CN115043817A

CN115043817A - SOS1 proteolysis regulator and preparation method and application thereof

Info

Publication number: CN115043817A
Application number: CN202210114053.0A
Authority: CN
Inventors: 吕彬华; 崔大为; 庞旭东; 刘连军
Original assignee: Suzhou Zelgen Biopharmaceutical Co Ltd; Shanghai Zelgen Pharmatech Co Ltd
Current assignee: Suzhou Zelgen Biopharmaceutical Co Ltd; Shanghai Zelgen Pharmatech Co Ltd
Priority date: 2021-03-09
Filing date: 2022-01-30
Publication date: 2022-09-13
Also published as: WO2022188819A1

Abstract

The invention relates to a SOS1 proteolysis regulator and a preparation method and application thereof. The compound has a structure shown in formula (I), and the invention also discloses a preparation method of the compound and application of the compound as a protein hydrolysis regulator SOS1, wherein the compound has a good selective regulation effect on SOS1 hydrolysis.

Description

SOS1 proteolysis regulator and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a SOS1 proteolysis regulator and a preparation method and application thereof.

Background

Lung cancer is one of the major causes of death in human cancer. Lung cancer can be divided into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients. The global NSCLC market was statistically estimated to be $ 209 billion in 2016, with the U.S. market taking up half, followed by Japan, Germany, and China. From the current trend, the market for non-small cell lung cancer remains continuously growing, with a projected worldwide market reaching $ 540 billion in 2023.

At present, the main therapeutic drugs for NSCLC include chemotherapeutic drugs, molecular targeted drugs, tumor immunotherapy and the like. The chemotherapy drugs mainly comprise gemcitabine, paclitaxel, platinum drugs and the like, but the drugs generally have poor selectivity and high toxicity, so that relatively strong toxic and side effects are caused. In recent years, molecular targeted drugs have become research hotspots due to the obvious advantages of high selectivity, relatively small toxic and side effects, accurate treatment and the like. The existing NSCLC molecular targeted drugs comprise EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotininib, Pyrotinib, Rociletinib, Osimertinib and the like), ALK inhibitors (such as Ceritinib, Alectoib, Brigatinib, Lorlatinib, Ocatinib and the like), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, doranib and the like).

KRAS mutations occur in 20-40% of lung adenocarcinomas, with a higher prevalence in the western (vs asia) population (26% vs 11%) and in smokers (vs non-smokers) (30% vs 10%). The most common mutations occur in codons 12 and 13, the most common mutations include G12C, G12V, and G12D. To date, no drug against KRAS mutations has been approved for marketing in the market.

Within the cell, the KRAS protein transitions between an inactive and an active state, when KRAS is bound to Guanosine Diphosphate (GDP), it is in the inactive state, when it is bound to Guanosine Triphosphate (GTP), it is in the active state, and downstream signaling pathways can be activated. The transition of KRAS between inactive and active states is regulated by two types of factors. One class is guanine nucleotide exchange factor (GEF), which catalyzes the binding of KRAS to GTP, thereby promoting KRAS activation, including the SOS1 protein. Another class is the Gtpase Activating Proteins (GAPs), which promote the hydrolysis of KRAS-bound GTP to GDP, thereby inhibiting KRAS activity.

To date, three major RAS-specific GEFs have been identified, with SOS proteins being primarily found in tumors. SOS proteins are widely expressed in vivo and contain two isoforms SOS1 and SOS 2. Published data indicate that SOS1 plays a critical role in mutant KRAS activation and oncogenic signaling. A decrease in the level of SOS1 resulted in a decrease in the proliferation and survival of tumor cells carrying the KRAS mutation, whereas KRAS wild-type cell lines were not affected. The effect of the loss of SOS1 could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role for SOS1 GEF activity in KRAS mutant cancer cells.

Since KRAS binding to GTP, whether mutated or wild-type, is dependent on SOS1, selective inhibition of SOS1, whether mutated or not, prevents interaction of SOS1 with KRAS and ultimately inhibits KRAS activation.

Proteolysis is crucial and tightly regulated in the normal life activities of cells, and is mainly accomplished by the participation of the ubiquitinase system. The protein to be decomposed is labeled by E1, E2 and E3 ubiquitin ligase system, and then recognized by protease and hydrolyzed. The proteolysis regulator molecule is a bifunctional active compound, one end of the molecule is tightly combined with a target protein, the other end is combined with E3 ubiquitin ligase, and the two ends are connected through various connecting chains. The bifunctional molecule can simultaneously recognize a target protein and E3 ubiquitin ligase in vivo, and the target protein is ubiquitinated after the target protein and the E3 ubiquitin ligase are drawn close and then hydrolyzed through a ubiquitin-proteasome pathway. After target proteolysis, the bifunctional molecule can be released to participate in the next cycle of proteolysis, so that the catalytic effect is achieved, and the high-efficiency therapeutic effect can be realized through less drug administration dosage clinically.

Since the SOS1 target protein is pathologically associated with a variety of diseases, there is also a need for novel SOS1 inhibitors for clinical therapy. The highly selective and active SOS1 proteolysis regulator can effectively treat diseases such as cancers caused by KRAS mutation and reduce the potential of off-target effect, thereby having more urgent clinical requirements.

Disclosure of Invention

The invention aims to provide a novel SOS1 proteolysis regulator, and a preparation method and application thereof.

In a first aspect of the present invention, there is provided a compound having a structure of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula:

ULM represents a small molecule ligand moiety that can bind to the E3 ligase;

PTM represents a small molecule ligand moiety that can bind to SOS 1;

l may be a bond or a linking group that may link the PTM and ULM.

In another preferred embodiment, the PTM is selected from PTM1 or PTM 2.

In another preferred embodiment, the PTM1 is preferably selected from:

in the formula:

the dotted line indicates the link to L;

in the formulae PTM1-IA and PTM1-IB, each substituent is independently defined as follows:

x is selected from the group consisting of: CR ⁶ Or N, wherein R ⁶ Selected from: hydrogen, deuterium, halogen, cyano, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl or 4-6 membered heterocyclyl;

y is selected from the group consisting of: bond, O, NH, CR ⁷ 、C＝CR ⁷ Or NR ⁷ Wherein R is ⁷ Selected from: c ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl or 4-6 membered heterocyclyl;

z is selected from the group consisting of substituted or unsubstituted groups: key, C ₁ -C ₁₈ Alkylene, deuterated C ₁ -C ₁₈ Alkylene, or halogeno C ₁ -C ₁₈ An alkylene group;

w is selected from the group consisting of substituted or unsubstituted: key, C ₁ -C ₁₈ Alkylene radical, C ₃ -C ₂₀ Cycloalkylene, 4-20 membered heterocyclylene, OR ¹¹ 、NR ¹¹ R ¹² 、SO ₂ 、NR ¹² SO ₂ CO or NR ¹² CO；R ¹¹ Independently selected from the group consisting of substituted or unsubstituted: c ₃ -C ₂₀ Cycloalkylene, 4-20 membered heterocyclylene, C ₃ -C ₂₀ Cycloalkylene radical C ₁ -C ₁₈ Alkylene, or 4-20 membered heterocyclylene C ₁ -C ₁₈ An alkylene group; r ¹² Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl or C ₃ -C ₆ A cycloalkyl group;

R ¹ 、R ² each independently selected from the group consisting of: a bond, hydrogen,Deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted; r is ⁸ 、R ⁹ 、R ¹⁰ Independently selected from the group consisting of substituted or unsubstituted: bond, hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl or 4-20 membered heterocyclyl;

R ³ selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₈ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

R ⁴ 、R ⁵ independently selected from the group consisting of substituted or unsubstituted: c ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl;

wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl4-20 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea;

m, n are each independently 0, 1, 2,3, 4 or 5;

p is 0, 1, 2,3, 4 or 5;

q is 1 or 2.

In another preferred embodiment, PTM1 is selected from the group consisting of:

in the formula: dotted line, R ¹ 、R ² 、R ³ 、R ⁴ X, Y, Z, W, and n are as defined above.

In another preferred embodiment, PTM1 is selected from the group consisting of:

in the formula:

dotted line, R ¹ 、R ² 、R ³ 、R ⁶ Y, Z, W, and n are as defined above.

In another preferred embodiment, PTM1 is selected from the group consisting of:

wherein each substituent is independently defined as follows:

R ¹³ and R ¹⁴ Each independently selected from the group consisting of substituted or unsubstituted: H. c ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl halogens, oxo groups, nitro groups, hydroxyl groups, cyano groups, ester groups, amine groups, amide groups, sulfonamide groups, or urea groups;

ring C is selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₂ Cycloalkylene, 4-12 membered heterocyclylene;

the substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

t is 1, 2,3, 4, 5 or 6;

dotted line, R ¹ 、R ² 、R ³ 、R ⁶ Y and n are as defined above.

In another preferred embodiment, PTM1-IVA and PTM1-IVB are linked through the C ring or through R2 and L, such as:

in another preferred embodiment, the PTM1 is preferably selected from:

wherein each substituent is independently defined as follows:

R ¹⁶ and R ¹⁷ Each independently selected from the group consisting of substituted or unsubstituted: H. c ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl halides, oxo, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea groups;

R ¹⁸ selected from: OR (OR) ¹¹ 、NR ¹¹ R ¹² 、NR ¹² SO ₂ R ² 、COR ² Or NR ¹² COR ² ；R ¹¹ Independently selected from the group consisting of substituted or unsubstituted: c ₁ -C ₁₈ Alkylene radical, C ₃ -C ₁₂ Cycloalkylene, 4-12 membered heterocyclylene, C ₃ -C ₁₂ Cycloalkylene radical C ₁ -C ₆ Alkylene, or 4-12 membered heterocyclylene C ₁ -C ₆ An alkylene group; r is ¹² Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl or C ₃ -C ₆ A cycloalkyl group;

t is 1, 2,3, 4, 5 or 6;

dotted line, R ¹ 、R ² 、R ³ Y and R ⁶ Is as defined above.

In a further preferred embodiment of the present invention,

in another preferred embodiment, the PTM2 is:

in the formula:

the dashed line represents a connection to L;

z' is selected from the following substituted or unsubstituted groups: key, C ₁ -C ₁₈ Alkylene, deuterated C ₁ -C ₁₈ Alkylene, or halogeno C ₁ -C ₁₈ An alkylene group;

w' is selected from the group consisting of substituted: key, C ₃ -C ₂₀ Cycloalkylene, 4-20 membered heterocyclylene;

R ^1’ substituted or unsubstituted groups of the following group: hydrogen, deuterium, halogen, cyano, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl or 4-6 membered heterocyclyl;

R ^2’ the same or different, each independently selected from the group consisting of: - (CH) ₂ ) _p R ^7’ 、-(CH ₂ ) _m O(CH ₂ ) _p R ^7’ 、-(CH ₂ ) _m SR ^7’ 、-(CH ₂ ) _m COR ^7’ 、-(CH ₂ ) _m C(O)OR ^7’ 、-(CH ₂ ) _m S(O) _q R ^7’ 、-(CH ₂ ) _m NR ^7’ R ^8’ 、-(CH ₂ ) _m C(O)NR ^7’ R ^8’ 、-(CH ₂ ) _m NR ^7’ C(O)R ^8’ 、-(CH ₂ ) _m NR ^7’ C(O)NR ^8’ R ^9’ 、-(CH ₂ ) _m S(O) _q NR ^7’ R ^8’ 、-(CH ₂ ) _m NR ^7’ S(O) _q R ^8’ 、-(CH ₂ ) _m NR ^7’ S(O) _q NR ^8’ R ^9’ In which CH ₂ H in (a) may be optionally substituted; r ^7’ 、R ^8’ And R ^9’ Each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C ₁ -C ₁₈ Alkyl, substituted or unsubstituted C ₃ -C ₂₀ Cycloalkyl, substituted or unsubstituted 4-20 membered heterocyclyl and substituted or unsubstituted C ₁ -C ₁₈ An alkoxy group; or in- (CH) ₂ ) _m NR ^7’ R ^8’ 、-(CH ₂ ) _m C(O)NR ^7’ R ^8’ 、-(CH ₂ ) _m S(O) _q NR ^7’ R ^8’ In, R ^7’ And R ^8’ And the N atom to which it is attached, to form a substituted or unsubstituted 4-20 membered heterocyclic group; or in- (CH) ₂ ) _m NR ^7’ C(O)R ^8’ 、-(CH ₂ ) _m NR ^7’ C(O)NR ^8’ R ^9’ 、-(CH ₂ ) _m NR ^7’ S(O) _q R ^8’ 、-(CH ₂ ) _m NR ^7’ S(O) _q NR ^8’ R ^9’ In, R ^8’ And R ^9’ Is cyclized with the N atom to which it is attached to form a substituted or unsubstituted 4-20 membered heterocyclic group, or R ^7’ And R ^8’ Ring-closing with its adjacent atom to form a substituted or unsubstituted 4-20 membered heterocyclic group; r ^3’ Selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₈ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

R ^4’ 、R ^5’ independently selected from the group consisting of substituted or unsubstituted: c ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl;

R ^6’ selected from: hydrogen, deuterium, halogen, amino, cyano, substituted or unsubstituted C ₁ -C ₆ Alkyl and substituted or unsubstituted C ₃ -C ₆ A cycloalkyl group; (ii) a

Wherein the above substitution means substitution with one or more groups selected from the group consisting of: deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

m' is 1, 2,3, 4 or 5;

n' is 1, 2,3, 4 or 5;

p' is 0, 1, 2,3, 4 or 5;

q' is 1 or 2.

In another preferred embodiment, the PTM2 is:

in the formula: dotted line, R ^1’ 、R ^2’ 、R ^3’ 、R ^4’ 、R ^5’ Z ', W ' and n ' are as defined above.

In another preferred example, PTM2 is:

in the formula: dotted line, R ^1’ 、R ^2’ 、R ^3’ 、R ^4’ Z ', W ' and n ' are as defined above.

In another preferred embodiment, the PTM2 is:

in the formula (I), the compound is shown in the specification,

R ^13’ and R ^14’ Each independently selected from the group consisting of substituted or unsubstituted: H. deuterium, C ₁ -C ₆ Alkyl, deuterated C ₁ -C ₆ Alkyl, or halo C ₁ -C ₆ An alkyl group; or R ^13’ And R ^14’ With adjacent C to form C ₃ -C ₆ A cycloalkyl group or a 4-6 membered heterocyclic group of (a);

ring W' is selected from the group of substituted: c ₃ -C ₁₂ Cycloalkylene, 4-12 membered heterocyclylene;

the substitution means substitution with one or more groups selected from the group consisting of: deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

t' is 1, 2,3, 4, 5 or 6;

dotted line, R ^1’ 、R ^2’ 、R ^3’ And n' is as defined above.

In another preferred embodiment, the PTM2 is selected from the group consisting of:

in another preferred embodiment, the ULM is a small molecule ligand moiety that can bind to a ligase selected from the group consisting of: VHL (Von Rippel-Lindau), CRBN (Cereblan), MDM2(Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP, DCAF15, DCAF16, RNF4, RNF114, AhR and the like.

In another preferred embodiment, the ULM is preferably selected from a small molecule VLM, CLM, MLM or ILM ligand moiety that can bind to a ligase such as VHL (Von Rippel-Lindau), CRBN (Cereblan), MDM2(Mouse double-minute homolog2), or IAP.

In another preferred embodiment, the ULM is selected from the group consisting of a small molecular VLM, or CLM ligand moiety, that binds to a ligase such as VHL (Von Rippel-Lindau), crbn (cereblon), and more preferably a small molecular CLM ligand moiety that binds to a crbn (cereblon) ligase.

