethane (30 mLx3), washed the organic phase with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. , the crude product was purified using column chromatography (methanol: dichloromethane=1:9) to obtain 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2) H )-yl)phenyl)piperidin-4-yl)(methyl)amino)propyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 576.2. Step 7: 1-(2-chloro-5-((4-(methyl(3-(piperidin-4-yl) Preparation of )propyl)amino)-1-yl)methyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)phenyl)piperidin-4-yl)(methyl) Amino)propyl)piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.31mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours. Concentrate under reduced pressure to obtain 1-(2-chloro-5-((4-(methyl(3-(piperidin-4-yl)propyl)amino)-1-yl)methyl)phenyl)dihydro Pyrimidine-2,4(1 H ,3 H )-dione was used directly in the next reaction without purification. LC-MS: (ESI, m/z ): [M+H] ⁺ = 476.3. Step 8: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)phenyl)piperidin-4-yl)(methyl) Amino)propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl) Preparation of tert-butyl phenylcarboxylate 1-(2-chloro-5-((4-(methyl(3-(piperidin-4-yl)propyl)amino)-1-yl)methyl)phenyl)dihydropyrimidine-2, 4(1 H ,3 H )-diketone (180 mg, 0.31 mmol) was dissolved in DMF (10 mL), and (1 R ,4 R )-4-(4-((( R )-1-( 3-(tert-Butoxycarbonyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.24 mmol), HATU (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol), stir at room temperature for 2 h, add water (100 mL), extract with ethyl acetate (30 mLx3), saturated brine (100 mL), washed the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (methanol:dichloromethane=1:9) to obtain (3-(( R )-1-(( 6-((1 R ,4 R )-4-(4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)) Phenyl)piperidin-4-yl)(methyl)amino)propyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amine tert-butyl)ethyl)-5-(trifluoromethyl)phenyl)carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1060.5. Step 9: 1- (5-((4-((3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl) Phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)(methyl) Preparation of amino)piperidin-1-yl)methyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(3-((1-(4-chloro-3-(2,4-dioxo) Ectoine-1(2 H )-yl)phenyl)piperidin-4-yl)(methyl)amino)propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2 -Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (200 mg, 0.19mmol) was treated with dichloromethane (5 mL) Dissolve, add trifluoroacetic acid (2 mL), stir at room temperature for 2 hours, then concentrate the reaction solution under reduced pressure. Dissolve the resulting oil with 10% methanol/dichloromethane mixed solution (20 mL), and add 5% sodium bicarbonate aqueous solution. (20mL) and stir for 1 hour. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to Pre-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5% ~ 95%) Purified to obtain 1-(5-((4-((3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl) (Methyl)amino)piperidin-1-yl)methyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 960.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.45 (s, 1H), 8.16 – 8.02 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H ), 6.70 (s, 1H), 5.64 – 5.47 (m, 3H), 4.45-4.35 (m, 1H), 3.96-3.85 (m, 4H), 3.76 – 3.54 (m, 2H), 3.47-3.40 (m , 2H), 3.08-2.90 (m, 2H), 2.89-2.77 (m, 2H), 2.77-2.60 (m, 3H), 2.35 (s, 6H), 2.15 (s, 3H), 1.98-1.40 (m , 23H), 1.24-1.18 (m, 2H), 1.08-0.82 (m, 2H).

Example 39: 5-(4-((2-(1-((1 S ,4 S ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl (yl)piperidin-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Step 1: 2-(2,6-dioxo Preparation of piperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (1.0 g, 5.21 mmol) was dissolved in AcOH (10 ml), potassium acetate (945 mg, 5.73 mmol) and 3 -Aminopiperidine-2,6-dione hydrochloride (945 mg, 5.73 mmol) was added, the reaction solution was heated to 90°C and stirred overnight, concentrated under reduced pressure, water (20 mL) was added to the crude product, and stirred for 10 minutes , filter, wash the filter cake with water (10 mL×3), and dry in vacuum to obtain crude product 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ =303.0. Step 2: 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Preparation of indoline-5-carboxylic acid pentafluorophenyl ester Dissolve 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid (1.4 g, 4.64 mmol) with DMF (20 ml). DCC (1.43 g, 6.96 mmol) and 2,3,4,5,6-pentafluorophenol (1.30 g, 6.96mmol) were added, the reaction solution was stirred at room temperature overnight, diluted with water (150 mL), and ethyl acetate ( 100 ml -1,3-dioxoisoindoline-5-carboxylic acid pentafluorophenyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 8.41 (dd, J = 7.8, 1.3 Hz, 1H), 8.28 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 5.20 (dd, J = 12.8, 5.4 Hz, 1H), 2.66 – 2.47 (m, 5H). Step 3: 4-(2-((1-(2-(2,6-dioxopiperine) Preparation of tert-butyl ester of (ridin-3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carboxylic acid pentafluorophenyl ester (480 mg, 1.02 mmol) was added to 4- (2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.22 mmol) in DMSO (10 mL), stirred at room temperature overnight, and added with water (50 mL), extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=1:10) to obtain 4-(2-(( 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperidin-4-yl)methoxy)ethyl ) piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =611.3. Step 4: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2 Preparation of -(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)isoindoline-1,3-dione 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperidine-4- Tert-butyl)methoxy)ethyl)piperidine-1-carboxylate (250 mg, 0.41 mmol) was dissolved in DCM (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature overnight. , concentrated under reduced pressure to obtain crude product 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine -1-Carbonyl)isoindoline-1,3-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =511.3. Step 5: (3-((1 R )-1-((6-((1 S ,4 S )-4- (4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperidine-4- yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoro Preparation of tert-butyl methyl)phenyl)carboxylate 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl) Isoindoline-1,3-dione (200 mg, 0.40 mmol), HATU (130 mg, 0.35 mmol) and DIEA (89 mg, 0.69 mmol) were added to (1 S ,4 S )-4-(4 -((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2- Dissolve the reaction solution of methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (140 mg, 0.23 mmol) in DMF (10 mL) at room temperature for 2 hours, dilute with water (50 mL), and stir for 10 minutes, filtered, and the solid was washed with water (5 mL×2) to obtain the crude product (3-((1 R )-1-((6-((1 S ,4 S )-4-(4-(2-() (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperidin-4-yl)methoxy)ethyl (yl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxy tert-butyl acid. LC-MS: (ESI, m/z ): [M+H] ⁺ =1095.5. Step 6: 5-(4-((2-(1-((1 S ,4 S )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindole Preparation of pholine-1,3-dione (3-((1 R )-1-((6-((1 S ,4 S )-4-(4-(2-((1-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy Tert-butyl-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate (250 mg, 0.23 mmol) was dissolved with DCM (5 mL ) was dissolved, trifluoroacetic acid (1 mL) was added, the reaction solution was stirred at room temperature overnight, concentrated under reduced pressure, and the crude product was purified by reverse phase preparation to obtain 5-(4-((2-(1-((1 S ,4 S ) -4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole Phin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)-2-(2,6-dioxopiperidine-3 -yl)isoindoline-1,3-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =995.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.13 (s, 1H), 8.15 (s, 1H), 8.11 ( d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.88 – 7.82 (m, 2H), 6.99 (s, 1H), 6.88 (s, 1H ), 6.85 (s, 1H), 6.70 (s, 1H), 5.59 – 5.50 (m, 3H), 5.18 (dd, J = 12.8, 5.4 Hz, 1H), 4.47-4.39 (m, 2H), 3.95- 3.85 (m, 4H), 3.41 (t, J = 6.4 Hz, 2H), 3.24 (d, J = 5.3 Hz, 2H), 3.12-2.77 (m, 5H), 2.70-2.55 (m, 4H), 2.36 (s, 3H), 2.09-1.40 (m, 21H), 1.22-0.90 (m, 4H).

Example 40: 1-(5-(4-(((1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoro Methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl-2,2, 6,6- d ₄ )oxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: Preparation of 1-phenylpiperidine-2,2,6,6- d _4-4 -ol Trifluoroacetic acid (2.34 g, 20.5 mmol) was dropped into benzylamine (2.19 g, 20.5 mmol), and CD ₂ O in D ₂ O solution (20%, 1.5 g CD ₂ O dissolved in 6 mL D ₂ O ), after ultrasonic for 10 minutes, stir at 20°C for 1 hour until the solution is clear, add allyltrimethylsilane (2.56 g, 22.5 mmol), raise the temperature to 40°C and stir overnight, dilute with water (10 mL), and use potassium carbonate solid Adjust to pH greater than 9, add water (50 mL), extract with ethyl acetate (50 mLx3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (MeOH). :DCM=1:9, add 1% ammonia water to the eluent) and purify to obtain 1-phenylpiperidin-2,2,6,6- d ₄ -4-ol. LC-MS: (ESI, m/z ): [M+H] ⁺ =196.3. Step 2: Preparation of piperidin-2,2,6,6- d ₄ -4-ol Dissolve 1-phenylpiperidine-2,2,6,6- d _4-4 -ol (470 mg, 2.4 mmol) in methanol (30 mL), add Pd/C (100 mg) and Pd(OH ) ₂ /C (100 mg), stir overnight at 70°C in a hydrogen atmosphere, filter, and concentrate under reduced pressure to obtain piperidin-2,2,6,6- d ₄ -4-ol. LC-MS: (ESI, m/z ): [M+H] ⁺ =106.4. Step 3: 4-Hydroxypiperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester Preparation Piperidin-2,2,6,6- d ₄ -4-ol (215 mg, 2.05 mmol) was dissolved in DCM (10 mL), (Boc) ₂ O (491 mg, 2.26 mmol), TEA (620 mg, 6.15 mmol) and DMAP (25 mg, 0.21 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mLx3), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (EA:PE =1:1) and purified to obtain 4-hydroxypiperidine-1-carboxylic acid-2,2,6,6- d ₄ -tert-butyl ester. LC-MS: (ESI, m/z ): [M+Na] ⁺ =228. Step 4: 4-(pyridin-4-ylmethoxy)piperidine-1-carboxylic acid-2,2,6, 6- Preparation of d ₄ tert-butyl ester 4-Hydroxypiperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester (200 mg, 0.98 mmol) was dissolved in THF (20 mL), and NaH (60%) was added at 0 °C. , 235 mg, 5.88 mmol), stir for 2 hours, bromomethylpyridine hydrobromide (296 mg, 1.18 mmol) was added, and the reaction solution was heated to 70 °C and stirred overnight. Dilute with water (50 mL), extract with ethyl acetate (50 mLx3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (MeOH:DCM=1 :19) Purification yields 4-(pyridin-4-ylmethoxy)piperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =297.2. Step 5: 4-(piperidin-4-ylmethoxy)piperidine-1-carboxylic acid-2,2,6 , Preparation of 6- d ₄ tert-butyl ester 4-(Pyridin-4-ylmethoxy)piperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester (150 mg, 0.51 mmol) was dissolved in isopropanol (6 mL) The mixed solution with water (7 mL) was dissolved, Pd(OH) ₂ /C (45 mg) was added, and the mixture was stirred at 70 °C overnight in a hydrogen atmosphere. Filter and concentrate under reduced pressure to obtain 4-(piperidin-4-ylmethoxy)piperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =303.2. Step 6: 4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1 Preparation of (2 H )-yl)benzoyl)piperidin-4-yl)methoxy)piperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester 4-(Piperidin-4-ylmethoxy)piperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester (130 mg, 0.43 mmol) was dissolved in DMSO (5 mL) , add DIEA (133 mg, 1.04 mmol) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl benzoate (150 mg, 0.35 mmol) ), the reaction solution was stirred at room temperature for 2 h, added water (30 mL) and stirred for 5 minutes, extracted with ethyl acetate (30 mLx3), washed the organic phase with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and reduced Concentrated under pressure, the crude product was purified by column chromatography (MeOH:DCM=1:9) to obtain 4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2 H )- yl)benzoyl)piperidin-4-yl)methoxy)piperidine-1-carboxylic acid-2,2,6,6- d _4- tert-butyl ester. LC-MS: (ESI, m/z ): [M+Na] ⁺ =575.3. Step 7: 1-(2-chloro-5-(4-(((piperidin-4-yl-2,2, Preparation of 6,6- d ₄ )oxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)piper 2,2,6,6- d _4- tert-butyl ester of 1-carboxylic acid (130 mg, 0.24 mmol) was dissolved in DCM (5 mL), trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 2 hours. , concentrated under reduced pressure to obtain 1-(2-chloro-5-(4-(((piperidin-4-yl-2,2,6,6- d ₄ )oxy)methyl)piperidine-1-carbonyl) Phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione was used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ =453.2. Step 8: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)piperidine -1-carbonyl-2,2,6,6- d ₄ )cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoro Preparation of tert-butyl methyl)phenyl)carboxylate 1-(2-chloro-5-(4-(((piperidin-4-yl-2,2,6,6- d ₄ )oxy)methyl)piperidin-1-carbonyl)phenyl)di Hydropyrimidine-2,4(1 H ,3 H )-dione (130 mg, 0.29 mmol) was dissolved in DMSO (5 mL), and (1 R ,4 R )-4-(4-((( R ) -1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline- 6-yl)cyclohexane-1-carboxylic acid (130 mg, 0.22 mmol), HATU (110 mg, 0.29 mmol) and DIEA (142 mg, 1.10 mmol), stir at room temperature for 2 hours, add water (30 mL) and mix Stir for 5 minutes, extract with ethyl acetate (30 mLx3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (MeOH:DCM=1:9 ) was purified to obtain (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-((1-(4-chloro-3-(2,4-dioxo) Tetrahydropyrimidine-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)piperidine-1-carbonyl-2,2,6,6- d ₄ )cyclohexyl)-7 -Methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =1037.5. Step 9: 1-(5-(4-(((1-((1 R ,4 R ))-4-(4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )cyclohexane-1-carbonyl)piperidin-4-yl-2,2,6,6- d ₄ )oxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine- Preparation of 2,4(1 H ,3 H )-diketone (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydro) Pyrimidine-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)piperidine-1-carbonyl-2,2,6,6- d ₄ )cyclohexyl)-7-methyl Oxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (130 mg, 0.13 mmol) was dissolved in DCM ( 5 mL), add TFA (1 mL), stir at room temperature for 2 hours, concentrate under reduced pressure, dissolve the crude product in DCM (20 mL), adjust the pH to neutral with saturated aqueous sodium bicarbonate solution (20 mL), and stir for 10 minutes. Extract with MeOH/DCM (v:v=1:9, 20 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by reverse phase preparation to obtain 1-(5-(4-((( 1-((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7- Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl-2,2,6,6- d ₄ )oxy)methyl)piperidine- 1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =937.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.14-8.02 (m, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 10.5 Hz, 2H), 6.70 (s, 1H), 5.64-5.46 (m, 3H), 4.51-4.39 (m, 1H), 3.88 (s, 3H), 3.75- 3.42 (m, 4H), 3.12 – 3.01 (m, 1H), 2.95 (t, J = 11.2 Hz, 1H), 2.83 – 2.57 (m, 5H), 2.35 (s, 3H), 1.95 -1.50 (m, 17H), 1.45-1.27 (m, 2H), 1.25-1.07 (m, 2H).

Example 41: 5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2-chloro-6-(() Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl) Piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)-2-(2,4-dioxocyclohexyl)isoindoline-1,3-dione Step 1: 4 -(2-((1-(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy) Preparation of tert-butyl ethyl)piperidine-1-carboxylate To 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (430 mg, 1.3 mmol) and 2-(2,6-dioxopipperidine To a solution of din-3-yl)-5-fluoroisoindoline-1,3-dione (718 mg, 2.6 mmol) in DMF (3 mL) was added DIEA (675 mg, 3.9 mmol), and the reaction mixture was heated to 110°C and stir overnight. The reaction solution was poured into water, and EA _{( 30} ml -(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1 -Tertiary butyl carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =583.4. Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2 Preparation of -(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione 4-(2-((1-(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy A solution of tert-butyl)ethyl)piperidine-1-carboxylate (210 mg, 0.36 mmol) in HCI/1,4-dioxane (4 M, 5 mL) was stirred at room temperature for 1 h. The reaction solution was directly concentrated to obtain 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine- 1-yl)isoindoline-1,3-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =483.3. Step 3: 5-(4-((2-(1-((1 R ,4 R ))-4-(4- ((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy- 2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)-2-(2,4-di Preparation of oxocyclohexyl)isoindoline-1,3-dione To (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophene-2- (ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (100 mg, 0.17 mmol and 2-(2,6-di Oxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3- HATU (77 mg, 0.20mmol) and DIEA (65 mg, 0.51 mmol) were added to a solution of diketone (87 mg, 0.17mmol) in DMF (5 mL). The reaction solution was stirred at room temperature for 2 h. The reaction solution was poured into water. Extract with EA (20 mL×3), dry over anhydrous Na ₂ SO ₄ , and concentrate under reduced pressure. The crude product obtained is purified by prep-HPLC to obtain 5-(4-((2-(1-((1 R ,4 R ))- 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)-2-( 2,4-Dioxocyclohexyl)isoindoline-1,3-dione. LC-MS: (ESI, m/z ): [MH] ^- =1057.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.49 – 7.38 (m, 2H) , 7.36 – 7.29 (m, 2H), 7.23 (dd, J = 9.8, 1.7 Hz, 2H), 7.02 (s, 1H), 6.96 (s, 1H), 6.03 – 5.87 (m, 1H), 5.10-5.00 (m, 1H), 4.42-4.31 (m, 1H), 4.10-4.00 (m, 2H), 3.97-3.85 (m, 4H), 3.41 (t, J = 6.3 Hz, 2H), 3.23 (d, J = 6.2 Hz, 2H), 3.18 – 3.07 (m, 2H), 3.05 – 2.81 (m, 5H), 2.71 – 2.52 (m, 3H), 2.42 (s, 3H), 2.01 (s, 6H), 1.89- 1.44 (m, 20H), 1.26-0.86 (m, 4H).

Example 42: ( R )-1-(5-(9-(((3-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl))ethyl) )Amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl)(methyl)amino)methyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: (3-hydroxypropyl)( Preparation of methyl)carboxylic acid benzyl ester Dissolve 3-(methylamino)propan-1-ol (5.0 g, 56.17 mmol) and benzyl chloroformate (10.5 g, 61.79 mmol) in 1,4-dioxane (40 mL), and then add The sodium hydroxide solution (2 mol/L, 48 mL) was stirred at 50°C for 0.5 hours, and directly concentrated under reduced pressure to obtain crude (3-hydroxypropyl)(methyl)carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =224.3. Step 2: Preparation of (3-bromopropyl)(methyl)carboxylic acid benzyl ester (3-Hydroxypropyl)(methyl)carboxylic acid benzyl ester (4.6 g, 20 mmol) was dissolved in tetrahydrofuran (40 mL), triphenylphosphine (7.8 g, 30 mmol) and carbon tetrabromide (10 g , 30 mmol) were added respectively, the reaction solution was stirred at room temperature for 2 hours, diluted with water (200 mL), extracted with ethyl acetate (200 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography (PE :EA=1:1) and purified to obtain (3-bromopropyl)(methyl)carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =288.1. Step 3: (3-(4-bromo-2-oxopyridin-1(2 H )-yl)propyl)( Preparation of methyl)carboxylic acid benzyl ester 4-Bromopyridin-2( 1H )-one (790 mg, 4.5 mmol) was dissolved in anhydrous DMF (5 mL) and lowered to 0°C. NaH (218 mg, 5.5 mmol) was added, and the reaction solution was stirred for 0.5 hours. Then (3-bromopropyl)(methyl)carboxylic acid benzyl ester (1.3 g, 4.5 mmol) was added at room temperature and stirred for 12 hours, diluted with water (100 mL), and extracted with ethyl acetate (150 mL×4) , the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=1:2) to obtain (3-(4-bromo-2-oxo) Pyridin-1( 2H )-yl)propyl)(methyl)carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): (ESI, m/z ): [M+H] ⁺ =379.0. Step 4: Methyl (3-(2-oxo-4-(4,4, Preparation of benzyl 5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)pyridin-1(2 H )-yl)propyl)carboxylate (3-(4-Bromo-2-oxopyridin-1(2 H )-yl)propyl)(methyl)carboxylic acid benzyl ester (1.2 g, 3.2 mmol) and 4,4,4',4 ',5,5,5',5'-Octamethyl-2,2'-bis(1,3,2-dioxaboropentane) (979 mg, 3.8 mmol) was treated with anhydrous 1,4-dimethyl Dissolve in alkane, add Pd(dppf)Cl ₂ (120 mg) and potassium carbonate (880 mg, 6.47 mmol), then stir at 100 °C overnight under nitrogen protection, dilute with water (100 mL), ethyl acetate (100 mL×3) Extract, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the product methyl (3-( 2-Oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)pyridin-1(2 H )-yl)propyl)carboxylic Benzyl acid ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =427.4. Step 5: (3-(4-(4-hydroxy-2,7-dimethylquinazolin-6-yl) Preparation of -2-oxopyridin-1(2 H )-yl)propyl)(methyl)carboxylic acid benzyl ester 6-Bromo-2,7-dimethylquinazolin-4-ol (450 mg, 1.77 mmol) and methyl (3-(2-oxo-4-(4,4,5,5-tetrakis) Methyl-1,3,2-dioxaboropentan-2-yl)pyridin-1(2 H )-yl)propyl)carboxylic acid benzyl ester (980 mg, 2.3 mmol) was dissolved in DMF/water ( 10/1, 4 mL), add potassium carbonate (480 mg, 3.5 mmol) and Pd(dppf)Cl ₂ (90 mg), replace with nitrogen, heat to 100 °C under nitrogen protection and stir for 2 hours, add water (50 mL ), extracted with ethyl acetate (50 mL×3), washed the organic phase with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography (DCM:MEOH=10:1) Purification gave the product (3-(4-(4-hydroxy-2,7-dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl) (methyl ) benzyl carboxylate. LC-MS: (ESI, m/z ): (ESI, m/z ): [M+H] ⁺ =473.3. Step 6: ( R )-(3-(4-(4-((1-( 3-(((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)-2- Preparation of oxopyridin-1( 2H )-yl)propyl)(methyl)carboxylic acid benzyl ester (3-(4-(4-Hydroxy-2,7-dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl)(methyl)carboxylic Dissolve benzyl acid ester (480 mg, 1.02 mmol) with DMF (4 mL), add DBU (388 mg, 2.55 mmol) and BOP (583 mg, 1.32 mmol), stir at room temperature for 0.5 hours, add ( R )- (3-(1-Aminoethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (403 mg, 1.32 mmol), heat the reaction solution to 70 °C and stir overnight, add water (50 mL) Dilute, extract with ethyl acetate (50 mL×3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (ethyl acetate:petroleum ether=1 :1) Purify to obtain the product ( R )-(3-(4-(4-((1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl)phenyl)ethyl) (yl)amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl)(methyl)carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =759.4. Step 7: ( R )-(3-(1-((2,7-dimethyl-6-(1-() 3-(methylamino)propyl)-2-oxo-1,2-dihydropyridin-4-yl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl Preparation of tert-butyl)phenyl)carboxylate ( R )-(3-(4-(4-((1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl)phenyl)ethyl)amino) -2,7-Dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl)(methyl)carboxylic acid benzyl ester (300 mg, 0.4 mmol) Dissolve ethyl acetate (4 mL), add Pd/C (60 mg), replace the hydrogen, stir at room temperature under a hydrogen atmosphere for 2 hours, filter and concentrate to obtain crude product ( R )-(3-(1-((2,7) -Dimethyl-6-(1-(3-(methylamino)propyl)-2-oxo-1,2-dihydropyridin-4-yl)quinazolin-4-yl)amino )ethyl)-tert-butyl 5-(trifluoromethyl)phenyl)carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =625.5. Step 8: ( R )-9-(((3-(4-(4-((1-(3-((() 3-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridine- Preparation of 1(2 H )-yl)propyl)methyl)amino)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ( R )-(3-(1-((2,7-dimethyl-6-(1-(3-(methylamino)propyl))-2-oxo-1,2-dihydro Pyridin-4-yl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (130 mg, 0.21 mmol) and 9-aldehyde -3-Azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (59 mg, 0.21 mmol) was dissolved in THF (4 mL), and sodium triacetyloxyborohydride (131 mg, 0.63 mmol ) was added, stirred at room temperature for 2 hours, diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), washed the organic phase with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate, and the crude product is purified using column chromatography (dichloromethane: methanol=10:1) to obtain the product ( R )-9-(((3-(4-(4-((1-(3-((3-butyl) Oxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridine-1(2 H )-(yl)propyl)methyl)amino)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =890.5. Step 9: ( R )-1-(3-(((3-azaspiro[5.5]undecane-9- methyl)(methyl)amino)propyl)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2 , Preparation of 7-dimethylquinazolin-6-yl)pyridin-2(1 H )-one ( R )-9-(((3-(4-(4-((1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl)phenyl)ethyl )Amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl)methyl)amino)methyl)-3- Azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (100 mg, 0.11 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 3 mL) and reacted at room temperature 2 hours, directly concentrate under reduced pressure to obtain the crude product ( R )-1-(3-(((3-azaspiro[5.5]undecan-9-yl)methyl)(methyl)amino)propyl )-4-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl) Pyridin-2( 1H )-one. LC-MS: (ESI, m/z ): [M+H] ⁺ =690.5. Step 10: ( R )-1-(5-(9-(((3-(4-(4-(((1) -(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridine-1(2 H )-yl)propyl)(methyl)amino)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( Preparation of 1 H ,3 H )-diketone ( R )-1-(3-(((3-azaspiro[5.5]undecan-9-yl)methyl)(methyl)amino)propyl)-4-(4-(( 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)pyridin-2(1 H )-one (80 mg, 0.12 mmol) and perfluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate (51 mg, 0.12 mmol) were dissolved in DMSO (3 mL), DIEA (60 mg, 0.48 mmol) were added, the reaction solution was stirred at room temperature for 2 hours, diluted with water (30 mL), extracted with ethyl acetate (30 mL*3), washed with saturated brine, and anhydrous sulfuric acid It was dried over sodium, filtered, and concentrated under reduced pressure. The crude product was purified using Prep-HPLC to obtain the product ( R )-1-(5-(9-(((3-(4-(4-((1-(3-amino-)) 5-(Trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)-2-oxopyridin-1(2 H )-yl)propyl )(methyl)amino)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone. LC-MS: (ESI, m/z ): [MH] ^- =940.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H) , 8.29 (s, 1H), 7.73 (d, J = 6.6 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 6.42 (s, 1H), 6.36 (d, J = 7.0 Hz, 1H), 5.60- 5.48 (m, 3H), 4.00-3.90 (m, 2H), 3.80-3.50 (m, 5H), 3.29-3.20 (m, 3H), 2.77-2.70 (m, 2H), 2.44-2.26 (m, 7H ), 2.20-2.06 (m, 4H), 1.87-1.78 (m, 2H), 1.74-1.65 (m, 2H), 1.62-1.20 (m, 10H), 1.16-0.92 (m, 4H).

Example 43: 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) (base)phenyl)ethyl)amino)-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperamide-1- (methyl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4 Preparation of -(2-methoxyethoxy)-2-nitrobenzoic acid methyl ester Add 2-methoxyethan-1-ol (365 mg, 4.8 mmol) to a three-necked flask, dissolve it in THF (10 mL), replace nitrogen three times, and add t-BuOK (1M/THF, 4.2 mL, 4.2 mmol), after reacting at 0 ℃ for 1 h, a solution of 4-fluoro-2-nitrobenzoic acid methyl ester (600 mg, 3.0 mmol) in THF (10 mL) was added dropwise, and after continuing to react at 0 ℃ for 2 h, Add water (50 mL), extract with ethyl acetate (50 mLx3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (EA:PE=2 :3) Purify to obtain 4-(2-methoxyethoxy)-2-nitrobenzoic acid methyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.87 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H) , 4.29 – 4.24 (m, 2H), 3.81 (s, 3H), 3.70 – 3.66 (m, 2H), 3.31 (s, 3H). Step 2: 2-Amino-4-(2-methoxyethyl Preparation of methyl benzoate Dissolve methyl 4-(2-methoxyethoxy)-2-nitrobenzoate (850 mg, 3.3 mmol) in EtOH (20 mL), add Raney Nickel (1 mL), and dissolve in H ₂ Stir at room temperature for 2 h in the atmosphere, filter, and concentrate under reduced pressure to obtain methyl 2-amino-4-(2-methoxyethoxy)benzoate. LC-MS: (ESI, m/z): [M+H] ⁺ =226.1. Step 3: 2-Amino-5-bromo-4-(2-methoxyethoxy)benzoic acid methyl ester Preparation Dissolve 2-amino-4-(2-methoxyethoxy)benzoic acid methyl ester (680 mg, 3.0 mmol) in DMF (10 mL), add NBS (484 mg, 2.7 mmol) at 0 °C, 0 React at ℃ for 1 h, add water (100 mL) and stir for 5 minutes, extract with ethyl acetate (100 mLx3), wash the organic phase with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use the crude product Column chromatography (EA:PE=2:3) purified to obtain 2-amino-5-bromo-4-(2-methoxyethoxy)benzoic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =304.0. Step 4: Preparation of 2-amino-5-bromo-4-(2-methoxyethoxy)benzoic acid Dissolve methyl 2-amino-5-bromo-4-(2-methoxyethoxy)benzoate (710 mg, 2.3 mmol) in THF/H ₂ O (15 mL, 2:1). Add LiOH (570 mg, 23.0 mmol), stir at 50°C overnight, add water (20 mL), adjust pH to 6 with 1M hydrochloric acid, extract with MeOH/DCM mixed solution (1/10, 30 mL x3), and dissolve with anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure to obtain 2-amino-5-bromo-4-(2-methoxyethoxy)benzoic acid. LC-MS: (ESI, m/z): [M+3] ⁺ =292.0. Step 5: 6-bromo-7-(2-methoxyethoxy)-2-methylquinazoline-4 -Preparation of alcohol Add 2-amino-5-bromo-4-(2-methoxyethoxy)benzoic acid (665 mg, 2.3 mmol) into a stuffy jar, dissolve it in MeOH (20 mL), and add ammonium acetate (2.66 g , 34.5 mmol) and trimethyl orthoacetate (4.14 g, 34.5 mmol), react at 120°C overnight, concentrate under reduced pressure to remove methanol, add water (50 mL), extract with ethyl acetate (50 mLx3), saturated brine (100 mL), washed the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH:DCM=1:4) to obtain 6-bromo-7-(2-methoxyethoxy) -2-Methylquinazolin-4-ol. LC-MS: (ESI, m/z): [M+H] ⁺ =312.9. Step 6: 4-(4-hydroxy-7-(2-methoxyethoxy)-2-methylquinazole Preparation of methyl pholin-6-yl)cyclohex-3-ene-1-carboxylate 6-Bromo-7-(2-methoxyethoxy)-2-methylquinazolin-4-ol (210 mg, 0.67 mmol) was mixed with DMF/H ₂ O mixed solution (11 mL, 10: 1) Dissolve and add methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl) cyclohex-3-ene-1-carboxylate (233 mg, 0.88 mmol), Na ₂ CO ₃ (143 mg, 1.34 mmol) and Pd(dppf)Cl ₂ (25 mg, 0.03 mmol), react at 110°C overnight under nitrogen protection, add water (100 mL) and stir 5 minutes, extract with ethyl acetate (50 mLx3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography (MeOH:DCM=1:9) Purification gave 4-(4-hydroxy-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =373.1. Step 7: (1 R ,4 R )-4-(4-hydroxy-7-(2-methoxyethoxy) Preparation of )-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester In the autoclave, add methyl 4-(4-hydroxy-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate Ester (500 mg, 1.3 mmol), dissolved in MeOH (30 mL), added Pd(OH) ₂ /C (150 mg, 20%), reacted in a hydrogen environment (2MPa) at 70°C for 48 hours, filtered, Concentrate under reduced pressure, and the crude product is separated using reverse phase preparation to obtain (1 R , 4 R )-4-(4-hydroxy-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl ) cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =375.2. Step 8: (1 R ,4 R )-4-(4-((( R )-1-(3-((( 3-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(2-methoxyethoxy)-2-methylquinazoline-6 -Preparation of cyclohexane-1-carboxylic acid methyl ester (1 R ,4 R )-4-(4-hydroxy-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl Ester (80 mg, 0.21 mmol) was dissolved in DMF (5 mL), BOP (123 mg, 0.28 mmol) and DBU (81 mg, 0.53 mmol) were added, and after stirring at room temperature for 0.5 h, ( R )-(3- (1-Aminoethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (70 mg, 0.23 mmol), and moved to a 70°C oil bath for reaction overnight, and added water (50 mL) Stir for 5 minutes, extract with ethyl acetate (30 mLx3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by reverse phase to obtain (1 R , 4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7- (2-Methoxyethoxy)-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =661.2. Step 9: (1 R ,4 R )-4-(4-((( R )-1-(3-((( 3-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(2-methoxyethoxy)-2-methylquinazoline-6 -Preparation of cyclohexane-1-carboxylic acid (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (66 mg, 0.10 mmol) dissolved in THF /H ₂ O mixed solution (15 mL, 2:1), add LiOH (48 mg, 2.0 mmol), stir at 50°C overnight, add water (20 mL), adjust the pH to 6 with concentrated hydrochloric acid, and use MeOH/DCM ( 10%, 30 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase to obtain (1 R ,4 R )-4-(4-((( R )-1-(3- (((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(2-methoxyethoxy)-2-methylquinazoline -6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ =647.4. Step 10: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecane- 9-yl)methyl)piperidine-1-carbonyl)cyclohexyl)-7-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)- Preparation of tert-butyl 5-(trifluoromethyl)phenyl)carboxylate (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (50 mg, 0.08 mmol) was dissolved in DMF (5 mL), add 1-(2-chloro-5-(9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone (48 mg, 0.10 mmol), DIEA (52 mg, 0.40 mmol) and pyBOP (50 mg, 0.10 mmol), react at room temperature for 1 h, add water (50 mL) And stir for 5 minutes, extract with ethyl acetate (30 mLx3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified using reverse phase preparation to obtain (3-(( R )-1-((6-((1 R ,4 R )-4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperbenzoyl)-1-carbonyl)cyclohexyl)-7-(2-methoxyethoxy )-2-Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =1130.4. Step 11: 1-(5-(9-((4-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(2-methoxyethoxy)-2-methylquin Zozolin-6-yl) cyclohexane-1-carbonyl) piperazine-1-yl) methyl)-3-azaspiro[5.5] undecane-3-carbonyl)-2-chlorophenyl) di Preparation of Hydropyrimidine-2,4(1 H ,3 H )-dione (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydro) Pyrimidine-1( 2H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperbenzoyl)-1-carbonyl)cyclohexyl)-7-(2- Methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (80 mg, 0.07 mmol ) was dissolved in DCM (5 mL), add TFA (1 mL), and stir at room temperature for 1 hour. After concentration under reduced pressure, add MeOH/DCM (1:9, 20 mL) to dissolve, and then add saturated aqueous sodium bicarbonate solution ( 20 mL) to adjust the pH to neutral, stir for 10 minutes, extract with MeOH/DCM (1:9, 20 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by reverse-phase preparation to obtain 1 -(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)) Ethyl)amino)-7-(2-methoxyethoxy)-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl) -3-Azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1030.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 6.98 (s, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.61 – 5.48 (m, 3H), 4.22-4.17 (m, 2H), 3.75 (d, J = 4.6 Hz , 3H), 3.65 – 3.52 (m, 3H), 3.51-3.41 (m, 4H), 3.36 (s, 3H), 3.02-2.88 (m, 1H), 2.79-2.71 (m, 2H), 2.68-2.60 (m, 1H), 2.29-2.38 (m, 5H), 2.28-2.21 (m, 2H), 2.16-2.06 (m, 2H), 1.95-1.85 (m, 2H), 1.84-1.80 (m, 2H) , 1.76-1.19 (m, 18H), 1.17-0.95 (m, 4H).