In another preferred embodiment, the compound of formula I above is selected from the group consisting of: PTM-VLM, PTM-CLM, PTM-MLM, PTM-ILM; PTM-L-VLM, PTM-L-CLM, PTM-L-MLM or PTM-L-ILM.

In another preferred embodiment, VLM is:

in the formula (I), the compound is shown in the specification,

the dashed line represents a connection to L;

X ^a1 ,X ^a2 independently selected from the group consisting of: key O, NR ^a2 、CR ^a3 R ^a4 C-O, C-S, SO, or SO ₂ (ii) a Wherein R is ^a2 、R ^a3 、R ^a4 Independently selected from the group consisting of substituted or unsubstituted: c ₁ -C ₁₈ Alkyl radical, C ₃ -C ₁₂ Cycloalkyl, 4-12 membered heterocyclyl;

R ^a1 same or different, independently selected from halogen, hydroxyl, C ₁ -C ₃ Alkyl, or (═ O); or different R ^a1 The two are cyclized to form a 3-4-membered ring;

n ^a1 selected from: 0.1, 2,3, or 4;

W ^a1 and W ^a2 Selected from the group consisting of substituted or unsubstituted: -X ^a3 -X ^a4 -; wherein X ^a3 、X ^a4 Independently selected from the group consisting of substituted or unsubstituted: - (CH) ₂ ) _m ^a1 R ^a5 -、-(CH ₂ ) _m ^a1 O(CH ₂ ) _m ^a2 R ^a5 -、-(CH ₂ ) _m ^a1 SR ^a5 -、-(CH ₂ ) _m ^a1 COR ^a5 -、-(CH ₂ ) _m ^a1 C(O)OR ^a5 -、-(CH ₂ ) _m ^a1 S(O) _m ^a3 R ^a5 -、-(CH ₂ ) _m ^a1 NR ^a5 R ^a6 -、-(CH ₂ ) _m ^a1 C(O)NR ^a5 R ^a6 -、-(CH ₂ ) _m ^a1 NR ^a5 C(O)R ^a6 -、-(CH ₂ ) _m ^a1 NR ^a5 C(O)NR ^a6 R ^a7 -、-(CH ₂ ) _m ^a1 S(O) _m ^a3 NR ^a5 R ^a6 -、-(CH ₂ ) _m ^a1 NR ^a5 S(O) _m ^a3 R ^a6 -、-(CH ₂ ) _m ^a1 NR ^a5 S(O) _m ^a3 NR ^a6 R ^a7 -, in which, CH ₂ H in (a) may be optionally substituted; r ^a5 、R ^a6 、R ^a7 Independently selected from the group consisting of substituted or unsubstituted: bond, hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl;

_m ^a1 、 _m ^a2 independently selected from 0, 1, 2,3, 4, 5, or 6;

_m ^a3 independently selected from 0, 1, or 2;

the substitution refers to substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, VLM is:

R ^a8 、R ^a9 、R ^a10 independently selected from the group consisting of substituted or unsubstituted: hydrogen, halogen, cyano, C ₁ -C ₁₈ Alkyl or alkylene radical, C ₃ -C ₁₂ Cycloalkyl or cycloalkylene, 4-12 membered heterocyclyl or heterocyclylene, C ₆ -C ₁₄ Aryl or arylene, 5-20 membered heteroaryl or heteroarylene, -N R ^a13 R ^a14 -; wherein R is ^a13 、R ^a14 Independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl;

R ^a11 independently selected from the group consisting of substituted or unsubstituted: hydrogen, halogen, cyano, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl;

R ^a12 independently selected from the group consisting of substituted or unsubstituted: c ₆ -C ₁₄ Aryl, or 5-20 membered heteroaryl;

the substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

The dotted line is as defined above.

In another preferred embodiment, the CLM is selected from the group consisting of:

in the formulae, each group is independently defined as follows:

the dashed line represents a connection to L;

W ^b1 same or different, independently selected from C-O, SO ² 、CR ^b3 R ^b4 、NR ^b5 (ii) a Wherein R is ^b3 、R ^b4 Independently selected from the group consisting of substituted or unsubstituted: hydrogen, halogen, cyano, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl; r ^b5 Selected from substituted or unsubstitutedThe following group of generations: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

X ^b1 、X ^b2 、X ^b3 the same or different, are independently selected from CH2, O or S;

Z ^b1 、Z ^b2 the same or different, are independently selected from CH2, O or S;

Y ^b1 selected from CH2, O, S or NR ^b6 ；R ^b6 Selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

G ^b1 、G ^b2 the same or different, are independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

A ^b1 、A ^b2 the same or different, are independently selected from the group consisting of substituted or unsubstituted: hydrogen, halogen, cyano, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, or 4-6 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

R ^b1 、R ^b2 、R ^b3 the same or different, are independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

n ^b1 、n ^b2 the same or different, are independently selected from: 0.1, 2,3, or 4;

the substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, the VLM is preferably selected from:

dotted line, W ^b1 、R ^b1 、R ^b2 、R ^b3 、A ^b1 、A ^b2 、G ^b2 、Y ^b1 、n ^b1 、n ^b2 As described above.

In another preferred embodiment, the VLM is selected from the group consisting of:

dotted line, R ^b1 、R ^b2 、R ^b3 、n ^b1 、n ^b2 As described above.

In another preferred embodiment, the MLM is preferably selected from the group consisting of:

in each formula, each group is independently defined as follows:

the dashed line represents a connection to L;

X ^c1 selected from the group consisting of: o, S, SO2, CR ^c29 R ^c30 、NR ^c31 Wherein R is ^c29 、R ^c30 The same or different, and is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide or urea, or R ^c29 And R ^c30 Cyclized to form a 3-6 membered heterocyclic group; r ^c31 Selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl;

Y ^c1 and Z ^c1 Independently selected from N or R ^C32 Wherein R is ^c32 (ii) a group selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

A ^c1 、A ^c2 or A ^c3 Independently selected from N, O, S or CR ^c33 Or A is ^c1 、A ^c2 Or A ^c3 Wherein two rings form C ₃ -C ₈ Cycloalkyl, 4-8 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl; r ^c33 Substituted or unsubstituted groups of the following group: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

represents a single or double bond;

R ^c” selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl;

R ^c1 -R ^c28 the same or different, are independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea; or independently selected from the group consisting of substituted or unsubstituted: - (CH) ₂ ) _m ^c1 R ^c34 -、-(CH ₂ ) _m ^c1 O(CH ₂ ) _m ^c2 R ^c34 -、-(CH ₂ ) _m ^c1 SR ^c34 -、-(CH ₂ ) _m ^c1 COR ^c34 -、-(CH ₂ ) _m ^c1 C(O)OR ^c34 -、-(CH ₂ ) _m ^c1 S(O) _m ^c3 R ^c34 -、-(CH ₂ ) _m ^c1 NR ^c34 R ^c35 -、-(CH ₂ ) _m ^c1 C(O)NR ^c34 R ^c35 -、-(CH ₂ ) _m ^c1 NR ^c34 C(O)R ^c35 -、-(CH ₂ ) _m ^c1 NR ^c34 C(O)NR ^c35 R ^c36 -、-(CH ₂ ) _m ^c1 S(O) _m ^c3 NR ^c34 R ^c35 -、-(CH ₂ ) _m ^c1 NR ^c34 S(O) _m ^c3 R ^c35 -、-(CH ₂ ) _m ^c1 NR ^c34 S(O) _m ^c3 NR ^c35 R ^c36 -, in which, CH ₂ H in (a) may be optionally substituted; r ^c34 、R ^c35 、R ^c36 Independently selected from the group consisting of substituted or unsubstituted: bond, hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl; or R ^c34 、R ^c35 、R ^c36 Wherein any two are cyclized to form a substituted or unsubstituted 4-20 membered heterocyclyl, or 5-20 membered heteroaryl;

m ^c1 、m ^c2 independently selected from 0, 1, 2,3, 4, 5, or 6;

m ^c3 independently selected from 0, 1, or 2;

In another preferred embodiment, MLM is:

wherein:

R ^c37 、R ^c38 the same or different, and is independently selected from the group consisting of substituted or unsubstituted: hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl; or R ^c37 、R ^c38 Ring closure to form a substituted or unsubstituted 4-20 membered heterocyclyl, or 5-20 membered heteroaryl;

R ^c39 、R ^c40 independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

m ^c4 、m ^c5 independently selected from 0, 1, 2,3, 4, 5, or 6;

dotted line, R ^c "and R ^c14 As claimed in claim 20;

In another preferred embodiment, the MLM is selected from the group consisting of:

in another preferred embodiment, the ILM is selected from the group consisting of:

in the formulae, each group is independently defined as follows:

the dotted line indicates the link to L;

R ^d1 -R ^d6 the same or different, and is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

or R ^d5 And R ^d6 A substituted or unsubstituted 4-20 membered heterocyclyl;

or R ^d3 And R ^d6 A substituted or unsubstituted 5-20 membered heterocyclyl;

R ^d7 selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido; or selected from the group consisting of substituted or unsubstituted: - (CH) ₂ ) _m ^d1 R ^d9 -、-(CH ₂ ) _m ^c1 O(CH ₂ ) _m ^d2 R ^d9 -、-(CH ₂ ) _m ^d1 SR ^d9 -、-(CH ₂ ) _m ^d1 COR ^d9 -、-(CH ₂ ) _m ^d1 C(O)OR ^d9 -、-(CH ₂ ) _m ^d1 S(O) _m ^d3 R ^d9 -、-(CH ₂ ) _m ^d1 NR ^d9 R ^d10 -、-(CH ₂ ) _m ^d1 C(O)NR ^d9 R ^d10 -、-(CH ₂ ) _m ^d1 NR ^d9 C(O)R ^d10 -、-(CH ₂ ) _m ^c1 NR ^d9 C(O)NR ^d10 R ^d11 -、-(CH ₂ ) _m ^d1 S(O) _m ^d3 NR ^d9 R ^d10 -、-(CH ₂ ) _m ^d1 NR ^d9 S(O) _m ^d3 R ^d10 -、-(CH ₂ ) _m ^d1 NR ^d9 S(O) _m ^d3 NR ^d10 R ^d11 -, in which, CH ₂ H in (a) may be optionally substituted; r is ^d9 、R ^d10 、R ^d11 Independently selected from the group consisting of substituted or unsubstituted: bond, hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl; or R ^d9 、R ^d10 、R ^d11 Wherein the two are cyclized to form a substituted or unsubstituted 4-20 membered heterocyclyl, or 5-20 membered heteroaryl;

m ^d1 or m ^d2 Selected from 0, 1, 2,3, 4, 5, or 6;

m ^d3 selected from 0, 1, or 2;

W ^d1 selected from the group consisting of substituted or unsubstituted: c ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl;

R ^d8 independently selected from the group consisting of substituted or unsubstituted: - (CH) ₂ ) _m ^d1 R ^d9 -、-(CH ₂ ) _m ^d1 O(CH ₂ ) _m ^d2 R ^d9 -、-(CH ₂ ) _m ^d1 SR ^d9 -、-(CH ₂ ) _m ^d1 COR ^d9 -、-(CH ₂ ) _m ^d1 C(O)OR ^d9 -、-(CH ₂ ) _m ^d1 S(O) _m ^d3 R ^d9 -、-(CH ₂ ) _m ^d1 NR ^d9 R ^d10 -、-(CH ₂ ) _m ^d1 C(O)NR ^d9 R ^d10 -、-(CH ₂ ) _m ^d1 NR ^d9 C(O)R ^d10 -、-(CH ₂ ) _m ^c1 NR ^d9 C(O)NR ^d10 R ^d11 -、-(CH ₂ ) _m ^d1 S(O) _m ^d3 NR ^d9 R ^d10 -、-(CH ₂ ) _m ^d1 NR ^d9 S(O) _m ^d3 R ^d10 -、-(CH ₂ ) _m ^d1 NR ^d9 S(O) _m ^d3 NR ^d10 R ^d11 -, in which, CH ₂ H in (a) may be optionally substituted; r ^d9 、R ^d10 、R ^d11 Independently selected from the group consisting of substituted or unsubstituted: bond, hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl; or R ^d9 、R ^d10 、R ^d11 Wherein the two are cyclized to form a substituted or unsubstituted 4-20 membered heterocyclyl, or 5-20 membered heteroaryl;

n ^d1 、m ^d1 or m ^d2 Selected from 0, 1, 2,3, 4, 5, or 6;

m ^d3 selected from 0, 1, or 2;

In another preferred embodiment, the ILM is preferably selected from:

in the formulae, each group is independently defined as follows:

R ^d” selected from hydrogen, halogen, cyano, C ₁ -C ₃ An alkyl group;

A ^d1 or A ^d2 Independently selected from the group consisting ofOr unsubstituted groups of the following group: c ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl.

The dotted line is defined as described above.

In another preferred embodiment, L is:

wherein R is ^L1 -R ^L6 The same or different, and is independently selected from the group consisting of substituted or unsubstituted: bond, CH ₂ 、C＝O、C＝C、C≡C、O、NH、SO、SO ₂ 、P＝O、

C ₁ -C ₁₈ Alkylene radical, C ₃ -C ₂₀ Cycloalkylene, 4-20 membered heterocyclylene, C ₆ -C ₁₄ Arylene, 5-20 membered heteroarylene, C ₁ -C ₁₈ Alkylene radical C ₃ -C ₂₀ Cycloalkylene radical, C ₁ -C ₁₈ Alkylene 4-20 membered heterocyclylene, - (CH) ₂ ) _m ^L1 O(CH ₂ ) _m ^L2 R ^L7 -、-(CH ₂ ) _m ^L1 SR ^L7 -、-(CH ₂ ) _m ^L1 COR ^L7 -、-(CH ₂ ) _m ^L1 C(O)OR ^L7 -、-(CH ₂ ) _m ^L1 S(O) _m ^L3 R ^L7 -、-(CH ₂ ) _m ^L1 NR ^L7 R ^L8 -、-(CH ₂ ) _m ^L1 C(O)NR ^L7 R ^L8 -、-(CH ₂ ) _m ^d1 NR ^L7 C(O)R ^L8 -、-(CH ₂ ) _m ^L1 NR ^L7 C(O)NR ^L8 R ^L9 -、-(CH ₂ ) _m ^d1 S(O) _m ^L3 NR ^L7 R ^L8 -、-(CH ₂ ) _m ^L1 NR ^L7 S(O) _m ^L3 R ^L8 -、-(CH ₂ ) _m ^L1 NR ^L7 S(O) _m ^L3 NR ^L8 R ^L9 -, in which, CH ₂ H in (a) may be optionally substituted; r ^L7 、R ^L8 、R ^L9 Independently selected from the group consisting of substituted or unsubstituted: bond, hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-20 membered heteroaryl;

p ^L1 -p ^L6 independently selected from 0, 1, 2,3, 4, 5, or 6;

m ^L1 or m ^L2 Independently selected from 0, 1, 2,3, 4, 5, or 6;

m ^L3 selected from 0, 1, or 2;

In another preferred embodiment, the ULM is selected from the group consisting of:

in another preferred embodiment, L is:

wherein R is ^L1 -R ^L6 The same or different, and independently preferably selected from the group consisting of substituted or unsubstituted: bond, CH ₂ 、C＝O、O、NH、SO、SO ₂ 、P＝O、NHCO、NHSO ₂ 、OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ OCH ₂ 、NHCH ₂ 、NMeCH ₂ 、NHCH ₂ CH ₂ 、NMeCH ₂ CH ₂ 、CH ₂ NHCO、NHCOCH ₂ 、

each p ^L1 -p ^L6 Independently selected from 0, 1, 2,3, 4, 5, or 6.

L may optionally pass through R ^L1 Terminal or R ^L6 The end is connected with PTM or ULM.