Example 44: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-() Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy Base)methyl)piperidine-1-carbonyl)-2-fluorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-((2-(1-((( 1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amine (yl)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid Preparation of benzyl ester (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl) Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (100 mg, 0.17 mmol) was dissolved in DMF (8 mL), 4-(( 2-(Piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester (72 mg, 0.2 mmol), HATU (90 mg, 0.23 mmol) and DIEA (64 mg, 0.5 mmol) ) are added separately. After the reaction solution was stirred at room temperature for 5 hours, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mLx3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure. The crude product was purified using column chromatography (methanol:dichloromethane=1:9) to obtain 4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-( 3-(((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =945.5. Step 2: (3-(( R )-1-((7-methoxy-2-methyl-6-( (1 R ,4 R )-4-(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carbonyl)cyclohexyl)quinolazol-4-yl)amino Preparation of tert-butyl)ethyl)-5-(trifluoromethyl)phenyl)carboxylate 4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-((tertiary butoxycarbonyl)amino))-5-(tri Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy )Methyl)piperidine-1-carboxylic acid benzyl ester (100 mg, 0.11 mmol) was dissolved in ethyl acetate (8 mL), Pd(OH) ₂ /C (50 mg, 0.14 mmol) was added, and the mixture was heated under a hydrogen atmosphere The temperature was raised to 70°C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R )-4- (4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carbonyl)cyclohexyl)quinolazol-4-yl)amino)ethyl)-5-(trifluoro Methyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =811.5. Step 3: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-fluorobenzoyl)piperidin-4-yl)methoxy )ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl ) Preparation of tert-butyl carboxylate (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R )-4-(4-(2-(piperidin-4-ylmethyl) Oxy)ethyl)piperidine-1-carbonyl)cyclohexyl)quinolinazol-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (80 mg, 0.098 mmol) was dissolved in DMSO (8 mL), and 1-(2-fluoro-5-(pentafluorobenzoyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione was added (40 mg, 0.098 mmol) and DIEA (40 mg, 0.28 mmol), stir at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (30 mLx3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (methanol : Dichloromethane=1:9) was purified to obtain (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(2-((1-(3-() 2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)-4-fluorobenzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl )-7-Methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =1045.3. Step 4: 1-(5-(4-((2-(1-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-fluorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(2-((1-(3-(2,4-dioxotetrahydropyrimidine- 1(2 H )-yl)-4-fluorobenzoyl)piperidin-4-yl)methoxy)ethyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2-methyl Tert-butylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate (50 mg, 0.047 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by Prep-HPLC to obtain 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1) -(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl )piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)-2-fluorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =945.4. ¹ H NMR (400 MHz, MeOD) δ 10.52 (s, 1H), 8.19 – 7.99 (m, 2H), 7.49 (d , J = 7.9 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 6.99 (s, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.65 – 5.47 (m, 3H), 4.50-4.33 (m, 2H), 3.96-3.85 (m, 4H), 3.74 (t, J = 6.7 Hz, 2H), 3.41 (t, J = 6.4 Hz, 2H), 3.23 (d, J = 6.2 Hz, 2H), 3.08 – 2.89 (m, 3H), 2.72 (t, J = 6.7 Hz, 2H), 2.69-2.60 (m, 1H), 2.40-2.30 (m, 4H) , 1.99-1.37 (m, 22H), 1.16-0.94 (m, 4H).

Example 45: 1-(5-(4-((1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)piper Dihydropyrimidine-1-carbonyl-2,2,6,6- d ₄ )-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-((1- ((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)piperidine-1-carboxylic acid Preparation of tributyl ester-2,2,6,6- d ₄ Dissolve 4-(piperidin-4-ylmethoxy)piperidine-1-carboxylic acid tert-butyl ester-2,2,6,6- d ₄ (150 mg, 0.50 mmol) in DMF (5 mL) , add (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl (150 mg, 0.25 mmol), HATU (123 mg, 0.32 mmol), and DIEA (161 mg, 1.25 mmol), stir at room temperature for 2 hours, add water (50 mL) and stir for 5 minutes, extract with ethyl acetate (30 mLx3), wash the organic phase with saturated brine (50 mL), and dry over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH:DCM=1:9) to obtain 4-((1-((1 R ,4 R )-4-(4-((( R )-1) -(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)piperidine-1-carboxylic acid tert-butyl ester-2,2,6,6- d ₄ . LC-MS: (ESI, m/z ): [M+H] ⁺ =887.4. Step 2: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(((piperidine- Preparation of 4-yl-2,2,6,6- d ₄ )oxy)methyl)piperidin-1-yl)methanone 4-((1-((1 R ,4 R )-4-(4-((( R ))-1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoromethyl Base)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)piper Dissolve tert-butyl ester-2,2,6,6- d ₄ of 1-carboxylic acid (200 mg, 0.23 mmol) in DCM (5 mL), add TFA (1 mL), and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(((piperidin-4-yl-2,2,6,6- d ₄ )oxy)methyl) Piperidin-1-yl)methanone was used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ =687.4. Step 3: 1-(5-(4-((1-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)piperidine-1-carbonyl-2,2,6,6- d ₄ )-2-chlorophenyl)dihydropyrimidine-2, Preparation of 4(1 H ,3 H )-diketone ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(((piperidin-4-yl-2,2,6,6- d ₄ )oxy)methyl)piperidine- 1-yl)methanone (200 mg, 0.29 mmol) was dissolved in DMSO (5 mL), DIEA (149 mg, 1.15 mmol) and 4-chloro-3-(2,4-dioxotetrahydropyrimidine-1) were added (2 H )-yl)pentafluorophenyl benzoate (100 mg, 0.23 mmol), stirred at room temperature for 2 h, added water (50 mL) and stirred for 5 minutes, extracted with ethyl acetate (30 mLx3), saturated brine (50 mL), washed the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using reverse phase preparation to obtain 1-(5-(4-((1-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)piperidine-1-carbonyl-2,2,6,6- d ₄ )-2-chlorophenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): (ESI, m/z ): [M+H] ⁺ =937.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H) , 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.62 – 5.50 (m, 3H), 4.42 (d, J = 11.5 Hz, 1H), 4.0 – 3.92 (m, 4H), 3.74 (s, 1H), 3.67 – 3.47 (m, 2H), 3.29 (d, J = 4.5 Hz, 2H), 3.09 – 2.87 (m, 2H), 2.76-2.73 ( m, 2H), 2.67-2.63 (m, 1H), 2.36 (s, 3H), 1.94 – 1.50 (m, 17H), 1.50 – 1.38 (m, 2H), 1.16 – 0.91 (m, 2H).

Example 46: 3-(2-chloro-5-(4-((2-(1-(4-(4-((( R )))-1-(4-(2-chloro-6-((di Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1 -Carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)piperidine-2,6-dione Step 1: 4-(4-((( R )- 1-(4-Bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester Preparation Dissolve ( R )-1-(4-bromo-2-yl)ethane-1-amine (607 mg, 3 mmol) in DMF (5 mL), add BOP (574.6 mg, 1.3 mmol) and DBU (456.0 mg, 3.0 mmol), the reaction solution was stirred at room temperature for 0.5 hours, and then 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexan- 3-ene-1-carboxylic acid methyl ester (328 mg, 1 mmol) and heated to 70°C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), the upper organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (MeOH: DCM=1:9) was purified to obtain 4-(4-((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazole Phenoline-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 516.1. Step 2: 4-(4-((( R )-1-(4-(2-chloro-6-benzaldehyde)) Preparation of methyl methyl ester of thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)benzaldehyde (206 mg, 0.77 mmol) and 4-(4 -((( R )-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)cyclohex-3-ene -1-Carboxylic acid methyl ester (400 mg, 0.77 mmol) was dissolved in DMF/H ₂ O (3 mL/0.3 mL), and Pd(dppf)Cl ₂ (100 mg) and K ₂ CO ₃ (214 mg, 1.55 mmol), replaced with nitrogen, and stirred at 100°C for 2 hours under nitrogen protection. After the reaction, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography ( MeOH:DCM=1:9) was purified to obtain 4-(4-((( R )-1-(4-(2-chloro-6-benzaldehyde)thiophen-2-yl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 576.3. Step 3: 4-(4-((( R )-1-(4-(2-chloro-6-((di Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1 -Preparation of methyl carboxylate 4-(4-((( R )-1-(4-(2-chloro-6-benzaldehyde)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl Methyl quinazolin-6-yl)cyclohex-3-ene-1-carboxylate (130 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane (5 mL), and triacetoxyboron was added Sodium hydride (143 mg, 0.68 mmol), the reaction solution was stirred at 80°C for 1 hour. The reaction solution was diluted with water (50 ml), extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH:DCM=1:19). 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 605.3. Step 4: 4-(4-((( R )-1-(4-(2-chloro-6-((di Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1 -Preparation of carboxylic acids 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) Methyl -7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate (170 mg, 0.28 mmol) was treated with MeOH/H ₂ O (2 mL/0.2 mL), add LiOH (52 mg, 1.3mmol), heat the reaction solution to 60 °C and stir for 1 hour. Cool, adjust the pH to 3-4 with dilute hydrochloric acid (1.0 mol/L), then add saturated NaHCO ₃ solution to adjust the pH to 7-8, extract with ethyl acetate (30 mL×3), combine the organic phases, and use anhydrous Na ₂ Dry over SO ₄ , filter, and concentrate under reduced pressure to obtain ( R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl) )thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ = 591.3. Step 5: 3-(2-chloro-5-(4-((2-(1-(4-(4-() (( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy- 2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)piperidine- Preparation of 2,6-dione 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid (125 mg, 0.22 mmol) and 3-(2-chloro-5-(4- ((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)piperidine-2,6-dione (108 mg, 0.22mmol) was dissolved in DMF (3 mL ), add HATU (96 mg, 0.25 mmol) and DIEA (82 mg, 0.64 mmol), and stir at room temperature for 1 hour. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified using Prep-HPLC to obtain product 3- (2-chloro-5-(4-((2-(1-(4-(4-((( R ))-1-(4-(2-chloro-6-(dimethylamino)methyl) Base)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidine- 4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)piperidine-2,6-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1049.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.41 (s, 1H), 8.05 ( s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.48 – 7.30 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s , 1H), 6.01 – 5.89 (m, 1H), 5.83 (s, 1H), 4.47-4.37 (m, 1H), 3.99-3.91 (m, 1H), 3.86 (s, 3H), 3.74 (s, 1H ), 3.68-3.52 (m, 2H), 3.44-3.37 (m, 2H), 3.26-3.18 (m, 3H), 3.18-2.96 (m, 3H), 2.90-2.82 (m, 1H), 2.81-2.70 (m, 2H), 2.43 (s, 3H), 2.39-2.29 (m, 2H), 2.25-2.16 (m, 1H), 2.03 (s, 6H), 1.89-1.55 (m, 10H), 1.49-1.40 (m, 2H), 1.30-1.20 (m, 2H), 1.20 – 0.95 (m, 4H).

Example 47: (1 R ,4 R ) -N- (3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl) )piperidin-4-yl)propyl)-4-(7-methoxy-2-methyl-4-((( R )-1-(4-(2-((methylamino)methyl) Base)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl) -N -methylcyclohexane-1-methamide step 1: 4-(3-hydroxypropyl) ) Preparation of piperidine-1-carboxylic acid benzyl ester Add CbzCl (5.40 ml, 38.40 mmol) to a solution of 3-(piperidin-4-yl)propan-1-ol (5.00 g, 34.91 mmol) in THF (20 mL) at 0°C, and react for 1 hour ^. After completion, the reaction solution was quenched with saturated NaHCO ₃ aqueous solution (50 mL) and extracted with ethyl acetate (100 mLx3). The organic phases were combined and washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:100~1:10) to obtain light yellow oily 4-(3-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =278.2. Step 2: Preparation of 4-(3-oxopropyl)piperidine-1-carboxylic acid benzyl ester Dess-Martin (5.50 g, 13.0 mmol) was added to a solution of 4-(3-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (3.00 g, 10.8 mmol) in DCM (60 mL) at 0 °C, and the reaction 1 hour. After the reaction was completed, the reaction solution was quenched with saturated Na ₂ S ₂ O ₃ (50 mL) and saturated NaHCO ₃ (50 mL), and extracted with DCM (80 mLx3). The organic phases were combined and washed with brine (100 mL), dried over sodium sulfate, filtered and spun dry. The crude product was purified by silica gel chromatography (EA:PE=3:17~3:7) to obtain 4-(3-oxopropyl)piperidine-1-carboxylic acid benzyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 7.38-7.28 (m, 5H), 5.12 (s, 2H), 4.28-4.02 (m, 2H), 2.90-2.65 (m, 2H ), 2.51-2.42 (m, 2H), 1.74-1.54 (m, 4H), 1.51-1.37 (m, 1H), 1.21-1.03 (m, 2H). Step 3: 4-(3-(methylamine) Preparation of benzyl)propyl)piperidine-1-carboxylate To a solution of benzyl 4-(3-oxopropyl)piperidine-1-carboxylate (1.50 g, 5.45 mmol) in THF (10 mL) was added methylamine (846 mg, 27.24 mmol) and AcOH (0.1 mL ), and reacted at 30°C for 4 hours, then added NaBH ₃ CN (684 mg, 10.90 mmol) and continued the reaction for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated NaHCO ₃ (50 mL) and extracted with ethyl acetate (100 mLx3). The organic phases were combined and washed with brine (100 mL), dried over sodium sulfate, filtered and spun dry. The crude product was purified by silica gel chromatography (using NH ₃ /MeOH:DCM=1:9~2:8) to obtain 4-(3-(methylamino)propyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =291.7. Step 4: 4-(3-((tert-butoxycarbonyl)(methyl)amino)propyl)piperidine- Preparation of 1-benzylformate To a solution of benzyl 4-(3-(methylamino)propyl)piperidine-1-carboxylate (295 mg, 1.02 mol) in DCM (3 mL) was added (Boc) ₂ O (1.2 mL, 5.10 mmol) and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mLx3). The organic phases were combined and washed with brine (100 mL), dried over sodium sulfate, filtered and spun dry. The crude product was purified by silica gel chromatography (NH ₃ /MeOH:DCM=1:19~1:9) to obtain 4-(3-((tert-butoxycarbonyl)(methyl)amino)propyl)piperidine-1 -Benzyl formate. LC-MS: (ESI, m/z ): [M-100+H] ⁺ =291.2. Step 5: Preparation of tert-butyl methyl(3-piperidin-4-yl)propyl)carboxylate To a solution of benzyl 4-(3-((tert-butoxycarbonyl)(methyl)amino)propyl)piperidine-1-carboxylate (291 mg, 0.75 mmol) in MeOH (5 mL) was added Pd /C (80 mg) and replaced with hydrogen three times, and reacted at room temperature for 16 hours. The reaction liquid was rotated to dryness to obtain crude product tert-butyl methyl (3-piperidin-4-yl)propyl)carboxylate, which could be used in the next step of reaction without further purification. LC-MS: (ESI, m/z ): [M+H] ⁺ =257.2. Step 6: (3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1 Preparation of tert-butyl (2 H )-yl)benzoyl)piperidin-4-yl)propyl)(methyl)carboxylate To a solution of tert-butyl methyl(3-(piperidin-4-yl)propyl)carbamate (150 mg, 0.59 mmol) in DMSO (2 mL) was added DIEA (232 mg, 1.8 mmol) and 4 -Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (381 mg, 0.88 mmol) and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mLx3). The organic phases were combined and washed with brine (100 mL), dried over sodium sulfate, filtered and spun dry. The crude product was purified by silica gel chromatography (using NH ₃ /MeOH:DCM=1:19~1:9) to obtain the target compound (3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine) -1(2 H )-yl)benzoyl)piperidin-4-yl)propyl)(methyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+Na] ⁺ =529.1. Step 7: 1-(2-chloro-5-(4-(3-(methylamino)propyl)piperidine) Preparation of -1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Compound (3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)propyl) ( Methyl)carboxylic acid tert-butyl ester (256 mg, 0.50 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added at room temperature, and the reaction was carried out for 0.5 hours. The reaction liquid was concentrated to obtain crude product 1-(2-chloro-5-(4-(3-(methylamino)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1 H ,3 H )-diketone was used in the next reaction without further purification. LC-MS: (ESI, m/z ): [M+H] ⁺ =407.0. Step 8: (2-(5-(( R )-1-((6-((1 R ,4 R )- 4-((3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)propyl) (Methyl)carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)phenyl)(methyl)carboxylic acid Preparation of tributyl ester To compound (1 R ,4 R )-4-(4-((( R )-1-(4-(2-((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl )thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (229 mg, 0.36 mmol) in DMF ( 3 mL) solution was added 1-(2-chloro-5-(4-(3-(methylamino)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone (216 mg, 0.53 mmol), TCFH (249 mg, 0.89 mmol) and NMI (146 mg, 1.78 mmol), and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mLx3). The organic phases were combined and washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (NH ₃ /MeOH:DCM=1:19~1:9) to obtain the target compound (2-(5-(( R )-1-((6-((1 R ,4 R )) -4-((3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)propyl )(methyl)carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)phenyl)(methyl)carboxylic acid 3rd butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =1033.2. Step 9: (1 R ,4 R )- N -(3-(1-(4-chloro-3-(2, 4-Dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)piperidin-4-yl)propyl)-4-(7-methoxy-2-methyl-4-(( ( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)- N -methyl Preparation of cyclohexane-1-methamide To compound (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-((3-(1-(4-chloro-3-(2) ,4-Dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)piperidin-4-yl)propyl)(methyl)carbonyl)cyclohexyl)-7-methoxy-2- Methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)phenyl)(methyl)carboxylic acid tert-butyl ester (107 mg, 0.10 mmol) in DCM (2 mL) TFA (1 mL) was added and allowed to react for 0.5 h. The reaction liquid was concentrated to obtain a crude product, which was purified by high-performance liquid chromatography to obtain the target compound (1 R , 4 R ) -N- (3-(1-(4-chloro-3-(2,4-dioxotetrakis) Hydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)propyl)-4-(7-methoxy-2-methyl-4-((( R )-1- (4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)- N -methylcyclohexane-1- Formamide. LC-MS: (ESI, m/z ): [M+H] ⁺ =933.4. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (s, 1H), 7.66-7.58 (m, 1H), 7.54 -7.48 (m, 1H), 7.43-7.36 (m, 2H), 7.33-7.26 (m, 3H), 7.18 (d, J = 1.2 Hz, 1H), 7.15-7.11 (m, 1H), 7.01 (m , 1H), 6.08-6.01 (m, 1H), 4.65-4.53 (m, 1H), 3.95 (s, 3H), 3.81-3.69 (m, 5H), 3.48-3.34 (m, 2H), 3.16-3.04 (m, 4H), 2.95-2.68 (m, 5H), 2.52 (s, 3H), 2.22 (s, 3H), 2.00-1.57 (m, 16H), 1.35-1.11 (m, 4H).

Example 48: 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2) -((dimethylamino)methyl))))phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)ring Hexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1 : Preparation of 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid benzyl ester Compound 4-(2-hydroxyethyl)piperidine-1-carboxylic acid benzyl ester (400 mg, 1.52 mmol) was dissolved in THF (5 mL), and triethylamine (230 mg, 2.28 mmol) was added. The reaction solution was cooled to 0°C, and methanesulfonyl chloride (208 mg, 1.82 mmol) was added dropwise. After the dropwise addition is completed, the temperature is raised to room temperature and the reaction proceeds for 2 hours. Add ammonium chloride aqueous solution to quench, extract with ethyl acetate (20 mLx3), combine several layers and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the intermediate. This intermediate product was dissolved in tetrahydrofuran and added to a mixture of potassium tert-butoxide (340 mg, 3.04 mmol) and compound 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (652 mg, 3.04 mmol). THF (6 mL) solution, and the reaction was continued at 30 °C for 16 hours. Add water to dilute, extract with ethyl acetate (20 mLx3), combine several layers and wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify through column chromatography (PE:EA=5:1) to obtain the target product 4-( 2-((1-(tert-Butoxycarbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+Na] ⁺ =483.2. Step 2: 4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1- Preparation of tert-butyl carboxylate Compound 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid benzyl ester was dissolved in methanol (180 mg, 0.39 mmol ), add palladium on carbon (70 mg). Replace three times under the protection of hydrogen (1 atmosphere), continue the reaction at room temperature for 16 hours, filter with diatomaceous earth, and concentrate the filtrate to obtain the crude product 4-((2-(piperidin-4-yl)ethoxy)methyl) Piperidine-1-carboxylic acid tert-butyl ester was used directly in the next step. Step 3: 4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2-((dimethylamino)methyl) )phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl) Preparation of tert-butyl ethoxy)methyl)piperidine-1-carboxylate To compound (1 R ,4 R )-4-(4-((( R )-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl) To a solution of methyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (130 mg, 0.23 mmol) in DMF (2 mL) was added compound 4 -((2-(Piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (114 mg, 0.35 mmol), TcFH (162 mg, 0.58 mmol) and NMI ( 94 mg, 1.15 mmol) and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mLx3). The organic phases were combined and washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (NH ₃ /MeOH:DCM=1:19~1:9) to obtain the target product 4-((2-(1-((1 R ,4 R )-4-(4-() (( R )-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =867.3. Step 4: ((1 R ,4 R )-4-(4-((( R )-1-(4-( 2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl) Preparation of (4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-yl)methanone Compound 4-((2-(1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-((dimethylamino)) Methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-4- Tert-butyl)ethoxy)methyl)piperidine-1-carboxylate (40 mg, 0.05 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added. The reaction was continued at room temperature for 0.5 hours. The reaction solution was concentrated to obtain crude product ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-(dimethylamino)methyl)phenyl)thiophene- 2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidin-4-ylmethoxy)ethyl) (yl)piperidin-1-yl)methanone was directly used in the next reaction without further purification. LC-MS: (ESI, m/z ): [M+H] ⁺ =767.3. Step 5: 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R )-4-(4-((( R )-1-(4-(2-((dimethylamino)methyl))))phenyl)thiophen-2-yl)ethyl)amino) -7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl ) Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione To ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl) base)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine- To a solution of 1-yl)methanone (50 mg, 0.07mmol) in DMSO (2mL) was added DIEA (103 mg, 0.80mmol) and 4-chloro-3-(2,4-dioxotetrahydropyrimidine-1( 2 H )-yl)pentafluorophenyl benzoate (42 mg, 0.10 mmol) and reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mLx3). The organic phases were combined and washed with brine (10 mL), dried over sodium sulfate, filtered and spun dry. The crude product was purified through preparation to obtain 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-() 2-((dimethylamino)methyl))))phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1017.3. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (s, 1H), 7.65-7.59 (m, 1H), 7.52 (s, 1H), 7.44-7.26 (m, 5H), 7.24-7.16 (m, 2H), 7.01 (s, 1H), 6.11-6.01 (m, 1H), 4.66-4.46 (m, 2H), 4.09 -3.98 (m, 1H), 3.95 (s, 3H), 3.81-3.67 (m, 3H), 3.53-3.40 (m, 4H), 3.16-3.00 (m, 3H), 2.93-2.57 (m, 5H) , 2.52 (s, 3H), 2.23-2.05 (m, 7H), 1.95-1.57 (m, 15H), 1.56-1.51 (m, 2H), 1.34-1.00 (m, 7H).

Example 49: (1 R ,4 R ) -N- (3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl) )-3-azaspiro[5.5]undecan-9-yl)propyl)-4-(7-methoxy-2-methyl-4-((( R )-1-(4-( 2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl) -N -methylcyclohexane-1-methamide step 1: ( E )-9-(3-Ethoxy-3-oxoprop-1-en-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Preparation NaH (214 mg, 5.33 mmol, 60%) was added to DMF (15 mL) at 0 °C, followed by ethyl 2-(diethoxyphosphoryl)acetate (1.20 g, 5.33 mmol). React at 0°C for 30 minutes, add 9-formyl-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.00 g, 3.55 mmol) and stir at room temperature for 3 h. After the reaction was completed, the reaction solution was cooled to 0°C, diluted with NH ₄ Cl aqueous solution (100 mL), and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by chromatography column (PE:EA=0~1:4) to obtain ( E )-9-(3 -Ethoxy-3-oxoprop-1-en-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H-56] ⁺ =296.2. Step 2: 9-(3-ethoxy-3-oxopropyl)-3-azaspiro[5.5 ] Preparation of tert-butyl undecane-3-carboxylate ( E )-9-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ( To a solution of 1.1 g, 3.13 mmol) in EtOH (20 mL) under H _atmosphere and room temperature was added Pd/C (150 mg) and stirred overnight. The mixture was filtered and concentrated to give 9-(3-ethoxy-3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H-56] ⁺ =298.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.12 (q, J = 7.2 Hz, 2H), 3.40-3.30 ( m, 4H), 2.30 (t, J = 7.6 Hz, 2H), 1.71-1.62 (m, 2H), 1.58-1.52 (m, 5H), 1.47-1.42 (m, 10H), 1.31-1.22 (m, 6H), 1.13-1.02 (m, 4H). Step 3: Preparation of 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester 9-(3-Ethoxy-3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 2.83 mmol) was dissolved in THF (25 mL), add LAH (3.4 mmol, 3.4 mL, 1 M/THF) dropwise at 0 °C. Continue the reaction at 0 °C for 1 h, then add Na ₂ SO ₄ .10H ₂ O to quench, and stir for more than 20 minutes. The mixture was filtered, and the filtrate was concentrated to obtain 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, which was directly used in the next reaction. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.63 (t, J = 7.2 Hz, 2H), 3.42-3.29 (m, 4H), 1.69-1.53 (m, 6H), 1.46-1.42 (m, 10H), 1.32-1.22 (m, 6H), 1.12-1.03 (m, 4H). Step 4: 9-(3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tertiary Preparation of butyl ester To a solution of 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (850 mg, 2.7 mmol) in DCM (25 mL) was added portionwise Martin's oxidant (1.37 g, 3.3 mmol). The mixture was stirred at room temperature for 1.5 h. Add aqueous Na ₂ SO ₃ (50 mL) and NaHCO ₃ (50 mL) to quench, and extract with DCM (100 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc=20:1~2:1) to obtain 9-(3-oxopropyl)-3-aza Spiro[5.5]Undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H-100] ⁺ =210.2. Step 5: 9-(3-((4-methoxybenzyl)(methyl)amino)propyl )-3-Azaspiro[5.5]Undecane-3-carboxylic acid tert-butyl ester 9-(3-Oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg, 1.29 mmol) and 1-(4-methoxyphenyl )-N-methylmethylamine (0.39 g, 2.58 mmol) was dissolved in DCM/AcOH (25 mL/0.5 mL) and stirred at room temperature for 1 h. Then NaBH ₃ CN (162 mg, 2.58 mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was diluted with NH ₄ Cl aqueous solution (50 mL), and extracted with DCM (50 mLx3). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated and purified through a chromatography column (DCM:MeOH=200:1~5:1) to obtain 9-(3-((4-methoxybenzyl)(methyl)). tert-butyl)amino)propyl)-3-azaspiro[5.5]undecane-3-carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =445.4. Step 6: N -(4-methoxybenzyl)- N -methyl-3-(3-azaspiro[ 5.5] Preparation of undecane-9-yl)propane-1-amine 9-(3-((4-Methoxybenzyl)(methyl)amino)propyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg , 0.89 mmol) was dissolved in DCM (4.5 mL), and TFA (1.5 mL) was added. The reaction solution was stirred at room temperature for 2 h, and concentrated to obtain N -(4-methoxybenzyl)- N -methyl-3-(3-azaspiro[5.5]undecan-9-yl)propane-1- The amine was used directly in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ =345.3. Step 7: 1-(2-chloro-5-(9-(3-((4-methoxybenzyl))( Preparation of methyl)amino)propyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione To N -(4-methoxybenzyl)- N -methyl-3-(3-azaspiro[5.5]undecan-9-yl)propan-1-amine (400 mg, 0.9 mmol) Perpentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate (470 mg, 1.08 mmol) and DIEA were added to DMSO (2 mL). (350 mg, 2.7 mmol). The reaction solution was stirred at room temperature for 2 h. Add water (10 mL) and extract with EtOAc (20 mLx2). The organic layers were combined and washed with saturated brine (50 mLx3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (DCM:MeOH=200:1~5:1) to obtain 1-(2-chloro-5) -(9-(3-((4-methoxybenzyl)(methyl)amino)propyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ = 595.2. Step 8: 1-(2-chloro-5-(9-(3-(methylamino)propyl)-3 -) Preparation of azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 1-(2-Chloro-5-(9-(3-((4-methoxybenzyl)(methyl)amino)propyl)-3-azaspiro[5.5]undecane-3 -Carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (130 mg, 0.218 mmol) and DIEA (14 mg, 0.11 mmol) were dissolved in DCM (3 mL), 0 °C 2-Chloroethyl chloroformate (47 mg, 0.33 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Then MeOH (3 mL) was added and reacted at 65 °C for 1 h. The mixture was concentrated and purified by column chromatography (DCM:MeOH=200:1~5:1) to obtain 1-(2-chloro-5-(9-(3-(methylamino)propyl)-3- )Azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =475.2. Step 9: (2-(5-(( R )-1-((6-((1 R ,4 R )- 4-((3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine)))-1(2 H )-yl)benzoyl)-3-azaspiro[5.5] Undecyl-9-yl)propyl)(methyl)aminoformyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophene Preparation of -3-yl)benzyl)(methyl)aminocarboxylic acid tert-butyl ester 1-(2-Chloro-5-(9-(3-(methylamino)propyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2 ,4(1 H ,3 H )-diketone (100 mg, 0.21 mmol) was dissolved in DMSO (2 mL), and (1 R ,4 R )-4-(4-((( R )-1- (4-(2-(((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexane-1-carboxylic acid pentafluorophenyl ester (187 mg, 0.23 mmol) and DIEA (82 mg, 0.63 mmol) were reacted at room temperature for 2 h. At the end of the reaction, water (2 mL) was added and extracted with ethyl acetate and water. The combined organic layers were dried over sodium sulfate, filtered and concentrated, and purified by chromatography column (DCM:MeOH=100:1~5:1) to obtain the target compound (2-(5-(( R )-1-((6 -((1 R ,4 R )-4-((3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine)))-1(2 H )-yl)benzyl )-3-azaspiro[5.5]undecan-9-yl)propyl)(methyl)aminoformyl)cyclohexyl)-7-methoxy-2-methylquinazoline-4 -(yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)aminocarboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [1/2(M-100)+H] ⁺ =501.2. Step 10: (1 R ,4 R )- N -(3-(3-(4- Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)propyl)-4 -(7-methoxy-2-methyl-4-((( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl Preparation of )amino)quinazolin-6-yl) -N -methylcyclohexane-1-methamide Compound (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-((3-(3-(4-chloro-3-(2,4-dioxo) Tetrahydropyrimidine))-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)(methyl)aminoformyl)cyclohexyl )-7-Methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)aminocarboxylic acid tert-butyl ester (170 mg , crude product) was dissolved in DCM (4.5 mL) and TFA (1.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated and purified by high performance liquid chromatography to obtain (1 R ,4 R ) -N- (3-(3-(4-chloro-3-(2,4-dioxo) Tetrahydropyrimidine-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)-4-(7-methoxy-2-methyl -4-((( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl) - N -Methylcyclohexane-1-methamide. LC-MS: (ESI, m/z ): [M+H] ⁺ =1001.4. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02-7.96 (m, 1H), 7.65-7.58 (m, 1H) , 7.54-7.48 (m, 1H), 7.42-7.36 (m, 2H), 7.32-7.26 (m, 3H), 7.20-7.10 (m, 2H), 7.01 (s, 1H), 6.06 (q, J = 6.8 Hz, 1H), 3.95 (s, 3H), 3.80-3.63 (m, 6H), 3.48-3.34 (m, 4H), 3.16-2.99 (m, 3H), 2.93-2.82 (m, 3H), 2.76 - 2.62 (m, 1H), 2.52 (s, 3H), 2.22 (s, 3H), 2.03-1.85 (m, 4H), 1.80-1.42 (m, 16H), 1.37-1.15 (m, 8H).

Example 50: 1-(2-chloro-5-(9-(2-(4-((1 R ,4 R ))-4-(7-methoxy-2-methyl-4-(((( R )-1-))4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1 -Carbonyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: Preparation of 9-(2-ethoxy-2-oxoethylene)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester To a stirred solution of NaH (230 mg, 5.61 mmol, 60%) in DMF (15 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (1.26 g, 5.61 mmol). The mixture was stirred at 0 °C for 30 min, then 9-oxo-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 3.74 mmol) was added and stirred at room temperature for 3 h. . The mixture was diluted with aqueous NH ₄ Cl (100 mL) and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (EA:PE=0~1:4) to obtain 9-(2-ethoxy- 2-Oxoethylene)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =338.3. Step 2: 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5.5]ten Preparation of tert-butyl monoalkane-3-carboxylate Dissolve 9-(2-ethoxy-2-oxoethylene)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.1 g, 3.26 mmol) in EtOH ( 20 mL) and stir overnight under _H2 atmosphere. The mixture was filtered and concentrated to give tert-butyl 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate. LC-MS: (ESI, m/z ): [M+H-56] ⁺ =284.2. Step 3: 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3- Preparation of tert-butyl carboxylate 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 3 mmol) was added to THF (1 g, 3 mmol) with stirring. LAH (3.6 mmol, 3.6 mL, 1 M/THF) was added to the solution, and the reaction was carried out at 0 °C to room temperature for 1 h. Na ₂ SO ₄ .10H ₂ O was added to the mixture at room temperature and stirred for more than 1 h. The mixture was filtered and concentrated to obtain the target compound 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H-56] ⁺ =242.2. Step 4: 9-(2-oxoethyl)-3-azaspiro[5.5]undecane-3 -Preparation of tert-butyl carboxylate To a solution of 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (850 mg, 2.5 mmol) in DCM (25 mL) was added with stirring. -Martin's oxidizing agent (1.42 g, 3.6 mmol). The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with aqueous _Na2SO3 (50 mL) and _NaHCO3 (50 mL) and extracted with DCM (100 mLx3 ₎ . The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (EA:PE=0~3:2) to obtain 9-(2-oxoethyl)-3-azaspiro[5.5 ] Undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H-56] ⁺ =240.2. Step 5: 9-(2-(4-(4-methoxybenzyl)piperidine-1-yl) Preparation of tert-butyl ethyl)-3-azaspiro[5.5]undecane-3-carboxylate Add 9-(2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (750 mg, 2.54 mmol) in DCM/HAc (25 mL/0.5 mL) with stirring. ) solution, add 1-(4-methoxybenzyl)piperazine (0.79 g, 3.81 mmol). The mixture was stirred at room temperature for 1 h. Then _NaBH3CN (320 mg, 5.08 mmol) was added. The mixture was diluted with aqueous NH ₄ Cl (50 mL) and extracted with DCM (50 mLx3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=0~1:4) to obtain 9-(2-(4-(4-methoxybenzyl)piperazine). 𠯤-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =486.4. Step 6: 9-(2-(4-(4-methoxybenzyl)piperidine-1-yl)ethyl )-3-Azaspiro[5.5]Undecane Preparation Add 9-(2-(4-(4-methoxybenzyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid to tert-butyl with stirring. To a solution of the ester (100 mg, 0.21 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) dropwise. The mixture was stirred at room temperature for 2 h, and the reaction solution was concentrated under reduced pressure to obtain 9-(2-(4-(4-methoxybenzyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5 ] Undecane. LC-MS: (ESI, m/z ): [M+H] ⁺ =386.4. Step 7: 1-(2-chloro-5-(9-(2-(4-(4-methoxybenzyl) )Piper-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione To 9-(2-(4-(4-methoxybenzyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane (100 mg, crude) in DMSO (2 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (99 mg, 0.23 mmol) and DIEA ( 80 mg, 0.62 mmol). The mixture was stirred at room temperature for 2 h and extracted with EA and water. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=0~1:4) to obtain 1-(2-chloro-5-(9-(2-(4- (4-Methoxybenzyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H , 3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =636.4. Step 8: 1-(2-chloro-5-(9-(2-(piperidine-1-yl)ethyl)) Preparation of ))-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 1-(2-Chloro-5-(9-(2-(4-(4-methoxybenzyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane -3-Carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (90 mg, 0.14 mmol) was dissolved in DCM (2 mL), and 2-chloroethyl chloroformate ( 30 mg, 0.22 mmol) and DIEA (9 mg, 0.071 mmol). The mixture was stirred from 0 °C to room temperature for 2 h. Then additional MeOH (3 mL) was added at 65 °C and stirring was continued for 1 h. The mixture was concentrated and purified by column chromatography (DCM:MeOH=0~1:4) to obtain 1-(2-chloro-5-(9-(2-(piperidine-1-yl)ethyl)))- 3-Azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =516.3. Step 9: (2-(5-(( R )-1-((6-((1 R ,4 R )- 4-(4-(2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2 H )-yl)benzoyl)-3-azaspiro[5.5 ]Undecyl-9-yl)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophene-3 Preparation of -(yl)benzyl)(methyl)aminocarboxylic acid tert-butyl ester 1-(2-Chloro-5-(9-(2-(piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-dione (63 mg, 0.12 mmol) was dissolved in DMSO (2 mL), and (1 R ,4 R )-4-(4-((( R )- 1-(4-(2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)cyclohexane-1-carboxylic acid pentafluorophenyl ester (109 mg, 0.13 mmol) and DIEA (48 mg, 0.36 mmol). The mixture was stirred at room temperature for 2 h and extracted with EA and water. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-(4-(2- (3- (4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)ethyl )Piper-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)amine tert-butyl carboxylate. LC-MS: (ESI, m/z ): [(M-56)/2+H]+=544.3. Step 10: 1-(2-chloro-5-(9-(2-(4-((( 1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-))4-(2-((methylamino)methyl)phenyl )Thien-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]eleven Preparation of alkyl-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Put (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-(4-(2-(3-(4-chloro-3-(2,4- Dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)ethyl)piper-1-carbonyl)cyclohexyl) -7-Methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)aminomethylcarboxylic acid tert-butyl ester (160 mg , crude) was dissolved in DCM (4.5 mL) and TFA (1.5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated and purified by preparative to obtain 1-(2-chloro-5-(9-(2-(4-((1 R ,4 R ))-4-(7-methoxy) -2-Methyl-4-((( R )-1-))4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazole Phin-6-yl) cyclohexane-1-carbonyl) piperazine-1-yl) ethyl)-3-azaspiro[5.5] undecane-3-carbonyl) phenyl) dihydropyrimidine-2, 4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =1042.4. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (s, 1H), 7.68-7.56 (m, 1H), 7.57 -7.48 (m, 1H), 7.45-7.35 (m, 2H), 7.34-7.24 (m, 3H), 7.22-7.10 (m, 2H), 7.01 (s, 1H), 6.06 (q, J = 6.9 Hz , 1H), 3.95 (s, 3H), 3.83-3.73 (m, 2H), 3.74-3.68 (m, 3H), 3.66-3.55 (m, 4H), 3.45-3.34 (m, 2H), 3.12-3.01 (m, 1H), 2.93-2.76 (m, 2H), 2.76-2.66 (m, 1H), 2.55-2.39 (m, 8H), 2.21 (s, 3H), 2.03-1.86 (m, 4H), 1.81 -1.75 (m, 4H), 1.70-1.57 (m, 6H), 1.45-1.16 (m, 14H).

Example 51: 1-(5-(9-((4-(4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)) Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[ 5.5]Undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 9-((4-(tertiary butoxycarbonyl)) Preparation of piperazine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester 9-(Piper-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (400 mg, 1.04 mmol) was dissolved in DCM (10 mL), and ( Boc) ₂ O (272 mg, 1.25 mmol), DMAP (13 mg, 0.1 mmol) and TEA (315 mg, 3.12 mmol). The reaction solution was stirred at room temperature overnight, and then concentrated under reduced pressure. The crude product was purified using column chromatography (PE:EA=1:1) to obtain 9-((4-(tert-butoxycarbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]eleven Alkane-3-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =486.3. Step 2: 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide- Preparation of tert-butyl 1-carboxylate 9-((4-(tert-Butoxycarbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester (300 mg, 0.62 mmol) Dissolve in ethyl acetate (10 mL), add Pd(OH) ₂ /C (100 mg), stir the reaction solution at 70°C for 3 hours, cool, filter, and wash the solid three times with ethyl acetate (10 mL×3). Concentrate under reduced pressure to obtain crude product tert-butyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =352.2. Step 3: 4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1) Preparation of tert-butyl ester of (2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperaniline-1-carboxylate Dissolve tert-butyl 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carboxylate (200 mg, 0.57 mmol) with DMSO (10 mL). Add 4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2 H )-yl)benzoate pentafluorophenyl ester (247 mg, 0.57 mmol) and DIEA (220 mg, 1.71 mmol), The reaction solution was stirred at room temperature for 2 hours, added water (50 mL), extracted with ethyl acetate (25 mL×4), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography (PE:EA =1:10) and purified to obtain 4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro [5.5] Undecan-9-yl)methyl) piperazine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =602.2. Step 4: 1-(2-chloro-5-(9-(piperidine-1-ylmethyl)-3-nitrogen) Preparation of heterospiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-((3-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecane -9-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.58 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and then the reaction solution was stirred at room temperature for 2 hours. Concentrate under reduced pressure, dilute the residue with water (20 mL), slowly add saturated sodium bicarbonate solution dropwise to adjust the reaction solution to neutral, extract with ethyl acetate (25 mL×4), wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain crude product 1-(2-chloro-5-(9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =502.3. Step 5: (3-((1 R )-1-((6-(4-(4-((3-( 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl) piperazine-1-carbonyl)cyclohexan-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzene Preparation of tert-butyl carboxylate 1-(2-Chloro-5-(9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4 (1 H ,3 H )-dione (125 mg, 0.25mmol) was dissolved in DMF (10 mL), and 4-(4-((( R )-1-(3-((tert-butoxycarbonyl) )Amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1- Carboxylic acid (140 mg, 0.23 mmol), HATU (114 mg, 0.30 mmol) and DIEA (129 mg, 1.00 mmol). Stir the reaction solution at room temperature for 2 hours. Add water (100 mL) to precipitate the solid. Filter and wash with water for 3 hours. times, dissolved in dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH:DCM=1:10) to obtain (3-((1 R )-1-((6-(4) -(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]eleven Alk-9-yl)methyl)piperidine-1-carbonyl)cyclohexan-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)- 5-(Trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =1095.5. Step 6: 1-(5-(9-((4-(4-(4-((( R ))-1- (3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1 -Carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-Diketone preparation (3-((1 R )-1-((6-(4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2 H )) -(yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carbonyl)cyclohexan-1-yl)-7-methoxy-2 -Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (100 mg, 0.09 mmol) was dissolved in DCM (5 mL). TFA (1 mL) was added, and the reaction solution was stirred at room temperature overnight, concentrated under reduced pressure, diluted with water (20 mL), slowly added sodium bicarbonate solution dropwise to adjust the reaction solution to neutral, and diluted with dichloromethane (25 mL × 4 ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse phase preparation to obtain 1-(5-(9-((4-(4-(4-((( R )))-1-(3-amino) -5-(Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperamide -1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =984.3. 1H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.18 (s, 1H), 8.06 (s , 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.89 (s , 1H), 6.85 (s, 1H), 6.69 (s, 1H), 5.83 (s, 1H), 5.59-5.47 (m, 3H), 3.85 (s, 3H), 3.80-3.70 (m, 1H), 3.67-3.45 (m, 7H), 2.94-2.82 (m, 1H), 2.77-2.71 (m, 2H), , 2.42-2.10 (m, 13H), 1.89-1.81 (m, 1H), 1.73-1.25 ( m, 15H), 1.18-0.94 (m, 4H).

Example 52: 3-(4-(9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-(( Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl )piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2,6-dione Step 1: 9-((4-( Preparation of tert-butyl (( 9H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate Dissolve 9-aldehyde-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (200 mg, 0.71 mmol) in tetrahydrofuran (4 mL) solution, and add piperazine-1-carboxylic acid (9 H -fluoren-9-yl) methyl ester (219 mg, 0.71 mmol) and sodium triacetyloxyborohydride (449 mg, 2.13 mmol). The reaction solution was stirred at room temperature overnight, and water (40 mL) was added. Dilute, extract with ethyl acetate (80 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 9-((4-( (( 9H -Fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =574.4. Step 2: 4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide- Preparation of 1-carboxylic acid (9 H -fluoren-9-yl) methyl ester 9-(((4-(((9 H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3- Tert-butyl carboxylate (400 mg, 0.7 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4 mmol/L, 5 mL). The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. 4-((3-Azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carboxylic acid ( 9H -fluoren-9-yl)methyl ester is obtained. LC-MS: (ESI, m/z ): [M+H] ⁺ =474.5. Step 3: 4-((3-(4-(2,6-dioxopiperidin-3-yl)benzyl) Preparation of (9H-fluoren-9-yl)methyl)-3-azaspiro[5.5]undecyl-9- yl )methyl)piperidine-1-carboxylate 4-((3-Azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carboxylic acid ( 9H -fluoren-9-yl)methyl ester (340 mg, 0.72 mmol ) was dissolved with DMSO (4 mL), 4-(2,6-dioxopiperidin-3-yl)benzoate pentafluorophenyl ester (287 mg, 0.72 mmol) and DIEA (371 mg, 2.87 mmol) were added, The reaction solution was stirred at room temperature overnight, diluted with water (40 mL), extracted with ethyl acetate (40 mL×3), washed the organic phase with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was used Column chromatography (PE:EA=1:2) purified 4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3-azaspiro[5.5 ]Undecyl-9-yl)methyl)piperamide-1-carboxylic acid ( 9H -fluoren-9-yl)methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =689.5. Step 4: 3-(4-(9-(piperamide-1-ylmethyl)-3-azaspiro[5.5 Preparation of undecane-3-carbonyl)phenyl)piperidine-2,6-dione 4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piper 𠯤-1-carboxylic acid (9 H -fluoren-9-yl) methyl ester (250 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL), then piperidine (0.25 mL) was added, and the reaction solution was at room temperature Stir for 3 hours, directly decompress and concentrate to obtain 3-(4-(9-(piperidin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2 ,6-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =467.4. Step 5: 3-(4-(9-((4-((1 R ,4 R )-4-(4- ((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl ) Preparation of piperidine-2,6-dione 3-(4-(9-(Piper-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2,6-dione (200 mg, 0.43 mmol) was dissolved in DMF (3 mL), (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamine) (yl)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (254 mg , 0.43 mmol), HATU (196 mg, 0.52 mmol) and DIEA (221 mg, 1.7 mmol) were added respectively. The reaction solution was stirred at room temperature for 3 hours, diluted with water (40 mL), and extracted with ethyl acetate (40 mL×3). , the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified using Prep-HPLC to obtain 3-(4-(9-((4-((1 R ,4 R )- 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3 -Carbonyl)phenyl)piperidine-2,6-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1041.6. 1H NMR (400 MHz, DMSO- d ₆ ) δ 10.86 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H ), 8.05 (s, 1H), 7.45 – 7.40 (s, 2H), 7.36 – 7.32 (s, 3H), 7.28 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 1.2 Hz, 1H) , 7.01 (s, 1H), 6.96 (s, 1H), 5.99 – 5.94 (m, 1H), 3.94 – 3.87 (m, 4H), 3.57 (s, 2H), 3.46 (s, 5H), 3.12 (s , 2H), 2.94 (s, 1H), 2.74 – 2.59 (m, 4H), 2.42 (s, 3H), 2.23 (d, J = 13.2 Hz, 5H), 2.17 – 2.04 (m, 4H), 2.01 ( s, 7H), 1.88 – 1.76 (m, 5H), 1.71 (d, J = 6.9 Hz, 4H), 1.68 (s, 1H), 1.64 – 1.48 (m, 8H), 1.23 (s, 2H), 1.07 (s, 3H).

Example 53: 1-(5-(4-((2-(4-(4-(4-(( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)) Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidine-1-yl)ethoxy)methyl) Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(2-((1-(4-chloro-3- (2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester Preparation Dissolve 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (140 mg, 0.32 mmol) with DMSO (5 mL), and add 4 -(2-(Piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (116 mg, 0.35 mmol) and DIEA (124 mg, 0.96 mmol), stirred at room temperature 2 hour, add water (50 mL) and stir for 5 minutes, extract with ethyl acetate (30 mLx3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography. (MeOH:DCM=1:9) was purified to obtain 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))benzoyl) )piperidin-4-yl)methoxy)ethyl)piperidin-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =578.2. Step 2: 1-(2-chloro-5-(4-((2-(piperidine-1-yl)ethoxy) Preparation of methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy Tert-butyl)ethyl)piperidine-1-carboxylate (170 mg, 0.29 mmol) was dissolved in DCM (5 mL), added TFA (1 mL), stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain 1 -(2-Chloro-5-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone, was used directly in the next step. LC-MS: (ESI, m/z ): [M+H] ⁺ =478.2. Step 3: (3-((1 R )-1-((6-(4-(4-(2-(( 1-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine- 1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzene Preparation of tert-butyl carboxylate 1-(2-Chloro-5-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione (170 mg, 0.36 mmol) was dissolved in DMF (5 mL), and 4-(4-((( R ))-1-(3-((tert-butoxycarbonyl)amine) was added (base)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid (150 mg, 0.25 mmol), HATU (124 mg, 0.32 mmol) and DIEA (161 mg, 1.25 mmol), stir at room temperature for 2 hours, add water (50 mL) and stir for 5 minutes, use ethyl acetate (30 mLx3) Extract, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (MeOH:DCM=1:9) to obtain (3-((1 R )- 1-((6-(4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))benzyl) Piperidin-4-yl)methoxy)ethyl)piperidin-1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2-methylquinazolin-4-yl )Amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =1060.4. Step 4: 1-(5-(4-((2-(4-(4-(4-((( R ) -1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-3- En-1-carbonyl)piperidine-1-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones Put (3-((1 R )-1-((6-(4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1() 2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2 -Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (140 mg, 0.13 mmol) was dissolved in DCM (5 mL) , add TFA (1 mL), stir at room temperature for 2 hours, concentrate under reduced pressure, add MeOH/DCM (1/9, 20 mL) to dissolve, then add saturated aqueous sodium bicarbonate solution (20 mL) to adjust the pH to neutral. After stirring for 10 minutes, extract with MeOH/DCM (1/9, 20 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by reverse phase preparation to obtain 1-(5-(4-(( 2-(4-(4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2 -Methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidine-1-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl) Dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =960.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 ( s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.69 (s, 1H), 5.83 (s, 1H), 5.55 – 5.45 (m, 3H), 4.50 – 4.36 (m, 1H) , 3.85 (s, 3H), 3.75 (d, J = 7.2 Hz, 1H), 3.67 – 3.37 (m, 9H), 3.06 (s, 1H), 2.87 (s, 1H), 2.81 – 2.69 (m, 3H ), 2.47 – 2.16 (m, 13H), 1.89 – 1.41 (m, 9H), 1.20 – 1.13 (m, 2H).

Example 54: 1-(2-chloro-5-(4-(3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidin-4-yl)propoxy)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4- Preparation of tert-butyl (3-(p-toluenesulfonyl)propyl)piperidine-1-carboxylate Dissolve tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (3.6 g, 14.81 mmol) in dichloromethane (20 mL), and add TsCl (3.4 g, 17.80 mmol) and DMAP respectively. (180 mg, 1.48 mmol) and TEA (4.5 g, 44.43 mmol), the reaction solution was stirred at room temperature overnight, the reaction solution was directly concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=5:1) to obtain 4-( 3-(p-Toluenesulfonyl)propyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =398.1. Step 2: 4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propoxy) Preparation of piperidine-1-carboxylic acid benzyl ester 4-Hydroxypiperidine-1-carboxylic acid benzyl ester (4.4 g, 18.51 mmol) was dissolved in anhydrous DMF (10 mL) and cooled to 0 °C. NaH (0.6 g, 24.68 mmol) was added, stirred for 0.5 hours, and then incubated. Stir at warm temperature for 1 hour, add tert-butyl 4-(3-(p-toluenesulfonyl)propyl)piperidine-1-carboxylate (4.9 g, 12.34 mmol), and stir the reaction solution at room temperature overnight. Water (100 mL) was added, extracted with ethyl acetate (100 mL×4), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=5:1) to obtain 4- (3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propoxy)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =461.2. Step 3: 4-(3-(piperidine-4-oxy)propyl)piperidine-1-carboxylic acid tertiary Preparation of butyl ester 4-(3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propoxy)piperidine-1-carboxylic acid benzyl ester (540 mg, 1.17 mmol) was dissolved in ethyl acetate (10 mL ) was dissolved, and Pd(OH) ₂ /C (20%, 170 mg) was added. The reaction solution was heated to 70 ℃ and stirred for 3 hours. Cool and filter. The solid was washed three times with ethyl acetate (20 mL×3) and concentrated under reduced pressure. The crude product tert-butyl 4-(3-(piperidin-4-oxy)propyl)piperidine-1-carboxylate was obtained. LC-MS: (ESI, m/z ): [M+H] ⁺ =327.3. Step 4: 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydro) Preparation of tert-butyl pyrimidine-1(2 H )-yl)benzoyl)piperidin-4-yl)oxy)propyl)piperidine-1-carboxylate Dissolve 4-(3-(piperidin-4-oxy)propyl)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.46 mmol) with DMSO (10 mL), and add 4-chloro- 3-(2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (200 mg, 0.46 mmol) and DIEA (178 mg, 1.38 mmol), the reaction solution was stirred at room temperature For 2 hours, add water (50 mL), extract with ethyl acetate (25 mL×4), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the crude product is purified by column chromatography (PE:EA=1:10) Obtain 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxy group )propyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =577.3. Step 5: 1-(2-chloro-5-(4-(3-(piperidin-4-yl)propoxy) ) Preparation of piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxy )Propyl)piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.58 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, the reaction solution was stirred at room temperature overnight, concentrated under reduced pressure, and washed with water ( 10 mL), slowly add saturated sodium bicarbonate solution dropwise, adjust the reaction solution to neutral, extract with ethyl acetate (25 mL×4), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 1- (2-Chloro-5-(4-(3-(piperidin-4-yl)propoxy)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =477.2. Step 6: 1-(2-chloro-5-(4-(3-(1-((1 R ,4 R ) ) -4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propoxy)piperidine-1-carbonyl)phenyl)dihydro Preparation of pyrimidine-2,4(1 H ,3H)-dione 1-(2-Chloro-5-(4-(3-(piperidin-4-yl)propoxy)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone (71 mg, 0.14 mmol), HATU (63 mg, 0.17 mmol) and DIEA (54 mg, 0.42 mmol) were added to (1 R ,4 R )-4-(4-((( R ) -1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl In a solution of quinazolin-6-yl)cyclohexane-1-carboxylic acid (80 mg, 0.14 mmol) in DMF (10 mL), the reaction solution was stirred at room temperature for 2 hours, then water (100 mL) was added, and the reaction mixture was stirred with ethyl acetate. The ester (25 mL R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl) base)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propoxy)piperidine-1-carbonyl) Phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1051.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.02 (s, 1H), 6.97 (s, 1H), 5.97 (s, 1H), 4.45-4.35 (m, 1H), 3.98-3.84 (m, 5H), 3.82 -3.71 (m, 1H), 3.67-3.57 (m, 1H), 3.61-3.50 (m, 2H), 3.41 (t, J = 6.3 Hz, 3H), 3.18-2.90 (m, 6H), 2.78-2.70 (m, 1H), 2.70-2.60 (m, 1H), 2.43 (s, 3H), 2.02 (s, 6H), 1.90-1.40 (m, 20H), 1.30-1.21 (m, 2H), 1.08-0.87 (m, 2H).

Example 55: 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(1,1- Dioxide-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(4-((1-(1,1-Dioxide-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2- Methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (70 mg, 0.14 mmol) was dissolved in DMF (3 mL), 1-(2-chloro-5-(4-((2-( Piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (73.3 mg, 0.15 mmol), HATU (79.8 mg, 0.21 mmol) and DIEA (91 mg, 0.7 mmol) were added respectively. The reaction solution was stirred at room temperature for 1 hour, diluted with water (40 mL), extracted with ethyl acetate (40 mL×3), and the organic phase was washed with saturated salt. Wash with water (40 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by prep-HPLC to obtain 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R )) -4-(4-((( R )-1-(1,1-dioxide-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =968.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.27 (d, J = 7.0 Hz, 1H), 8.06 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.67-7.57 (m, 2H), 7.56 – 7.48 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H ), 6.98 (s, 1H), 5.59 (t, J = 7.4 Hz, 1H), 4.39 (d, J = 11.8 Hz, 2H), 3.91 (s, 1H), 3.87 (s, 3H), 3.81-3.70 (m, 2H), 3.67 – 3.59 (m, 3H), 3.54-3.46 (m, 1H), 3.42 (t, J = 6.4 Hz, 2H), 3.29 (s, 1H), 3.24 (d, J = 6.4 Hz, 2H), 3.11 – 2.90 (m, 3H), 2.82-2.62 (m, 4H), 2.32 (s, 3H), 2.12 – 1.23 (m, 20H), 1.20-0.90 (m, 4H).

Example 56: 1-(2-chloro-5-(4-(4-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidin-4-yl)butyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-( 4-(4-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidine-1-yl)butyl)piperidine-1 -Preparation of tert-butyl carboxylate 4-(4-(Piper-1-yl)butyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) and 4-chloro-3-(2,4-dioxo Tetrahydropyrimidine-1(2 H )-yl)pentafluorophenyl benzoate (133 mg, 0.31 mmol) was dissolved in DMSO (3 mL), DIEA (198 mg, 1.54 mmol) was added with stirring, and stirred at room temperature for 1 hours. After the reaction, the reaction solution was poured into water (30 mL), extracted with EA (30 mL =10:1) was purified to obtain 4-(4-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)piperidine-1 -(yl)butyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =576.3. Step 2: 1-(2-chloro-5-(4-(4-(piperidin-4-yl)butyl)) Preparation of piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-(4-(4-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidine-1-yl)butyl) Dissolve piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.19 mmol) in DCM (2 mL), add 0.2 mL TFA, react at room temperature for 1 hour, and directly concentrate under reduced pressure to obtain 1-(2 -Chloro-5-(4-(4-(piperidin-4-yl)butyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 476.3 Step 3: 1-(2-chloro-5-(4-(4-(1-((1 R ,4 R ))- 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)- 7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)butyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine- Preparation of 2,4(1 H ,3 H )-diketone 1-(2-Chloro-5-(4-(4-(piperidin-4-yl)butyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone (165 mg, 0.195 mmol) and (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino) )methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (115 mg, 0.195 mmol), dissolved in DMF (3 mL), added HATU (86 mg, 0.227 mmol) and DIEA (75 mg, 0.584 mmol) with stirring, and reacted at room temperature for 1 h. After the reaction, the reaction solution was poured into water (50 mL), and extracted with EA (30 mL×3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified using prep-HPLC to obtain 1- (2-chloro-5-(4-(4-(1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-(( Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl )Piperidin-4-yl)butyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ) : [M+H] ⁺ = 1050.7. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.46 – 7.30 (m, 4H), 7.24 (d, J = 1.4 Hz, 1H), 7.02 (s, 1H) , 6.96 (s, 1H), 5.96 (dd, J = 14.4, 7.2 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.89 (s, 4H), 3.78 – 3.71 (m, 1H), 3.62 (d, J = 6.0 Hz, 3H), 3.11 (d, J = 15.8 Hz, 2H), 3.01-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.68 – 2.58 (m, 2H) , 2.42 (s, 6H), 2.34 – 2.18 (m, 4H), 2.01 (s, 6H), 1.85 (d, J = 9.6 Hz, 2H), 1.79 (d, J = 11.5 Hz, 2H), 1.72 ( d, J = 7.0 Hz, 4H), 1.65 (d, J = 12.4 Hz, 2H), 1.60 – 1.50 (m, 3H), 1.42 (d, J = 7.4 Hz, 3H), 1.34 – 1.14 (m, 5H ), 1.02 – 0.82 (m, 2H).