In another preferred embodiment, L is a substituted or unsubstituted group selected from the group consisting of:

in another preferred embodiment, for formula L, where in each formula, CH ₂ CH may independently be optionally substituted; and said substitution means substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea; NH may independently optionally be deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkyl acyl, sulfonyl substitution; p is a radical of formula ^L1 -p ^L6 As described above.

For example:

can be selected from

In another preferred embodiment, in L, each R ^L1 -R ^L6 Two adjacent groups among the groups may be each independently bonded to each other through C, N, O or an S atom or the like.

For example:

can be selected from

In a further preferred embodiment of the present invention,

selected from substituted or unsubstituted groups selected from:

in the formulae (II) to (III) ₂ H in CH and NH may independently be optionally substituted; and said substitution means substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea; NH may independently optionally be deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkyl acyl and sulfonyl.

In another preferred embodiment, PTM, L and ULM are each independently the corresponding moieties of the compounds of the examples of the present invention.

In another preferred embodiment, the compound with the structure of the general formula (I) is selected from the compounds prepared in the embodiment of the invention.

In another preferred embodiment, the compound of the structure of formula (I) is selected from the group consisting of:

in a second aspect of the present invention, there is provided a process for the preparation of a modulator of the proteolysis of SOS1 having the structure of general formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, selected from the following synthetic routes:

route one:

(i) formula (PTM 1-IA-LG) ₁ )、(PTM1-IB-LG ₁ ) Or (PTM 2-I-LG) ₁ ) Compounds and compounds of formula (LG) ₂ -L-LG ₃ ) In a base (e.g., DIPEA, TEA, Py, or DMAP), a condensing agent (e.g., DCC, EDCI, PyBOP, HATU, or BOP), or in a catalyst (e.g., Pd (OAc)) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl ₂ (dppf), CuI, or Cu (OAc) ₂ Etc.) to respectively obtain the formula (PTM 1-IA-LG) ₃ )、(PTM1-IB-L-LG ₃ ) Or (PTM 2-I-L-LG) ₃ ) A compound;

(ii) formula (PTM 1-IA-LG) ₃ )、(PTM1-IB-L-LG ₃ ) Or (PTM 2-I-L-LG) ₃ ) Compounds of formula (LG) ₄ ULM) in a base (e.g. DIPEA, TEA, Py, or DMAP), a condensing agent (e.g. DCC, EDCI, PyBOP, HATU, or BOP) or in a catalyst (e.g. Pd (OAc) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl ₂ (dppf)、CuI、Cu(OAc) ₂ Etc.) to respectively obtain a compound of a formula (PTM1-IA-L-ULM), a formula (PTM1-IB-L-ULM) or a formula (PTM 2-I-L-ULM);

LG ₁ 、LG ₂ 、LG ₃ or LG ₄ Identical or different, are leaving groups, each preferably selected from: hydrogen, OH, halogen, OTs, OMs, OTf, B (OH) ₂ Etc.;

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ x, Y, Z, W, and n are as defined above;

R ^1’ 、R ^2’ 、R ^3’ 、R ^4’ 、R ^5’ 、R ^6’ z ', W ', and n ' are as defined above.

And a second route:

(i) formula (LG) ₄ ULM) Compounds and formula (LG) ₂ -L-LG ₃ ) In a base (e.g., DIPEA, TEA, Py, or DMAP), a condensing agent (e.g., DCC, EDCI, PyBOP, HATU, or BOP), or in a catalyst (e.g., Pd (OAc)) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl ₂ (dppf), CuI, or Cu (OAc) ₂ Etc.) to obtain the formula (LG) ₂ -L-ULM) compound;

(ii) formula (LG) ₂ -L-ULM) Compounds with formula (PTM1-IA-LG ₁ )、(PTM1-IB-LG ₁ ) Or (PTM 2-I-LG) ₁ ) In a base (e.g., DIPEA, TEA, Py, or DMAP), a condensing agent (e.g., DCC, EDCI, PyBOP, HATU, or BOP) or in a catalyst (e.g., Pd (OAc) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl ₂ (dppf), CuI, or Cu (OAc) ₂ Etc.) to respectively obtain the compounds of the formula (PTM1-IA-L-ULM), the formula (PTM1-IB-L-ULM) or the formula (PTM 2-I-L-ULM);

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ x, Y, Z, W, and n are as defined above

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising I) one or more compounds of formula (I) according to the first aspect of the present invention, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and ii) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises one or more therapeutic agents selected from the group consisting of: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obizumab, ofatumumab, tositumomab, MSB 131, tositumomab, TSB 90, TSB-55, TSB-35, TSB-102, TSB-35, TSB-52, TSB-35, TSC-35, TSB-35, TSC-35, TSB-55, TSB-D2, TSB-D-, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.

In a fourth aspect of the present invention, there is provided a compound having a structure represented by general formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to the first aspect of the present invention, or a use of a pharmaceutical composition according to the third aspect of the present invention, for preparing a pharmaceutical composition for preventing and/or treating a disease associated with activity or expression of SOS 1.

In another preferred embodiment, the disease is cancer.

In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

In a fifth aspect of the present invention, there is provided a method for preventing and/or treating a disease associated with SOS1 activity or expression, comprising the steps of: administering to a subject in need thereof an effective amount of a compound of general formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to the first aspect of the invention, or administering a pharmaceutical composition according to the third aspect of the invention.

In another preferred embodiment, the subject is a mammal, such as a human, rat or mouse.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows the measurement of SOS1 and β -actin content in H358 cells after 6 hours of treatment with different concentrations of compound example 26.

Detailed Description

The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a novel class of proteolytic modulators directed to SOS 1. On this basis, the inventors have completed the present invention.

Term(s) for

In the present invention, unless otherwise specified, the terms used have the ordinary meaning known to those skilled in the art.

The term "alkyl" by itself or as part of another substituent means a straight or branched chain alkyl group having the indicated number of carbon atoms, which may contain 1 to 20 carbon atoms, such as including 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-butyl,

N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl 4, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like.

The term "substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl ₃ Alkyl group of (i), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR _a 、SR _a 、S(＝O)R _e 、S(＝O) ₂ R _e 、P(＝O) ₂ R _e 、S(＝O) ₂ OR _e ,P(＝O) ₂ OR _e 、NR _b R _c 、NR _b S(＝O) ₂ R _e 、NR _b P(＝O) ₂ R _e 、S(＝O) ₂ NR _b R _c 、P(＝O) ₂ NR _b R _c 、C(＝O)OR _d 、C(＝O)R _a 、C(＝O)NR _b R _c 、OC(＝O)R _a 、OC(＝O)NR _b R _c 、NR _b C(＝O)OR _e ,NR _d C(＝O)NR _b R _c 、NR _d S(＝O) ₂ NR _b R _c 、NR _d P(＝O) ₂ NR _b R _c 、NR _b C(＝O)R _a Or NR _b P(＝O) ₂ R _e Wherein R is present therein _a May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b 、R _c And R _d May independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R _b And R _c Together with the N atom may form a heterocyclic ring; r _e May independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.

The term "alkylene" by itself or as part of another substituent refers to a group formed by the removal of one hydrogen atom from an "alkyl" group, which may contain from 1 to 18 carbon atoms, including, for example, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms. For example, methylene, ethylene, propylene, isopropylene (e.g. propylene

Butylene (e.g. of

) Pentylene (e.g. ethylene)

) Hexamethylene (e.g. hexamethylene)

) Heptylene (e.g. as

) And so on.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group, including 1 to 4 rings, each containing 3 to 30 carbon atoms, such as including 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 4 substituents, which may be at any positionAnd (4) carrying out substitution. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl ₃ Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR _a 、SR _a 、S(＝O)R _e 、S(＝O) ₂ R _e 、P(＝O) ₂ R _e 、S(＝O) ₂ OR _e ,P(＝O) ₂ OR _e 、NR _b R _c 、NR _b S(＝O) ₂ R _e 、NR _b P(＝O) ₂ R _e 、S(＝O) ₂ NR _b R _c 、P(＝O) ₂ NR _b R _c 、C(＝O)OR _d 、C(＝O)R _a 、C(＝O)NR _b R _c 、OC(＝O)R _a 、OC(＝O)NR _b R _c 、NR _b C(＝O)OR _e ,NR _d C(＝O)NR _b R _c 、NR _d S(＝O) ₂ NR _b R _c 、NR _d P(＝O) ₂ NR _b R _c 、NR _b C(＝O)R _a Or NR _b P(＝O) ₂ R _e Wherein R is present therein _a May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b 、R _c And R _d May independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R _b And R _c Together with the N atom may form a heterocyclic ring; r _e May independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spiroalkenyl, spiroheterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged alkenyl, bridged heterocycle (excluding heteroaromatic rings), fused cycloalkyl, fused alkenyl, fused heterocyclyl, or fused aromatic ring groups, which may be optionally substituted. Any two on the ringOr two or more atoms may be further ring-connected with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

The term "cycloalkylene" by itself or as part of another substituent refers to a group formed by the above-mentioned cycloalkyl group minus two hydrogen atoms, such as:

and the like.

The term "cycloalkylene" refers to a cycloalkylalkyl or alkylcycloalkyl group as defined above, wherein "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning, preferably C1-C6 alkylene C3-C12 cycloalkylene, excluding, but not limited to:

and the like.

The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group that may include 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms (including but not limited to, e.g., 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring systems) in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocyclic ring may carry 1, 2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate groups, wherein any two or more atoms on the ring may be further ring-connected to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

The term "heterocyclylene" refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclic group, such as, but not limited to:

and the like.

The term "heterocycloalkylalkylene" refers to a group formed by a cycloalkylalkyl or alkylcycloalkyl group minus two hydrogen atoms, wherein "4-20 membered heterocycloalkylene C1-C18 alkylene "or" C1-C18 alkylene 4-20 membered heterocycloalkylene ", having the same meaning, is preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to:

and the like.

The term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, which may be substituted at any position.

The term "arylene" refers to a group formed by the removal of two hydrogen atoms from an aryl group as described above.

The term "heteroaryl" refers to a heteroaromatic system containing 1-4 (e.g., 2 or 3) heteroatoms, selected from oxygen, nitrogen and sulfur, 5-14 ring atoms, and a heterocyclyl group can include 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.

The term "heteroarylene" refers to a group formed by removing two hydrogen atoms from a heteroaryl group as described above.

The term "C1-C18 alkoxy" refers to a straight or branched chain or cyclic alkyl oxy group having 1 to 18 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. Preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy or C1-C4 alkoxy.

The term "C1-C18 alkyleneoxy" means a group resulting from the removal of one hydrogen atom from a "C1-C18 alkoxy group".

The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

The term "halo" means substituted with halogen.

The term "deuterated" refers to a compound that is deuterated ( ² H) And (4) substitution.

The term "hydroxy" refers to a group with the structure OH.

The term "nitro" refers to a group with the structure NO ₂ A group of (2).

The term "cyano" refers to a group with the structure CN.

The term "ester group" refers to a group with the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.

The term "amine" refers to a group having the structure-NRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' may be the same or different in the dialkylamine fragment.

The term "amido" refers to a group with the structure-CONRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' may be the same or different in the dialkylamine fragment.

The term "sulfonamide" refers to a sulfonamide group having the structure-SO ₂ NRR' group wherein R andr' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' may be the same or different in the dialkylamine fragment.

The term "ureido" refers to a group having the structure — NRCONR 'R ", where R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "alkylaminoalkyl" refers to a group having the structure-RNHR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle as defined above. R and R' may be the same or different.

The term "dialkylaminoalkyl" refers to a group having the structure-RNHR 'R ", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, a heterocycle or a substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "heterocyclylalkyl" refers to a group having the structure-RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; r' represents a heterocycle or a substituted heterocycle.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, a certain substituted group may have one substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position.It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Preferably, the substitution may be substituted with one or more substituents selected from the group consisting of: such as (but not limited to): halogen, hydroxy, cyano, carboxy (-COOH), C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ Cycloalkyl, 4-12 membered heterocyclyl, aryl, heteroaryl, C ₁ -C ₈ Aldehyde group, C ₂ -C ₁₀ Acyl radical, C ₂ -C ₁₀ Ester group, amino group, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₁₀ Sulfonyl, and C ₁ -C ₆ Urea groups, and the like.

Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.

When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.

SOS1 proteolysis regulator

As used herein, "SOS 1 proteolytic regulator" and "protease-degrading agent targeting SOS 1" are used interchangeably to refer to a protease-degrading agent targeting SOS1 (PROTAC) that utilizes the intracellular "cleaner" -ubiquitin-proteasome system to degrade SOS1 protein.

Preferably, the SOS1 proteolytic regulator is a compound of formula I of the present invention.

Targeting ligands

A targeting ligand (or target protein moiety or target protein ligand or ligand) is a small molecule capable of binding a target protein of interest.

In the present invention, the targeting ligand (PTM moiety) is formed from a small molecule compound targeting SOS1, preferably from a PTM1 or PTM2 compound as described above.

E3 ligase ligand

In the present invention, the E3 ligase ligand moiety (ULM moiety) is used to bind the E3 ligase. The invention has no special requirement on the type of the E3 ligase ligand, and the molecule or the structural fragment which can be combined with the E3 ligase and is commonly used in the invention can be used.

Typically, the ULM is formed from a small molecule ligand that can bind to a ligase selected from the group consisting of (but not limited to): VHL (Von Rippel-Lindau), CRBN (Cereblan), MDM2(Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP, DCAF15, DCAF16, RNF4, RNF114, AhR and the like.

Preferably, the ULM is formed from a small molecule ligand selected from the group consisting of: VLM, CLM, MLM, or ILM.

Linking group (L as described herein)

The linker of the invention is used to link a target molecule and an E3 ligase ligand.

Preferably, the target molecule (moiety) or E3 ligase ligand (moiety) may be linked by-O-, -S-, -NH-, -NR-, - (C ═ O) O-, - (C ═ O) NR-, -SO — ₂ -、-SO ₂ NR-, etc., are attached to the linking group.

The linking group of the present invention may further contain various other functional groups, for example, functional groups such as-OH, -NHR, -SH, etc.

Typically, the target molecule or E3 ligase ligand contains, for example, -OH, -SH, -NH ₂ Functional groups such as-NHR, -SOOH, or-COOH, which can undergo a substitution reaction, can be attached to the target molecule and/or E3 ligase ligand by reacting a linker molecule containing the corresponding reactive functional group (e.g., OH/SH/NH2 with-COOH/-COCl, etc.). Functional groups capable of undergoing the above substitution reaction, and methods for introducing the above functional groups on a molecule are known to those skilled in the art.

In the context of the present invention, the direction of attachment of the linking group L to the PTM and ULM moieties may be arbitrary, and the L group may be attached to the PTM on the left and to the ULM on the right, or to the PTM on the right and to the ULM on the left, for example, when L is-C ₁ -C ₄ Alkylene groups CO-or-C ₁ -C ₄ Alkylene CO-and-CO-C ₁ -C ₄ Alkylene-.

Active ingredient

As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs of compounds of formula I:

in the formula:

ULM represents a small molecule ligand moiety that can bind to E3 ligase;

PTM represents a small molecule ligand moiety that can bind to SOS 1;

l may be a bond or a linking group that may link the PTM and ULM.

The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may form are included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps during manufacture. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and salting out in a medium, or lyophilizing in an aqueous solution.

The compounds of the invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetates (e.g. with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglycolates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g. 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionates), phosphates, propionates, citrates, and the like, Picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g. with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, e.g. p-toluenesulfonate, dodecanoate and the like

Acidic moieties that certain compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (salt with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. The basic nitrogen-containing groups may be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound, salt, or solvate of the invention when used in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the invention may exist in tautomeric forms (e.g. amides and imino ethers). All of these tautomers are part of the present invention.