Example 57: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2-chloro-6 -((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone step 1: 4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-(trifluoromethyl)benzyl Preparation of tert-butyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate 4-(2-(Piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol), 3-(2,4-dioxotetrakis Hydropyrimidin-1(2 H )-yl)-4-(trifluoromethyl)benzoic acid pentafluorophenyl ester (133 mg, 0.31 mmol) was dissolved in DMSO (3 mL), and DIEA (198 mg, 1.54 mmol), react at room temperature for 1 hour. After the reaction, dilute with water (30 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is separated by column chromatography to obtain 4- (2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-(trifluoromethyl)benzoyl)piperidin-4-yl) Methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+Na] ⁺ =633.2. Step 2: 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl) ) Preparation of piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-(trifluoromethyl)benzoyl)piperidine-4 -(Methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.8 mL) was added, and the reaction solution React at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl) Base)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione was directly used in the next reaction without purification. Step 3: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1 -Carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H ) -Preparation of diketones 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone (TFA salt, 165 mg , 0.195 mmol) and (1 R ,4 R )-4-(4-((( R )-1-(4-( 2-Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl ) Cyclohexane-1-carboxylic acid (115.3 mg, 0.195 mmol) was dissolved in DMF (3 mL), and HATU (86.3 mg, 0.227 mmol) and DIEA (75.4 mg, 0.584 mmol) were added with stirring. The reaction solution was allowed to react at room temperature for 1 h. After the reaction, it was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using prep-HPLC to obtain 1- (5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2-chloro-6-((dimethyl Amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine -4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1085.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.53 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.37 – 7.31 (m, 1H), 7.24 (d, J = 1.3 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.00-5.92 (m, 1H), 4.53-4.31 (m, 2H), 3.94 – 3.82 (m, 5H), 3.52-3.37 (m, 4H), 3.23 (d, J = 6.1 Hz, 2H), 3.12 (d, J = 2.1 Hz, 2H), 3.07 – 2.90 (m, 3H), 2.85-2.74 (m, 1H), 2.72-2.58 (m, 3H), 2.42 (s, 3H), 2.01 (s, 6H), 1.89-1.50 (m, 18H), 1.48- 1.40 (m, 2H), 1.21-0.91 (m, 4H).

Example 58: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2-chloro-6 -((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethoxy)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-(trifluoromethoxy) Preparation of tert-butyl benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate 3-(2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)-4-(trifluoromethoxy)benzoate pentafluorophenyl ester (150 mg, 0.31 mmol) and 4-( 2-(Piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) was dissolved in DMSO (3 mL), and DIEA (198 mg, 198 mg, 1.54 mmol) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was poured into water (30 mL), extracted with EA (30 mL =10:1) purified to obtain 4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-(trifluoromethoxy)benzene Formyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+Na] ⁺ = 649.3. Step 2: 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl) ) Preparation of piperidine-1-carbonyl)-2-(trifluoromethoxy)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))-4-(trifluoromethoxy)benzoyl)piperidine- 4-yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.17 mmol) was dissolved in DCM (2 mL), TFA (0.2 mL) was added, and the reaction solution was kept at room temperature. React for 1 hour, and directly concentrate under reduced pressure to obtain 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl) Oxy)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 527.3 Step 3: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-( 4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoro Preparation of methoxy)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethoxy)phenyl)dihydro Pyrimidine-2,4(1 H ,3 H )-dione (90 mg, 0.17 mmol) and (1 R ,4 R )-4-(4-((( R )-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carboxylic acid (100 mg, 0.17 mmol), dissolved in DMF (3 mL), added HATU (84 mg, 0.22 mmol) and DIEA (66 mg, 0.51 mmol) with stirring, and reacted at room temperature 1 h. After the reaction, the reaction solution was poured into water (50 mL), extracted with EA (30 mL 5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamine) Base)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine- 4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethoxy)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1101.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.54 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4, 1.4 Hz, 1H), 7.49-7.30 (m, 4H), 7.24 (d, J = 1.3 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.02 – 5.91 (m, 1H), 4.52 – 4.33 (m, 2H), 3.98-3.90 (m, 4H), 3.80- 3.65 (m, 2H), 3.61-3.51 (m, 1H), 3.41 (t, J = 6.3 Hz, 2H), 3.23 (d, J = 6.2 Hz, 2H), 3.15 – 2.89 (m, 5H), 2.82 -2.60 (m, 4H), 2.42 (s, 3H), 2.01 (s, 6H), 1.89 – 1.40 (m, 20H), 1.20-0.90 (m, 4H).

Example 59: 1-(5-(9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-(( Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl )Piper-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone step 1: 9-((4-((benzyloxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tertiary Preparation of butyl ester 9-Aldehyde-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (300 mg, 1.06 mmol) and piperazine-1-carboxylic acid benzyl ester (235 mg, 1.06 mmol) were used Tetrahydrofuran (10 mL) was dissolved, and sodium triacetoxyborohydride (674 mg, 3.18 mmol) was added with stirring. After stirring at room temperature for 2 hours, add water (50 mL), extract with dichloromethane (30 mLx3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Use a column for the crude product. Purification by chromatography (methanol:dichloromethane=1:9) yielded 9-((4-((benzyloxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]eleven Alkane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =486.2. Step 2: 9-(piperidine-1-ylmethyl)-3-azaspiro[5.5]undecane-3 -Preparation of tert-butyl carboxylate 9-((4-((Benzyloxy)carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (500 mg, 1.02 mmol) was dissolved in ethyl acetate (15 mL), Pd(OH) ₂ /C (250 mg, 0.35 mmol) was added, the temperature was raised to 70 °C under a hydrogen atmosphere, and the mixture was stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 9-(piperidine-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. The crude product was not needed The purification was used directly in the next reaction. LC-MS: (ESI, m/z ): [M+H] ⁺ =352.2. Step 3: 9-((4-((1 R ,4 R )-4-(4-((( R )- 1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquin Preparation of tert-butyl ester of oxazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate 9-(Piper-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (130 mg, 0.36 mmol) was dissolved in DMF (10 mL) and added (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl))thiophen-2-yl )ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (200 mg, 0.33 mmol), HATU (188 mg, 0.49 mmol) and DIEA (127 mg, 0.99 mmol), stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (3 x 30 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography. (Methanol:dichloromethane=1:9) purified to obtain 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6) -((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-Carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =926.4. Step 4: (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide -1-yl)((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl) Preparation of )thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)methanone 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)methyl)benzene yl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl )-3-Azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (230 mg, 0.25 mmol) was dissolved in DCM (3 mL), added TFA (1 mL), and stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide-1-yl)((1 R ,4 R )-4-( 4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)methanone. LC-MS: (ESI, m/z ): [M+H] ⁺ =826.5. Step 5: 1-(5-(9-((4-((1 R ,4 R )-4-(4- ((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2 Preparation of -methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (4-((3-azaspiro[5.5]undecan-9-yl)methyl)pipero-1-yl)((1 R ,4 R )-4-(4-((( R ) -1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexyl)methanone (110 mg, 0.12 mmol) was dissolved in DMSO (10 mL), and 3-(2,4-dioxotetrahydropyrimidine-1(2 H )- was added (57 mg, 0.13 mmol) and DIEA (46 mg, 0.36 mmol), and stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, extracted with dichloromethane (30 mLx3), the organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by pre-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5% ~ 95%) to obtain 1-(5-(9-((4-((1 R ,4 R ))-4-( 4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl) -2-Methoxyphenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1072.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.43 (t, J = 8.1 Hz, 2H), 7.38 – 7.33 (m, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.00 – 5.92 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.49-3.37 (m, 4H), 3.17 – 3.09 (m, 2H), 2.94 (t, J = 12.0 Hz, 1H), 2.68 (t, J = 6.6 Hz, 2H), 2.65-2.43 (m, 2H), 2.42 (s, 3H), 2.33-2.26 (m, 4H), 2.16-2.08 (m, 2H), 2.02 (s, 6H), 1.83-1.46 (m, 21H), 1.35-1.24 (m, 2H), 1.16-0.90 (m, 4H).

Example 60: 1-(5-(9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-(( Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl )Piper-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-fluorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone (4-((3-azaspiro[5.5]undecan-9-yl)methyl)pipero-1-yl)((1 R ,4 R )-4-(4-((( R ) -1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexyl)methanone (110 mg, 0.12 mmol) was dissolved in DMSO (5 mL), and 3-(2,4-dioxotetrahydropyrimidine-1(2 H )- was added Pentafluorophenyl)-4-fluorobenzoate (54 mg, 0.13 mmol) and DIEA (46 mg, 0.36 mmol) were stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, extracted with dichloromethane (30 mLx3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by pre-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5%~95%) to obtain 1-(5-(9-((4-((1 R ,4 R ))-4-( 4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl) -2-Fluorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ =1060.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.52 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.38 (m, 5H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.04 – 5.88 (m, 1H), 3.89 (s, 3H), 3.75 (t, J = 6.6 Hz, 2H), 3.57 (s, 2H), 3.46 (s, 4H), 3.30 – 3.26 (m, 1H) , 3.11 (d, J = 15.1 Hz, 2H), 2.94 (m, 1H), 2.73 (t, J = 6.6 Hz, 2H), 2.63 (m, 1H), 2.42 (s, 3H), 2.32 (s, 2H), 2.29 (s, 2H), 2.11 (s, 2H), 2.01 (s, 6H), 1.90 – 1.39 (m, 19H), 1.34 (m, 2H), 1.07 (m, 4H).

Example 61: 1-(2-chloro-5-(4-(3-((1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2) -Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(3-((1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)methyl) Base)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl Preparation of )oxy)propyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(Piperidin-4-oxy)propyl)piperidine-1-carboxylic acid tert-butyl ester (105 mg, 0.32 mmol), HATU (145 mg, 0.38 mmol) and DIEA (123 mg , 0.96 mmol) was added to (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl) )thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (190 mg, 0.32 mmol) in DMF ( 5 mL) solution, stirred at room temperature for 2 hours, diluted with water (50 mL), extracted with ethyl acetate (25 mL×4), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 4-(3- ((1-((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)) Thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl ) piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =901.4. Step 2: ((1 R ,4 R )-4-(4-((( R )-1-(4-( 2-Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl Preparation of )cyclohexyl)(4-(3-(piperidin-4-yl)propoxy)piperidin-1-yl)methanone 4-(3-((1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)) Methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-4- tert-butyl)oxy)propyl)piperidine-1-carboxylate (170 mg, 0.19 mmol) was dissolved in DCM (5 mL), added TFA (1 mL), stirred at room temperature for 2 hours, and the reaction solution was reduced to Concentrate under pressure to obtain crude product ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)) Thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)propoxy base)piperidin-1-yl)methanone. LC-MS: (ESI, m/z ): [M+H] ⁺ =801.4. Step 3: 1-(2-chloro-5-(4-(3-((1-((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amine )-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperidine-1-carbonyl)phenyl) Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)thiophene-2 -yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperidin-4-yl)propoxy)piper Dissolve din-1-yl)methanone (150 mg, 0.19 mmol) with DMSO (10 mL), and add 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl) ) Pentafluorophenyl benzoate (97 mg, 0.23 mmol) and DIEA (72 mg, 0.56 mmol), stir at room temperature for 2 hours, dilute with water (50 mL), extract with ethyl acetate (25 mL×4), saturated salt Wash with water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by reverse phase preparation to obtain 1-(2-chloro-5-(4-(3-((1-((1 R ,4 R ))-4- (4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7- Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =1051.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.48 – 7.30 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.03-5.87 (m, 1H), 4.53-4.33 (m, 1H), 3.93-3.81 (m, 4H), 3.79-3.45 (m, 5H), 3.41 (t, J = 6.2 Hz, 2H), 3.27 – 3.20 (m, 1H), 3.18 – 2.99 (m, 4H), 2.99-2.89 (m, 1H), 2.80-2.60 (m, 4H), 2.42 ( s, 3H), 2.01 (s, 6H), 1.88 – 1.23 (m, 22H), 1.10-1.00 (m, 2H).

Example 62: 1-(2-chloro-5-(9-(2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone step 1: 4-(2-(3-azaspiro[5.5]undecan-9-yl)ethyl)piperidine-1-carboxylic acid ( 9H -fluoren-9-yl)methyl Preparation of esters Compound 9-(2-(4-((9 H -fluoren-9-yl)methoxy)carbonyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane -Tert-butyl-3-carboxylate (70 mg, 0.12 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4M, 7 mL), stirred at room temperature for 1 hour, and directly concentrated under reduced pressure to obtain 4-( 2-(3-Azaspiro[5.5]undecan-9-yl)ethyl)piperidine-1-carboxylic acid ( 9H -fluoren-9-yl)methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 488.5. Step 2: 4-(2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidine) -1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)ethyl)piperbenzoyl)-1-carboxylic acid (9 H -fluoren-9-yl) Preparation of methyl ester 4-(2-(3-Azaspiro[5.5]undecan-9-yl)ethyl)piperidine-1-carboxylic acid (9 H -fluoren-9-yl)methyl ester (70 mg, 0.12 mmol ) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (52 mg, 0.12 mmol) were dissolved in DMSO (4 mL) and added DIPEA (46 mg, 0.36 mmol), and the reaction solution was stirred at room temperature overnight. Dilute with water (40 mL), extract with ethyl acetate (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography (EA in PE=0-4:1) to obtain 4-(2- (3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl )ethyl)piperidine-1-carboxylic acid ( 9H -fluoren-9-yl)methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 738.5. Step 3: 1-(2-chloro-5-(9-(2-(piperidine-1-yl)ethyl)) Preparation of -3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione 4-(2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[5.5]eleven Alk-9-yl)ethyl)piperidine-1-carboxylic acid ( 9H -fluoren-9-yl)methyl ester (70 mg, 0.09 mmol) was dissolved in DCM (2 mL), and piperidine (0.3 mL) was added , the reaction solution was stirred at room temperature for 3 hours, diluted with water (20 mL), extracted with dichloromethane (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to column chromatography (DCM:MeOH=95:5) Purification yields 1-(2-chloro-5-(9-(2-(piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydro Pyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z ): [M+Na] ⁺ = 516.3. Step 4: 1-(2-chloro-5-(9-(2-(4-((1 R ,4 R ) ) -4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane- Preparation of 3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 1-(2-Chloro-5-(9-(2-(piperidine-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine- 2,4(1 H ,3 H )-diketone (30 mg, 0.06 mmol) and (1 R ,4 R )-4-(4-((( R )-1-(4-(2-(( Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxy Acid (34 mg, 0.06 mmol) was dissolved in DMF (3 mL), HATU (27 mg, 0.07 mmol) and DIEA (23 mg, 0.18 mmol) were added, and the reaction solution was stirred at room temperature overnight. Dilute with water (30 mL), extract with ethyl acetate (30 mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product using prep-HPLC to obtain 1-(2-chloro-5-(9-(2- (4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophene -2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)ethyl)-3 -Azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1090.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.47 – 7.28 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H ), 6.96 (s, 1H), 6.00-5.92 (m, 1H), 3.89 (s, 3H), 3.80-3.71 (m, 1H), 3.66-3.42 (m, 8H), 3.12 (s, 2H), 3.00-2.90 (m, 1H), 2.78-2.71 (m, 2H), 2.65-2.57 (m, 2H), 2.42 (s, 3H), 2.36-2.23 (m, 6H), 2.01 (s, 6H), 1.89-1.75 (m, 4H), 1.72-1.29 (m, 18H), 1.16-1.00 (m, 4H).

Example 63: 1-(5-(4-((3-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-() Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl )(methyl)amino)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(3-hydroxypropyl) ) Preparation of piperidine-1-carboxylic acid tert-butyl ester Dissolve 3-(piperidin-4-yl)propan-1-ol (700 mg, 4.9 mmol) in 1,4-dioxane (7 mL), then add Boc anhydride (2.1 g, 9.8 mmol) and DMAP (30 mg, 0.24 mmol), the reaction solution was heated to 80 °C overnight. After the reaction, pour into water (60 mL), extract with ethyl acetate (30 mL×3), dry over anhydrous sodium sulfate, spin the organic phase to dryness, and purify the crude product using column chromatography (EA:PE=0-3:7) 4-(3-hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester is obtained. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.34 (t, J = 5.1 Hz, 1H), 3.91 (d, J = 12.3 Hz, 2H), 3.37 (dd, J = 11.9, 6.3 Hz, 2H) , 2.66 (s, 2H), 1.61 (d, J = 12.3 Hz, 2H), 1.50 – 1.28 (m, 12H), 1.20 (dd, J = 15.2, 6.9 Hz, 2H), 0.93 (m, 2H). Step 2: Preparation of tert-butyl 4-(3-propionaldehyde)piperidine-1-carboxylate Dissolve tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (300 mg, 1.2 mmol) in acetonitrile (5 mL), then add IBX (567 mg, 2.4 mmol), and heat the reaction solution React at 70°C for 2 hours, filter, wash the filter cake with ethyl acetate (10 mL×2), spin the organic phase to dryness, and purify the crude product using column chromatography (EA:PE=0-1:4) to obtain 4-( 3-Propanal) piperidine-1-carboxylic acid tert-butyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.68 (t, J = 1.5 Hz, 1H), 3.91 (d, J = 12.0 Hz, 2H), 2.65 (m, 2H), 2.46 (td, J = 7.5, 1.5 Hz, 2H), 1.61 (d, J = 13.0 Hz, 2H), 1.46 (dd, J = 14.5, 7.3 Hz, 2H), 1.42 – 1.33 (m, 10H), 0.94 (m, 2H). Step 3: Preparation of benzyl 4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylate Combine 4-(3-propionaldehyde)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.82 mmol) and 4-(methylamino)piperidine-1-carboxylic acid benzyl ester (205 mg, 0.82 mmol) was dissolved in tetrahydrofuran (4 mL), then sodium triacetoxyborohydride (525 mg, 2.48 mmol) was added, and the reaction solution was stirred at room temperature overnight. Dilute with water (40 mL), extract with ethyl acetate (30 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography (EA:PE=0-3:7) to obtain white oil 4 -((3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =474.3. Step 4: 4-(methyl(3-(piperidin-4-yl)propyl)amino)piperidine-1 -Preparation of benzyl carboxylate 4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester (90 mg, 0.19 mmol) Dissolve in DCM (5 mL), then trifluoroacetic acid (0.5 mL) was added, the reaction solution was stirred at room temperature for 1 hour, and directly concentrated under reduced pressure to obtain an oily substance 4-(methyl(3-(piperidine- 4-yl)propyl)amino)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 374.1. Step 5: 4-((3-(1-((1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazole Preparation of phenylin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester Put (1 R ,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl )Amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (110 mg, 0.18 mmol) and 4-(methyl(3-(piperidine) -4-yl)propyl)amino)piperidine-1-carboxylic acid benzyl ester (trifluoroacetate, 90 mg, 0.18 mmol) was dissolved in DMF (3 mL), HATU (83 mg, 0.22 mmol) and DIEA (70 mg, 0.54 mmol) was added, the reaction solution was stirred at room temperature overnight, diluted with water (30 mL), extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to column chromatography ( MeOH:DCM=0-1:9) was purified to obtain 4-((3-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-((third Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- Carbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =958.2. Step 6: (3-(( R )-1-((7-methoxy-2-methyl-6-( (1 R ,4 R )-4-(4-(3-(methyl(piperidin-4-yl)amino)propyl)piperidin-1-carbonyl)cyclohexyl)quinazolin-4-yl Preparation of tert-butyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate Put 4-((3-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino))-5-( Trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl )(Methyl)amino)piperidine-1-carboxylic acid benzyl ester (100 mg, 0.1 mmol) was dissolved in MeOH (5 mL), added Pd/C (20 mg), replaced with hydrogen three times, and placed under hydrogen protection Stir at room temperature for 1 hour. Filter, wash the filter cake with methanol (5 mL×3), and concentrate the filtrate under reduced pressure to obtain (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R )-4-(4-(3-(methyl(piperidin-4-yl)amino)propyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl tert-butyl)-5-(trifluoromethyl)phenyl)carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =824.1. Step 7: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)(methyl )Amino)propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl )Phenyl) Preparation of tert-butyl carboxylate Compound (3-(( R )-1-((7-methoxy-2-methyl-6-((1 R ,4 R ))-4-(4-(3-(methyl(piperidine) -4-yl)amino)propyl)piperidine-1-carbonyl)cyclohexyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid Tributyl ester (75 mg, 0.09 mmol) and pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate (39 mg, 0.09 mmol) Dissolve in DMSO (2 mL), add DIEA (35 mg, 0.27 mmol), and stir the reaction solution at room temperature overnight. Dilute with water (20 mL), extract with ethyl acetate (30 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography (MeOH:DCM=0-5:95) to obtain (3-(( R )-1-((6-((1 R ,4 R )-4-(4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1) (2 H )-yl)benzoyl)piperidin-4-yl)(methyl)amino)propyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquin Zozolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ = 1074.3. Step 8: 1-(5-(4-((3-(1-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( Preparation of 1 H ,3 H )-diketone Put (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(3-((1-(4-chloro-3-(2,4-dioxo) Substituted ectoine-1(2 H )-yl)benzyl)piperidin-4-yl)(methyl)amino)propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy -2-Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (40 mg, 0.04 mmol) was dissolved in dichloromethane ( 3 mL), then add trifluoroacetic acid (0.3 mL), stir at room temperature for 1 hour, directly concentrate under reduced pressure, adjust the pH to 8-9 with saturated sodium bicarbonate aqueous solution, and extract with dichloromethane (20 mL×3) , dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified using prep-HPLC to obtain 1-(5-(4-((3-(1-((1 R ,4 R ))-4-(4-((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carbonyl)piperidin-4-yl)propyl)(methyl)amino)piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =974.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.15 – 8.02 (m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 10.8 Hz, 2H), 6.70 (s, 1H), 5.64 – 5.47 (m, 3H), 4.54-4.48 (m, 2H), 3.96-3.88 (m, 4H), 3.88-3.80 (m, 1H), 3.80- 3.74 (m, 2H), 3.05-2.95 (m, 3H), 2.91-2.85 (m, 2H), 2.40-2.30 (m, 6H), 2.15 (s, 3H), 1.91-1.42 (m, 23H), 1.25-1.15 (m, 2H), 1.06 – 0.84 (m, 2H).

Example 64: 1-(5-(4-((2-(1-(4-(4-(( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)) Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-en-1-carbonyl)piperidin-4-yl)ethoxy)methyl) Piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(4-hydroxy-7-methoxy-2-methyl Preparation of methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate 6-Bromo-7-methoxy-2-methylquinazolin-4-ol (6.2 g, 23.22 mmol) was added to Pd(dppf)Cl ₂ (850 mg, 1.16 mmol), sodium carbonate (4.9 g , 46.44 mmol) and 4-(4,4,5,5-tetramethyl-1,3-dioxopent-2-yl)cyclohex-3-ene-1-carboxylic acid tert-butyl ester (8.1 g, 30.19 mmol) in a mixed solution of DMF/H ₂ O (80 mL/8 mL), stir at room temperature overnight, after the reaction is complete, add water (800 mL) to dilute, and use ethyl acetate (200 mL×5) Extract, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified using column chromatography (PE:EA=1:100) to obtain 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1- Methyl carboxylate. LC-MS: (ESI, m/z ): [M+H] ⁺ =329.0. Step 2: 4-(4-((( R )-1-(3-((tert-butoxycarbonyl))amine )-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl Preparation of esters 4-(4-Hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (600 mg, 1.82 mmol) was added to DBU ( 820 mg, 5.37 mmol) and BOP (1.19 g, 2.69 mmol) in DMF (10 mL), stirred at room temperature for 30 min, ( R )-(3-(1-aminoethyl)-5- (Trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (600 mg, 1.97 mmol) was added, and the reaction solution was stirred at 70°C overnight. Dilute with water (100 mL) to precipitate a solid, filter, and wash with water three times. Dissolve the solid with dichloromethane (100 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (PE:EA=1:1). Obtain 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =615.2. Step 3: 4-(4-((( R )-1-(3-((tert-butoxycarbonyl))amine )-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid Preparation 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (1.1 g, 1.79 mmol) was added to lithium hydroxide (430 mg, 17.9 mmol) in THF/ H ₂ O (20 mL/10 mL) solution, under nitrogen protection, stir overnight at 50°C. Under an ice bath, slowly add 10% citric acid dropwise, adjust the solution to weak acidity or neutrality, and use ethyl acetate ( 100 ml -5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid. LC-MS: (ESI, m/z ): [M+H] ⁺ =601.2. Step 4: (3-((1 R )-1-((6-(4-(4-(2-(( 1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine- 1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzene Preparation of tert-butyl carboxylate 4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid (130 mg, 0.22 mmol), HATU (100 mg, 0.26 mmol) and DIEA (85 mg, 0.66 mmol) ) was added to 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2, A solution of 4(1 H , 3 H )-diketone (140 mg, 0.23 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. Water (100 mL) was added to precipitate the solid, filtered, washed with water 3 times, and Dissolve in dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product (3-((1 R )-1-((6-(4-(4-(2-((1-(4-chloro- 3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexan- 1-En-1-yl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)tert-butylcarboxylate ester. LC-MS: (ESI, m/z ): [M+H] ⁺ =1059.5. Step 5: 1-(5-(4-((2-(1-(4-(4-((( R ) -1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-3- En-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-di Preparation of ketones Put (3-((1 R )-1-((6-(4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine-1() 2 H )-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidin-1-carbonyl)cyclohex-1-en-1-yl)-7-methoxy-2 -Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (190 mg, 0.18 mmol) with dichloromethane (5 mL) Dissolve, add trifluoroacetic acid (1 mL), stir the reaction solution at room temperature for 2 hours, concentrate under reduced pressure, and purify the crude product using reverse phase preparation to obtain 1-(5-(4-((2-(1-(4-(4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )cyclohex-3-en-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z ): [M+H] ⁺ =959.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.19 (s, 1H), 8.07 ( s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), 6.99 (s, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.69 (s, 1H), 5.83 (s, 1H), 5.61-5.43 (m, 3H), 4.51-4.37 (m, 2H), 4.00-3.90 ( m, 1H), 3.85 (s, 3H), 3.80-3.70 (m, 1H), 3.67-3.52 (m, 2H), 3.41 (t, J = 6.3 Hz, 2H), 3.24 (d, J = 6.4 Hz , 2H), 3.12-2.97 (m, 2H), 2.92-2.70 (m, 4H), 2.42-2.16 (m, 7H), 1.90-1.56 (m, 8H), 1.56-1.41 (m, 5H), 1.21 -0.90 (m, 4H).

Example 65: 1-(2-chloro-5-(4-(((1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2-chloro -6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan Alk-1-carbonyl)piperidin-4-yl)methoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: Preparation of tert-butyl 4-((pyridin-4-ylmethoxy)methyl)piperidine-1-carboxylate 4-(Hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.65 mmol) was dissolved in THF (40 mL) solution, and NaH (744 mg, 18.6 mmol, 60%) was added at 0 °C. ), stir for 2 h, then add 4-(bromomethyl)pyridine (795 mg, 4.65 mmol), continue stirring the reaction solution at room temperature for 2 h, dilute with water (100 mL), and extract with ethyl acetate (100 mL×2) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:0) to obtain 4-((pyridin-4-ylmethoxy)methyl)piperidine- 1-tert-butylcarboxylate. LC-MS: (ESI, m/z): [M+Na] ⁺ =329.1. Step 2: 4-((piperidin-4-ylmethoxy)methyl)piperidine-1-carboxylic acid tertiary Preparation of butyl ester Dissolve 4-((pyridin-4-ylmethoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.98 mmol) in i-PrOH/H ₂ O (6:7, 26 mL) solution under a hydrogen atmosphere, add Pd(OH)/C (100 mg, 20%), the reaction solution was stirred at 75°C overnight, filtered through diatomaceous earth, and the filtrate was directly concentrated under reduced pressure to obtain 4-((piperidine- 4-ylmethoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =313.2. Step 3: 4-(((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidine- Preparation of tert-butyl 1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)methyl)piperidine-1-carboxylate To DMSO (10 mL), then add 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (165 mg, 0.38 mmol), and the reaction solution is at room temperature. Stir for 30 min, dilute with water (40 mL), extract with ethyl acetate (40 mL×3), wash the organic phase with saturated brine (40 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to column chromatography (PE :EA=10:1) was purified to obtain 4-(((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidine- 4-yl)methoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+NH ₄ ] ⁺ =580.2. Step 4: 1-(2-chloro-5-(4-((piperidin-4-ylmethoxy)methyl) Preparation of piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy) Methyl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), hydrogen chloride dihexane solution (4M, 2 mL) was added, and the reaction solution was stirred at room temperature for 3 hour, directly concentrate under reduced pressure to obtain 1-(2-chloro-5-(4-((piperidin-4-ylmethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2, 4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z): [M+H] ⁺ =463.1. Step 5: 1-(2-chloro-5-(4-(((1-((1 R ,4 R ))- 4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)- 7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)methyl)piperidin-1-carbonyl)phenyl) Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl))thiophen-2-yl )ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (65 mg, 0.11mmol) was dissolved in DMF (5 mL), HATU (50 mg, 0.13 mmol), DIEA (50 mg, 0.39 mmol) and 1-(2-chloro-5-(4-((piperidin-4-ylmethoxy)methyl)piperidine-1-carbonyl) )phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (60 mg, 0.13 mmol) was added respectively, the reaction solution was stirred at room temperature for 30 min, diluted with water (20 mL), and ethyl acetate ( 20 mL 1-((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)thiophene- 2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)methyl )piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1037.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.47-7.29 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.02 - 5.90 (m, 1H), 4.52 - 4.32 (m, 2H), 3.98-3.91(m, 1H), 3.89 (s, 3H), 3.80- 3.69 (m, 1H), 3.66-3.54 (m, 2H), 3.28-3.17 (m, 4H), 3.15-3.09 (m, 2H), 3.09 - 2.89 (m, 3H), 2.84 - 2.69 (m, 3H ), 2.69-2.60 (m, 2H), 2.42 (s, 3H), 2.01 (s, 6H), 1.91 - 1.46 (m, 17H), 1.20-0.89 (m, 4H).

Example 66: 1-(5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(1,1-dioxide- 2,3-Dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl) Piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 1-(5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-dione (120 mg, 0.24 mmol) and (1 R ,4 R )-4-(4-((( R ))-1-(1,1-dioxido di Oxide-2,3-dihydrobenzo[b]thiophen-4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1 -Carboxylic acid (120 mg, 0.24 mmol) was dissolved in DMF (3 mL), HATU (108 mg, 0.28 mmol) and DIEA (90 mg, 0.71 mmol) were added, and the reaction solution was stirred at room temperature for 1 hour. Dilute with water (30 mL), extract with ethyl acetate (30 mL (2-(1-((1 R ,4 R )-4-(4-((( R ))-1-(1,1-dioxide-2,3-dihydrobenzo[b]thiophene- 4-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl )piperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1002.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.53 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.70 (s, 1H), 7.59 (t, J = 6.6 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 6.98 (s, 1H), 5.58 (t, J = 7.0 Hz, 1H), 4.57 – 4.33 (m, 2H), 3.99 – 3.84 (m, 5H ), 3.81 – 3.70 (m, 1H), 3.68 – 3.60 (m, 2H), 3.52-3.40 (m, 5H), 3.24 (d, J = 6.2 Hz, 2H), 3.14 – 2.89 (m, 3H), 2.85-2.65 (m, 4H), 2.32 (s, 3H), 1.92 – 1.40 (m, 20H), 1.23 – 0.89 (m, 4H).

Example 67: 1-(2-chloro-5-(4-((2-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2 -Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidine-1-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 1-(2-Chloro-5-(4-((2-(piperidin-1-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1 H ,3 H )-diketone (150 mg, crude) was dissolved in DMF (5 mL), (1 R ,4 R )-4-(4-((( R )-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carboxylic acid (94 mg, 0.22 mmol), HATU (107 mg, 0.28 mmol) and DIEA (145 mg, 1.1 mmol) were added respectively, stirred at room temperature for 2 hours, added water (50 mL) and stirred for 5 minutes , extracted with ethyl acetate (30 mLx3), washed the organic phase with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparation to obtain 1-(2-chloro-5- (4-((2-(4-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)) Methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1- Base)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1052.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.48 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.45 – 7.31 (m, 4H), 7.23 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 5.96 (t, J = 7.1 Hz, 1H), 4.52 – 4.28 (m, 1H), 3.89 (s, 3H), 3.80 – 3.40 (m, 10H) , 3.26 (d, J = 6.3 Hz, 2H), 3.12 (s, 2H), 2.97 – 2.88 (m, 1H), 2.79 – 2.59 (m, 4H), 2.45 – 2.39 (m, 5H), 2.38 – 2.33 (m, 2H), 2.01 (s, 6H), 1.94 – 1.46 (m, 16H), 1.13 (d, J = 10.9 Hz, 2H).

Example 68: 1-(2-chloro-5-(4-(3-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidine-1-yl)propoxy)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4- Preparation of tert-butyl (3-(piperidin-4-yloxy)propyl)piperidine-1-carboxylate 4-(3-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxy)propyl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.87mmol) and Pd/ C (10%, 100 mg) was dissolved in ethyl acetate (10 mL), the reaction solution was heated to 70 °C and stirred for 3 hours, filtered, the solid was washed three times with ethyl acetate (10 mL×3), and concentrated under reduced pressure to obtain 4 -(3-(Piperidin-4-yloxy)propyl)piperidin-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =328.3. Step 2: 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydro) Preparation of tert-butyl pyrimidine-1( 2H )-yl)benzoyl)piperidin-4-yl)oxy)propyl)piperidin-1-carboxylate Dissolve 4-(3-(piperidin-4-yloxy)propyl)piperidin-1-carboxylic acid tert-butyl ester (230 mg, 0.70 mmol) with DMSO (10 mL), 4-chloro-3- (2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)pentafluorophenyl benzoate (360 mg, 0.82 mmol) and DIEA (271 mg, 2.10 mmol) were added respectively, and stirred at room temperature overnight. Dilute with water (50 mL), extract with ethyl acetate (25 mL×4), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (PE:EA=1:10) to obtain 4-( 3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxy)propyl)piperyl 𠯤-1-tert-butylcarboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =578.3. Step 3: 1-(2-chloro-5-(4-(3-(piperidine-1-yl)propoxy) ) Preparation of piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)oxy) Dissolve propyl)piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.47 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), stir the reaction solution at room temperature overnight, and slowly add dropwise Saturated sodium bicarbonate aqueous solution, adjust the pH value of the reaction solution to 7-8, extract with a five-to-one mixed solution of methylene chloride and isopropanol (25 mL×4), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 1 -(2-Chloro-5-(4-(3-(piperidin-1-yl)propoxy)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H ) -Diketones. LC-MS: (ESI, m/z): [M+H] ⁺ =478.2. Step 4: 1-(2-chloro-5-(4-(3-(4-((1 R ,4 R ) ) -4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)propoxy)piperidine-1-carbonyl)phenyl)dihydro Preparation of pyrimidine-2,4(1 H ,3 H )-dione 1-(2-Chloro-5-(4-(3-(piperidin-1-yl)propoxy)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-diketone (90 mg, 0.19 mmol), HATU (87 mg, 0.23 mmol) and DIEA (74 mg, 0.57 mmol) were added to (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methyl Quinazolin-6-yl)cyclohexane-1-carboxylic acid (106 mg, 0.19 mmol) in DMF (10 mL), stirred at room temperature for 2 hours, diluted with water (100 mL), precipitated solid, filtered , washed 3 times with water, dissolved the solid with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified using reverse phase preparation to obtain 1-(2-chloro-5-(4-(3-(4-(( 1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl) Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)propoxy)piperidine-1-carbonyl )phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1052.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.47 – 7.30 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H ), 6.97 (s, 1H), 5.97 (t, J = 7.2 Hz, 1H), 4.00-3.84 (s, 4H), 3.80-3.71 (m, 1H), 3.66-3.57 (m, 1H), 3.49- 3.35 (m, 8H), 3.20-3.07 (m, 3H), 3.00-2.84 (m,1H), 2.78-2.58 (m, 3H), 2.42 (s, 3H), 2.40-2.26 (m, 6H), 2.01 (s, 6H), 1.92-1.75 (m, 6H), 1.75 – 1.38 (m, 12H).

Example 69: 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2) -Chloro-6-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1 : (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((methylamino)methyl)phenyl)thiophen-2-yl) Preparation of tert-butyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate Compound (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-aldehydephenyl)thiophen-2-yl)ethyl)amino)- Methyl 7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (450 mg, 0.78 mmol) and methylamine (2 M/THF solution, 7.8 mmol) were dissolved in To dichloroethane (10 mL), sodium triacetylborohydride (496 mg, 2.34 mmol) was added. The reaction solution was heated to 80°C and stirred for 1 hour. Directly concentrate under reduced pressure, and the crude product is purified using column chromatography (MeOH:DCM=1:10, flow rate 40 ml/min) to obtain (1 R ,4 R )-4-(4-((( R )-1-(4 -(2-chloro-6-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazoline-6- base) tert-butyl cyclohexane-1-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =593.3. Step 2: (1 R ,4 R )-4-(4-((( R )-1-(4-(2 -Chloro-6-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Preparation of hexane-1-carboxylic acid (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((methylamino)methyl)phenyl))thiophen-2-yl )ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid tert-butyl ester (300 mg, 0.5 mmol) and lithium hydroxide ( 60 mg, 2.5 mmol) was dissolved in mixed solution (MeOH/H ₂ O=10/1, 5 mL). The reaction solution was heated to 70°C and stirred for 2 hours. Cool, use 1M HCl to adjust the pH value of the reaction solution to 3~4, then use saturated sodium bicarbonate aqueous solution to adjust the pH value of the reaction solution to 7~8, extract with ethyl acetate (100 mL×3), and combine the organic phases. Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified using reverse phase (ACN:H ₂ O=1:1) to obtain (1 R , 4 R )-4-(4-((( R ) -1-(4-(2-chloro-6-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquin Zozolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ =579.2. Step 3: 1-(2-chloro-5-(4-((2-(1-((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl ) Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((methylamino)methyl)phenyl))thiophen-2-yl )Ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (80 mg, 0.14 mmol) was dissolved in DMF (5 mL), HATU (65 mg, 0.17 mmol), 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-carbonyl)phenyl)di Hydropyrimidine-2,4(1 H ,3 H )-dione (80 mg, 0.17 mmol) and DIEA (54 mg, 0.42 mmol) were added, the reaction solution was stirred at room temperature for 1 hour, diluted with water (20 mL), and acetic acid Extract with ethyl ester (20 mL×3), wash the organic phase with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified using prep-HPLC to obtain 1-(2-chloro-5-( 4-((2-(1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2-chloro-6-((methylamino)methyl) )phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl) Ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1037.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.42 – 7.30 ( m, 3H), 7.28 (s, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 6.07 – 5.86 (m, 1H), 4.38 (d, J = 12.6 Hz, 2H), 3.89 (s , 4H), 3.73 (d, J = 7.1 Hz, 1H), 3.66 – 3.51 (m, 2H), 3.44 – 3.36 (m, 4H), 3.23 (d, J = 6.2 Hz, 2H), 3.11 – 2.88 ( m, 3H), 2.78 – 2.59 (m, 4H), 2.42 (s, 3H), 2.12 (s, 3H), 1.92 – 1.39 (m, 21H), 1.18 – 0.87 (m, 4H).

Example 70: 1-(2-chloro-5-(4-(2-((1-((1 R ,4 R ))-4-(4-((( R )-1-(4-(2) -Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione step 1: 4-(2-((1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino) )methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-4 Preparation of -(yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophene-2- (ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (80 mg, 0.13 mmol), HATU ( 62 mg, 0.16 mmol ) and DIEA (50 mg, 0.39 mmol) were added to tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (43 mg, 0.13 mmol). DMF (5 mL) solution, stirred at room temperature for 1 hour, diluted with water (50 mL), precipitated solid, filtered, washed with water 3 times, dissolved the solid with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, used reverse phase for the crude product Preparation and purification gave 4-(2-((1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamine) Base)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine- 4-yl)methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =901.4. Step 2: ((1 R ,4 R )-4-(4-((( R )-1-(4-( 2-Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl Preparation of )cyclohexyl)(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)methanone 4-(2-((1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)) Methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-4- (Methoxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.09 mmol) was added to a solution of hydrogen chloride in dioxane (4M, 2 mL), and the reaction solution was stirred at room temperature for 1 hour. , directly concentrated under reduced pressure to obtain crude product ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)) Phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-((2-(piperidine-4- yl)ethoxy)methyl)piperidin-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ =801.3. Step 3: 1-(2-chloro-5-(4-(2-((1-((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amine )-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)benzene Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)thiophene-2 -yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-((2-(piperidin-4-yl)ethoxy) Methyl)piperidin-1-yl)methanone (70 mg, 0.09 mmol) was added to 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoic acid penta A solution of fluorophenyl ester (39 mg, 0.08 mmol) and DIEA (35 mg, 0.27 mmol) in DMSO (5 mL) was stirred at room temperature overnight, diluted with water (50 mL), and extracted with ethyl acetate (25 mL×4) , washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by reverse phase preparation to obtain 1-(2-chloro-5-(4-(2-((1-((1 R ,4 R ))-4 -(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperidin-1-carbonyl)phenyl)di Hydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1051.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.45-7.31 (m, 4H), 7.24 (d, J = 1.3 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.03 – 5.89 (m, 1H), 4.48-4.32 (m, 2H), 3.97-3.85 (m, 4H), 3.79-3.68 ( m, 1H), 3.66-3.52 (m, 2H), 3.40 (t, J = 6.4 Hz, 2H), 3.21 (d, J = 6.1 Hz, 2H), 3.16 – 2.90 (m, 5H), 2.82 – 2.52 (m, 7H), 2.42 (s, 3H), 2.01 (s, 6H), 1.88 – 1.43 (m, 20H), 1.19 – 0.90 (m, 4H).

Example 71: 1-(2-chloro-5-(4-(4-(4-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-( 4-(4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl) )thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl) Preparation of piperidine-1-carboxylic acid tert-butyl ester (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophene-2- (ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (120 mg, 0.20 mmol), 4-(4-(piperate) 𠯤-1-yl)butyl)piperidine-1-carboxylic acid tert-butyl ester (66 mg, 0.20 mmol) and HATU (91 mg, 0.24 mmol) were dissolved in DMF (3mL), and DIEA (78 mg, 0.61 mmol), stir the reaction solution at room temperature for 1 hour, dilute with water (30 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and use the crude product Column chromatography (DCM:MeOH=10:1) gave 4-(4-(4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro) -6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan Alk-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =900.6. Step 2: ((1 R ,4 R )-4-(4-((( R )-1-(4-( 2-Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl Preparation of )cyclohexyl)(4-(4-(piperidin-4-yl)butyl)piperidin-1-yl)methanone 4-(4-(4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-(dimethylamino)methyl) Base)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl )Butyl) piperidine-1-carboxylic acid tert-butyl ester (149 mg, 0.17 mmol) was dissolved with hydrogen chloride in 1,4-dioxane solution (4M, 5 mL), stirred at room temperature for 1 hour, and then directly reduced the pressure Concentration gave ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)thiophene- 2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(4-(piperidin-4-yl)butyl)piper 𠯤-1-yl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ =800.4. Step 3: 1-(2-chloro-5-(4-(4-(4-((1 R ,4 R ) ) -4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-Methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)butyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine Preparation of -2,4(1 H ,3 H )-dione ((1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-(dimethylamino)methyl)phenyl)thiophene-2 -yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(4-(piperidin-4-yl)butyl)piperidine𠯤 -1-yl)methanone (158 mg, 0.11 mmol), 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (47 mg , 0.11 mmol) was dissolved in DMSO (2 mL), DIEA (42 mg, 0.32 mmol) was added with stirring, and stirred at room temperature for 1 hour. Dilute with water (30 mL), extract with ethyl acetate (30 mL Chloro-5-(4-(4-(4-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethyl Amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine -1-yl)butyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1050.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.47 – 7.31 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H ), 6.96 (s, 1H), 6.01 – 5.90 (m, 1H), 4.50-4.42 (m, 1H), 3.89 (s, 3H), 3.80-3.68 (m, 1H), 3.66-3.52 (m, 2H ), 3.50-3.40 (m, 4H), 3.18-3.10 (m, 2H), 3.02-2.90 (m, 2H), 2.80-2.65 (m, 4H), 2.42 (s, 3H), 2.38-2.20 (m , 6H), 2.01 (s, 6H), 1.82-1.42 (m, 18H), 1.30-1.22 (m, 4H), 1.13-0.96 (m, 2H).

Example 72: 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl) Base)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-aza Spiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(4-hydroxy-2,7- Preparation of methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate 6-Bromo-2,7-dimethylquinazolin-4-ol (900 mg, 3.56 mmol) was dissolved in DMF/H ₂ O (22 mL, 10/1), and 4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (1135 mg, 4.27 mmol), sodium carbonate (755 mg, 7.12 mmol) and Pd(dppf)Cl ₂ (264 mg, 0.36 mmol), stir overnight at 110°C under nitrogen protection, add water (100 mL) and stir for 5 minutes, extract with ethyl acetate (100 mLx3), saturated brine (200 mL), wash the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (MeOH:DCM=1:9) to obtain 4-(4-hydroxy-2,7-methylquin). Zozolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =313.1. Step 2: (1 R ,4 R )-4-(4-hydroxy-2,7-dimethylquinazoline- Preparation of 6-yl)cyclohexane-1-carboxylic acid methyl ester In the autoclave (100 mL), add 4-(4-hydroxy-2,7-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (380 mg, 1.22 mmol), dissolve it with MeOH (30 mL), add Pd(OH) ₂ /C (115 mg, 30%), react in a hydrogen environment (2MPa) at 70 °C for 48 h, filter, concentrate under reduced pressure, and use the crude product (1 R ,4 R )-4-(4-hydroxy-2,7-dimethylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester was obtained by reverse phase preparation and purification. LC-MS: (ESI, m/z): [M+H] ⁺ =315.2. ¹ H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 8.15 (s, 1H), 7.56 (s, 1H ), 3.92 (s, 3H), 2.95 (t, J = 11.6 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 2.35 – 2.24 (m, 1H), 2.06 (d, J = 10.7 Hz, 2H), 1.90 – 1.84 (m, 2H), 1.67 – 1.40 (m, 4H). Step 3: (1 R ,4 R )-4-(2,7-dimethyl-4-(( Preparation of ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester Dissolve (1 R ,4 R )-4-(4-hydroxy-2,7-dimethylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (250 mg, 0.80 mmol) in DMF (5 mL), add BOP (506 mg, 1.19 mmol) and DBU (303 mg, 1.99 mmol), stir at room temperature for 0.5 hours, add (R)-1-(3-nitro-5-(trifluoro Methyl)phenyl)ethane-1-amine (224 mg, 0.96 mmol), heated to 70°C and stirred overnight, added water (50 mL) and stirred for 5 minutes, extracted with ethyl acetate (30 mLx3), saturated brine (50 mL), washed the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase to obtain (1 R , 4 R )-4-(2,7-dimethyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =531.3. Step 4: (1 R ,4 R )-4-(2,7-dimethyl-4-((( R ) Preparation of -1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid (1 R ,4 R )-4-(2,7-dimethyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) Amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (210 mg, 0.40 mmol) was dissolved in THF/H ₂ O (15 mL, 2:1), and lithium hydroxide ( 190 mg, 8.00 mmol), stir at 50°C overnight, add water (20 mL), adjust pH to 6 with 1M hydrochloric acid, extract with MeOH/DCM (1/9, 30 mL×3), dry over anhydrous sodium sulfate, filter, Concentrate under reduced pressure to obtain (1 R ,4 R )-4-(2,7-dimethyl-4-((( R ))-1-(3-nitro-5-(trifluoromethyl)phenyl) )ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid was used directly in the next step. LC-MS: (ESI, m/z): [M+H] ⁺ =517.4. Step 5: (1 R ,4 R )-4-(4-((( R )-1-(3-amino) Preparation of -5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)cyclohexane-1-carboxylic acid (1 R ,4 R )-4-(2,7-dimethyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl) Amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.29 mmol), dissolved in ethanol (10 mL), added Raney nickel (0.5 mL) and N ₂ H ₄ -H ₂ O (85%, 0.5 mL), react at room temperature for 0.5 hours, filter, and concentrate under reduced pressure to obtain (1 R ,4 R )-4-(4-((( R )-1-(3-amino- 5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)cyclohexane-1-carboxylic acid. LC-MS: (ESI, m/z): [M+H] ⁺ =487.2. Step 6: 1-(5-(9-((4-((1 R ,4 R )-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl)cyclohexane -1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone (1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7- Dimethylquinazolin-6-yl)cyclohexane-1-carboxylic acid (70 mg, 0.14 mmol) was dissolved in DMF (5 mL), and 1-(2-chloro-5-(9-(piperamide)) was added -1-ylmethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (84 mg, 0.17 mmol ), DIEA (55 mg, 0.42 mmol) and pyBOP (88 mg, 0.17 mmol), react at room temperature for 1 h, add water (50 mL) and stir for 5 minutes, extract with ethyl acetate (30 mL×3), saturated salt The organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparation to obtain 1-(5-(9-((4-((1 R ,4 R ))-4 -(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylquinazolin-6-yl )cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4 (1 H ,3 H )-diketone. LC-MS: (ESI, m/z): [M+H] ⁺ =970.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.45 – 7.31 (m, 2H), 6.87 (d, J = 11.3 Hz, 2H), 6.70 (s, 1H), 5.67 – 5.45 (m, 3H), 3.82-3.70 (m, 1H), 3.67 – 3.42 (m, 8H), 2.87 – 2.64 (m, 5H), 2.43 ( s, 3H), 2.39 -2.22 (m, 7H), 2.18-2.09 (m, 2H), 1.90-1.78 (m, 4H), 1.73-1.24 (m, 14H), 1.18-0.94 (m, 4H).

Example 73: 1-(2-methoxy-5-(9-(((4-((1 R ,4 R ))-4-(7-methoxy-2-methyl-4-(((( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1- Carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione step 1: (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-(4-((3-(3-(2,4-dioxotetrahydro) Pyrimidine-1(2 H )-yl)-4-methoxybenzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperamide-1-carbonyl)cyclohexane Preparation of )-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylic acid tert-butyl ester 3-(2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoate pentafluorophenyl ester (118 mg, 0.27 mmol) and (2-(5-( ( R )-1-((6-((1 R ,4 R )-4-(4-((3-azaspiro[5.5]undecan-9-yl)methyl)piper𠯤-1- Carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylic acid (300 mg, 0.34 mmol) in DMSO (6 mL), then DIEA (132 mg, 1.02 mmol) was added. The reaction solution was stirred at room temperature for 2 h. The reaction was diluted with water (50 mL) and EA (50 mLx3). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (/MeOH(NH ₃ )/DCM 0% ~ 20%) to obtain (2-(5-(( R )-1-((6-((1 R ,4 R ))-4- (4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-methoxybenzoyl)-3-azaspiro[5.5]ten Alk-9-yl)methyl)piperidine-1-carbonyl)cyclohexane)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophene-3- (Byl)benzyl)(methyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M/2+H] ⁺ = 563.5 . Step 2: 1-(2-methoxy-5-(9-((4-((1 R ,4 R )-4-(7-methoxy-2-methyl-4-((( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophene-2- Base)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl Preparation of )phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione At room temperature, add (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-(4-((3-(3-(2,4-) Dioxotetrahydropyrimidine-1(2 H )-yl)-4-methoxybenzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)pipermethol-1- Carbonyl)cyclohexane)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylic acid tert-butyl ester (72 mg, 0.064 mmol) in DCM (3 mL) was added with TFA (1 ml), and the reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain 1-(2-methoxy-5-(9-((4-((1 R ,4 R ))-4-(7-methoxy-2-methyl-4- ((( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane -1-Carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )- diketone. LC-MS: (ESI, m/z): [M+H] ⁺ =1024.4. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (s, 1H), 7.46 – 7.36 (m, 3H), 7.34 – 7.27 (m, 3H), 7.22-7.12 (m, 3H), 7.01 (s, 1H), 6.10-6.02 (m, 1H), 3.95-3.91 (m, 6H), 3.75-3.45 (m, 12H) , 3.12-3.01 (m, 1H), 2.80 (t, J = 6.7 Hz, 2H), 2.75–2.66 (m, 1H), 2.52 (s, 3H), 2.44 (m, 2H), 2.38 (m, 2H ), 2.25 – 2.16 (m, 5H), 2.00 – 1.84 (m, 4H), 1.79 (d, J = 7.0 Hz, 4H), 1.71-1.54 (m, 9H), 1.37-1.12 (m, 7H).

Example 74: 1-(2-fluoro-5-(9-((4-((1 R ,4 R ))-4-(7-methoxy-2-methyl-4-((( R ) -1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl) Pipera-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-(4-((3-(3-(2,4-dioxotetrahydropyrimidine- 1(2 H )-yl)-4-fluorobenzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperbenzoyl)-1-carbonyl)cyclohexyl)-7-methyl Preparation of tert-butyl oxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate 3-(2,4-Dioxotetrahydropyrimidin-1(2 H )-yl)-4-fluorobenzoic acid pentafluorophenyl ester (133 mg, 0.32 mmol) and (2-(5-(( R )-1-((6-((1 R ,4 R )-4-(4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide-1-carbonyl) Cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylic acid tert-butyl ester (350 mg , 0.39 mmol) was dissolved in DMSO (6 mL), and DIEA (132 mg, 1.02 mmol) was added. The reaction solution was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with EA (50 mLx3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH(NH ₃ )/DCM, 0% ~20%) to obtain (2-(5-(( R )-1-((6-((1 R ,4 R ))-4- (4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)-4-fluorobenzoate)-3-azaspiro[5.5]undecane -9-yl)methyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl (Methyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M/2+H] ⁺ = 556.9. Step 2: 1-(2-fluoro-5-(9-((4-((1 R ,4 R ) -4-(7-methoxy-2-methyl-4-((( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl) Ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)benzene Preparation of dihydropyrimidine-2,4(1 H ,3 H )-dione At room temperature, to (2-(5-(( R )-1-((6-((1 R ,4 R ))-4-(4-((3-(3-(2,4-dioxo) Substituted ectoine-1(2 H )-yl)-4-fluorobenzyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-carbonyl)cyclohexyl )-7-Methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylic acid tert-butyl ester (100 mg, 0.09 mmol) in DCM (3 mL) was added TFA (1 ml). The reaction solution was stirred at room temperature for 2 h. The reaction solution was directly concentrated. The crude product was purified by prep-HPLC to obtain 1-(2-fluoro-5-(9-((4-((1 R ,4 R ))-4-(7-methoxy-2-methyl-4-(( ( R )-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1 -Carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione . LC-MS: (ESI, m/z): [M+H] ⁺ =1012.3. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (s, 1H), 7.52 (dd, J = 7.1, 1.9 Hz , 1H), 7.46-7.39 (m, 2H), 7.36-7.27 (m, 4H), 7.21-7.17 (m, 1H), 7.15-7.11 (m, 1H), 7.01 (s, 1H), 6.08-6.03 (m, 1H), 3.95 (s, 3H), 3.83 (t, J = 6.7 Hz, 2H), 3.77–3.55 (m, 8H), 3.50-3.37 (m, 2H), 3.10-3.00 (m, 1H ), 2.83 (t, J = 6.7 Hz, 2H), 2.76-2.65 (m, 1H), 2.52 (s, 3H), 2.44 (b, 2H), 2.38 (b, 2H), 2.25-2.16 (m, 5H), 2.00-1.83 (m, 4H), 1.82-1.75 (m, 4H), 1.69–1.46 (m, 9H), 1.36-1.06 (m, 7H).

Example 75: 1-(5-(4-(((1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(trifluoro) Methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy) Methyl-d ₂ )piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 4-(hydroxymethyl-d ₂ ) Preparation of piperidine-1-carboxylic acid tert-butyl ester 1-(tert-butyl)4-ethylpiperidine-1,4-dicarboxylate (500 mg, 1.93 mmol) was dissolved in ethanol (20 mL), and NaBD ₄ (325 mg, 7.75) was added at 0 °C. mmol) and stir for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mLx3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 4-(hydroxymethyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.42 (s, 1H), 3.93 (d, J = 11.9 Hz, 2H), 2.67 (s, 2H), 1.62 (d, J = 12.9 Hz, 2H) , 1.55 – 1.44 (m, 1H), 1.39 (s, 9H), 0.96 (m, 2H). Step 2: 4-((pyridin-4-ylmethoxy)methyl-d ₂ )piperidine-1 -Preparation of tert-butyl carboxylate 4-(Hydroxymethyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.14 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and the temperature was lowered to 0 °C in a nitrogen atmosphere and NaH (364 mg, 9.12 mmol), after stirring for 3 hours, add 4-(bromomethyl)pyridine hydrobromide (576 mg, 2.28 mmol), and stir at room temperature overnight. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mLx3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using column chromatography (methanol:dichloromethane=1:9) to obtain 4-((pyridin-4-ylmethoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =309.1 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.53 (dd, J = 4.5, 1.5 Hz, 2H), 7.31 (d , J = 5.8 Hz, 2H), 4.51 (s, 2H), 3.94 (d, J = 12.0 Hz, 2H), 2.70 (s, 2H), 1.76 (m, 1H), 1.67 (d, J = 12.9 Hz , 2H), 1.39 (s, 9H), 1.06 (m, 2H). Step 3: 4-((piperidin-4-ylmethoxy)methyl-d ₂ )piperidine-1-carboxylic acid tertiary Preparation of butyl ester Dissolve 4-((pyridin-4-ylmethoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.58 mmol) in isopropyl alcohol (10 mL) and water ( 10 mL), add Pd/C (60 mg, 0.058 mmol), raise the temperature to 70 °C under a hydrogen atmosphere and stir overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-((piperidin-4-ylmethoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester. The crude product was directly processed without purification. used for the next reaction. LC-MS: (ESI, m/z): [M+H] ⁺ =315.2. Step 4: 4-(((1-((1 R ,4 R )-4-(4-((( R ) -1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline- Preparation of 6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester 4-((Piperidin-4-ylmethoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.41 mmol) was dissolved in DMF (10 mL), and ( 1R,4 R )-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (150 mg, 0.25 mmol), HATU (123 mg, 0.32 mmol) and DIEA (96 mg, 0.74 mmol) and stirred at room temperature for 1 hour. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (30 mLx3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (methanol :Dichloromethane=1:9) purified to obtain 4-(((1-((1 R ,4 R )-4-(4-((( R ))-1-(3-((tert-butoxycarbonyl) )Amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piper (ridin-4-yl)methoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =899.5. Step 5: ((1 R ,4 R )-4-(4-((( R )-1-(3-amine Base-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-((piperidine-4 Preparation of -ylmethoxy- _d2 )methyl)piperidin-1-yl)methanone 4-(((1-((1 R ,4 R ))-4-(4-((( R )-1-(3-((tert-butoxycarbonyl)amino))-5-(trifluoro Methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy) Methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.22 mmol) was dissolved in DCM (5 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amine base)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-((piperidin-4-ylmethoxy-d ₂ )methyl)piperidine-1- base) methanone. LC-MS: (ESI, m/z): [M+H] ⁺ =699.4 Step 6: 1-(5-(4-(((1-((1 R ,4 R ))-4-(4- ((( R )-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone ((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)cyclohexyl)(4-((piperidin-4-ylmethoxy-d ₂ )methyl)piperidin-1-yl)methanone (crude Product, 200 mg, 0.22 mmol) was dissolved in DMSO (10 mL) and 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorobenzene was added Ester (95 mg, 0.22 mmol) and DIEA (86 mg, 0.66 mmol), stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, extracted with dichloromethane (30 mLx3), and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by pre-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5%~95%) to obtain 1-(5-(4-(((1-((1 R ,4 R ))-4- (4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-diketone. LC-MS: (ESI, m/z): [M+H] ⁺ =949.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ δ 10.50 (s, 1H), 8.15 – 8.02 (m, 2H) , 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.63 – 5.48 (m, 3H), 4.51-4.36 (m, 2H), 3.99 – 3.86 (m, 4H), 3.78-3.71 (m, 1H), 3.65-3.53 (m, 2H), 3.23 (d, J = 6.1 Hz, 2H), 3.09-2.90 (m, 3H), 2.81-2.62 (m, 4H), 2.35 (s, 3H), 1.91 – 1.52 (m, 18H), 1.18-0.92 (m, 4H).

Example 76: 1-(5-(4-(((1-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoro Methyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy- d ₂ )Methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 4-(((1-(4- Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidine-1- Preparation of tert-butyl carboxylate Dissolve 4-((piperidin-4-ylmethoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.57 mmol) with dimethylsulfoxide (5 mL). Then 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (247 mg, 0.57 mmol) and N,N-diisopropyl were added Ethylamine (220 mg, 1.71 mmol), stir the reaction solution at room temperature for 2 hours, dilute with water (50 mL), extract with dichloromethane (30 mLx3), wash the organic phase with saturated brine (100 mL), and filter with anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography (methanol: dichloromethane=1:9) to obtain 4-(((1-(4-chloro-3-(2,4-dioxotetrakis) Hydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =565.2. Step 2: 1-(2-chloro-5-(4-((piperidin-4-ylmethoxy-d ₂ Preparation of )methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione 4-(((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy) Methyl-d ₂ )piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 2 hour, directly concentrate under reduced pressure to obtain 1-(2-chloro-5-(4-((piperidin-4-ylmethoxy-d ₂ )methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone was used directly in the next reaction without purification. LC-MS: (ESI, m/z): [M+H] ⁺ =465.3. Step 3: (3-(( R )-1-((6-((1 R ,4 R )-4-( 4-(((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)methane Base-d ₂ )piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)benzene Preparation of tert-butyl carboxylate 1-(2-Chloro-5-(4-((piperidin-4-ylmethoxy-d ₂ )methyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H , 3H )-diketone (220 mg, 0.39 mmol) was dissolved in DMF (10 mL), and then ( 1R , 4R )-4-(4-((( R ))-1-(3- (((tert-Butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan Alkane-1-carboxylic acid (150 mg, 0.24 mmol), HATU (118 mg, 0.31 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol), stir at room temperature for 2 hours, add water ( 100 mL), extracted with ethyl acetate (30 mLx3), washed the organic phase with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography (methanol:dichloromethane=1 :9) purified to obtain (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(((1-(4-chloro-3-(2,4-) Dioxotetrahydropyrimidine-1(2 H )-yl)benzyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidine-1-carbonyl)cyclohexyl)-7-methyl Oxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =1049.3. Step 4: 1-(5-(4-(((1-((1 R ,4 R ))-4-(4 -((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl )cyclohexane-1-carbonyl)piperidin-4-yl)methoxy-d ₂ )methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H , Preparation of 3 H )-diketone Put (3-(( R )-1-((6-((1 R ,4 R ))-4-(4-(((1-(4-chloro-3-(2,4-dioxotetra) Hydropyrimidin-1(2 H )-yl)benzoyl)piperidin-4-yl)methoxy)methyl-d ₂ )piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2 -Methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylic acid tert-butyl ester (200 mg, 0.19mmol) was dissolved in dichloromethane (5 mL) Dissolve, add trifluoroacetic acid (2 mL), stir at room temperature for 2 hours, then concentrate the reaction solution under reduced pressure. Dissolve the crude product in a 10% methanol/dichloromethane mixed solution (20 mL), and then add 5% sodium bicarbonate. aqueous solution (20 mL) and stirred for 1 hour, left to separate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was subjected to pre-HPLC (CH ₃ CN/0.08% NH ₄ HCO ₃ aqueous solution, 5%~ 95%) purified to obtain 1-(5-(4-(((1-((1 R ,4 R ))-4-(4-((( R )-1-(3-amino-5-(tri) Fluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy -d ₂ )methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =949.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 ( s, 1H), 6.86 (d, J = 10.1 Hz, 2H), 6.70 (s, 1H), 5.57 (dd, J = 17.7, 10.2 Hz, 3H), 4.42 (d, J = 12.0 Hz, 2H), 3.92 (m, 4H), 3.81 – 3.51 (m, 3H), 3.24 (d, J = 6.2 Hz, 2H), 3.09 – 2.88 (m, 3H), 2.78 – 2.60 (m, 4H), 2.36 (s, 3H), 1.90 – 1.52 (m, 18H), 1.19 – 0.92 (m, 4H).