Stereoisomers of all compounds (e.g. those asymmetric carbon atoms which may exist due to various substitutions), including enantiomeric and diastereomeric forms, are contemplated within the scope of the invention. The individual stereoisomers of the compounds of the invention may not be present in combination with the other isomers (e.g. as a pure or substantially pure optical isomer having a particular activity), or may be present as a mixture, e.g. as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the invention has two S or R configurations, and is defined by the International Union of theory and applied chemistry (IUPAC) proposed in 1974. The racemic forms can be resolved by physical methods such as fractional crystallization, or by separation of the crystals by derivatization into diastereomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

The compounds of the present invention, obtained by preparing, isolating and purifying the compound in sequence, have a weight content of 90% or more, for example, 95% or more, 99% or more ("very pure" compounds), as set forth in the text. Such "very pure" compounds of the invention are also part of the invention herein.

All configurational isomers of the compounds of the invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of compounds in the present invention encompasses both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and definitions of chemical terms are described in detail below. For purposes of the present invention, the chemical Elements are compatible with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75 ^th D. as defined in. The definition of a particular functional group is also described herein. In addition, the basic principles of Organic Chemistry, as well as specific functional groups and reactivities are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomer, (L) isomer, racemic mixtures and other mixtures thereof. Further, the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are encompassed by the present invention.

According to the present invention, the mixture of isomers may contain a variety of isomer ratios. For example, in a mixture of only two isomers, the following combinations are possible: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, all ratios of isomers are within the scope of the invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention, as would be readily understood by one of ordinary skill in the art.

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight or mass number. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g. ³ H and ¹⁴ among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C, their preparation and detection are relatively easy. Is the first choice among isotopes. In addition, heavier isotopes such as deuterium, i.e. ² H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples.

If it is desired to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary agents, separation of the resulting diastereomeric mixture and removal of the chiral auxiliary agent to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith with an appropriate optically active acid or base, and the isolated enantiomers can be obtained in pure form by conventional means such as fractional crystallization or chromatography.

As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.

Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.

Preparation method

The following describes more specifically the processes for the preparation of the compounds of formula (I) according to the invention, but these particular processes do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

Typically, the process for the preparation of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available without specific reference.

Route one:

(i) formula (PTM 1-IA-LG) ₁ )、(PTM1-IB-LG ₁ ) Or (PTM 2-I-LG) ₁ ) Compounds of formula (LG) ₂ -L-LG ₃ ) In a base (e.g., DIPEA, TEA, Py, or DMAP), a condensing agent (e.g., DCC, EDCI, PyBOP, HATU, or BOP), or in a catalyst (e.g., Pd (OAc)) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ PdCl2(dppf), CuI or Cu (OAc) ₂ Etc.) to respectively obtain the formula (PTM 1-IA-LG) ₃ )、(PTM1-IB-L-LG ₃ ) Or (PTM 2-I-L-LG) ₃ ) A compound;

(ii) formula (PTM 1-IA-LG) ₃ )、(PTM1-IB-L-LG ₃ ) Or (PTM 2-I-L-LG) ₃ ) Compounds of formula (LG) ₄ ULM) in a base (e.g. DIPEA, TEA, Py, or DMAP), a condensing agent (e.g. DCC, EDCI, PyBOP, HATU, or BOP) or in a catalyst (e.g. Pd (OAc) ₂ 、Pd2(dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl ₂ (dppf)、CuI、Cu(OAc) ₂ Etc.) to respectively obtain the compounds of the formula (PTM1-IA-L-ULM), the formula (PTM1-IB-L-ULM) and the formula (PTM 2-I-L-ULM);

LG ₁ 、LG ₂ 、LG ₃ or LG ₄ Identical or different, are leaving groups, each independently selected from: hydrogen, OH, halogen, OTs, OMs, OTf, or B (OH) ₂ Etc.;

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ x, Y, Z, W, n are as defined in claim 3

R ^1’ 、R ^2’ 、R ^3’ 、R ^4’ 、R ^5’ 、R ^6’ Z ', W ', n ' are as defined in claim 9.

Each containing at least one LG ₁ 、LG ₂ 、LG ₃ Or LG ₄ When two molecules of the group are reacted, the leaving groups of the two molecules may form at least one small molecule (e.g., H) ₂ O, HCl, TsOH, MsOH, TfOH, etc.).

And a second route:

(i) formula (LG) ₄ ULM) Compounds and formula (LG) ₂ -L-LG ₃ ) In a base (e.g., DIPEA, TEA, Py, or DMAP), a condensing agent (e.g., DCC, EDCI, PyBOP, HATU, or BOP), or in a catalyst (e.g., Pd (OAc)) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl2(dppf)、CuI、Cu(OAc) ₂ Etc.) to obtain the formula (LG) ₂ -L-ULM) compound;

(ii) formula (LG) ₂ -L-ULM) Compounds with formula (PTM1-IA-LG ₁ )、(PTM1-IB-LG ₁ ) Or (PTM 2-I-LG) ₁ ) In a base (e.g., DIPEA, TEA, Py, or DMAP), a condensing agent (e.g., DCC, EDCI, PyBOP, HATU, or BOP), or in a catalyst (e.g., Pd (OAc)) ₂ 、Pd ₂ (dba) ₃ 、Pd(PPh ₃ ) ₄ 、PdCl ₂ (dppf), CuI, or Cu (OAc) ₂ Etc.) to respectively obtain the compounds with the formulas (PTM1-IA-L-ULM), (PTM1-IB-L-ULM) and (PTM 2-I-L-ULM);

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ x, Y, Z, W, and n are defined as in claim 3

R ^1’ 、R ^2’ 、R ^3’ 、R ^4’ 、R ^5’ 、R ^6’ Z ', W ' and n ' are as defined in claim 9.

Pharmaceutical compositions, uses and methods of administration

The pharmaceutical composition comprises the active ingredients and a pharmaceutically acceptable carrier.

The compound of the invention can reduce the activity and expression amount of SOS1, promote the degradation of SOS1 protein and/or reduce the level of SOS1, and thus can be used for preventing and/or treating diseases related to SOS1 activity or expression amount. The pharmaceutical composition of the invention can be used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, metabolic disease.

In another preferred example, the cancer is a KRAS mutation-induced cancer.

In another preferred embodiment, the cancer includes (but is not limited to): lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, large intestine cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may be maintained unchanged while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. The pharmaceutical combination also includes administration of the compound of formula I in an overlapping time period with one or more other known drugs. When a compound of formula I is administered in a pharmaceutical combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose at which they are administered alone.

Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obiumumab, ofutatumab, NI, tositumomab, 131-tositumomab, MSB-90, TSM-55, TSB-35, TSM-55, TSB-55, TSI-55, TSB-35, TSB-10, TSB-35, TSC-55, TSB-I-II-III-I inhibitors, TSB-II-III, TSB-III-I inhibitors, TSB-III-I inhibitors, such as, TSB inhibitors, TSB-I inhibitors, TSB-II inhibitors, TSB-III-II inhibitors, TSB-F-III-F-II-F-III-F-III inhibitors, TSB-III, TSB, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.

Dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, topical liniment, controlled release type or delayed release type or nanometer preparation.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers

Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if desired.

The treatment methods of the present invention can be administered alone or in combination with other therapeutic means or agents.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.

The present invention also provides a method of treatment comprising the steps of: administering a compound of formula (I), or a crystalline form, a pharmaceutically acceptable salt, hydrate, or solvate thereof, as described herein, or a pharmaceutical composition as described herein, to a subject in need of such treatment, for selectively inhibiting SOS 1.

Compared with the prior art, the invention has the following main advantages:

(1) the compound can selectively promote the proteolysis of SOS1, thereby preventing and/or treating diseases related to SOS1 activity or expression (particularly high selectivity to tumor cells), and having high activity and good safety;

(2) the compound of the present invention can exert an effect of inhibiting cell proliferation in a catalytic amount. The intracellular can circularly play a role in degrading target protein, so that the administration dosage is reduced, the administration period is prolonged, and the safe and effective anti-tumor effect is achieved;

(3) the compounds have better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and/or lower toxic and side effects.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS).

NMR was detected using a Bruker AVANCE-400 NMR spectrometer, and the assay solvents contained deuterated Dimethylsulfoxide (DMSO), deuterated acetone (CD) ₃ COCD ₃ ) Deuterated chloroform (CDCl) ₃ ) And deuterated methanol (CD) ₃ OD), internal standard using Tetramethylsilane (TMS), chemical shifts are measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC measurements were performed using an Agilent1100 high pressure chromatograph (Microsorb 5micron C18100 x 3.0.0 mm column).

Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC is 0.15-0.20mm, and preparative thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available or may be used or synthesized according to literature reports in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry inert gas (e.g., nitrogen or argon) at temperatures in degrees celsius, unless otherwise specified.

Examples

EXAMPLE 1 preparation of N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -2- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) acetamide

The first step is as follows: preparation of (R) - (1- (((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl 4-methylbenzenesulfonate

In a round bottom flask were added (R) -4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-ol (100mg, 0.25mmol), cyclopropane-1, 1-diylbis (methylene) bis (p-toluenesulfonate) (519mg, 1.26mmol), potassium carbonate (140mg, 1.01mmol), and acetonitrile (5mL) in that order. The reaction was heated to 60 ℃ for 2 hours and then concentrated under reduced pressure. The residue was subjected to preparative chromatography to give the objective compound (100mg, yield: 63.1%).

LC-MS：m/z 634(M+H) ⁺ 。

The second step is that: preparation of (R) -N- (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ((1- ((methylamino) methyl) cyclopropyl) methoxy) quinazolin-4-amine

To a round bottom flask were added in sequence (R) - (1- (((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) 7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl p-toluenesulfonate (90mg, 0.14mmol), methylamine hydrochloride (96mg, 1.42mmol), potassium carbonate (196mg, 1.42mmol) and acetonitrile (5 mL). The reaction was heated to 60 ℃ for 4 hours and then concentrated under reduced pressure. The residue was subjected to preparative chromatography to give the objective compound (50mg, yield: 72.6%).

LC-MS：m/z 493(M+H) ⁺ 。

Preparation of N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -2- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) acetamide

In a round bottom flask were added in sequence (R) -N- (1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ((1- ((methylamino) methyl) cyclopropyl) methoxy) quinazolin-4-amine (7.7mg, 0.015mmol), 2-chloro-N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) acetamide (11mg, 0.03mmol), potassium carbonate (7mg, 0.045mmol), and acetonitrile (1 mL). The reaction was heated to 60 ℃ for 2 hours and then concentrated under reduced pressure. The residue was subjected to preparative chromatography to give the objective compound (3mg, yield: 24.8%).

LC-MS：m/z 806(M+H) ⁺ 。 ¹ H NMR(400MHz，DMSO)δ10.62-10.54(m,1H),8.70-8.62(m,1H),7.95-7.93(m,1H),7.81-7.71(m,2H),7.62-7.57(m,2H),7.48-7.43(m,1H),7.29(m,1H),6.60(s,1H),5.65-5.60(m,1H),4.73-4.69(m,1H),4.30-4.25(m,1H),3.87-3.81(m,1H),3.53-3.49(m,3H),2.68-2.58(m,2H),2.44-2.39(m,4H),2.33-2.26(m,2H),2.19-1.99(m,6H),1.56(d,J＝6.8Hz,3H),0.70-0.56(m,4H).

The following compounds were synthesized according to the procedure of example 1, starting from different starting materials:

EXAMPLE 2 preparation of N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) -2- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) acetamide

LC-MS：m/z 806(M+H) ⁺ 。 ¹ H NMR(400MHz，DMSO)δ10.19(s,1H),8.05-7.98(m,2H),7.86(s,1H),7.80(t,J＝7.2Hz,1H),7.63-7.59(m,3H),7.38-7.30(m,2H),6.73(d,J＝9.6Hz,1H),5.76-5.69(m,1H),5.12-5.03(m,1H),4.14-3.99(m,2H),3.69(d,J＝7.2Hz,3H),3.33-3.27(m,2H),2.92-2.84(m,1H),2.67-2.55(m,2H),2.43(s,3H),2.22(s,3H),2.14-1.98(m,2H),1.63-1.61(m,3H),0.67-0.54(m,4H).

EXAMPLE 32 preparation of- (((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) -N- (2- (2, 6-dioxopiperidin-3-yl) 1, 3-dioxoisoindol-4-yl) acetamide

LC-MS：m/z 803(M+H) ⁺ 。

EXAMPLE 42 preparation of- (((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) -N- (2- (2, 6-dioxopiperidin-3-yl) 1, 3-dioxoisoindol-3-yl) acetamide

LC-MS：m/z 803(M+H) ⁺ 。

EXAMPLE 5 preparation of N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) -3- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) propionamide

LC-MS:m/z 820(M+H) ⁺ 。

EXAMPLE 6 preparation of N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) -3- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) propionamide

LC-MS:m/z 820(M+H) ⁺ 。

Example 72 preparation of- (2, 6-dioxopiperidin-3-yl) -4- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) amino) isoindole-1, 3-dione

LC-MS:m/z 735(M+H) ⁺ 。1H NMR(400MHz，DMSO)δ8.47(brs,1H),7.87-7.78(m,1H),7.66-7.61(m,1H),7.48-7.42(m,1H),7.38-7.18(m,2H),7.07-6.93(m,3H),6.53-6.50(m,1H),5.81-5.78(m,1H),5.34-5.04(m,1H),4.29-4.04(m,1H),3.98-3.84(m,4H),3.06-2.98(m,1H),2.78-2.56(m,2H),2.33-2.23(m,3H),2.13-1.91(m,3H),1.64-1.59(m,3H),0.87-0.58(m,4H).

Example preparation of 82- (2, 6-dioxopiperidin-3-yl) -5- (((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) amino) isoindole-1, 3-dione

LC-MS:m/z 735(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.16(m,1H),7.85(m,1H),7.79–7.66(m,1H),7.65–7.51(m,2H),7.41(m,1H),7.14–7.06(m,1H),7.05–6.96(m,1H),6.96–6.84(m,1H),6.68(m,2H),5.91–5.76(m,1H),5.34–5.04(m,1H),4.10–3.88(m,5H),2.95–2.73(m,2H),2.73–2.61(m,1H),2.50(m,1H),2.36(s,3H),2.19–1.97(m,2H),1.70(t,J＝8.0Hz,3H),0.88(m,2H),0.67(m,2H).

Example 94- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- ((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -N-methylbutanamide formate

LC-MS:m/z 834(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.27(s,1H),8.03(m,1H),7.75(d,J＝6.9Hz,1H),7.69–7.52(m,2H),7.30(t,J＝7.5Hz,1H),7.18(m,1H),7.01(t,J＝13.6Hz,1H),6.84(m,1H),6.73–6.53(m,1H),6.42(d,J＝8.1Hz,1H),5.71(m,1H),5.04(m,1H),3.99–3.78(m,6H),3.13–2.97(m,3H),2.99–2.78(m,4H),2.56(m,2H),2.44(m,2H),2.37–2.21(m,5H),2.02(m,1H),1.71–1.51(m,5H),0.67(m,4H).

Example 107- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- ((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -N-methylheptamide formate

LC-MS:m/z 876(M+H)+。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.23(s,1H),8.04(t,J＝7.1Hz,1H),7.76(s,1H),7.66–7.42(m,3H),7.32(t,J＝7.4Hz,1H),7.11–6.77(m,3H),6.38(m,1H),5.72(m,1H),5.05(m,1H),4.02–3.76(m,5H),3.45(m,2H),3.08(m,2H),3.03–2.75(m,5H),2.66–2.51(m,2H),2.37–2.12(m,5H),2.12–1.86(m,1H),1.60(d,J＝7.0Hz,3H),1.38–1.18(m,4H),0.97(m,4H),0.69(m,4H).

Example 113- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) -N- ((1- (((4- (((R) -1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -N-methylpropanamide formate

LC-MS:m/z 908(M+H)+。 ¹ H NMR(400MHz,DMSO)δ11.11(d,J＝12.0Hz,1H),8.28(s,1H),8.05(d,J＝6.9Hz,1H),7.77(d,J＝6.5Hz,1H),7.69–7.49(m,3H),7.33(t,J＝7.5Hz,1H),7.16–6.95(m,3H),6.55(m,1H),5.74(m,1H),5.05(m,1H),3.99–3.78(m,5H),3.49–3.24(m,10H),3.05(m,1H),2.94–2.77(m,3H),2.60(m,4H),2.47(s,3H),2.27(t,J＝5.1Hz,3H),2.01(m,1H),1.60(d,J＝6.9Hz,3H),0.65(m,4H).

Example 121- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethyl) cyclopropane-1-carboxamide

The first step is as follows: preparation of ethyl (R) -1- (((7-methoxy-2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylate

The compound (R) -7-methoxy-2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-ol (450mg, 1.07mmol), 1- (iodomethyl) cyclopropyl-1-carboxylic acid ethyl ester (300mg, 1.17mmol), potassium carbonate (442mg, 3.20mmol), and acetonitrile (10mL) were added sequentially to a round bottom flask. The reaction solution was heated to 80 ℃ for 16 hours, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the objective compound (500mg, 85% yield).

LC-MS:m/z 549(M+H) ⁺ 。

The second step is that: preparation of (R) -1- (((7-methoxy-2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylic acid

To a round bottom flask was added the compound (R) -ethyl 1- (((7-methoxy-2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylate (500mg, 0.91mmol), sodium hydroxide (73mg, 1.82mmol), tetrahydrofuran (10mL) and water (2mL) in that order. The reaction mixture was heated to 60 ℃ for 20 hours, followed by concentration under reduced pressure to obtain the desired product (474 mg). The reaction mixture was used in the next reaction without further purification.

LC-MS:m/z 521(M+H) ⁺ 。

The third step: preparation of (R) -1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylic acid

The compound (R) -1- (((7-methoxy-2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylic acid (474mg, 0.91mmol), 10% Pd/C (50mg), and methanol (10mL) were added sequentially to a round bottom flask under nitrogen blanket. The resulting reaction solution was reacted at room temperature for 16 hours under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to give the objective product (650 mg). The reaction mixture was used in the next reaction without further purification.

LC-MS:m/z 491(M+H) ⁺ 。

The fourth step: preparation of 1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethyl) cyclopropane-1-carboxamide

A round-bottomed flask was charged with a mixture of the compound (R) -1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylic acid (45mg, 0.09mmol), 4- ((2-aminoethyl) amino-2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione hydrochloride (33mg, 0.09mmol), pyridine (29mg, 0.37mmol) and N, N-dimethylformamide (1mL) in this order, stirred to dissolve, subsequently EDCI (26mg, 0.14mmol) was added in portions, and after the addition was completed, the reaction solution was reacted at room temperature for 3 hours, followed by separation with a preparative liquid phase to obtain the objective compound (25mg, 35% yield).

LC-MS:m/z 789(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.18(s,1H),7.93(t,J＝8.8Hz,1H),7.89(s,1H),7.69(s,1H),7.62–7.48(m,1H),7.19(d,J＝8.6Hz,1H),7.05–6.95(m,2H),6.86(d,J＝9.6Hz,2H),6.77–6.63(m,2H),5.55(m,3H),5.02(dd,J＝12.8,5.4Hz,1H),4.16(d,J＝11.9Hz,2H),3.85(s,3H),3.33(m,4H),2.97–2.80(m,1H),2.59(m,2H),2.34(m,3H),2.03(m,1H),1.54(d,J＝7.0Hz,3H),1.17(s,2H),0.87(s,2H).

The following compounds were synthesized according to the procedure of example 12, starting from different starting materials:

example 131- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) propyl) cyclopropane-1-carboxamide

LC-MS:m/z 803(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),8.16(s,1H),7.96(d,J＝7.8Hz,1H),7.74(dd,J＝15.6,10.1Hz,2H),7.57–7.40(m,1H),7.01(dd,J＝17.5,8.9Hz,3H),6.86(d,J＝9.1Hz,2H),6.80–6.61(m,2H),5.56(dd,J＝14.5,7.1Hz,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.30–4.14(m,2H),3.83(s,4H),3.37–3.28(m,8H),3.19(d,J＝5.9Hz,4H),2.89(dd,J＝22.7,8.5Hz,2H),2.70–2.55(m,2H),2.36(s,4H),2.03(dd,J＝15.8,10.6Hz,1H),1.76–1.64(m,2H),1.54(d,J＝7.0Hz,3H),1.17(s,2H),0.88(s,2H).

Example 141- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) butyl) cyclopropane-1-carboxamide formate

LC-MS:m/z 817(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.11(s,1H),8.16(s,1H),7.94(d,J＝7.9Hz,1H),7.66(dd,J＝13.1,7.7Hz,2H),7.59–7.44(m,1H),7.10–6.94(m,3H),6.86(d,J＝9.2Hz,2H),6.70(s,1H),6.51(t,J＝5.5Hz,1H),5.55(m,3H),5.04(dd,J＝12.7,5.4Hz,1H),4.25–4.12(m,2H),3.85(s,3H),3.29(m,2H),3.20–3.10(m,2H),2.94–2.77(m,1H),2.70–2.55(m,2H),2.39–2.31(m,3H),2.04(m,1H),1.53(m,7H),1.15(s,2H),0.86(s,2H).

Example 151- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) pentyl) cyclopropane-1-carboxamide

LC-MS:m/z 831(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),7.94(d,J＝8.0Hz,1H),7.71(s,1H),7.59(t,J＝5.4Hz,1H),7.55–7.47(m,1H),7.07–6.93(m,3H),6.86(d,J＝8.5Hz,2H),6.70(s,1H),6.49(t,J＝5.7Hz,1H),5.55(m,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.29–4.10(m,2H),3.88(s,3H),3.28–3.18(m,2H),3.16–3.05(m,2H),2.89(m,1H),2.70–2.55(m,2H),2.35(s,3H),2.12–1.92(m,1H),1.56(t,J＝10.1Hz,5H),1.45(m,2H),1.35–1.19(m,2H),1.14(s,2H),0.85(s,2H).

Example 161- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) hexyl) cyclopropane-1-carboxamide formate

LC-MS:m/z 845(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.10(s,1H),8.17(s,1H),7.93(d,J＝8.0Hz,1H),7.70(s,1H),7.65–7.44(m,2H),7.13–6.93(m,3H),6.86(d,J＝8.0Hz,2H),6.70(s,1H),6.49(t,J＝5.6Hz,1H),5.55(m,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.28–4.11(m,2H),3.87(s,3H),3.25(m,2H),3.10(m,2H),2.96–2.80(m,1H),2.71–2.56(m,2H),2.33(m,3H),2.04(m,1H),1.58(m,5H),1.50–1.21(m,6H),1.14(s,2H),0.85(s,2H).

Example 171- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) heptyl) cyclopropane-1-carboxamide formate

LC-MS:m/z 859(M+H) ⁺ 。 ¹ HNMR(400MHz,DMSO)δ11.10(s,1H),8.16(s,1H),7.93(d,J＝7.9Hz,1H),7.71(s,1H),7.55(t,J＝7.8Hz,2H),7.02(m,3H),6.86(d,J＝8.0Hz,2H),6.70(s,1H),6.48(t,J＝5.7Hz,1H),5.55(m,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.25–4.12(m,2H),3.88(s,3H),3.24(m,2H),3.10(m,2H),2.95–2.80(m,1H),2.60(m,2H),2.33(s,3H),2.12–1.94(m,1H),1.54(m,5H),1.45–1.37(m,2H),1.26(m,6H),1.14(d,J＝2.4Hz,2H),0.85(s,2H).

Example 181- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) octyl) cyclopropane-1-carboxamide formate

LC-MS:m/z 873(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.14(s,1H),8.01(d,J＝7.0Hz,1H),7.72(s,1H),7.56(m,2H),7.11–6.93(m,3H),6.86(d,J＝7.8Hz,2H),6.70(s,1H),6.49(t,J＝5.6Hz,1H),5.56(m,3H),5.05(dd,J＝12.8,5.3Hz,1H),4.26–4.14(m,2H),3.88(s,3H),3.24(m,2H),3.09(m,2H),2.96–2.81(m,1H),2.70–2.56(m,2H),2.36(s,3H),2.04(m,1H),1.54(m,5H),1.40(m,2H),1.24(m,8H),1.14(s,2H),0.85(s,2H).

Example 191- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -2-oxoethoxy) ethoxy) propane-1-carboxamide formate

LC-MS:m/z 847(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.20(m,1H),10.21(m,1H),8.53(m,1H),8.14(s,1H),7.88(d,J＝5.4Hz,1H),7.67(m,2H),7.55(m,1H),7.39(d,J＝7.3Hz,1H),6.82(m,3H),6.68(s,1H),5.64–5.35(m,3H),5.18(m,1H),4.37–4.22(m,1H),4.16(m,2H),4.03–3.88(m,1H),3.85(s,3H),3.72(m,2H),3.59(m,2H),2.99–2.85(m,1H),2.70–2.54(m,2H),2.36(t,J＝8.2Hz,3H),2.1(m,1H),1.52(m,3H),1.21(m,2H),0.88(m,2H).

Example 201- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -2-oxoethoxy) ethoxy) ethyl) cyclopropane-1-carboxamide formate salt

LC-MS:m/z 891(M+H) ⁺ 。 ¹ HNMR(400MHz,DMSO)δ11.15(s,1H),10.27(s,1H),8.66(d,J＝8.4Hz,1H),8.14(s,1H),7.90(d,J＝7.9Hz,1H),7.79(t,J＝7.9Hz,1H),7.68(d,J＝13.0Hz,1H),7.63(dd,J＝16.3,10.9Hz,1H),7.57(d,J＝7.3Hz,1H),7.01(s,1H),6.86(d,J＝8.7Hz,2H),6.70(s,1H),5.62–5.44(m,3H),5.16(dd,J＝12.9,5.3Hz,1H),4.22–4.09(m,4H),3.89(s,3H),3.66(m,4H),3.47(m,2H),2.98–2.82(m,1H),2.69–2.56(m,2H),2.34(s,3H),2.16–1.94(m,1H),1.54(d,J＝7.0Hz,3H),1.14(m,2H),0.92–0.78(m,2H).

Example 21(2S,4R) -1- ((S) -2- (4- (1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxamido) butanamide) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrroline-2-carboxamide formate

LC-MS:m/z 988(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.98(s,1H),8.61(t,J＝5.9Hz,1H),8.18(s,1H),7.92(dd,J＝29.4,8.6Hz,2H),7.70(s,1H),7.65(t,J＝5.3Hz,1H),7.40(q,J＝8.2Hz,4H),7.04(s,1H),6.86(d,J＝8.6Hz,2H),6.70(s,1H),5.61–5.46(m,3H),4.52(d,J＝9.3Hz,1H),4.49–4.38(m,2H),4.35(s,1H),4.27–4.14(m,3H),3.87(s,3H),3.63(m,2H),3.10(m,2H),2.44(s,3H),2.35(s,3H),2.30–2.10(m,2H),2.08–1.83(m,2H),1.69–1.59(m,2H),1.54(d,J＝7.0Hz,3H),1.16(s,2H),0.93(s,9H),0.86(s,2H).

Example 22 preparation of N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylpropanamide formate

The first step is as follows: preparation of (R) -1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N-methylcyclopropane-1-carboxamide

The compound (R) -1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxylic acid (1g, 2mmol), methylamine hydrochloride (688mg, 10mmol), N-diisopropylethylamine (1.3g, 10mmol) and N, N-dimethylformamide (15mL) were added sequentially in a round-bottomed flask, dissolved with stirring and HATU (1.5g, 4mmol) was added in portions. After the addition, the reaction solution was stirred at room temperature for 16 hours, and then water and ethyl acetate were added thereto to conduct layer extraction. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the objective compound (1.2 g).

LC-MS:m/z 504(M+H) ⁺ 。

The second step is that: preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ((1- ((methylamino) methyl) cyclopropyl) methoxy) quinazolin-4-amine

The compound (R) -1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N-methylcyclopropane-1-carboxamide (1.2g, 2.38mmol) and tetrahydrofuran (25mL) were added sequentially in a round bottom flask, dissolved with stirring, followed by addition of lithium aluminum hydride (181mg, 4.77mmol) in portions. After the addition, the reaction solution was heated under reflux for 2 hours. After cooling to room temperature, water (0.2mL), sodium hydroxide solution (15% wt, 0.2mL), and water (0.3mL) were added in that order, followed by filtration. The filtrate was concentrated under reduced pressure to give the objective compound (1.1g), which was used in the next reaction without purification.

LC-MS:m/z 490(M+H) ⁺ 。

The third step: preparation of N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylpropanamide formate

The compound (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ((1- ((methylamino) methyl) cyclopropyl) methoxy) quinazolin-4-amine (40mg, 0.08mmol), 3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) propanoic acid (26mg, 0.08mmol), pyridine (19mg, 0.24mmol), and N, N-dimethylformamide (1mL) were added sequentially in a round bottom flask, dissolved with stirring, followed by addition of EDCI (31mg, 0.16mmol) in portions. After the addition was completed, the reaction mixture was reacted at room temperature for 1 hour, and then separated by preparative liquid phase to obtain the objective compound (24mg, 36.8% yield).

LC-MS:m/z 817(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.07(s,1H),8.22(s,1H),7.83(m,1H),7.50-7.25(m,2H),6.97(d,J＝7.1Hz,1H),6.92–6.74(m,4H),6.71–6.40(m,2H),5.52(m,3H),5.00(dd,J＝12.7,5.2Hz,1H),4.00–3.70(m,5H),3.55(m,2H),2.92(m,5H),2.74–2.55(m,4H),2.32(d,J＝8.1Hz,3H),2.00(m,1H),1.53(d,J＝6.6Hz,3H),0.65(m,4H).

The following compounds were synthesized according to the procedure of example 22, starting from different starting materials:

example 23N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylbutanamide formate

LC-MS:m/z 831(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),8.27(s,1H),7.91–7.76(m,1H),7.65–7.45(m,1H),7.28(m,1H),7.01(m,1H),6.88(m,3H),6.81–6.59(m,2H),6.43(d,J＝5.9Hz,1H),5.51(m,3H),5.08–4.92(m,1H),3.98–3.70(m,5H),3.48(m,2H),2.99–2.78(m,4H),2.70–2.58(m,2H),2.33(m,5H),2.09–1.98(m,1H),1.61(m,2H),1.53(m,3H),0.65(m,4H).

Example 24N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylpentanamide formate

LC-MS:m/z 845(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),8.19(s,1H),7.94–7.78(m,1H),7.62–7.40(m,2H),7.11–6.76(m,5H),6.69(s,1H),6.40(m,1H),5.56(m,3H),5.04(dd,J＝12.5,5.0Hz,1H),3.98–3.74(m,5H),3.51(m,2H),3.08(m,1H),2.86(m,3H),2.62(m,2H),2.45–2.20(m,5H),2.10–1.97(m,1H),1.51(m,3H),1.49–1.17(m,4H),0.64(m,4H).