Example 77: ( R )-2-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazole Phin-6-yl)piperidin-1-yl) -N- (2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl))benzene Formamide)-3-azaspiro[5.5]undecan-9-yl)ethyl)acetamide Step 1: Preparation of 6-bromo-2-methylquinazolin-4-ol Add 2-amino-5-bromobenzamide (4.0 g, 14.55 mmol) to a solution of trimethyl orthoacetate (17.46 g, 145.5 mmol) in methanol (100 mL), and stir in a stuffy tank at 120 °C. Leave overnight, cool and then concentrate under reduced pressure to obtain crude product 6-bromo-2-methylquinazolin-4-ol, which can be directly used in the next reaction without purification. LC-MS: (ESI, m/z): [M+H] ⁺ =238.9. Step 2: 4-(4-hydroxy-2-methylquinazolin-6-yl)-3,6-dihydro Preparation of tert-butyl pyridine-1( 2H )-carboxylate Dissolve 6-bromo-2-methylquinazolin-4-ol (5.00 g, 16.67 mmol) with DMF/H ₂ O (200 mL/20 ml), and then add potassium carbonate (5.80 g, 42.03 mmol) respectively. , Pd(dppf)Cl ₂ (1.54 g, 2.10 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-3,6 -Dihydropyridine-1( 2H )-tert-butylcarboxylate (7.79 g, 25.21 mmol), the reaction solution was stirred at 110°C overnight under nitrogen protection, diluted with water (500 mL), and diluted with ethyl acetate (200 mL) ×3) extraction, the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=1:2) to obtain 4-(4-hydroxy- 2-Methylquinazolin-6-yl)-3,6-dihydropyridine-1( 2H )-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =342.1. Step 3: 4-(4-hydroxy-2-methylquinazolin-6-yl)piperidine-1-carboxylic acid Preparation of tert-butyl ester 4-(4-Hydroxy-2-methylquinazolin-6-yl)-3,6-dihydropyridine-1( 2H )-carboxylic acid tert-butyl ester (2.5 g, 14.55 mmol) was added A solution of Pd(OH) ₂ (800 mg, 20 %) in methanol (100 mL) was stirred at 70°C overnight (10 atm) in an autoclave under H ₂ atmosphere. After cooling, it was filtered and concentrated under reduced pressure to obtain crude product 4. -(4-Hydroxy-2-methylquinazolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =344.1. Step 4: ( R )-4-(2-methyl-4-((1-(3-nitro-5- Preparation of tert-butyl (trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylate Combine BOP (3.30 g, 7.47 mmol) and DBU (1.90 g, 12.5 mmol) and ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine (1.53 g, 6.54 mmol) were added to tert-butyl 4-(4-hydroxy-2-methylquinazolin-6-yl)piperidine-1-carboxylate (1.73 g, 5.03 mmol) in DMF (100 mL ) solution, the reaction solution was stirred at 70°C overnight, diluted with water (300 mL), extracted with ethyl acetate (100 mL), washed the organic phase with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using reversed-phase column chromatography (H ₂ O:ACN=1:2) to obtain ( R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl) Base)phenyl)ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =560.4. Step 5: ( R )-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl) Preparation of (yl)phenyl)ethyl)-6-(piperidin-4-yl)quinazolin-4-amine ( R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl) Piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.537 mmol) was added to TFA (2 mL) in dichloromethane (20 mL), stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain the crude product ( R ) -2-Methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)quinazolin-4-amine. LC-MS: (ESI, m/z): [M+H] ⁺ =460.4. Step 6: ( R )-2-(4-(2-methyl-4-((1-(3-nitro) Preparation of -5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidin-1-yl)tert-butyl acetate ( R )-2-methyl- N- (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)quinazoline- 4-amine (250 mg, 0.543 mmol) and potassium carbonate (300 mg, 2.17 mmol) were added to a solution of tert-butyl 2-bromoacetate (138 mg, 0.708 mmol) in THF (20 mL) and stirred at 70 °C. Wait overnight. The reaction solution was diluted with water (50 ml), extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=5:1). Obtain ( R )-2-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -(yl)piperidin-1-yl)tert-butyl acetate. LC-MS: (ESI, m/z): [M+H] ⁺ =574.3. Step 7: ( R )-2-(4-(2-methyl-4-((1-(3-nitro) Preparation of -5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidin-1-yl)acetic acid ( R )-2-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -(yl)piperidin-1-yl)tert-butyl acetate (300 mg, 0.524 mmol) was added to HCl/1,4-dioxane (4 M, 20 mL), stirred at room temperature overnight, and the reaction solution was directly reduced to Concentrate under pressure to obtain crude product ( R )-2-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quino Zozolin-6-yl)piperidin-1-yl)acetic acid. LC-MS: (ESI, m/z): [M+H] ⁺ =518.1. Step 8: ( R )-9-(2-(2-(4-(2-methyl-4-((1 -(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidin-1-yl)acetamide)ethyl)-3-nitrogen Preparation of tert-butyl heterospiro[5.5]undecane-3-carboxylate ( R )-2-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -Piperidin-1-yl)acetic acid (167 mg, 0.323 mmol), HATU (154 mg, 0.405 mmol) and DIEA (105 mg, 0.814 mmol) were added to 9-(2-aminoethyl)-3- In a solution of azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (80 mg, 0.27 mmol) in DMF (20 mL), the reaction solution was stirred at room temperature overnight, diluted with water (50 mL), and diluted with acetic acid Extract with ethyl ester (50 mL×3), and the crude product is purified using reversed-phase column chromatography (ACN:H ₂ O=1:3) to obtain ( R )-9-(2-(2-(4-(2-methyl) -4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidin-1-yl)acetamide)b tert-butyl)-3-azaspiro[5.5]undecane-3-carboxylate. LC-MS: (ESI, m/z): [M+H] ⁺ =796.4. Step 9: ( R )-9-(2-(2-(4-(4-((1-(3-amine) Base-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)piperidin-1-yl)acetamide)ethyl)-3-nitrogen Preparation of tert-butyl heterospiro[5.5]undecane-3-carboxylate ( R )-9-(2-(2-(4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethyl)amino )quinazolin-6-yl)piperidin-1-yl)acetamide)ethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (70 mg, 0.088 mmol ) was dissolved in ethanol (10 mL), and then Raney nickel (0.3 mL, water suspension) and hydrazine hydrate monohydrate (0.2 mL) were added respectively. The reaction solution was stirred at room temperature for 1 hour, filtered, and concentrated under reduced pressure to obtain crude product. ( R )-9-(2-(2-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)amino)-2-methyl Quinazolin-6-yl)piperidin-1-yl)acetylamine)ethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =766.6. Step 10: ( R )- N -(2-(3-azaspiro[5.5]undecan-9-yl) Ethyl)-2-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Preparation of piperidin-1-yl)acetamide ( R )-9-(2-(2-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino))-2-methyl Quinazolin-6-yl)piperidin-1-yl)acetamide)ethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (65 mg, 0.085 mmol ) was dissolved in DCM (10 mL), TFA (1 mL) was added, the reaction solution was stirred at room temperature for 1 hour, and directly concentrated under reduced pressure to obtain the crude product ( R ) -N- (2-(3-azaspiro[5.5] Monoalk-9-yl)ethyl)-2-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl Quinazolin-6-yl)piperidin-1-yl)acetamide. LC-MS: (ESI, m/z): [M+H] ⁺ =666.4. Step 11: ( R )-2-(4-(4-((1-(3-amino-5-(tri) Fluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)piperidin-1-yl) -N- (2-(3-(4-chloro-3-( Preparation of 2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzyl)-3-azaspiro[5.5]undecan-9-yl)ethyl)acetamide ( R )- N -(2-(3-azaspiro[5.5]undecan-9-yl)ethyl)-2-(4-(4-((1-(3-amino-5) -(Trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)piperidin-1-yl)acetamide (50 mg, 0.075 mmol) was dissolved in DMSO (10 mL), then 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoate pentafluorophenyl ester (40 mg, 0.092 mmol) and DIEA (30 mg, 0.232 mmol), the reaction solution was stirred at room temperature overnight, diluted with water (20 mL), extracted with dichloromethane (30 mL×3), the organic phase was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparation to obtain ( R )-2- (4-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)piperidine-1 -yl)- N -(2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2 H )-yl)benzoyl)-3-azaspiro[ 5.5]Undecan-9-yl)ethyl)acetamide. LC-MS: (ESI, m/z): [M+H] ⁺ =916.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 7.70-7.58 (m, 3H), 7.52 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 8.2, 1.8 Hz, 1H), 6.90 (s, 1H ), 6.86 (s, 1H), 6.70 (s, 1H), 5.64 – 5.43 (m, 3H), 3.79 – 3.69 (m, 1H), 3.59-3.45 (m, 3H), 3.28 – 3.20 (m, 2H ), 3.17-3.07 (m, 2H), 2.98-2.86 (m, 4H), 2.77 – 2.70 (m, 2H), 2.69 – 2.56 (m, 1H), 2.38 (s, 3H), 2.26-2.14 (m , 2H), 1.92 – 1.77 (m, 4H), 1.74-1.63 (m, 2H), 1.56 – 1.20 (m, 12H), 1.14-0.94 (m, 4H).

Example 78: 1-(5-(9-((4-((1 R ,4 R ))-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl Base)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)- 3-Azaspiro[5.5]Undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Step 1: 9-((4-( (1 R ,4 R )-4-(2-methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyridine And[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl Preparation of esters (1 R ,4 R )-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3 ,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid (170 mg, 0.337 mmol), HATU (192 mg, 0.505 mmol) and DIEA (130 mg, 1.01 mmol) were added to 9-(piperazine) 𠯤-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester in DMF (30 mL), stirred at room temperature overnight, and the reaction solution was diluted with water (50 mL). Extract with dichloromethane (50 mL×3), and the crude product is purified by reversed-phase column chromatography (ACN:H ₂ O=1:2) to obtain 9-((4-((1 R ,4 R )-4-(2) -Methyl-4-((( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidine-6- (yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =871.6. Step 2: 9-((4-((1 R ,4 R )-4-(4-((( R )- 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1 Preparation of -carbonyl)piperidin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester 9-((4-((1 R ,4 R )-4-(2-methyl-4-((( R ))-1-(3-nitro-5-(trifluoromethyl)phenyl) )ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]ten Alkane-3-carboxylic acid benzyl ester (240 mg, 0.276 mmol) was dissolved in ethanol (20 mL), Raney nickel (aqueous suspension, 0.3 mL) and hydrazine hydrate monohydrate (85%, 0.5 mL) were added. The reaction solution was stirred at room temperature for 1 hour, filtered, and concentrated under reduced pressure to obtain crude product 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino- 5-(Trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-1- methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid benzyl ester. LC-MS: (ESI, m/z): [M+H] ⁺ =841.6. Step 3: (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperamide -1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino) Preparation of -2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexyl)methanone 9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amine base)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]ten Alkane-3-carboxylic acid benzyl ester (220 mg, 0.262 mmol) was dissolved in ethyl acetate (20 mL), Pd(OH) ₂ (44 mg, 20%) was added, and the reaction solution was stirred at 70 °C under H ₂ atmosphere Leave overnight, filter, and concentrate under reduced pressure to obtain crude product (4-((3-azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )- 4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d] Pyrimidin-6-yl)cyclohexyl)methanone. LC-MS: (ESI, m/z): [M+H] ⁺ =707.4. Step 4: 1-(5-(9-((4-((1 R ,4 R )-4-(4- ((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl )cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4 Preparation of (1 H ,3 H )-diketone (4-((3-Azaspiro[5.5]undecan-9-yl)methyl)piperidine-1-yl)((1 R ,4 R )-4-(4-((( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexyl) Methyl ketone (200 mg, 0.283 mmol) was dissolved in DMSO (20 mL), and perfluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (147 mg, 0.338 mmol) and DIEA were added respectively. (110 mg, 0.853 mmol), the reaction solution was stirred at room temperature overnight, diluted with water (50 mL), extracted with dichloromethane (50 mL×3), the organic phase was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparation to obtain 1-(5 -(9-((4-((1 R ,4 R )-4-(4-((( R ))-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidine-1-yl)methyl)-3-azaspiro[5.5] Undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =957.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ10.51 (s, 1H), 8.91 (s, 1H), 8.58 (d, J = 7.9 Hz, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 5.61 – 5.47 (m, 3H), 3.78 – 3.72 (m, 1H ), 3.64 – 3.56 (m, 3H), 3.54-3.41 (m, 6H), 3.30-3.24 (m, 2H), 2.82-2.71 (m, 3H), 2.70-2.61 (m, 1H), 2.43 (s , 3H), 2.36-2.21 (m, 4H), 2.17-2.07 (m, 2H), 2.04 – 1.98 (m, 2H), 1.85-1.71 (m, 2H), 1.77-1.31 (m, 18H), 1.16 -0.90 (m, 4H).

Example 79: 1-(2-chloro-5-(4-(3-(1-((1 R ,4 R ))-4-(4-((( R ))-1-(4-(2- Chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) ring Hexane-1-carbonyl)piperidin-4-yl)propyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione Step 1: 1-( 2-Chloro-5-(4-(3-(piperidin-4-yl)propyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione Preparation Dissolve 1,3-bis(piperidin-4-yl)propane (193.5 mg, 0.92 mmol) and DIEA (178 mg, 1.38 mmol) in DMSO (10 mL), and add 4-chloro-3-(2, 4-Dioxotetrahydropyrimidine-1(2 H )-yl)benzoate pentafluorophenyl ester (200 mg, 0.46 mmol), react at room temperature for 30 min. Dilute with water (30 mL), extract with ethyl acetate (30 mL×3), wash the organic phase with saturated brine (40 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to column chromatography (MeOH:DCM=1 :9, flow rate 40 ml/min) and purified to obtain 1-(2-chloro-5-(4-(3-(piperidin-4-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine -2,4(1 H ,3 H )-diketone. LC-MS: (ESI, m/z): [M+H] ⁺ =461.2. Step 2: 1-(2-chloro-5-(4-(3-(1-((1 R ,4 R ) ) -4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino) -7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine Preparation of -2,4(1 H ,3 H )-dione (1 R ,4 R )-4-(4-((( R )-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophene-2- (ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (100 mg, 0.17 mmol), 1-(2-chloro- 5-(4-(3-(piperidin-4-yl)propyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (80 mg, 0.17 mmol) and DIEA (65.8 mg, 0.51 mmol) were dissolved in DMF (5 mL), and finally HATU (77.5 mg, 0.20 mmol) was added. The reaction solution was stirred at room temperature for 30 min, diluted with water (20 mL), and ethyl acetate ( 20 mL (1-((1 R ,4 R )-4-(4-((( R ))-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophene -2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)propyl)piperidine -1-Carbonyl)phenyl)dihydropyrimidine-2,4( 1H , 3H )-dione. LC-MS: (ESI, m/z): [M+H] ⁺ =1035.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.43-7.35 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.05-5.83 (m, 1H), 4.52-4.35 (m, 2H), 3.95-3.80 (m, 4H), 3.80-3.69 (m, 1H), 3.67-3.50 (m, 2H), 3.20-3.08 (m, 2H), 3.06-2.87 (m, 3H), 2.83 - 2.70 (m, 3H), 2.68-2.57 (m, 1H), 2.42 (s, 3H ), 2.01 (s, 6H), 1.92-1.39 (m, 18H), 1.36-1.15 (m, 6H), 1.13-0.82 (m, 4H).

ⅡBiological Activity Test Example

Test Example 1: KRAS-G12C/SOS1 Binding Assay The following method was used to determine the degree of inhibition of KRAS-G12C/SOS1 binding by the preferred compounds of the present invention under in vitro conditions. This method uses the KRAS-G12C/SOS1 binding assay kit (Cisbio, 63ADK000CB16PEG) to determine the competitive inhibition of KRAS-G12C/SOS1 binding by the selected compounds using homogeneous time-resolved fluorescence technology (HTRF). The experimental process is as follows (refer to the kit instructions for detailed methods): Dissolve the compounds of the present invention in DMSO at a concentration of 20 mM, and perform equal gradient dilution with the buffer in the kit to make the test compound in the reaction system The final concentration range is 10000 nM ~ 0.04 nM, and the final concentration of DMSO is 0.5%. Incubate 2 μL compound with 4 μL 1x Tag1-SOS1 and 4 μL 1xTag2-KRAS-G12C (containing 10 μM guanosine triphosphate, GTP) for 15 min at 25°C, and then add 5 μL 1x Anti-Tag1 to the reaction system. -Tb3+ and 5 μL 1x Anti-Tag2-XL665 were incubated on and off ice for 3 h. After the incubation, use the HTRF mode on the microplate reader EnVision (PerkinElmer, 2105) to measure the excitation wavelength of each well at 337 nm, read the fluorescence intensity of each well at the emission wavelengths of 620 nm and 665 nm, and use the formula Ratio = ( 665 nm/620 nm)×10 ⁴ to calculate the Ratio value. By comparing the fluorescence intensity ratio with the control group, the inhibition rate of the compound at each concentration was calculated, and then nonlinear curve fitting was performed using logarithmic concentration-inhibition rate through GraphPad Prism 8 to obtain the IC50 value of the compound, as shown in Table 1.

Test Example 2: SOS1 degradation test in KRAS G12C mutated human non-small cell lung cancer cells NCI-H358 (ATCC or Chinese Academy of Sciences Stem Cell Bank), KRAS G12D mutated human lung cancer cells A-427 (ATCC), KRAS G12V mutated human lung cancer cells The degradation effect of compounds on SOS1 was investigated on colorectal adenocarcinoma cells SW-620 (ATCC) and KRAS G13D mutated human colorectal adenocarcinoma epithelial cells DLD-1 (ATCC). The specific method is: Plate 0.95 mL of cells in each well of a 24-well cell culture plate to achieve a cell density of 5 × 10 ⁵ cells/well; place the cell plate in a 5% CO ₂ incubator at 37°C overnight. Then add 50 μL of the diluted compound solution to the corresponding wells plated with cells so that the final concentration of the compound ranges from 0.03 to 3000 nM. The final concentration of DMSO is 0.25%. After administration, the cell plate was placed in a 5% _CO2 incubator at 37°C for 24 hours. After removing the cell culture medium in the 24-wells, it was washed twice with 1×PBS. NCI-H358 adhered to the bottom of the cell culture plate. Add 180 μL RIPA (strong) lysis buffer (Beyotime, P0013B) to the cells, supplemented with 1 mM phenylmethylsulfonate fluoride, protease inhibitor cocktail (Beyotime, P1008) and protease phosphatase inhibitor cocktail (Beyotime, P1045) Lyse, and after standing on ice for 30 minutes, transfer the protein lysate in each well to a 1.5 mL centrifuge tube, and centrifuge at 15,000 g and 4°C for 20 minutes. The centrifuged cell lysate supernatant was frozen at -80°C for testing and used for WB method to detect SOS1 protein degradation level. The total protein concentration in the cell lysis supernatant was determined using the BCA protein quantification kit (Tiangen, PA115-02).

Test Example 3: Human SOS1 protein immunoblot test. Detect the concentration of total protein in the cell lysate according to BCA. Use PBS and 5×SDS-PAGE protein loading buffer (Beyotime, P0015L) to adjust to 0.5 μg/μL, 100 ℃ water bath for 15 min, then placed on ice for 5 min, centrifuged at 14000 g, 4 ℃ for 1 min, and mixed evenly to serve as the loading sample for WB. Use precast gel (KGI, KGMG010W15) for protein electrophoresis, with a sample volume of 10 μL (total protein 5 μg), Tris-MOPS-SDS electrophoresis solution (Adamas, P1598253), and 120 V 55 min constant voltage electrophoresis. After electrophoresis, , transfer the protein on the strip to the PVDF membrane at a constant current of 250 mA for 65 minutes. After the transfer, the membrane was placed in 1× QuickBlock blocking solution (Beyotime, P0235) and incubated at room temperature for 30 minutes. After blocking, the PVDF membrane was incubated with SOS1 primary antibody (Abcam, ab140621) at 4°C overnight, and washed with TBST buffer (2.4g Tris, 8.8 g NaCl, 1.5 mL Tween 20, adjust the pH to 7.4, and dilute to 1 L). The membrane was incubated for 30 min (10 min/time), incubated with secondary antibody (Abcam, ab205718) for 2 h at room temperature, washed with TBST buffer for 30 min (10 min/time), and finally washed with Clarity Western ECL Substrate (BIO-RAD, 170- 5061) for 5 min for luminescence color development, and the chemiluminescence imaging system (Qinxiang, ChemiScope 6200 Touch) was used for color development and protein map photography. The protein map was analyzed by gray value using Qinxiang chemiluminescence analysis software. Use the formula: grayscale correction value = (target protein grayscale value/corresponding internal reference grayscale value) × 10 ³ to calculate the grayscale correction value of each sample. Then compare it with the grayscale correction value of the control group to calculate the degradation rate. Then, nonlinear curve fitting was performed using logarithmic concentration-inhibition rate through GraphPad Prism 8 to obtain the DC50 and Dmax values of the compound.

Test Example 4: 3D cell proliferation inhibition test on KRAS G12C mutated human non-small cell lung cancer cell NCI-H358 (ATCC or Chinese Academy of Sciences Stem Cell Bank), KRAS G12D mutated human metastatic pancreatic adenocarcinoma cell AsPC-1 (ATCC), The inhibitory effect of compounds on 3D cell proliferation was investigated on KRAS G12V mutated human lung adenocarcinoma cells NCI-H441 (ATCC) and KRAS G13D mutated human colorectal adenocarcinoma epithelial cells DLD-1 (ATCC). The specific method is as follows: Use the Echo sonic pipetting system (Labcyte, Echo 550) to add 200 nL compound gradient dilution solution to the corresponding microwells of a 384-well low-adsorption microplate (Corning, 3657), so that the test compound is in the reaction system. The final concentration range is 20000 nM ~ 0.008 nM. Then add 40 μL of cells of a certain density into the corresponding microwell plate. In addition to the test compound test wells, DMSO control wells and culture medium control wells are also set up. The DMSO control wells contain DMSO and cells, and the culture wells contain only culture medium. After adding the sample, cover the plate, place the 384-well low-adsorption microplate in a 5% carbon dioxide incubator, and incubate at 37°C for 7 days. After 7 days, take out the microplate, add 40 μL CTG reagent (Promega, G9683) to each well, incubate at room temperature for 30 minutes, and then read using the chemiluminescence program on the microplate reader EnVision. The formula for calculating the percentage of cell proliferation inhibition: Inhibition rate % = (average value of DMSO control group - single concentration reading of compound) / (average value of DMSO control group - average value of culture medium control group) × 100. Calculate the inhibition of the compound at each concentration. rate, and then use GraphPad Prism 8 to perform nonlinear curve fitting using logarithmic concentration-inhibition rate to obtain the IC50 value of the compound. Table 1 Example KRAS G12C:SOS1 NCI-H358 (G12C) A427 (G12D) SW620 (G12V) DLD-1 (G13D) IC ₅₀ (nM) DC ₅₀ (nM) D _max (%) DC ₅₀ (nM) D _max (%) DC ₅₀ (nM) D _max (%) DC ₅₀ (nM) D _max (%) Example 1 B A A A A A A A A Example 2 A A A A A A A A A Example 3 A A A - - - - - - Example 4 - B C - - - - - - Example 5 - B A - - - - - - Example 6 - E C - - - - - - Example 7 - E C - - - - - - Example 8 - B A - - - - - - Example 9 - E D - - - - - - Example 10 - A B A A A A A A Example 11 - E C - - - - - - Example 12 - E C - - - - - - Example 13 - E C - - - - - - Example 14 - A B - - - - - - Example 15 - E D - - - - - - Example 16 - D B - - - - - - Example 17 - E C - - - - - - Example 18 - E D - - - - - - Example 19 - C B A B A A B A Example 20 - A A A A A A B A Example 21 - E C - - - - - - Example 22 - E C - - - - - - Example 23 - A B - - - - - - Example 24 - A A - - - - - - Example 25 - E D - - - - - - Example 26 - E D - - - - - - Example 27 - E D - - - - - - Example 28 A A B - - - - - - Example 29 - A A - - - - - - Example 30 - E D - - - - - - Example 31 - E D - - - - - - Example 32 - A A Example 33 - A A A A A A C A Example 34 - E C - - - - - - Example 35 - E C - - - - - - Example 36 - C B - - - - - - Example 37 - E D - - - - - - Example 38 - E D - - - - - - Example 39 - A A - - - - - - Example 40 - E D - - - - - - Example 41 - C A - - - - - - Example 42 - E C - - - - - - Example 43 A A B - - - - - - Example 44 A A - - - - - - - Example 45 A C B - - - - - - Example 46 A A B - - - - - - Example 47 A E D - - - - - - Example 48 - A A - - - - - - Example 49 A C B - - - - - - Example 50 A A A - - - - - - Example 51 A A A - - - - - - Example 52 A C B - - - - - - Example 53 A A B - - - - - - Example 54 A A A - - - - - - Example 55 A - - - - - - - - Example 56 A A A - - - - - - Example 57 A A - - - - - - - Example 58 A - - - - - - - - Example 59 A A A - - - - - - Example 60 A A B - - - - - - Example 61 A C B - - - - - - Example 62 A A A - - - - - - Example 63 - - - - - - - - - Example 64 A A B - - - - - - Example 65 A E D - - - - - - Example 66 A - - - - - - - - Example 67 A A A - - - - - - Example 68 A A B - - - - - - Example 69 A A B - - - - - - Example 70 A A A - - - - - - Example 71 A A A - - - - - - Example 72 A A B - - - - - - Example 73 - A A A A A A B A Example 74 - A A - - - - - - Example 75 A A B - - - - - - Example 76 - A B - - - - - - Example 77 - D A - - - - - - Example 78 - C B - - - - - - Example 79 A B B - - - - - - Table 2 Example IC ₅₀ (nm) NCI-H358 (G12C) NCI-H441 (G12V) DLD-1 (G13D) AsPC-1 (G12D) Example 1 A C C B Example 2 A E B E Example 10 A A B C Example 19 A D E E Example 20 A A B D Example 33 A E D E Example 73 A E D E In Table 1 and Table 2: "-" means not detected; when DC ₅₀ ≤ 50 nM, it is A, when 50 nM < DC ₅₀ ≤ 100 nM, it is B, when 100 nM < DC ₅₀ ≤ 500 nM, it is C, when 500 nM＜DC ₅₀ ≤1000 nM is D; 1000 nM＜DC ₅₀ ≤10 μM is E; when 80≤D _max (%)≤100, it is A, when 50≤D _max (%)＜80, it is B, when When 30≤D _max (%)＜50, it is C, when D _max (%)＜30, it is D; when IC ₅₀ ≤15nM, it is A, when 15nM＜IC ₅₀ ≤30nM, it is B, when 30nM＜IC ₅₀ ≤ 50nM is C, when 50nM＜IC ₅₀ ≤100nM is D, when 100nM＜IC ₅₀ ≤1000 nM is E. Experimental conclusion: The compound of the present invention can effectively bind to the SOS1 target protein or produce an inhibitory effect, and the compound of the present invention can effectively and specifically degrade the SOS1 protein.

without

without

Claims (28)

A compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or its pharmaceutically acceptable salts: S-L-E Ⅰ in: S is a small molecule compound that can inhibit the activity of SOS1 protein or bind to SOS1 protein; L is the connecting chain, which connects S and E through covalent bonds; E is a small molecule ligand of the E3 ubiquitin ligase complex. The compound of formula I as described in claim 1, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, the S is S1, S1', -X-S1', S1'', -X-S1'', S2, S2', -X-S2', S2'', -X- S2'', S3, S4, S5, S5' or -X-S2'': X is O, NH or S, preferably O; S1 S1' S1'' wherein among S1, S1' and S1'': R ₁ is selected from hydrogen, halogen, -OH, -CN, -NO ₂ , C ₁ -C ₆ alkyl mercapto or -NR _a R _b , so The R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is selected from C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ heterocycloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl , phenyl, heteroaryl, C ₁ -C ₆ haloalkyl, -COOH, -COOR _c ; the R _c is -C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ Alkynyl, C ₃ -C ₈ cycloalkyl or -C ₄ -C ₈ cycloalkenyl; R ₁ is -NS(O)(R _d )(R _e ), each of the C ₁ -C ₆ and R _e Independently are C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, 6-10 yuan aromatic base or 5-10 membered heteroaryl; R ₁ is -NHC(O)-(C ₁ -C ₆ alkyl), -NHC(O)-NR _a R _b , and the R _a and R _b are each independent is hydrogen, -C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -NH-(CH ₂ ) _k -NH-C(O)- R _aa , the R _aa is C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl, and k is 1 or 2; R ₁ is -NH-(CH ₂ ) _i -R _f , the i is 0, 1 or 2 and R _f is a 4-7 membered heterocycloalkyl group, heteroaryl group, C ₁ -C ₆ alkyl sulfonyl group; In addition, the above-mentioned C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally 1, 2 or 3 selected from halogen, -OH, oxo, - CN, -NO2, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, 4-7 membered heterocycloalkyl, C ₁ - C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH ₂ )- Heteroaryl, -NHC(O)(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkoxy, phenoxy, heteroaryloxy or -NR _a R _b group substitution; so The above-mentioned R _a and R _b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -O-(CH ₂ ) _z -phenyl, -O-(CH ₂ ) _z - (4-7 membered heterocycloalkyl), -O-(CH ₂ ) _z -heteroaryl, the z is 0, 1 or 2, the z is 0, 1 or 2, Phenyl, heterocycloalkyl and heteroaryl are optionally substituted from -OH, heterocycloalkyl or heterocycloalkenyl, and can be substituted by methyl or oxo; or R ₁ is , , , , , , , , , , , , or , or two adjacent R _1s together with their respective connected carbon atoms form a 5-7-membered cycloalkyl group or a 5-7-membered heterocycloalkyl group; and the x is 1, 2 or 3; A ₁ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R ₂ is hydrogen, -OH, oxo, halogen, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy Base, C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₃ -C ₈ cycloalkoxy, -C ₃ -C ₈ halocycloalkyl Oxygen group, -C ₄ -C ₈ cycloalkenyl group, 4-7 membered heterocycloalkyl group, -O-CH ₂ -4-7 membered heterocycloalkyl group, 5-10 membered heterocycloalkenyl group, spiroheterocycloalkyl group base, condensed heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, -C ₁ -C ₆ haloalkyl, -C _{1 -C 6} haloalkoxy, -C ₁ -C ₆ alkyl sulfonyl base; R ₂ is -NR _a R _b , and R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl or -C(O)C ₁ -C ₃ alkyl; R ₂ is -C (O)NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is -C(O)OR _g , the R _g is hydrogen or C ₁ -C ₆ alkyl; R ₂ is -OR _h ; the R _h is C ₁ -C ₆ alkyl; R ₂ is -(CH ₂ ) NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; and w is 1 , 2, 3 or 4; the A ₂ (R ₃ ) _Y is hydrogen; or A ₂ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and R ₃ is hydrogen, Halogen, -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₇ -C ₈ cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl; so The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally substituted by 1, 2 or 3 Selected from halogen, -OH, oxo, -CN, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ haloalkyl, phenyl, heteroaryl or -C (O) NR _i R _j is substituted with a substituent, and each of R _i and R _j is independently hydrogen or C ₁ -C ₆ alkyl; or the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by -NR _k R _l , and R _k and R _l are each independently hydrogen, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylsulfonyl, phenyl, heteroaryl, -CH ₂ -C(O)-R _m , -C(O)R _p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and Each heterocycloalkyl group is independently optionally selected from 1, 2 or 3 C ₁ -C ₆ haloalkyl, -OH, oxo, phenyl, -CN, C ₁ -C ₆ alkoxy Or heteroaryl substituted, and the heteroaryl is optionally substituted by methyl; and the R _m is a bicyclic heteroaryl, C ₁ -C ₆ alkoxy or -NR _n R _o , the R _n and R _o is each independently hydrogen, C ₁ -C ₆ alkyl or phenyl, the alkyl group is optionally substituted by C ₁ -C ₆ alkoxy or phenyl, or -NR _n R _o is 4-7 yuan Azacycloalkyl, the azacycloalkyl is connected to other parts of the molecule through N atoms, and also contains one or more heteroatoms selected from N or O; the R _p is selected from C ₁ -C ₆ alkane Oxy group, C ₁ -C 6 alkyl optionally substituted by 1, 2 or 3 selected from -OH or C ₁ -C ₆ alkoxy, monocyclic or bicyclic heteroaryl, 4-7 membered _heteroaryl Cycloalkyl or R _p is -CH ₂ -NR _q R _r , and said R _q and R _r are each independently selected from hydrogen, phenyl or C ₁ -C ₆ alkyl optionally substituted by F; or said Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl are optionally substituted by -NR _s R _t , the -NR _s R _t is a 4-7-membered nitrogen heterocycloalkyl group connected to other parts of the molecule through a nitrogen atom or a 6-10-membered nitrogen spirocycloalkyl group connected to other parts of the molecule through a nitrogen atom, and further includes up to two heteroatoms selected from N or O, and optionally 1, 2 or 3 heteroatoms selected from -OH, oxo group, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, - C(O)OR _z is substituted with a substituent, and the R _z is C ₁ -C ₆ alkyl, halogen, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ N(C ₁ -C ₆ alkyl) base) ₂ , -C(O)NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ Cycloalkyl; or R ₃ is C(O)R _v , -C(O)NH ₂ , -C(O)NHR _v , -C(O)NR _v R _w , -C(O)OR _v , so The R _v and R _w are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, phenyl or -(CH ₂ ) ₂ NR _x R _y , and the R _x and R _y are each independently Independently hydrogen, C ₁ -C ₄ alkyl or -(CH ₂ ) ₂ N(CH ₃ ) ₂ ; or R ₃ is -NH ₂ , -NHR _z , -NR _z R _za , -NHC(O)R _z , -NHC(O)OR _z , -NHS(O) ₂ R _z , 4-7 membered heterocycloalkyl, heteroaryl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, The R _z and R _za are each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl; or R ₃ is C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy. Base, -O(CH ₂ ) _s -C ₃ -C ₈ cycloalkyl, -O(CH ₂ ) _s -phenyl, -O(CH ₂ ) _s -heterocycloalkyl, -O(CH ₂ ) _s -Heteroaryl, the s is 0, 1, 2 or 3; or R ₃ is -S(O) ₂ R _z , -S(O) ₂ NH ₂ , -S(O) ₂ NHR _z , -S (O) ₂ NR _z R _za , said R _z and R _za are each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl, said y is 0, 1, 2 or 3 ; Y is 0, 1, 2, 3, 4 or 5; L' is a bond, -(CH ₂ ) _k -, -O(CH ₂ ) _k -, -(CH ₂ ) _k -O- or -O- (CH ₂ ) _k -O-, the k is 0, 1, 2 or 3, or L' is -CH=CH-(CH ₂ ) _n -, the n is 0, 1 or 2; R ₄ , R ₅ is each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkoxy, the alkyl, alkoxy , cycloalkyl and cycloalkoxy are optionally substituted by cyano, hydroxyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or halogen; S2 S2' S2'' wherein in S2, S2', S2'': R ₁ is hydrogen, halogen, -OH, -CN, -NO ₂ , C ₁ -C ₆ alkyl mercapto or -NR _a R _b ; R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ heterocycloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C _8- cycloalkyl, C ₄ -C _8- cycloalkenyl, 4-7-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, Phenyl, heteroaryl, C ₁ -C ₆ haloalkyl, -COOH, -COOR _c ; the R _c is -C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkyne group, C ₃ -C ₈ cycloalkyl or -C ₄ -C ₈ cycloalkenyl; R ₁ is -NS(O)(R _d )(R _e ), and the R _d and R _e are each independently C ₁ -C ₆ alkyl, C ₂ -C 6 alkenyl, C ₂ -C ₆ alkynyl, C _{3 -C 8 cycloalkyl} , C ₄ -C ₈ cycloalkenyl; R ₁ is -NHC(O)- (C ₁ -C ₆ alkyl), -NHC(O)-NR _a R _b , the R _a and R _b are each independently hydrogen, -C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycle Alkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -NH-(CH ₂ ) _k -NH-C(O)-(C ₁ -C ₆ alkyl), and the k is 1 or 2; R ₁ is -NH-(CH ₂ ) _i -R _f , i is 0, 1 or 2 and R _f is 4-7 membered heterocycloalkyl, heteroaryl, C ₁ -C ₆ alkylsulfonyl group ; In addition, the above-mentioned C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, 4-7 membered heterocycloalkyl group and heteroaryl group are optionally selected from halogen, halogen, 2 or 3. -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, 4-7 yuan Heterocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylsulfonyl, phenyl, benzyl, heteroaryl base, -(CH ₂ )-heteroaryl, -NHC(O)(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkoxy, phenoxy, heteroaryloxy or -NR _a R _b is substituted by a group; the R _a and R _b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₁ is -O-(CH ₂ ) _z -phenyl, -O-(CH ₂ ) _z - (4-7 membered heterocycloalkyl), -O-(CH ₂ ) _z -heteroaryl, and the z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted by -OH, heterocycloalkyl or heterocycloalkenyl, and can be substituted by methyl or oxo group; Or R ₁ is , , , , the L ₂ a is C(O), L ₂ b is a bond or C ₁ -C ₆ alkylene group, and X ₂ is , , , Rx ₂ is , or , or R ₁ is , , , , , , , , , , , , or ; Or two adjacent R _1s together with their respective connected carbon atoms form a 5-7-membered cycloalkyl group or a 5-7-membered heterocycloalkyl group; and the x is 1, 2, 3 or 4; A ₁ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R ₂ is hydrogen, -OH, oxo, halogen, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₃ -C ₈ cycloalkoxy, -C ₃ -C ₈ halogenated Cycloalkoxy, -C ₄ -C ₈ cycloalkenyl, 4-7 membered heterocycloalkyl, -O-CH ₂ -4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiro hetero Cycloalkyl, condensed heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ alkyl Sulfonyl group; R ₂ is -NR _a R _b , and R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ ring Alkyl; R ₂ is -C(O)NR _a R _{b ,} and R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ - C ₈ cycloalkyl; R ₂ is -C(O)OR _g , the R _g is hydrogen or C ₁ -C ₆ alkyl; R ₂ is -OR _h ; the R _h is C ₁ -C ₆ alkyl base; R ₂ is -(CH ₂ ) NR _a R _b , and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ Cycloalkyl; and w is 1, 2, 3 or 4; the A ₂ (R ₃ ) _Y is hydrogen; or A ₂ is C ₄ -C ₁₂ cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, and R ₃ is hydrogen, halogen, -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl; The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally 1, 2 or 3 selected from halogen, -OH, oxo, -CN, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkoxy, -C ₁ -C ₆ haloalkyl, benzene substituted by a substituent of a group, a heteroaryl group or -C(O)NR _i R _j , where each of the R _i and R _j is independently hydrogen or a C ₁ -C ₆ alkyl group; or the alkyl group, alkenyl group, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and _{heterocycloalkenyl} are optionally substituted with _-NRkRl , each of _Rk and _Rl Independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylsulfonyl, benzene base, heteroaryl, -CH ₂ -C(O)-R _m , -C(O)R _p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl , phenyl, heteroaryl and heterocycloalkyl are each independently optionally selected from 1, 2 or 3 C ₁ -C ₆ haloalkyl, -OH, oxo group, phenyl, -CN, C ₁ -C ₆ alkoxy or heteroaryl substituted, and the heteroaryl is optionally substituted by methyl; and the R _m is a bicyclic heteroaryl, C ₁ -C ₆ alkoxy or -NR _{n Ro} , the R _n and _Ro are each independently hydrogen, C ₁ -C ₆ alkyl or phenyl, the alkyl is optionally substituted by C ₁ -C ₆ alkoxy or phenyl, or -NR _n R _o is a 4-7 membered nitrogen heterocycloalkyl group, the nitrogen heterocycloalkyl group is connected to other parts of the molecule through N atoms, and also contains 1 or more heteroatoms selected from N or O; the R _p Selected from C ₁ -C ₆ alkoxy, _C 1 -C 6 alkyl optionally substituted by 1, 2 or 3 selected from -OH or _{C 1 -C 6} alkoxy, monocyclic or bicyclic hetero Aryl, 4-7 membered heterocycloalkyl or R _p is -CH ₂ -NR _q R _r , and R _q and R _r are each independently selected from hydrogen, phenyl or C ₁ - optionally substituted by F. C ₆ alkyl; or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally - NR _s R _t is substituted, and the -NR _s R _t is a 4-7-membered nitrogen heterocycloalkyl group connected to other parts of the molecule through a nitrogen atom or a 6-10-membered nitrogen spiroheterocycle connected to other parts of the molecule through a nitrogen atom Alkyl, and further includes up to two heteroatoms selected from N or O, and optionally 1, 2 or 3 selected from -OH, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR _z is substituted with a substituent, and the R _z is C ₁ -C ₆ alkyl, halogen, -N(C ₁ -C ₆ alkyl) ₂ , -CH ₂ N(C ₁ -C ₆ alkyl) ₂ , -C(O)NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycle Alkyl or C ₃ -C ₈ cycloalkyl; or R ₃ is C(O)R _v , -C(O)NH ₂ , -C(O)NHR _v , -C(O)NR _v R _w , - C(O)OR _v , the R _v and R _w are each independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, phenyl or -(CH ₂ ) ₂ NR _x R _y , The R _x and R _y are each independently hydrogen, C ₁ -C ₄ alkyl or -(CH ₂ ) ₂ NH(CH ₃ ) ₂ ; or R ₃ is -NH ₂ , -NHR _z , -NR _z R _za , -NHC(O) R _z , -NHC(O)OR _z , -NHS(O) ₂ R _z , 4-7 membered heterocycloalkyl, heteroaryl, spiroheterocycloalkyl, condensed heterocycloalkyl group, bridged heterocycloalkyl, the R _z and R _za are each independently a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a phenyl group; or R ₃ is a C ₁ -C ₆ alkoxy group , C ₁ -C ₆ haloalkoxy, -O(CH ₂ ) _s -C ₃ -C ₈ cycloalkyl, -O(CH ₂ ) _s -phenyl, -O(CH ₂ ) _s -heterocycloalkyl , -O(CH ₂ ) _s -heteroaryl, the s is 0, 1, 2 or 3; or R ₃ is -S(O) ₂ R _z , -S(O) ₂ NH ₂ , -S( O) ₂ NHR _z , -S(O) ₂ NR _z R _za , the R _z and R _za are each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or phenyl; Y is 0 , 1, 2, 3, 4 or 5; L' is a bond, -(CH ₂ ) _k -, -O(CH ₂ ) _k -, -(CH ₂ ) _k -O- or -O-(CH ₂ ) _k -O-, the k is 0, 1, 2 or 3, or L' is -CH=CH-(CH ₂ ) _n -, the n is 0, 1 or 2; R ₄ and R ₅ are each independent is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkoxy, the alkyl, alkoxy, cycloalkyl and cycloalkoxy is optionally substituted by cyano, hydroxyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or halogen; T and V are both N, or T is C and V is N, or T is N and V is C; S3 wherein in S3: Q ¹ and Q ² are each independently CH or N; Q ³ , Q ⁴ and Q ⁷ are each independently C or N, at least one of Q ³ and Q ⁴ is C, and the Q ³ , Q ⁴ and Q ⁷ are not all N; Q ⁵ is CH, N, NH, O or S; Q ⁶ is CH, N, NH, N (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ heteroalkyl), N (3-7 membered cycloalkyl), N (3-7 membered heterocycle), O or S; the Q ¹ , Q ² , Q ³ , Q ⁴ , Q ⁵ , At least one of Q ⁶ and Q ⁷ is N, NH, O or S; R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, -NHR _1a , -OR _1a , C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or -CN; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ cycloalkoxy is optionally substituted with a substituent selected from halogen, -NHR ^1a or -OR ^1a ; the R ^1a is hydrogen, C ₁ -C ₆ alkyl, 3-6 membered hetero Ring or C ₁ -C ₆ haloalkyl; L ² is selected from bond, -C(O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S(O) ₂ -, -S(O)-, -S(=O)(=NH)-, -S(=O)[=N(C ₁ -C ₆ alkyl)]-, -N(C ₁ -C ₆ Alkyl)-, -C(O)(CH ₂ ) _p -, -(CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R is selected from ² From hydrogen, halogen, -CN, -NO ₂ , C 1 -C ₆ alkylmercapto _{, C 2 -C 6} alkynyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NR ^2b R ^2c , -OR ^2a , 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; the C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered hetero Each aryl group is independently optionally selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OH, -OR ^2a , oxo, halogen, -C(O)R ^2a , -C (O)OR ^2a , -C(O)NR ^2b R ^2c , -CN, -NR ^2b R ^2c , 3-6-membered cycloalkyl, 3-7-membered heterocycloalkyl, 6-10-membered aryl or 5 -10-membered heteroaryl substituent substitution; the R ^2a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, or -(CH ₂ ) _r OCH ₃ , the r is 1, 2 or 3; the R ^2b is hydrogen or C ₁ -C ₆ alkyl; the R ^2c is hydrogen or C ₁ -C ₆ alkyl; R ² is -NHC(O )-(C ₁ -C ₆ alkyl), -NHC(O)-NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ hetero Cycloalkyl or C ₃ -C ₈ cycloalkyl; R ² is -NH-(CH ₂ ) _k -NH-C(O)-(C ₁ -C ₆ alkyl), and the k is 1 or 2; R ² is -NH-(CH ₂ ) _i -R _f , i is 0, 1 or 2 and R _f is 4-7 membered heterocycloalkyl, heteroaryl, C ₁ -C ₆ alkyl sulfonyl group; R ³ and R ⁴ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₃ -C ₆ cycloalkoxy; said R ³ and R ⁴ have at least one is not hydrogen, or the R ³ and R ⁴ and the atom to which they are connected together form a 3-6-membered cycloalkyl group; the alkyl group, alkoxy group, cycloalkyl group and cycloalkoxy group are optionally cyanide base, hydroxyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or halogen substitution; A is an optionally substituted 6-membered aryl group or optionally substituted 5-6 membered heteroaryl; S4 wherein in S4: Q ¹ is CH or N; Q ⁴ is CH, C or N; each Q ² is independently CR ¹ or N, one of the Q ² is N and the other Q ² is CR ¹ ; Each Q ³ and Q ⁵ molecule is independently C(R ^QC ) ₂ , NR ^QN , C(O), O, S or SO ₂ , and the R ^QC is independently hydrogen, F, Cl, Br , or a 6-10-membered aryl group, each of the R ^QN is independently hydrogen, a C ₁ -C ₆ alkyl group or a 6-10-membered aryl group; the Q ¹ , Q ² , Q ³ , Q ⁴ , and Q At least one of ⁵ is N, NR ^QN , O or SO ₂ ; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; and when m is 0, n is not 0; R ¹ is selected from Hydrogen, C ₁ -C ₆ alkyl, halogen, -C(O)NHR ^1a , -NHR ^1a , -OR ^1a , cyclopropyl, azetidine or -CN; the C ₁ -C ₆ alkyl and azetidine is optionally substituted with a substituent selected from halogen, R ^1a , -NHR ^1a or -OR ^1a ; said R ^1a is hydrogen, C ₁ -C ₆ alkyl, cyclopropyl, 3- 6-membered heterocycle or C ₁ -C ₆ haloalkyl; L ² is selected from bond, -C(O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S( O) ₂ -, -S(O)-, -S(=O)(=NH)-, -S(=O)[=N(C ₁ -C ₆ alkyl)]-, -N(C ₁ -C ₆ alkyl)-, -C(O)(CH ₂ ) _p -, -(CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R ² is selected from hydrogen, C ₁ -C ₆ alkyl, -NR ^2b R ^2c , -OR ^2a , 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6 -10-membered aryl, 5-10-membered heteroaryl; the C ₁ -C ₆ alkyl, 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6 -The 10-membered aryl group and the 5-10-membered heteroaryl group are each independently optionally selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ methoxyalkyl, -OH, -OR ^2a , oxo group, halogen, =N, -C(O)R ^2a , -C(O)OR ^2a , -C(O)NR ^2b R ^2c , -S(O) ₂ R ^2a , -CN, -NR ^2b R ^2c , 3-6-membered cycloalkyl, 3-7-membered heterocycloalkyl, 6-10-membered aryl or 5-10-membered heteroaryl Substituent substitution; the R ^2a is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 3-7 membered heterocycloalkyl, or -(CH ₂ ) _r OCH ₃ , and the r is 1, 2 or 3; The R ^2b is hydrogen or C ₁ -C ₆ alkyl; The R ^2c is hydrogen or C ₁ -C ₆ alkyl; R ³ and R ⁴ are each independently hydrogen, optionally Halogen, -OH substituted C ₁ -C ₆ alkyl, at least one of R ³ and R ⁴ is hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6 membered cycloalkyl group ; A is an optionally substituted 6-membered aryl group or an optionally substituted 5-6-membered heteroaryl group; The condition is that when for , , , , , , , , , , , , , , , or When, R ¹ is not hydrogen; S5 S5' wherein in S5 and S5': R ¹ is hydrogen or R ^a1 ; R ^a1 is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ membered aryl or 5-10 membered heteroaryl base, the C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₄ -C ₁₀ Cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ membered aryl and 5-10 membered heteroaryl are optionally substituted by one or more identical or different R ^b1 and/or R ^c1 Substitution; Each R ^b1 is independently -OR ^c1 , -NR ^c1 R ^c1 , halogen, -CN, -C(O)R ^c1 , -C(O)OR ^c1 , -C(O)NR ^c1 R ^c1 , -S(O) ₂ R ^c1 , -S(O) ₂ NR ^c1 R ^c1 , -NHC(O)R ^c1 , -N(C ₁ -C ₄ alkyl)C(O)R ^c1 , -NHC( O)OR ^c1 or -N(C ₁ -C ₄ alkyl)C(O)OR ^c1 ; each R ^c1 is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl , C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more identical or different R ^d1 and/or R ^e1 ; each R ^d1 is independently -OR ^e1 , -NR ^e1 R ^e1 , halogen, -CN, -C(O)R ^e1 , -C(O)OR ^e1 , -C (O)NR ^e1 R ^e1 , -S(O)2R ^e1 , -S(O) ₂ NR ^e1 R ^e1 , -NHC(O)R ^e1 , -N(C ₁ -C ₄ alkyl)C(O) R ^e1 , -NHC(O)OR ^e1 or -N(C ₁ -C ₄ alkyl)C(O)OR ^e1 ; each R ^e1 is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 3-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; R ² is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkyl or halogen; Ring A Selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 9-10 membered biheterocycloalkyl; p is 1, 2 or 3; each R ⁴ is independently hydrogen, hydroxyl, oxo , Halogen, cyano, C ₁ -C ₄ alkyl, -NH ₂ , C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ hydroxyalkyl , hydroxy-C ₁ -C ₄ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 3-6 membered heterocycloalkyl, C ₃ -C ₆ hydroxycycloalkyl, C ₁ -C ₄ haloalkyl substituted by 3-6 membered heterocycloalkyl, 3 substituted by hydroxyl, halogen, -NH ₂ , -S(O) ₂ -(C ₁ -C ₄ alkyl) or oxo group -6-membered heterocycloalkyl, and the oxo group is only substituted on the non-aromatic ring; R ⁴ is -NR _a R _b , and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ⁴ is -C(O)NR _a R _{b ,} and the R _a and R _b are each independently hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ⁴ is -C(O)OR _g , and the R _g is hydrogen or C ₁ -C ₆ alkyl; R ⁴ is -OR _h ; the R _h is a C ₁ -C ₆ alkyl group; or, R ⁴ is -(CH ₂ ) NR _a R _b , and the R _a and R _b are each independent hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ³ and R ⁵ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkoxy group, the alkyl group, alkoxy group, cycloalkyl group and cycloalkoxy group are optionally replaced by cyano group, hydroxyl group, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or halogen substitution. The compound of formula I as described in claim 1 or 2, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or Its pharmaceutically acceptable salt, the S is S1a, S1a', -X-S1a', S1a'', -X-S1a'', S2a, S2a', -X-S2a', S2a'', - X-S2a'', S3a, S4a, S5a, S5a' or -X-S5a': X is O, NH or S, preferably O; S1a S1a' S1a'' wherein among S1a, S1a' and S1a'': R ₁ is selected from hydrogen, -OCH ₃ , -OCH ₂ CH ₃ , , -CH ₂ OH, -C(O)OH, -C(O)OCH ₃ , -Br, -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ CH(CH ₃ ) ₂ , -O(CH ₂ ) ₃ CH ₃ , -O(CH ₂ ) ₂ OCH ₃ , , -O(CH ₂ )-phenyl, -N=S(O)(CH ₃ ) ₂ , -CH ₃ , cyclopropyl, -N(CH ₃ ) ₂ , -NHCH ₃ , -NH ₂ , , , , , , , -C(CH ₃ ) ₂ -OH, , , -NH(CH ₂ )-NH-C(O)CH ₃ , -NH(CH ₂ )-morpholine, -NH-C(O)CH ₃ , -NH-C(O)NHCH ₃ , -NH- C(O)-N(CH ₃ ) ₂ , nitro group, -NH-S(O) ₂ CH ₃ , -N=S(O)(CH ₃ ) ₂ , hydroxyl group, -O-(CH ₂ ) ₂ - S(O) ₂ CH ₃ ,-F, , , , , , , , , , , , , , , , cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azetidinyl, piperidinyl, piperazyl, oxetane, oxygen Thietanyl, oxetanyl, thietanyl, thietanyl, thietanyl, azetidinyloxy, azetidinyloxy, piperidyloxy, piperidyloxy, oxetaneoxy, oxolaneoxy, oxaneoxy, thietaneoxy, thiolaneoxy base, thianeoxy group, , , , , , , , , , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ OH, , , -OCH ₂ CH ₂ NC(O)CH ₃ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ OH, , , , , , -SCH ₃ , -N(CH ₃ ) ₂ , ,or ; x is 1 or 2; A ₁ is selected from , , , , , , , , , , , , , , , , , , , , , , , , or ; R ₂ is selected from: hydrogen, hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH ₂ )CH ₃ , -C(CH ₃ )(= CH ₂ )CH ₃ , -CH=CH(CH ₂ ) ₂ CH ₃ , -CH=CHCH ₃ , -CH=CH-cyclopropyl, -C(O)NH ₂ , -C(O)OCH ₃ , - S(O) ₂ CH ₃ , -OCH ₃ , -CH ₂ NH ₂ , trifluoromethyl, methyl, trifluoromethoxy, halogen (F, Cl, Br), -NH ₂ , -NHC(O) CH ₃ , -NHCH ₂ CH ₃ or -NHCH(CH ₃ ) ₂ ; w is 1, 2 or 3; A ₂ is selected from , , , , , , , , , , , , , , , , , , , , , , or ; R ₃ is selected from -C(O)NH(CH ₂ ) ₂ CH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NH ₂ , -C(O)NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , -CH ₂ C(O)NH ₂ , hydrogen, -F, -Cl, -Br, cyano, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , -CH ₂ CN, -CH(CH ₃ )-NH ₂ , -CH=CH-CN, -C(O)-OH, -C(O)OCH ₃ , -C(O)CH ₃ , -C( CH ₃ ) ₂ -C(O)-OCH ₃ , -C(CH ₃ ) ₂ -CN, oxo group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, -NH ₂ , -NH-C( O)CH ₃ , -NH-S(O) ₂ CH ₃ , -NH-C(O)OC(CH ₃ ) ₃ , , , , , , -S(O) ₂ CH ₃ , -S(O) ₂ NCH ₃ , -S(O) ₂ NH ₂ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCF ₃ , , -OCH ₂ cyclopropyl, -OCH ₃ , -O(CH ₂ ) ₃ CH ₃ , -OCH ₂ phenyl, -O-phenyl, -(CH ₂ )-OH, -(CH ₂ ) ₂ -OH , -(CH ₂ )-OCH ₃ , -(CH ₂ )-OCH ₂ CH ₃ , -CH(OH)-CH ₂ -phenyl, -CH(OH)-CH ₂ CH ₃ , -CH(OH)- CH ₂ CH ₂ CH ₃ , -CH(OH)-CH ₂ CH ₂ CH ₂ CH ₃ , -CH(OH)-CH(CH ₃ ) ₂ , -CH(OH)-phenyl, -CH(OH)- CN, -CH(OH)-CH ₂ -OH, -CH(OH)-CF ₃ , -CH(OH)-(CH ₂ ) ₂ -phenyl, , -CH(NH ₂ )-CH ₂ -C(O)OH, -CH ₂ -NH-S(O) ₂ -CH ₃ , -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ - NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -NH-CH ₂ CH ₃ , -CH(CH ₃ )-NH ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ - NH ₂ , -CH ₂ NH-CH ₂ -phenyl, -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH-cyclopropyl, -CH ₂ NH-cyclobutyl, -CH ₂ NH-cyclo Pentyl, -CH ₂ NH-pyridyl, -CH ₂ NH-phenyl, -CH ₂ NH-(CH ₂ ) ₂ -OH, -CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -OH, - CH ₂ NH-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CF ₃ , -CH ₂ N(CH ₃ )-CH ₂ - CF ₂ H, -CH ₂ NH-CH ₂ -CF ₂ H, -CH ₂ NH-(CH ₂ ) ₂ -OCH ₃ , , , , , , , , , , , , , , , , , , , , , , , , , -CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₂ NOH , -CH ₂ NH-C(O)-CH ₂ OCH ₃ , -CH(CH ₃ )NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)-CH ₃ , , -CH ₂ NHCH ₂ -C(O)-NH ₂ , -CH ₂ NHCH ₂ -C(O)-(CH ₃ ) ₂ , -CH ₂ NHCH ₂ -C(O)-OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₃ , -CH ₂ NHCH ₂ -C(O)-NH(CH ₂ ) ₂ -OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₂ -phenyl, , -CH ₂ NHCH ₂ -C(O)-NH-phenyl, ,-CH ₂ NH-C(O)-CH ₂ NH-phenyl, , , , Or -CH ₂ NH-C(O)-CH ₂ NH-CH ₂ CF ₃ ; y is 1 or 2; L' is a bond, -(CH ₂ ) _k - or -O(CH ₂ ) _k -, as described k is 1 or 2, or L' is -CH=CH-(CH ₂ ) _n -, and n is 0, 1 or 2; S2a S2a' S2a'' wherein in S2a, S2a', S2a'': T and V are both N, or T is C and V is N, or T is N and V is C; R ₁ is selected from hydrogen and -OCH ₃ , -OCH ₂ CH ₃ , , -CH ₂ OH, -C(O)OH, -C(O)OCH ₃ , -Br, -OCH(CH ₃ ) ₂ , -O(CH ₂ ) ₂ CH(CH ₃ ) ₂ , -O(CH ₂ ) ₃ CH ₃ , -O(CH ₂ ) ₂ OCH ₃ , , -O(CH ₂ ) _z -phenyl, -N=S(O)(CH ₃ ) ₂ , -CH ₃ , cyclopropyl, -N(CH ₃ ) ₂ , -NHCH ₃ , -NH ₂ , , , , , , , -C(CH ₃ ) ₂ -OH, , , -NH(CH ₂ )-NH-C(O)CH ₃ , -NH(CH ₂ )-morpholine, -NH-C(O)CH ₃ , -NH-C(O)NHCH ₃ , -NH- C(O)-N(CH ₃ ) ₂ , nitro group, -NH-S(O) ₂ CH ₃ , -N=S(O)(CH ₃ ) ₂ , hydroxyl group, -O-(CH ₂ ) ₂ - S(O) ₂ CH ₃ ,-F, , , , , , , , , , , , , , , Cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azetidinyl, piperidinyl, piperazyl, oxetane, oxa Cyclopentyl, oxanyl, thietanyl, thiolyl, thietanyl, azetidinyloxy, azetidinyloxy, pipera Aldyloxy, piperayloxy, oxetanoxy, oxolanoxy, oxanyloxy, thietanyloxy, thiolyloxy , Thianexyloxy, , , , , , , , , , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ OH, , , -OCH ₂ CH ₂ NC(O)CH ₃ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH ₂ CH ₂ OH, , , , , , -SCH ₃ , -N(CH ₃ ) ₂ , ,or ; z is 1 or 2; x is 1 or 2; A ₁ is selected from , , , , , , , , , , , , , , , , , , , , , , , , or ; R ₂ is selected from: hydrogen, hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH ₂ )CH ₃ , -C(CH ₃ )(= CH ₂ )CH ₃ , -CH=CH(CH ₂ ) ₂ CH ₃ , -CH=CHCH ₃ , -CH=CH-cyclopropyl, -C(O)NH ₂ , trifluoromethyl, methyl, tris Fluoromethoxy, -C(O)OCH ₃ , -S(O) ₂ CH ₃ , -OCH ₃ , -CH ₂ NH ₂ or halogen (F, Cl, Br); w is 1, 2 or 3; A ₂ selected from , , , , , , , , , , , , , , , , , , , , , , or ; R ³ is selected from -C(O)NH(CH ₂ ) ₂ CH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NH ₂ , -C(O)NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , -CH ₂ C(O)NH ₂ , hydrogen, -F, -Cl, -Br, cyano, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , -CH ₂ CN, -CH(CH ₃ )-NH ₂ , -CH=CH-CN, -C(O)-OH, -C(O)OCH ₃ , -C(O)CH ₃ , -C( CH ₃ ) ₂ -C(O)-OCH ₃ , -C(CH ₃ ) ₂ -CN, oxo group, hydroxyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, -NH ₂ , -NH-C( O)CH ₃ , -NH-S(O) ₂ CH ₃ , -NH-C(O)OC(CH ₃ ) ₃ , , , , , , -S(O) ₂ CH ₃ , -S(O) ₂ NCH ₃ , -S(O) ₂ NH ₂ , -OCH ₂ CH ₃ , -O(CH ₂ ) ₂ CH ₃ , -OCF ₃ , , -OCH ₂ cyclopropyl, -OCH ₃ , -O(CH ₂ ) ₃ CH ₃ , -OCH ₂ phenyl, -O-phenyl, -(CH ₂ )-OH, -(CH ₂ ) ₂ -OH , -(CH ₂ )-OCH ₃ , -(CH ₂ )-OCH ₂ CH ₃ , -CH(OH)-CH ₂ -phenyl, -CH(OH)-CH ₂ CH ₃ , -CH(OH)- CH ₂ CH ₂ CH ₃ , -CH(OH)-CH ₂ CH ₂ CH ₂ CH ₃ , -CH(OH)-CH(CH ₃ ) ₂ , -CH(OH)-phenyl, -CH(OH)- CN, -CH(OH)-CH ₂ -OH, -CH(OH)-CF ₃ , -CH(OH)-(CH ₂ ) ₂ -phenyl, , -CH(NH ₂ )-CH ₂ -C(O)OH, -CH ₂ -NH-S(O) ₂ -CH ₃ , -CH ₂ -NH-(CH ₂ ) ₃ CH ₃ , -CH ₂ - NH-CH ₃ , -CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -NH-CH ₂ CH ₃ , -CH(CH ₃ )-NH ₂ , -CH ₂ -NH ₂ , -CH ₂ CH ₂ - NH ₂ , -CH ₂ NH-CH ₂ -phenyl, -CH ₂ N(CH ₂ CH ₃ ) ₂ , -CH ₂ NH-cyclopropyl, -CH ₂ NH-cyclobutyl, -CH ₂ NH-cyclo Pentyl, -CH ₂ NH-pyridyl, -CH ₂ NH-phenyl, -CH ₂ NH-(CH ₂ ) ₂ -OH, -CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -OH, - CH ₂ NH-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CN, -CH ₂ N(CH ₃ )-CH ₂ -CF ₃ , -CH ₂ N(CH ₃ )-CH ₂ - CF ₂ H, -CH ₂ NH-CH ₂ -CF ₂ H, -CH ₂ NH-(CH ₂ ) ₂ -OCH ₃ , , , , , , , , , , , , , , , , , , , , , , , , , -CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ CH ₂ NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₂ NOH , -CH ₂ NH-C(O)-CH ₂ OCH ₃ , -CH(CH ₃ )NH-C(O)-OC(CH ₃ ) ₃ , -CH ₂ NH-C(O)- CH ₃ , , -CH ₂ NHCH ₂ -C(O)-NH ₂ , -CH ₂ NHCH ₂ -C(O)-(CH ₃ ) ₂ , -CH ₂ NHCH ₂ -C(O)-OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₃ , -CH ₂ NHCH ₂ -C(O)-NH(CH ₂ ) ₂ -OCH ₃ , -CH ₂ NHCH ₂ -C(O)-NHCH ₂ -phenyl, , -CH ₂ NHCH ₂ -C(O)-NH-phenyl, ,-CH ₂ NH-C(O)-CH ₂ NH-phenyl, , , , Or -CH ₂ NH-C(O)-CH ₂ NH-CH ₂ CF ₃ ; Y is 1 or 2; L' is a bond, -(CH ₂ )k- or -O(CH ₂ ) _k -, as described k is 1 or 2, or L' is -CH=CH-(CH ₂ ) _n -, and n is 0 or 1; S3a wherein in S3a: Q ¹ and Q ² are each independently CH or N; Q ³ and Q ⁴ are each independently C or N, and at least one of Q ³ and Q ⁴ is C; Q ⁶ is CH, N, NH, O or S; Q ⁵ is CH, N, NH, O or S; at least one of the Q ¹ , Q ² , Q ³ , Q ⁴ , Q ⁵ and Q ⁶ is N, NH, O Or S; R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, halogen, -OR ^1a , cyclopropyl or -CN; the R ^1a is hydrogen or C ₁ -C ₆ alkyl; L ² is selected from bond , -C(O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S(O) ₂ -, -C(O)(CH ₂ ) _p -, - (CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R ² is selected from hydrogen, -(CH ₂ ) _q CH ₃ , 3-14-membered cycloalkanes base, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; the q is an integer from 1 to 5; the 3-14 membered Cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl and 5-10-membered heteroaryl are each independently optionally selected from C ₁ -C ₆ alkane group, -OH, halogen, -C(O)R ^2a , -C(O)NR ^2b R ^2c substituents; the R ^2a is C ₁ -C ₆ alkyl or -(CH ₂ ) _r OCH ₃ , the r is 1, 2 or 3; the R ^2b is hydrogen or C ₁ -C ₆ alkyl; the R ^2c is hydrogen or C ₁ -C ₆ alkyl; R ³ and R ⁴ are each independently Hydrogen or C ₁ -C ₆ alkyl, at least one of R ³ and R ⁴ is not hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6 membered cycloalkyl group; A is Optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl; S4a wherein in S4a: Q ¹ is CH or N; Q ⁴ is CH, C or N; each Q ² is independently CR ¹ or N; each Q ³ and Q ⁵ molecule is independently C (R ^QC ) ₂ , NR ^QN , C(O), O, S or SO ₂ , each of the R ^QC is independently hydrogen, F, Cl, Br, or a 6-10 membered aryl group, each of the R ^QN is independently is hydrogen, C ₁ -C ₆ alkyl or 6-10 membered aryl group; at least one of Q ¹ , Q ² , Q ³ , Q ⁴ , and Q ⁵ is N, NR ^QN , O or SO ₂ ; R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, halogen, cyclopropyl, cyano or -OR ^1a , said R ^1a is hydrogen or C ₁ -C ₆ alkyl; L ² is selected from bond, -C ( O)-, -C(O)O-, -C(O)NH(CH ₂ ) _o -, -S(O) ₂ -, -C(O)(CH ₂ ) _p -, -(CH ₂ ) _p - or O; the o is 0, 1 or 2; the p is an integer from 1 to 6; R ² is selected from hydrogen, -(CH ₂ ) _q CH ₃ , 3-14-membered cycloalkyl, 3- 14-membered cycloalkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; the q is a multiple of 1 to 5; the 3-14-membered cycloalkyl, 3-14-membered ring alkenyl, 3-14-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl are each independently selected from C ₁ -C ₆ alkyl, hydroxyl, Halogen, -C(O)R ^2a or -C(O)NR ^2b R ^2c group substitution; the R ^2a is selected from C ₁ -C ₆ alkyl or -(CH ₂ ) _r OCH ₃ ; the r is 1, 2 or 3; R ^2b and R ^2c are each independently hydrogen or C ₁ -C ₆ alkyl; R ³ and R ⁴ are each independently hydrogen or C ₁ -C ₆ alkyl, and R At least one of ³ and R ⁴ is hydrogen, or R ³ and R ⁴ and the atoms to which they are connected together form a 3-6-membered cycloalkyl group; A is an optionally substituted 6-membered aryl group or an optionally substituted 5-6 membered heteroaryl; S5a S5a' wherein, among the S5a and S5a', R ¹ , R ² , R ³ , R ⁴ , ring A and p are as defined and described in S5 in claim 2. The compound of formula I as described in claim 1, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Above acceptable salts, the S is S6, S6', -X-S6', S6'', S6''', -X-S6''', S6a, S6a'', S6c, S6c'', -X-S6c or -X-S6c'', preferably S6c: wherein, X is O, NH or S, preferably O; S6 S6' S6''S6''' S6a S6a'' S6c S6c'' wherein among the S6, S6', S6'', S6''', S6a, S6a'', S6c, S6c'': R ₂ is selected from hydrogen, halogen, -OH, -CN, -NO _2. C ₁ -C ₆ alkyl mercapto or -NR _a R _b , the R _a and R _b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ heterocycloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl , spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C ₁ -C ₆ haloalkyl, -COOH, -COOR _c ; the R _c is -C ₁ - C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or -C ₄ -C ₈ cycloalkenyl; R ₂ is -NS(O)(R _d )(R _e ), the R _d and R _e are each independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl , C ₄ -C ₈ cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl; R ₂ is -NHC(O)-(C ₁ -C ₆ alkyl), -NHC(O)- NR _a R _b , the R _a and R _b are each independently hydrogen, -C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl; R ₂ is - NH-(CH ₂ ) _k -NH-C(O)-R _aa , the R _aa is C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ -C ₈ cycloalkyl, And k is 1 or 2; R ₂ is -NH-(CH ₂ ) _i -R _f , i is 0, 1 or 2 and R _f is 4-7 membered heterocycloalkyl, heteroaryl, C ₁ -C ₆ alkylsulfonyl group; In addition, the above-mentioned C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, 4-7 membered heterocycloalkyl group and heteroaryl group are optionally substituted by 1, 2 One or three are selected from halogen, -OH, oxo, -CN, -NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ Cycloalkyl, 4-7 membered heterocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylsulfonyl, Phenyl, benzyl, heteroaryl, -(CH ₂ )-heteroaryl, -NHC(O)(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkoxy, phenoxy, hetero Aryloxy or -NR _a R _b group substitution; the R _a and R _b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ heterocycloalkyl or C ₃ - C ₈ cycloalkyl; R ₂ is -O-(CH ₂ ) _z -phenyl, -O-(CH ₂ ) _z - (4-7 membered heterocycloalkyl), -O-(CH ₂ ) _z - Heteroaryl, the z is 0, 1 or 2, the phenyl, heterocycloalkyl and heteroaryl are optionally selected from -OH, heterocycloalkyl or heterocycloalkenyl substituted, and can be substituted by methyl or oxo group substitution; or R ₂ is , , , , , , , , , , , , or ; R ₁ is hydrogen or -OR ^A ; R ^A is hydrogen, C ₃ -C ₁₀ cycloalkyl or 3-10 membered heterocycloalkyl; the C ₃ -C ₁₀ cycloalkyl and 3-10 membered heterocycle The alkyl group is optionally substituted by one or more identical or different R ^a1 and/or R ^c1 ; each R ^a1 is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are independently are optionally substituted by one or more identical or different R ^b1 and/or R ^c1 ; each R ^b1 is independently -OR ^c1 , -NR ^c1 R ^c1 , halogen, -CN, -C(O )R ^c1 , -C(O)OR ^c1 , -C(O)NR ^c1 R ^c1 , -S(O) ₂ R ^c1 , -S(O) ₂ NR ^c1 R ^c1 , -NHC(O)R ^c1 , -N(C ₁ -C ₄ alkyl)C(O)R ^c1 , substituted by oxo group, and the oxo group is only substituted on the non-aromatic ring; each R ^c1 is independently hydrogen, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 Heteroaryl; or R ₁ is selected from C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl base; the C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally One or more R ^a2 and/or R ^b2 are substituted; each R ^a2 is independently selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by 1 or more R ^c2 and/or R ^b2 substitution; each R ^b2 is independently selected from -OR ^c2 , -NR ^c2 R ^c2 , halogen, -CN, -C(O)R ^c2 , -C(O)OR ^c2 , -C( O)NR ^c2 R ^c2 , -OC(O)R ^c2 , -S(O) ₂ R ^c2 , -S(O) ₂ NR ^c2 R ^c2 , -NHC(O)R ^c2 , -N(C ₁ -C _4Alkyl )C(O)R ^c2 , -NHC(O)OR ^c2 , oxo group, =NH, and the oxo group, =NH is only substituted on the non-aromatic ring; each R ^c2 is independent Selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 yuan hetero Cycloalkyl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ - C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by one or more R ^d2 and/or R ^e2 ; each R ^d2 is independently -OR ^e2 , -NR ^e2 R ^e2 , halogen, -CN, -C(O)R ^e2 , -C(O)OR ^e2 , -C(O)NR ^e2 R e2 , ^-S (O) ₂ R ^e2 , -S(O ) ₂ NR ^e2 R ^e2 , -NHC(O)R ^e2 , -N(C ₁ -C ₄ alkyl)C(O)R ^e2 , oxo group, the oxo group is only substituted on the non-aromatic ring; Each R ^e2 is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aromatic base, 3-10 membered heterocycloalkyl group or 5-10 membered heteroaryl group, the C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₁₀ Cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by 1 or more R ^f2 and/or R ^g2 ; each R ^f2 is independently Independently selected from -OR ^g2 , -NR ^g2 R ^g2 , halogen, -CN, -C(O)R ^g2 , -C(O)OR ^g2 , -C(O)NR ^g2 R ^g2 , -S(O) ₂ R ^g2 , -S(O) ₂ NR ^g2 R ^g2 , -NHC(O)R ^g2 , -N(C ₁ -C ₄ alkyl)C(O)R ^g2 , oxo group, the oxo group Only substituted on non-aromatic rings; each R ^g2 is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; or R ₁ is selected from C ₂ -C ₄ alkyl, C ₂ -C ₄ alkenyl; the C ₂ -C ₄ alkyl and C ₂ -C ₄ alkenyl are optionally substituted by R ^b3 ; R ^b3 is selected from -C(O)R ^c3 , -C(O)OR ^c3 , -C(O)NR ^c3 R ^c3 , -C(O)NHOR ^c3 or -C(O)N(C ₁ -C ₄ alkyl)OR ^c3 ; Each R ^c3 is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5 -10-membered heteroaryl is optionally substituted by one or more R ^d3 and/or R ^e3 ; each R ^d3 is independently selected from -OR ^e3 , -NR ^{e3 Re3} , halogen, -CN, -C( O)R ^e3 , -C(O)OR ^e3 , -C(O)NR ^e3 R ^e3 , -S(O) ₂ R ^e3 , -S(O) ₂ NR ^e3 R ^e3 , -NHC(O)R ^e3 , -N(C ₁ -C ₄ alkyl)C(O)R ^e3 , oxo group, the oxo group is only substituted on the non-aromatic ring; each R ^e3 is independently selected from hydrogen, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 3-10 membered heterocycloalkyl or 5-10 Metaheteroaryl; R ₃ is selected from hydrogen, C ₁ -C ₄ alkyl, -O(C ₁ -C ₄ alkyl), -NH ₂ , -NH(C ₁ -C ₄ alkyl), -N( C ₁ -C ₄ alkyl) ₂ or halogen; R ₅ is selected from hydrogen, hydroxyl or -NHR';R' is selected from hydrogen, C ₁ -C ₃ alkyl and -C(O)C ₁ -C ₃ alkyl ; R ₄ is selected from C ₁ -C ₄ alkyl, hydroxyl, oxo, cyano, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, hydroxyl-C ₁ -C ₄ haloalkyl, C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkoxy, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocycloalkane group, 3-6 membered hydroxyheterocycloalkyl, halogen or -SO ₂ -C ₁ -C ₄ alkyl; R ₆ is selected from hydrogen, C ₁ -C ₄ alkyl or halogen; or R ₄ and R ₆ are combined with them The connected carbon atoms together form optionally substituted C ₅ -C ₆ cycloalkyl and 5-6 membered heterocycloalkyl, the heteroatoms in the 5-6 membered heterocycloalkyl being selected from the group consisting of 1, 2, 3 Or 4 heteroatoms or heteroatom groups independently selected from -NH, -O-, -S- and N; R ₇ and R ₈ are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkoxy group, the alkyl group, alkoxy group, cycloalkyl group and cycloalkoxy group are optionally replaced by cyano group, hydroxyl group, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy or halogen substitution. The compound of formula I as described in claim 4, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof The acceptable salt above, wherein R ₁ is hydrogen or -OR ^A ; R ^A is hydrogen; R ₂ is hydrogen, C ₁ -C ₄ alkyl or -O (C ₁ -C ₄ alkyl), and the - O(C ₁ -C ₄ alkyl) is optionally substituted by -O(C ₁ -C ₄ alkyl); R ₃ is hydrogen; R ₅ is hydrogen or -NHR';R' is selected from hydrogen, C ₁ - C ₃ alkyl and -C(O)C ₁ -C ₃ alkyl; R ₄ is C ₁ -C ₄ haloalkyl; R ₆ is hydrogen or halogen; or R ₄ and R ₆ are formed together with the carbon atoms to which they are connected. Ring Maker S6 The fragment is ; R ₇ is C ₁ -C ₆ alkyl; R ₈ is C ₁ -C ₆ alkyl. The compound of formula I as described in claim 4 or 5, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or Its pharmaceutically acceptable salt, wherein each S in the structure The fragment is , or ,For example , , , , or , preferably or , further preferably ; And/or, R ₃ is hydrogen; and/or, R ₇ is methyl. The compound of formula I as described in claim 4, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof The acceptable salt above, wherein said S6, S6', S6a or S6c is any of the following structures: , , , , , , , , ; And/or, the S6'', S6''', S6a'' or S6c'' has the following structure: ; Preferably, the S has the following structure: or ; Further preferably, the S has the following structure: . The compound of formula I as described in any one of claims 1-7, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, and prodrugs and/or a pharmaceutically acceptable salt thereof, characterized in that said L is -(CH ₂ ) _j -, and one or more methylene groups in said -(CH ₂ ) _j - are optionally substituted Selected from -NR ^3' -, -O-, -CR ^1' R ^2' -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O- , -OC(O)-, -C(O)NR ^3' -, -NR ^3' C(O)-, -S(O) ₂ NR ^3' -, -NR ^3' S(O) ₂ -, Vinylene, ethynylene, phenyl, 8-10-membered bicyclic arylene, 3-7-membered saturated or partially unsaturated cycloalkylene, 5-11-membered saturated or partially unsaturated spirocycloalkane radical, 5-11 membered saturated or partially unsaturated fused cycloalkylene group, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, with 1-2 independently selected from nitrogen, oxygen or thia 4-7 membered saturated or partially unsaturated heterocycloalkylene groups, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene groups with 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur atoms base, a 5-11 membered saturated or partially unsaturated subfused heterocycloalkyl group with 1-2 independently selected from nitrogen, oxygen or sulfur heteroatoms, with 1-2 independently selected from nitrogen, oxygen or sulfur 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene with 1-4 heteroatoms, 5-6 membered heteroarylene with 1-4 independently selected from nitrogen, oxygen or sulfur heteroatoms, or 1-4 5 8-10 membered bicyclic heteroaryl groups selected from nitrogen, oxygen or sulfur heteroatoms are substituted, and the vinylidene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, ethylene Spiroheterocycloalkyl, fused heterocycloalkylene, spirocycloalkylene, fused cycloalkylene, and heteroarylene are each independently optionally substituted by one or more selected from halogen, oxo, and -NR. ^3' R ^4' , -OR ^3' , nitro, -CN, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl substituents are substituted, as described Alkyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more halogen, -OH, -NH ₂ , -CN, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl Substituent substitution, R ^1' and R ^2' are each independently halogen, -OH, -NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ chloroalkyl, C ₁ -C ₄ hydroxyalkyl, -O(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), C ₃ -C ₆ cycloalkyl, -O(C ₃ -C ₆ cycloalkyl), -NH(C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ heterocycloalkyl, -O(C ₃ -C ₆ heterocycloalkyl), -NH(C ₃ -C ₆ cycloalkyl); R ^3' and R ^4' are each independently hydrogen, deuterium, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Preferably, the L is -(CH ₂ ) _j -, and the -(CH ₂ ) _j - 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -CHF-, -CHCF ₃ -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC(O)-, - NCH ₃ C(O)-, vinylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxepropylene, oxetylene, cyclohexylene Oxanyl, oxanyl, aziridyl, azetidinyl, aziridyl, piperidinyl, piperidine, methylphenylene, ethylene Homomorphinyl, phenylene, pyrrole, thienylene, furylene, imidazolylene, pyrazolylene, triazoleylidene, tetrazolylene, ethoylene, isozylene base, thiazolyl group, isothiazolyl group, pyridylene group, pyrimidinyl group, pyrimidinyl group, pyrimidinyl group, , , , , , , , , , , , , is replaced by a group, and the replacement group is optionally replaced by one or more substituents selected from halogen, oxo, -NR ^3' R ^4' , -OR ^3' , C ₁ -C ₄ alkyl Substituted, the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH ₂ , R ^3' and R ^4' are each independently hydrogen, deuterium, C ₁ -C ₄ alkane Base, j is 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, the L is -(CH ₂ ) _j -, and 1 of the -(CH ₂ ) _j - , 2 or 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH ₃ -, -O-, -C(O)-, -C(O)NH-, - NHC(O)-, -NCH ₃ C(O)-, -C(O)NCH ₃ -, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, aziridylene, Azetidinyl, azitidine, piperidinyl, piperidinyl, , , , , , or group substitution, j is 5, 6, 7, 8, 9 or 10. The compound of formula I as described in claim 8, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof an acceptable salt, the L is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . The compound of formula I as described in any one of claims 1-7, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, and formers medicine and/or its pharmaceutically acceptable salt, the L is LA: LA wherein: Ring A is a bond, a C ₃ -C ₁₂ cycloalkylene group or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S, and the cycloalkylene group is Cycloalkyl and heterocycloalkylene groups are optionally selected from halogen, oxo, cyano, amine, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl Substituted with a base or -O-(C ₁ -C ₆ alkyl) substituent; Ring B is a bond, C ₃ -C ₁₂ cycloalkylene or 3 containing 1-2 heteroatoms selected from N, O or S -12-membered heterocycloalkylene, the cycloalkylene and heterocycloalkylene are optionally selected from halogen, oxo, cyano, amine, hydroxyl, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent; Ring C is C ₃ -C ₁₂ cycloalkylene or contains 1-2 options A 3-12 membered heterocycloalkylene group from N, O or S heteroatoms, the cycloalkylene group and heterocycloalkylene group are optionally selected from halogen, oxo, cyano, amine, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl or -O-(C ₁ -C ₆ alkyl) substituent substitution; X'' is a bond, -NH- , -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -S-, -C=C-, -C≡C-, -CHF-, -CHCF ₃ -, -C(O)- , -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH ₃ -, -NHC (O)-, -NCH ₃ C(O)- or -C(O)CH ₂ O-; L ₃ is -(CH ₂ ) _k , one or two methylene groups in L ₃ are optional Selected from -O-, -NH-, -C≡C-, -N(C ₁ -C ₆ alkyl)-, -N(C ₁ -C ₆ haloalkyl)-, -C(O)-, -N(C ₁ -C ₆ hydroxyalkyl) - or -N (C ₃ -C ₈ cycloalkyl) - substitution, k is 0, 1, 2, 3, 4, 5, 6 or 7; X''' is a bond, -NH-, -NCH ₃ -, -O-, -C(CH ₃ ) ₂ -, -S-, -C=C-, -C≡C-, -CHF-, -CHCF ₃ - , -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O )NCH ₃ -, -CH ₂ NCH ₃ -, -NHC(O)- or -NCH ₃ C(O)-. The compound of formula I as described in claim 10, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, in the LA, ring A is a 3-6 membered saturated cycloalkylene group; ring B contains 1 or 2 nitrogen heteroatoms, a 4-7 membered saturated monocyclic heterocycloalkylene group; ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a subcondensed Heterocycloalkyl; X'' is a bond or -C(O)-; L ₃ is -(CH ₂ ) _k , k is 1, 2, 3, 4 or 5. The compound of formula I as described in claim 10, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, the LA is LA-1: LA-1 wherein, in said LA-1, ring A, ring B, ring C, L ₃ and X'' are as defined and described in claim 10. The compound of formula I as described in claim 10, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, wherein the LA is LA-2, LA-3, LA-4 or LA-5: LA-2 wherein in LA-2, Ring A is , , , , or , where the a end is connected to S and the b end is connected to X'''; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally replaced by F; X''' is -C(O)- ; Ring B is , , , or , where the c end is connected to X'''', and the d end is connected to L ₃ ; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally replaced by F; L ₃ is -(CH ₂ ) _k - , wherein one or two CH ₂ contained in said L ₃ are each independently optionally replaced by -O-, -NH- or -N(C ₁ -C ₆ alkyl)-, or in said L ₃ One -CH ₂ CH ₂ - included is optionally replaced by -C≡C-; k is 1, 2, 3 or 4; ring C is , , , or , where the e end is connected to L ₃ , and the f end is connected to X''; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F; X'' is -C(O)-; LA-3 wherein, in said LA-3, ring A is , , , , or , where the a end is connected to S and the b end is connected to X'''; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally replaced by F; X''' is -C(O)- ; Ring B is , , , or , where the c end is connected to X'''', and the d end is connected to L ₃ ; 1, 2, 3 or 4 hydrogen atoms in the ring B are optionally replaced by F; L ₃ is -(CH ₂ ) _k - , wherein one CH ₂ contained in L ₃ is optionally replaced by -O-, -NH- or -N(C ₁ -C ₆ alkyl)-; k is 1 or 2; ring C is , , or , where the e end is connected to L ₃ , and the f end is connected to X''; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F; X'' is -C(O)-; LA-4 Wherein, in the LA-4, ring A is , , , , , , , where the a end is connected to S, and the b end is connected to X'''; 1, 2, 3 or 4 hydrogen atoms in the ring A are optionally replaced by F; X''' is a bond, -C(O )NH- or -C(O)NCH ₃ -; Ring B is a bond; L ₃ is -(CH ₂ ) _k , and one or two methylene groups in L ₃ are optionally replaced by -O-, - NH-, -C(O)-, -C≡C- or -N(C ₁ -C ₆ alkyl)-substitution, k is 0, 1, 2, 3, 4, 5, 6 or 7; Ring C for , , , , , , , or , where the e end is connected to L ₃ , and the f end is connected to X''; 1, 2, 3 or 4 hydrogen atoms in the ring C are optionally replaced by F; X'' is -C(O)-; LA-5 Wherein, ring A, X''', ring B, L ₃ and ring C are as defined in LA-2 or LA-3; X'' is -C(O)CH ₂ O-, X'' -C(O)- in is connected to ring C. The compound of formula I as described in claim 13, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, wherein in the LA-2, Ring A is , , , , or , where the a end is connected to S, and the b end is connected to X'''; and/or, in the LA-2, ring B is , or , wherein the c end is connected to X'''', and the d end is connected to L ₃ ; and/or, in the LA-2, L ₃ is -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, , , , , , or , wherein the k'' end is connected to ring B, and the k' end is connected to ring C; and/or, in the LA-2, ring C is , or , where the e end is connected to L ₃ and the f end is connected to X''; and/or, in the LA-3, ring A is , or , where the a end is connected to S, and the b end is connected to X'''; and/or, in the LA-3, ring B is , or , wherein the c end is connected to X'''', and the d end is connected to L ₃ ; and/or, in the LA-3, L ₃ is -(CH ₂ ) _k -, k is 1 or 2; and/or, In the LA-3, Ring C is , or , where the e end is connected to L ₃ and the f end is connected to X''; and/or, in the LA-4, ring A is , or , where the a end is connected to S, and the b end is connected to X'''; and/or, in the LA-4, L ₃ is -CH ₂ -, -(CH ₂ ) ₂ -, , or , wherein the k'' end is connected to ring B, and the k' end is connected to ring C; and/or, in the LA-4, ring C is or , where the e end is connected to L ₃ and the f end is connected to X''; and/or, in the LA-5, ring A is , where the a end is connected to S, and the b end is connected to X'''; and/or, in the LA-5, ring B is , wherein the c-terminal is connected to X'''', and the d-terminal is connected to L ₃ ; and/or, in the LA-5, L ₃ is -(CH ₂ )-; and/or, in the LA-5, Ring C is , where the e end is connected to L ₃ and the f end is connected to X''. The compound of formula I as described in claim 10 or 13, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or Its pharmaceutically acceptable salt, the LA has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Preferably, the LA has any of the following structures: , , , , , , , , , , , , , . The compound of formula I as described in any one of claims 1-15, and/or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, and formers Drug and/or its pharmaceutically acceptable salt, the E is E21: _{E21 wherein in E21 : _} N; R ₃ '' are each independently hydrogen, deuterium, hydroxyl, amine, cyano, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -O(C ₁ -C ₆ alkyl), -O-(C ₃ -C ₈ cycloalkyl), -O-(3-8 membered heteroaryl) Cycloalkyl), N(C ₁ -C ₆ alkyl) _1-2 , NH (C ₃ -C ₈ cycloalkyl), NH (3-8 membered heterocycloalkyl), -O-(6-10 Aryl), -O-(5-10 membered heteroaryl); the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally selected from 1 to 3 independently selected from hydroxyl , halogen, cyano, amine group substitution; m'' is 1, 2 or 3; R ₁ '' is independently hydrogen, deuterium, hydroxyl, amine, cyano, halogen, C ₁ -C ₆ Alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -O(C ₁ -C ₆ alkyl), the Alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by 1-3 independently selected groups from hydroxyl, halogen, cyano, and amine; R ₂ '' is hydrogen , deuterium, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, the C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl are optionally selected from 1-3 independently Substitution of hydroxyl, halogen, cyano, and amine groups. The compound of formula I as described in claim 16, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, the E21 has the formula E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1aa, E21-1bb, E21-1cc , E21-1dd, E21-1ee, E21-1ff or E21-1gg structure: E21-1a E21-1b E21-1c E21-1d E21-1e E21-1f E21-1g E21-1aa E21-1bb E21-1cc E21-1dd E21-1ee E21-1ff E21-1gg wherein Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ , R ₁ '', R ₂ '', R ₃ '', m'' are as defined in request item 16 and describe. The compound of formula I as described in claim 17, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof The acceptable salt above, wherein said E21 has the structure of formula E21-1h, E21-1i, E21-1j or E21-1hh, preferably E21-1h: E21-1h E21-1i E21-1j E21-1hh where R ₃ '' is as defined in request 17. The compound of formula I as described in any one of claims 16-18, and/or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, and precursors thereof medicine and/or its pharmaceutically acceptable salt, wherein R ₃ '' is hydrogen, halogen, C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl), and the C ₁ -C ₆ Alkyl and -O (C ₁ -C ₆ alkyl) are optionally substituted by 1 to 3 halogens, such as hydrogen, F, Cl, CF ₃ , -OCF ₃ or -OCH ₃ . The compound of formula I as described in claim 16, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts for E21 are: , , , , , , , , , , , , , , , , , , , , , , ; Preferably, the E21 is any one of the following structures: , , , , . The compound of formula I as described in claim 1, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof The above acceptable salts, the compound of formula I is any of the following compounds: . The compound of formula I as described in claim 1, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceuticals thereof Acceptable salts above, wherein the deuterated compound has any of the following structures: . A pharmaceutical composition comprising the compound described in any one of claims 1-22, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, and solvates , prodrugs and/or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients. A compound described in any one of claims 1-22, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or Its pharmaceutically acceptable salt or the pharmaceutical composition described in claim 23 is prepared for the treatment and/or prevention of SOS1-mediated diseases or conditions, or diseases caused by the interaction between SOS1 and Ras or SOS1 and Rac, or diseases, or applications in medicines for cancer. The use as claimed in claim 24, wherein said cancer is selected from: Heart: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma group; Lung: Bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, interstitial carcinoma skin tumors; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, Carcinoid tumors, vasoactive intestinal peptide tumors), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, Carcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary system: kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (spermatogonia) tumor, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, cholangiocarcinoma; Bone: Osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, enchondroma (osteochondral exostoses), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis malformans), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytoma, medulloblastoma, glioma, ventricle) Angiomangiomas, germinal cell tumors (pineal tumors), glioblastoma multiforme, oligodendroglioblastoma, schwannomas, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, Glioma, sarcoma); Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, agerminoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: Hematology (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's disease Lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland: Neuroblastoma. The application as described in claim 24, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer , prostate cancer, glioblastoma, kidney cancer or sarcoma. A compound described in any one of claims 1-22, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or Its pharmaceutically acceptable salt or the pharmaceutical composition described in claim 23 is useful in the preparation of the treatment and/or prevention of neurofibromatosis type 1 (NF1), Noonan syndrome (NS), and Noonan syndrome with freckles (NSML). ), capillary malformation-arteriovenous malformation syndrome (CM-AVM), congenital varicella syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Legacy syndrome and hereditary gingival fibromatosis. A compound described in any one of claims 1-22, and/or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs and/or The application of a pharmaceutically acceptable salt thereof or the pharmaceutical composition described in claim 23 in the preparation of a medicament for the treatment and/or prevention of KRAS-mediated diseases or conditions, where the KRAS is preferably a mutant KRAS, so The mutant KRAS is preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D and KRAS G12V.