Example 25N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylhexanamide formate

LC-MS:m/z 859(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.30(s,1H),7.91(m,1H),7.64–7.40(m,3H),7.12–6.97(m,2H),6.83(m,2H),6.68(s,1H),6.37(m,1H),5.63–5.41(m,3H),5.04(dd,J＝13.1,4.4Hz,1H),3.96–3.73(m,5H),3.47(m,2H),2.93(m,3H),2.71–2.54(m,2H),2.38–2.15(m,5H),2.10–1.91(m,1H),1.56(m,3H),1.48–1.08(m,6H),0.67(m,4H).

Example 26N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide formate

LC-MS:m/z 873(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.21(s,1H),7.87(m,1H),7.56(m,2H),7.14–6.95(m,3H),6.94–6.80(m,2H),6.69(s,1H),6.41(m,1H),5.56(m,3H),5.04(dd,J＝12.9,5.3Hz,1H),3.98–3.79(m,5H),3.51(m,2H),3.04(m,1H),2.95–2.79(m,3H),2.69–2.55(m,2H),2.38–2.13(m,5H),2.10–1.90(m,1H),1.56(m,3H),1.41–0.78(m,8H),0.67(m,4H).

Example 27N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -10- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylquinamide formate

LC-MS:m/z 915(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.23(s,1H),7.87(m,1H),7.65–7.49(m,2H),7.11–6.94(m,3H),6.85(s,2H),6.69(s,1H),6.48(s,1H),5.56(m,3H),5.05(dd,J＝12.8,5.3Hz,1H),3.84(m,5H),3.44(m,2H),3.28–3.20(m,1H),2.96–2.79(m,3H),2.62(m,2H),2.38–2.22(m,4H),2.17(t,J＝7.1Hz,1H),2.01(m,1H),1.66–1.41(m,5H),1.37–0.78(m,12H),0.67(m,4H).

Example 28N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethoxy) -N-methylacetamide formate

LC-MS:m/z 847(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.10(d,J＝9.4Hz,1H),8.15

(s,1H),7.88(d,J＝7.8Hz,1H),7.63–7.46(m,2H),7.10–6.89(m,3H),6.85(d,J＝8.1Hz,2H),6.69(s,1H),6.56(d,J＝5.5Hz,1H),5.64–5.42(m,3H),5.05(dd,J＝12.4,5.2Hz,1H),4.25(m,1H),4.13(m,1H),3.90(m,4H),3.77(m,1H),3.44(m,5H),2.99(s,2H),2.94–2.78(m,3H),2.69–2.55(m,2H),2.34(s,3H),2.08–1.94(m,1H),1.53(d,J＝7.0Hz,3H),0.66(m,4H).

Example 29N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethoxy) -N-methylpropanamide

LC-MS:m/z 861(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.13(d,J＝12.9Hz,1H),7.87(t,J＝7.7Hz,1H),7.68–7.40(m,2H),7.07–6.80(m,5H),6.68(s,1H),6.61–6.39(m,1H),5.52(m,3H),5.05(dd,J＝12.8,5.2Hz,1H),3.94–3.72(m,5H),3.56–3.39(m,6H),3.16(m,3H),2.89(m,3H),2.65(m,2H),2.33(d,J＝1.8Hz,3H),2.13–2.05(m,1H),1.53(m,3H),0.66(m,4H).

Example 30N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethoxy) -N-methylpropanamide

LC-MS:m/z 905(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.11(d,J＝14.1Hz,1H),7.89(d,J＝7.9Hz,1H),7.57(dd,J＝14.1,5.8Hz,2H),7.06(dt,J＝11.4,6.0Hz,3H),6.85(d,J＝7.8Hz,2H),6.69(s,1H),6.56(d,J＝7.2Hz,1H),5.53(m,3H),5.05(dd,J＝12.3,4.8Hz,1H),3.89(t,J＝9.9Hz,4H),3.82–3.72(m,1H),3.58–3.38(m,10H),3.04(m,3H),2.95–2.79(m,3H),2.59(m,3H),2.46(m,1H),2.34(d,J＝2.2Hz,3H),2.07(t,J＝7.5Hz,1H),1.53(d,J＝7.0Hz,3H),0.66(m,4H).

Example 31N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) acetamido) -N-methylacetamide formate

LC-MS:m/z 860(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.15(s,1H),8.01(t,J＝4.7Hz,1H),7.86(d,J＝7.5Hz,1H),7.66–7.46(m,2H),7.09–6.98(m,2H),6.93(s,1H),6.83(m,3H),6.69(s,1H),5.64–5.44(m,3H),5.06(dd,J＝12.8,5.0Hz,1H),4.19–3.73(m,9H),3.06(s,3H),2.95–2.80(m,3H),2.60(m,2H),2.34(s,3H),2.10–1.92(m,1H),1.54(d,J＝7.0Hz,3H),0.66(m,4H).

Example 32N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) acetamido) -N-methylpropanamide

LC-MS:m/z 874(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.04–7.76(m,2H),7.63–7.41(m,2H),7.13–6.93(m,2H),6.86(t,J＝8.3Hz,3H),6.70(dm,2H),5.53(m,3H),5.07(dd,J＝12.7,4.6Hz,1H),3.97–3.61(m,7H),3.47(m,2H),3.27–2.98(m,3H),2.90(m,3H),2.61(m,3H),2.42(m,1H),2.30(m,3H),2.08(d,J＝4.8Hz,1H),1.53(d,J＝7.0Hz,3H),0.66(m,4H).

Example 33N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) acetamido) -N-methylbutanamide formate

LC-MS:m/z 888(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),8.15(s,1H),7.98(dd,J＝27.2,22.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.65–7.47(m,2H),7.03(dd,J＝14.8,6.0Hz,2H),6.97–6.77(m,4H),6.69(s,1H),5.63–5.44(m,3H),5.07(dd,J＝12.8,5.3Hz,1H),4.00–3.74(m,5H),3.09–2.77(m,7H),2.60(m,2H),2.35(m,4H),2.22(m,1H),2.04(m,1H),1.58–1.39(m,5H),0.66(m,4H).

Example 34N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) acetamido) -N-methylacetamide formate

LC-MS:m/z 861(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.12(s,1H),8.16(s,1H),7.95(d,J＝7.6Hz,1H),7.87(d,J＝7.4Hz,1H),7.75(dt,J＝13.1,8.1Hz,1H),7.59(d,J＝29.9Hz,1H),7.46(t,J＝7.9Hz,1H),7.35(dd,J＝13.5,7.8Hz,1H),7.00(d,J＝2.0Hz,1H),6.85(d,J＝9.4Hz,2H),6.68(s,1H),5.54(m,3H),5.17–4.96(m,1H),4.78(s,2H),4.20(m,1H),4.03(m,1H),3.95–3.75(m,5H),3.07(s,3H),2.97–2.79(m,3H),2.70–2.55(m,2H),2.34(s,3H),2.11–1.91(m,1H),1.51(t,J＝16.1Hz,3H),0.80–0.52(m,4H).

Example 35N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) acetamido) -N-methylpropanamide formate

LC-MS:m/z 875(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.28–11.02(m,1H),8.21(s,1H),7.85(s,1H),7.73(dt,J＝23.4,8.1Hz,1H),7.48(dd,J＝14.2,9.9Hz,2H),7.36–7.23(m,1H),7.01–6.90(m,2H),6.88–6.52(m,3H),5.63–5.30(m,3H),5.16(dd,J＝27.0,8.6Hz,1H),4.80–4.31(m,2H),3.90(m,5H),3.65(m,2H),3.04(s,3H),2.99–2.82(m,3H),2.61(m,2H),2.40–2.21(m,3H),2.20–1.93(m,1H),1.62–1.35(m,3H),0.78–0.48(m,4H).

Example 36N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) acetamido) -N-methylbutanamide formate

LC-MS:m/z 889(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.13(s,1H),8.15(s,1H),7.97–7.83(m,2H),7.77(dd,J＝11.4,4.4Hz,1H),7.56(d,J＝15.1Hz,1H),7.47(dd,J＝7.2,2.2Hz,1H),7.34(dd,J＝11.2,8.8Hz,1H),7.01(d,J＝3.3Hz,1H),6.85(d,J＝9.1Hz,2H),6.69(s,1H),5.53(m,3H),5.11(dd,J＝12.9,5.2Hz,1H),4.73(t,J＝12.8Hz,2H),3.88(t,J＝10.1Hz,4H),3.77(m,1H),3.13–2.78(m,8H),2.61(m,2H),2.42–2.18(m,5H),2.02(m,1H),1.61–1.41(m,5H),0.66(m,4H).

Example 37N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) amino) acetamido) -N-methylacetamide formate

LC-MS:m/z 860(M+H) ⁺ 。 ¹ HNMR(400MHz,DMSO)δ11.05(d,J＝4.0Hz,1H),8.20(s,1H),7.91(dd,J＝13.3,8.5Hz,1H),7.86(d,J＝7.8Hz,1H),7.67–7.50(m,2H),7.34(d,J＝6.0Hz,1H),7.01(t,J＝7.7Hz,1H),6.93(s,1H),6.84(t,J＝9.1Hz,3H),6.69(s,1H),5.63–5.42(m,3H),5.03(dd,J＝12.2,4.2Hz,1H),4.18–3.76(m,9H),3.05(s,3H),2.97–2.78(m,3H),2.70–2.55(m,2H),2.35(s,3H),2.00(d,J＝8.9Hz,1H),1.54(d,J＝7.0Hz,3H),0.75–0.49(m,4H).

Example 38N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) amino) acetamido) -N-methylpropanamide formate

LC-MS:m/z 874(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.06(s,1H),8.17(s,1H),7.97–7.77(m,2H),7.64–7.48(m,2H),7.27(d,J＝23.3Hz,1H),7.02(t,J＝8.7Hz,1H),6.94–6.71(m,4H),6.69(s,1H),5.52(m,3H),5.04(dd,J＝12.9,5.3Hz,1H),4.01–3.65(m,7H),3.15(m,2H),3.01(s,3H),2.93–2.78(m,3H),2.63(m,2H),2.42–2.26(m,5H),2.04–1.95(m,1H),1.53(d,J＝7.0Hz,3H),0.65(m,4H).

Example 39N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) amino) acetamido) -N-methylbutanamide formate

LC-MS:m/z 888(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.06(s,1H),8.17(s,1H),8.05–7.93(m,1H),7.88(d,J＝5.5Hz,1H),7.62–7.47(m,2H),7.32(d,J＝5.6Hz,1H),7.01(d,J＝5.2Hz,1H),6.93(s,1H),6.85(d,J＝9.0Hz,3H),6.69(s,1H),5.53(m,3H),5.03(dd,J＝12.7,4.9Hz,1H),3.94–3.84(m,4H),3.77(m,3H),3.44(m,2H),3.01(m,3H),2.96–2.77(m,4H),2.62–2.53(m,2H),2.34(m,4H),2.20(t,J＝7.1Hz,1H),2.00(d,J＝5.8Hz,1H),1.53(d,J＝7.0Hz,3H),1.46(d,J＝5.8Hz,2H),0.65(m,4H).

Example 40N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) acetamido) -N-methylacetamide formate

LC-MS:m/z 861(M+H) ⁺ 。 ¹ HNMR(400MHz,DMSO)δ11.11(s,1H),8.17(s,1H),8.06(d,J＝37.0Hz,1H),7.91–7.74(m,2H),7.59(d,J＝31.7Hz,1H),7.38(dd,J＝17.6,6.0Hz,1H),7.33–7.20(m,1H),6.99(s,1H),6.85(d,J＝8.8Hz,2H),6.68(s,1H),5.52(m,3H),5.12(dd,J＝12.9,5.3Hz,1H),4.70(m,2H),4.17(m,1H),4.02–3.74(m,6H),3.07(s,3H),2.95–2.80(m,3H),2.61(m,2H),2.32(m,3H),2.12–1.91(m,1H),1.54(d,J＝7.0Hz,3H),0.68(m,4H).

Example 41N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) acetamido) -N-methylpropanamide formate

LC-MS:m/z 875(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.12(s,1H),8.16(s,1H),7.99(dd,J＝24.4,18.5Hz,1H),7.80(t,J＝10.8Hz,2H),7.54(d,J＝21.8Hz,1H),7.32(d,J＝2.5Hz,1H),7.28–7.17(m,1H),6.98(s,1H),6.83(d,J＝7.8Hz,2H),6.68(s,1H),5.61–5.37(m,3H),5.13(dd,J＝12.9,5.1Hz,1H),4.63–4.40(m,2H),4.03–3.69(m,5H),3.64–3.52(m,2H),3.05(s,3H),2.97–2.81(m,3H),2.61(m,3H),2.46(m,1H),2.39–2.21(m,3H),2.13–1.94(m,1H),1.52(d,J＝7.0Hz,3H),0.66(m,4H).

Example 42N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) acetamido) -N-methylbutanamide formate

LC-MS:m/z 889(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.11(s,1H),8.21–8.09(m,2H),7.90–7.81(m,2H),7.56(d,J＝19.2Hz,1H),7.42(dd,J＝6.2,1.9Hz,1H),7.35(td,J＝8.6,2.1Hz,1H),7.01(d,J＝7.4Hz,1H),6.85(d,J＝8.5Hz,2H),6.69(s,1H),5.53(s,3H),5.12(dd,J＝12.9,5.3Hz,1H),4.65(d,J＝10.0Hz,2H),3.97–3.81(m,4H),3.77(m,1H),3.48–3.43(m,2H),3.12–2.80(m,6H),2.68–2.54(m,2H),2.41–2.30(m,4H),2.23(t,J＝7.2Hz,1H),2.11–1.93(m,1H),1.52(t,J＝9.6Hz,5H),0.66(t,J＝18.4Hz,4H).

Example 435- (4- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) tetrahydropyrroln-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 801(M+H) ⁺ 。

Example 443- (5- (4- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) tetrahydropyrrole-1-yl) piperidin-1-yl) -1-oxoisoquinolin-2-yl) piperidine-2, 6-dione

LC-MS:m/z 787(M+H) ⁺ 。

Example 455- (4- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) tetrahydropyrrol-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindole-1, 3-dione

LC-MS:m/z 819(M+H) ⁺ 。

Example 463- (5- (4- (((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) tetrahydropyrrole-1-yl) methyl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione

LC-MS:m/z 801(M+H) ⁺ 。

Example 473- (5- (4- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) tetrahydropyrrole-1-formyl) piperidin-1-yl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione

LC-MS:m/z 815(M+H) ⁺ 。

Example 485- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) -N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) pentanamide

LC-MS:m/z 748(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.10(s,1H),10.59(s,1H),8.26(s,1H),7.97–7.83(m,3H),7.70(s,1H),7.02(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.64–5.46(m,3H),5.12(dd,J＝12.9,5.4Hz,1H),4.17–4.07(m,2H),3.86(s,3H),2.99–2.78(m,1H),2.68–2.45(m,4H),2.34(s,3H),2.09–1.97(m,1H),1.94–1.79(m,4H),1.55(d,J＝7.1Hz,3H).

Example 493- (2- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) ethoxy) -N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) propionamide

LC-MS:m/z 764(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.10(s,1H),10.63(s,1H),8.24(s,1H),7.93–7.81(m,3H),7.69(s,1H),7.00(s,1H),6.86(s,1H),6.84(s,1H),6.68(s,1H),5.60–5.47(m,3H),5.12(dd,J＝12.8,5.4Hz,1H),4.26–4.16(m,2H),3.89–3.79(m,7H),2.97–2.83(m,1H),2.70(t,J＝6.1Hz,2H),2.64–2.49(m,2H),2.34(s,3H),2.09–1.97(m,1H),1.53(d,J＝7.1Hz,3H).

Example 503- (2- (2- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) ethoxy) -N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) propionamide

LC-MS:m/z 808(M+H) ⁺ 。 ¹ H NMR(400MHz，DMSO)δ1H NMR(400MHz,DMSO)δ11.08(s,1H),10.59(s,1H),8.23(s,1H),7.95–7.81(m,3H),7.69(s,1H),7.01(s,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.61–5.46(m,3H),5.10(dd,J＝12.7,5.3Hz,1H),4.24–4.15(m,2H),3.88–3.79(m,5H),3.76(t,J＝6.1Hz,2H),3.66–3.56(m,4H),2.93–2.82(m,1H),2.70–2.46(m,4H),2.35(s,3H),2.09–2.00(m,1H),1.54(d,J＝7.0Hz,3H).

Example 514- (4- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 801(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.07(s,1H),7.95(d,J＝8.0Hz,1H),7.72–7.62(m,2H),7.34(dd,J＝7.8,4.8Hz,2H),7.04(s,1H),6.89(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.47(m,3H),5.13–5.04(m,2H),3.87(s,3H),3.74–3.63(m,2H),3.21–3.14(m,1H),3.00–2.90(m,2H),2.89–2.64(m,4H),2.64–2.53(m,1H),2.46–2.28(m,5H),2.08–1.92(m,4H),1.88–1.75(m,1H),1.72–1.58(m,2H),1.55(d,J＝7.0Hz,3H).

Example 524- (4- (((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 815(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.07(s,1H),7.95(d,J＝8.1Hz,1H),7.67(dd,J＝8.5,7.1Hz,1H),7.62(s,1H),7.36–7.28(m,2H),7.03(s,1H),6.89(s,1H),6.85(s,1H),6.69(s,1H),5.62–5.47(m,3H),5.13–5.04(m,2H),3.87(s,3H),3.74–3.64(m,2H),3.12–3.05(m,1H),2.95–2.81(m,3H),2.72–2.65(m,1H),2.65–2.53(m,4H),2.45–2.29(m,5H),2.07–1.96(m,2H),1.92–1.76(m,3H),1.76–1.62(m,1H),1.55(d,J＝7.0Hz,3H),1.42–1.27(m,2H).

Example 53(2S,4R) -1- ((S) -2- (1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide

LC-MS:m/z 904(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.94(s,1H),8.52(t,J＝6.1Hz,1H),7.81(s,1H),7.40–7.30(m,5H),7.06(s,1H),6.88(s,1H),6.86(s,1H),6.70(s,1H),5.64–5.46(m,3H),5.14(d,J＝3.5Hz,1H),4.61(d,J＝9.2Hz,1H),4.46–4.30(m,4H),4.28–4.18(m,1H),4.06(d,J＝10.9Hz,1H),3.90(s,3H),3.71–3.58(m,2H),2.43–2.35(m,6H),2.09–1.86(m,2H),1.55(d,J＝7.0Hz,3H),1.30–1.14(m,4H),0.92(s,9H).

Example 541- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) cyclopropane-1-carboxamide

LC-MS:m/z 746(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.03(d,J＝5.6Hz,1H),10.12(s,1H),8.66(d,J＝8.5Hz,1H),7.98–7.92(m,1H),7.85(t,J＝7.9Hz,1H),7.79(s,1H),7.60(d,J＝7.3Hz,1H),7.01(s,1H),6.89(s,1H),6.87(s,1H),6.70(s,1H),5.61–5.46(m,3H),5.01–4.93(m,1H),4.44–4.30(m,2H),3.76(d,J＝3.4Hz,3H),2.87–2.73(m,1H),2.57–2.45(m,1H),2.43–2.28(m,4H),2.03–1.89(m,1H),1.55(dd,J＝7.1,3.3Hz,3H),1.45–1.34(m,2H),1.19–1.10(m,2H).

Example 551- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) -N- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) cyclopropane-1-carboxamide

LC-MS:m/z 746(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),9.90(s,1H),8.23(s,1H),8.04(dd,J＝8.2,1.9Hz,1H),7.99–7.92(m,1H),7.89(d,J＝8.2Hz,1H),7.77(s,1H),7.07(s,1H),6.88(s,1H),6.86(s,1H),6.71(s,1H),5.63–5.47(m,3H),5.12(dd,J＝12.9,5.4Hz,1H),4.45–4.32(m,2H),3.87(s,3H),2.95–2.83(m,1H),2.68–2.48(m,2H),2.37(s,3H),2.09–1.95(m,1H),1.56(d,J＝7.0Hz,3H),1.47–1.37(m,2H),1.13–1.04(m,2H).

Example 56N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperidin-4-yl) -N-methylacetamide

LC-MS:m/z 872(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.07(s,1H),7.87(dd,J＝12.3,7.9Hz,1H),7.61–7.51(m,2H),7.27(t,J＝6.4Hz,1H),7.06–6.93(m,2H),6.87(s,1H),6.85(s,1H),6.68(d,J＝9.4Hz,1H),5.59–5.44(m,3H),5.12–5.02(m,1H),3.94–3.84(m,4H),3.84–3.73(m,1H),3.66–3.33(m,4H),3.13–2.82(m,4H),2.75–2.50(m,4H),2.36–2.24(m,4H),2.24–2.17(m,1H),2.09–1.93(m,1H),1.84–1.64(m,1H),1.64–1.48(m,5H),1.23–0.81(m,2H),0.77–0.61(m,4H).

Example 57N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 857(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09–10.97(m,1H),7.92–7.84(m,1H),7.70–7.52(m,2H),7.35–7.11(m,2H),7.02(d,J＝10.1Hz,1H),6.89–6.81(m,2H),6.69(s,1H),5.59–5.45(m,3H),5.09–5.00(m,1H),3.95–3.77(m,5H),3.69–3.38(m,4H),3.21–2.74(m,5H),2.63–2.43(m,2H),2.34(s,3H),2.13–2.06(m,1H),2.05–1.95(m,1H),1.74–1.30(m,8H),0.80–0.57(m,4H).

Example 584- (4- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidine-1-carbonyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 829(M+H)+。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.96(d,J＝7.9Hz,1H),7.81(d,J＝26.7Hz,1H),7.73–7.63(m,1H),7.39–7.29(m,2H),7.07(d,J＝5.0Hz,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.46(m,3H),5.27–5.02(m,2H),3.96–3.85(m,4H),3.83–3.64(m,4H),3.63–3.53(m,1H),3.04–2.80(m,3H),2.78–2.51(m,3H),2.36(s,3H),2.31–1.94(m,3H),1.89–1.70(m,4H),1.60–1.53(m,3H).

Example 594- (4- (2- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) -2-oxyethyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 843(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.96(d,J＝8.0Hz,1H),7.79(d,J＝19.0Hz,1H),7.72–7.61(m,1H),7.38–7.24(m,2H),7.09–7.03(m,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.44(m,3H),5.27–5.02(m,2H),3.93–3.80(m,4H),3.74–3.54(m,5H),3.52–3.40(m,1H),2.96–2.76(m,3H),2.69–2.52(m,2H),2.40–2.20(m,6H),2.17–1.87(m,3H),1.87–1.71(m,2H),1.56(dd,J＝6.8,3.4Hz,3H),1.51–1.30(m,2H).

Example 60N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) azetidin-3-yl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 912(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.05(s,1H),7.87(dd,J＝8.2,3.5Hz,1H),7.59–7.51(m,2H),7.11(d,J＝7.0Hz,1H),7.08–6.81(m,3H),6.75(d,J＝8.6Hz,1H),6.69(s,1H),5.62–5.45(m,3H),5.03(dd,J＝12.8,5.5Hz,1H),4.27–4.10(m,2H),3.99–3.70(m,7H),3.52–3.41(m,2H),3.18–2.81(m,5H),2.76–2.47(m,4H),2.34(s,3H),2.05–1.75(m,2H),1.53(d,J＝7.0Hz,3H),1.49–1.35(m,4H),1.34–1.21(m,2H),0.79–0.58(m,4H).

Example 614- ((2- (5- (1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carbonyl) hexahydropyrrolyl [3,4-c ] pyrrol-2 (1H) -yl) -2-oxoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 899(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.86(d,J＝7.9Hz,1H),7.69–7.49(m,5H),7.05(s,1H),7.04(s,1H),6.97(s,1H),6.86(s,1H),6.84(s,1H),6.69(s,1H),5.62–5.44(m,3H),5.06(dd,J＝12.9,5.5Hz,1H),4.42–3.98(m,5H),3.98–3.80(m,4H),3.79–3.51(m,2H),3.50–3.32(m,2H),3.07–2.81(m,3H),2.69–2.49(m,2H),2.34(s,3H),2.09–1.95(m,1H),1.53(dd,J＝7.2,3.7Hz,3H),0.98–0.89(m,4H).

Example 624- ((2- (2- (1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carbonyl) -2, 7-diaminospiro [3.5] nonan-7-yl) -2-oxoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 913(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.89(d,J＝8.0Hz,1H),7.65(s,1H),7.60(dd,J＝8.5,7.1Hz,1H),7.15–7.04(m,4H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.44(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.32–4.02(m,6H),3.91(s,3H),3.72–3.56(m,2H),3.54–3.35(m,4H),2.96–2.82(m,1H),2.66–2.52(m,2H),2.36(s,3H),2.10–1.97(m,1H),1.80–1.70(m,2H),1.70–1.62(m,2H),1.55(d,J＝7.0Hz,3H),1.12–1.03(m,2H),0.94–0.84(m,2H).

Example 634- ((2- (2- (1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropane-1-carbonyl) -2, 8-diaminospiro [4.5] decan-8-yl) -2-oxoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 926(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(d,J＝8.0Hz,1H),7.66(s,1H),7.63–7.56(m,1H),7.17–6.99(m,4H),6.87(s,1H),6.86(s,1H),6.70(s,1H),5.65–5.45(m,3H),5.07(dd,J＝12.8,5.4Hz,1H),4.32–3.96(m,5H),3.94–3.80(m,3H),3.80–3.39(m,6H),3.27–3.15(m,1H),2.98–2.83(m,1H),2.66–2.52(m,2H),2.35(s,3H),2.10–2.01(m,1H),1.91–1.68(m,2H),1.64–1.39(m,7H),1.13–0.87(m,4H).

Example 644- (5- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pent-1-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 715(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),8.01–7.92(m,1H),7.90–7.77(m,3H),7.74(s,1H),7.03(s,1H),6.87(s,1H),6.84(s,1H),6.68(s,1H),5.61–5.44(m,3H),5.15–5.06(m,1H),4.29–4.22(m,2H),3.88(s,3H),2.96–2.86(m,1H),2.76(t,J＝7.1Hz,2H),2.63–2.45(m,2H),2.35(s,3H),2.21–2.10(m,2H),2.04–1.96(m,1H),1.54(d,J＝7.0Hz,3H).

Example 65N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -N-methyl-7- ((2- (1-methyl-2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) heptanamide

LC-MS:m/z 887(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ7.93–7.87(m,1H),7.62–7.51(m,2H),7.07–6.90(m,3H),6.88–6.83(m,2H),6.70(s,1H),6.40(dt,J＝20.5,5.9Hz,1H),5.60–5.45(m,3H),5.11(dd,J＝13.0,5.4Hz,1H),3.96–3.75(m,5H),3.56–3.35(m,2H),3.17–3.08(m,1H),3.08–2.86(m,8H),2.80–2.71(m,1H),2.60–2.52(m,1H),2.32(d,J＝8.1Hz,3H),2.23(dt,J＝34.8,7.5Hz,2H),2.09–2.00(m,1H),1.53(d,J＝7.0Hz,3H),1.41–1.25(m,4H),1.20–0.89(m,4H),0.76–0.58(m,4H).

Example 66N- ((1- (((4- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 858(M+H) ⁺ 。1HNMR((400MHz,DMSO)δ11.08(s,1H),8.03–7.95(m,1H),7.69–7.50(m,2H),7.50–7.43(m,1H),7.39–7.18(m,2H),7.13–6.85(m,3H),6.39(dt,J＝24.4,5.9Hz,1H),5.82–5.73(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.99–3.75(m,5H),3.56–3.42(m,2H),3.16–2.81(m,6H),2.65–2.55(m,2H),2.35–2.15(m,5H),2.07–1.97(m,1H),1.58(d,J＝7.1Hz,3H),1.36–1.22(m,4H),1.19–0.84(m,4H),0.75–0.63(m,4H).

Example 67N- ((1- (((4- (((R) -1- (3-amino-5- (difluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 855(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.90–7.82(m,1H),7.65–7.52(m,2H),7.11–6.95(m,3H),6.94–6.64(m,3H),6.58(s,1H),6.42(dt,J＝18.0,5.9Hz,1H),5.59–5.50(m,1H),5.32(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),3.99–3.72(m,5H),3.54–3.37(m,2H),3.19–3.09(m,1H),3.10–2.82(m,5H),2.63–2.52(m,2H),2.33(d,J＝6.0Hz,3H),2.23(dt,J＝36.0,7.4Hz,2H),2.10–1.99(m,1H),1.52(d,J＝7.0Hz,3H),1.43–1.22(m,4H),1.21–0.91(m,4H),0.76–0.58(m,4H).

Example 68N- ((1- (((4- (((R) -1- (3- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 917(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),8.01–7.93(m,1H),7.67–7.49(m,3H),7.33–7.25(m,1H),7.23–7.14(m,1H),7.08–6.87(m,3H),6.40(dt,J＝21.4,5.9Hz,1H),5.82–5.73(m,1H),5.30(s,1H),5.04(dd,J＝12.8,5.4Hz,1H),4.02–3.77(m,5H),3.59–3.38(m,2H),3.17–2.98(m,3H),2.95–2.82(m,3H),2.63–2.51(m,2H),2.32–2.16(m,5H),2.09–1.99(m,1H),1.56(d,J＝7.0Hz,3H),1.42–1.25(m,4H),1.25–1.18(m,6H),1.17–0.90(m,4H),0.79–0.59(m,4H).

EXAMPLE 69(3- (4- ((7- (((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) (methyl) amino) -7-oxoheptyl) amino) -1, 3-dioxoisoindol-2-yl) -2, 6-dioxopiperidin-1-yl) methylpivalate

LC-MS:m/z 988(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ7.93–7.85(m,1H),7.63–7.53(m,2H),7.07–6.91(m,3H),6.90–6.85(m,2H),6.70(s,1H),6.46–6.34(m,1H),5.66(s,2H),5.60–5.47(m,3H),5.24(dd,J＝12.9,5.4Hz,1H),3.97–3.75(m,5H),3.55–3.35(m,2H),3.18–3.10(m,1H),3.10–2.99(m,2H),2.93–2.80(m,3H),2.63–2.54(m,2H),2.33(d,J＝7.2Hz,3H),2.24(dt,J＝34.5,7.4Hz,2H),2.14–2.05(m,1H),1.54(d,J＝7.0Hz,3H),1.41–1.22(m,4H),1.20–0.85(m,13H),0.76–0.59(m,4H).

Example 70(1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl 7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) heptanoate

LC-MS:m/z 860(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.09(s,1H),7.94(d,J＝8.0Hz,1H),7.66(s,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.04–6.94(m,3H),6.87(s,1H),6.85(s,1H),6.69(s,1H),6.43(t,J＝6.0Hz,1H),5.61–5.46(m,3H),5.04(dd,J＝12.8,5.4Hz,1H),4.13–4.05(m,2H),4.03–3.92(m,2H),3.87(s,3H),3.19–3.10(m,2H),2.94–2.81(m,1H),2.64–2.52(m,2H),2.34(s,3H),2.29(t,J＝7.3Hz,2H),2.06–1.99(m,1H),1.54(d,J＝7.1Hz,3H),1.51–1.39(m,4H),1.33–1.17(m,4H),0.76–0.65(m,4H).

Example 71N- ((1- (((4- (((R) -1- (3-cyano-2-methylphenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 829(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),8.12–8.03(m,1H),7.77(dd,J＝8.0,3.8Hz,1H),7.64–7.48(m,3H),7.38–7.29(m,1H),7.09–6.81(m,3H),6.44–6.27(m,1H),5.65–5.53(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.01–3.75(m,5H),3.58–3.44(m,2H),3.12–3.01(m,2H),2.99–2.81(m,4H),2.70(s,3H),2.64–2.53(m,2H),2.35–2.15(m,5H),2.11–2.00(m,1H),1.52(d,J＝7.0Hz,3H),1.40–1.17(m,4H),1.17–0.81(m,4H),0.79–0.60(m,4H).

Example 72N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) -N-methyl- [1,4' -bipiperidine ] -4-carboxamide

LC-MS:m/z 941(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.92(s,1H),7.74(d,J＝7.9Hz,1H),7.64(t,J＝7.8Hz,1H),7.55(s,1H),7.32–7.25(m,2H),7.03(s,1H),6.86(s,2H),6.70(s,1H),5.58–5.50(m,1H),5.36(s,2H),5.05(dd,J＝12.6,5.5Hz,1H),3.98–3.76(m,5H),3.71(d,J＝12.0Hz,2H),3.49–3.41(m,2H),2.95–2.79(m,6H),2.69–2.52(m,4H),2.39–2.26(m,4H),2.22–2.09(m,1H),2.10–1.99(m,1H),1.89–1.64(m,3H),1.62–1.50(m,5H),1.50–1.23(m,5H),0.79–0.54(m,4H).

Example 73N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperazin-1-yl) -N-methylpropanamide

LC-MS:m/z 886(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.94–7.85(m,1H),7.68–7.54(m,2H),7.33(dd,J＝7.2,4.9Hz,1H),7.22–6.97(m,2H),6.87(s,1H),6.85(s,1H),6.68(s,1H),5.58–5.49(m,3H),5.09(dd,J＝13.1,5.4Hz,1H),4.01–3.76(m,5H),3.57–3.41(m,4H),3.22–2.96(m,5H),2.96–2.81(m,3H),2.65–2.55(m,2H),2.49–2.43(m,4H),2.39–2.26(m,5H),2.08–1.96(m,1H),1.54(d,J＝7.1Hz,3H),0.79–0.59(m,4H).

Example 74N- ((1- (((4- (((R) -1- (3-amino-5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 914(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.85(dd,J＝8.0,5.0Hz,1H),7.62–7.51(m,2H),7.06–6.93(m,3H),6.71(s,1H),6.69(s,1H),6.56(s,1H),6.48–6.38(m,1H),5.58–5.46(m,1H),5.16(s,2H),5.11–5.01(m,2H),3.98–3.69(m,5H),3.56–3.45(m,2H),3.20–3.02(m,3H),2.95–2.82(m,3H),2.64–2.52(m,2H),2.32(d,J＝4.3Hz,3H),2.30–2.16(m,2H),2.07–2.00(m,1H),1.52(d,J＝7.0Hz,3H),1.45–1.23(m,4H),1.20–0.92(m,4H),0.76–0.57(m,4H).

Example 75N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) -N-methylheptamide

LC-MS:m/z 859(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.01(s,1H),7.93–7.85(m,1H),7.58(d,J＝20.3Hz,1H),7.27(t,J＝7.7Hz,1H),7.03(d,J＝11.0Hz,1H),6.92(d,J＝7.4Hz,1H),6.89–6.83(m,2H),6.70(s,1H),6.68–6.60(m,1H),5.61–5.49(m,3H),5.43(dt,J＝19.6,5.5Hz,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.28–4.08(m,2H),3.97–3.74(m,5H),3.56–3.39(m,2H),3.11–2.84(m,6H),2.66–2.58(m,1H),2.39–2.16(m,6H),2.10–2.00(m,1H),1.54(d,J＝7.0Hz,3H),1.42–1.18(m,5H),1.18–0.92(m,3H),0.77–0.58(m,4H).

Example 76 cis-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperazin-1-yl) -N-methylcyclohexane-1-carboxamide and trans N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-e- 6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperazin-1-yl) -N-methylcyclohexane-1-carboxamide

Isomer 1: LC-MS M/z 941(M + H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),8.03–7.86(m,1H),7.70(t,J＝7.8Hz,1H),7.66–7.45(m,1H),7.38–7.28(m,2H),7.10–7.00(m,1H),6.90–6.82(m,2H),6.70(s,1H),5.65–5.47(m,3H),5.13–5.05(m,1H),4.01–3.81(m,5H),3.79–3.70(m,1H),3.55–3.41(m,1H),3.29–3.20(m,4H),3.16–3.11(m,1H),2.95–2.81(m,4H),2.73–2.54(m,4H),2.40–2.23(m,4H),2.10–1.99(m,1H),1.96–1.73(m,1H),1.64–1.39(m,8H),1.36–1.15(m,4H),0.92–0.57(m,4H).

Isomer 2: LC-MS M/z 941(M + H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.99–7.87(m,1H),7.69(t,J＝7.7Hz,1H),7.56(d,J＝20.2Hz,1H),7.37–7.27(m,2H),7.10–6.99(m,1H),6.87–6.83(m,2H),6.68(d,J＝11.7Hz,1H),5.63–5.47(m,3H),5.12–5.05(m,1H),3.97–3.71(m,6H),3.29–3.19(m,3H),3.15–3.10(m,1H),3.04–2.78(m,6H),2.72–2.54(m,4H),2.42–2.23(m,6H),2.10–1.99(m,3H),1.95–1.86(m,1H),1.81–1.43(m,6H),1.16–0.99(m,2H),0.80–0.58(m,4H).

Example 77N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -5- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperazin-1-yl) -N-methylpentanamide

LC-MS:m/z 915(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),8.00–7.88(m,1H),7.72–7.54(m,2H),7.34(dd,J＝7.1,3.2Hz,1H),7.24–7.01(m,2H),6.89–6.83(m,2H),6.67(s,1H),5.64–5.45(m,3H),5.09(dd,J＝12.8,5.5Hz,1H),4.00–3.74(m,5H),3.51–3.43(m,4H),3.19–2.97(m,5H),2.96–2.81(m,3H),2.64–2.52(m,2H),2.42–2.32(m,3H),2.29(d,J＝11.9Hz,3H),2.26–2.14(m,3H),2.11–1.98(m,1H),1.54(d,J＝7.0Hz,3H),1.40–1.19(m,3H),1.14–1.05(m,1H),0.79–0.57(m,4H).

EXAMPLE 78N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperazin-1-yl) -N-methylbutanamide

LC-MS:m/z 900(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.92(d,J＝7.9Hz,1H),7.74–7.54(m,2H),7.34(t,J＝6.5Hz,1H),7.19(dd,J＝34.5,8.5Hz,1H),7.04(d,J＝9.5Hz,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.61–5.46(m,3H),5.09(dd,J＝12.9,5.4Hz,1H),4.00–3.77(m,5H),3.54–3.44(m,2H),3.21–3.05(m,5H),2.97–2.80(m,3H),2.64–2.53(m,2H),2.42–2.27(m,8H),2.26–2.12(m,2H),2.08–1.96(m,2H),1.63–1.43(m,5H),0.80–0.57(m,4H).

Example 79N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) piperidin-4-yl) oxy) -N-methylpropanamide

LC-MS:m/z 901(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(d,J＝7.9Hz,1H),7.71–7.54(m,2H),7.32(dd,J＝7.2,4.1Hz,1H),7.17(dd,J＝53.5,8.5Hz,1H),7.03(s,1H),6.88(s,1H),6.86(s,1H),6.69(s,1H),5.63–5.45(m,3H),5.09(dd,J＝12.9,5.4Hz,1H),4.01–3.74(m,5H),3.56–3.41(m,5H),3.30–3.04(m,3H),3.00–2.72(m,5H),2.65–2.53(m,4H),2.32(d,J＝8.7Hz,3H),2.10–1.97(m,1H),1.87–1.65(m,2H),1.62–1.35(m,5H),0.79–0.57(m,4H).

Example 80N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (5- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -N-methylacetamide

LC-MS:m/z 898(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.88(d,J＝7.9Hz,1H),7.65–7.52(m,2H),7.27–7.19(m,1H),7.13–6.97(m,2H),6.90–6.82(m,2H),6.69(s,1H),5.61–5.46(m,3H),5.13–5.05(m,1H),3.98–3.72(m,5H),3.58–3.37(m,6H),3.28–3.03(m,3H),2.96–2.82(m,3H),2.82–2.54(m,6H),2.35(d,J＝5.2Hz,3H),2.33–2.22(m,2H),2.08–1.98(m,1H),1.53(d,J＝7.1Hz,3H),0.75–0.56(m,4H).

Example 81N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (9- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) -3, 9-diazaspiro [5.5] undecan-3-yl) -N-methylacetamide

LC-MS:m/z 941(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.97–7.86(m,1H),7.74–7.53(m,2H),7.31(t,J＝7.8Hz,1H),7.26–7.08(m,1H),7.04(d,J＝16.5Hz,1H),6.88(s,1H),6.86(s,1H),6.71–6.63(m,1H),5.59–5.48(m,3H),5.12–5.03(m,1H),4.00–3.70(m,5H),3.68–3.37(m,2H),3.17–2.80(m,10H),2.64–2.53(m,2H),2.33–2.23(m,3H),2.23–2.10(m,4H),2.08–1.95(m,1H),1.54(d,J＝5.5Hz,3H),1.47–1.15(m,8H),0.80–0.58(m,4H).

Example 82N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) butoxy) -N-methylacetamide

LC-MS:m/z 875(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.86(dd,J＝8.1,4.2Hz,1H),7.64–7.50(m,2H),7.07–6.97(m,3H),6.86(s,1H),6.85(s,1H),6.69(s,1H),6.47(t,J＝6.1Hz,1H),5.59–5.47(m,3H),5.05(dd,J＝12.9,5.4Hz,1H),4.22–3.74(m,7H),3.56–3.35(m,2H),3.24–3.12(m,4H),3.05–2.82(m,4H),2.64–2.53(m,2H),2.33(s,3H),2.09–1.97(m,1H),1.53(d,J＝7.0Hz,3H),1.49–1.36(m,4H),0.78–0.57(m,4H).

Example 83N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) oxy) -N-methylheptamide

LC-MS:m/z 874(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.88(t,J＝7.6Hz,1H),7.83–7.74(m,1H),7.57(d,J＝20.7Hz,1H),7.48–7.30(m,2H),7.03(d,J＝11.2Hz,1H),6.87(s,1H),6.86(s,1H),6.69(s,1H),5.62–5.44(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.09–3.75(m,7H),3.53–3.42(m,2H),3.06(s,1H),2.97–2.81(m,3H),2.64–2.53(m,2H),2.39–2.17(m,5H),2.09–1.96(m,1H),1.62–1.43(m,5H),1.39–1.23(m,3H),1.21–1.10(m,2H),1.08–0.94(m,1H),0.78–0.59(m,4H).

Example 84N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) amino) -N-methylheptamide

LC-MS:m/z 873(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.04(s,1H),7.88(t,J＝7.6Hz,1H),7.58(d,J＝14.3Hz,1H),7.55(d,J＝2.7Hz,1H),7.03(d,J＝11.1Hz,1H),7.00–6.89(m,2H),6.87(s,1H),6.85(s,1H),6.83–6.72(m,1H),6.70(s,1H),5.62–5.44(m,3H),5.03(dd,J＝12.8,5.4Hz,1H),3.98–3.74(m,5H),3.56–3.40(m,2H),3.10–2.81(m,6H),2.63–2.52(m,2H),2.33(d,J＝7.6Hz,3H),2.24(dt,J＝33.7,7.4Hz,2H),2.04–1.96(m,1H),1.54(d,J＝7.1Hz,3H),1.42–1.23(m,4H),1.22–1.04(m,3H),1.02–0.91(m,1H),0.78–0.57(m,4H).

Example 85N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) -N-methylheptamide

LC-MS:m/z 874(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.89(t,J＝8.2Hz,1H),7.81(dd,J＝8.3,3.0Hz,1H),7.58(d,J＝23.2Hz,1H),7.35(dd,J＝11.0,2.3Hz,1H),7.32–7.20(m,1H),7.03(d,J＝13.4Hz,1H),6.88–6.83(m,2H),6.68(s,1H),5.61–5.45(m,3H),5.12(dd,J＝13.0,5.3Hz,1H),4.03–3.74(m,7H),3.54–3.42(m,2H),3.07(s,1H),2.96–2.83(m,3H),2.65–2.53(m,2H),2.38–2.16(m,5H),2.10–2.02(m,1H),1.54(d,J＝7.0Hz,3H),1.50–1.38(m,2H),1.38–1.04(m,4H),1.03–0.85(m,2H),0.77–0.58(m,4H).

Example 86N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-1, 3-dioxoisoindol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 891(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.94(s,1H),7.58(d,J＝16.2Hz,1H),7.48–7.36(m,1H),7.07(dd,J＝7.9,3.4Hz,1H),7.03(d,J＝9.4Hz,1H),6.87–6.83(m,2H),6.70(s,1H),6.44–6.32(m,1H),5.66–5.43(m,3H),5.07(dd,J＝12.7,5.3Hz,1H),3.97–3.72(m,5H),3.57–3.35(m,4H),3.05(s,1H),2.96–2.82(m,3H),2.65–2.53(m,2H),2.34(d,J＝5.8Hz,3H),2.23(dt,J＝37.1,7.5Hz,2H),2.10–1.97(m,1H),1.54(d,J＝7.0Hz,3H),1.43–1.22(m,4H),1.22–1.02(m,3H),1.02–0.90(m,1H),0.77–0.57(m,4H).

Example 87N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindol-5-yl) amino) -N-methylheptamide

LC-MS:m/z 891(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(t,J＝8.4Hz,1H),7.57(d,J＝21.7Hz,1H),7.50(dd,J＝8.2,1.3Hz,1H),7.03(d,J＝12.2Hz,1H),6.95–6.74(m,4H),6.70(s,1H),5.65–5.44(m,3H),5.05(dd,J＝12.7,5.4Hz,1H),3.99–3.74(m,5H),3.57–3.37(m,2H),3.12–2.81(m,6H),2.66–2.53(m,2H),2.33(d,J＝7.9Hz,3H),2.23(dt,J＝34.8,7.3Hz,2H),2.09–1.97(m,1H),1.54(d,J＝7.0Hz,3H),1.39–1.22(m,4H),1.20–0.90(m,4H),0.77–0.57(m,4H).

Example 88N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindol-4-yl) amino) -N-methylheptanoyl

LC-MS:m/z 891(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.13(s,1H),7.91(t,J＝7.6Hz,1H),7.58(d,J＝22.9Hz,1H),7.49–7.38(m,1H),7.09–6.94(m,2H),6.90–6.83(m,2H),6.69(s,1H),6.38(dt,J＝22.0,5.9Hz,1H),5.66–5.43(m,3H),5.06(dd,J＝12.8,5.4Hz,1H),3.97–3.84(m,4H),3.84–3.73(m,1H),3.57–3.41(m,2H),3.14–3.08(m,1H),3.06(s,1H),3.04–2.95(m,1H),2.95–2.82(m,3H),2.64–2.54(m,2H),2.32(d,J＝8.8Hz,3H),2.30–2.15(m,2H),2.10–1.99(m,1H),1.53(d,J＝7.0Hz,3H),1.39–1.20(m,4H),1.20–0.82(m,4H),0.77–0.58(m,4H).

Example 89N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (8- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) -2, 8-diazaspiro [4.5] decan-2-yl) -N-methylacetamide

LC-MS:m/z 926(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(dd,J＝14.3,7.9Hz,1H),7.68–7.54(m,2H),7.31(d,J＝7.1Hz,1H),7.13(dd,J＝8.5,5.3Hz,1H),7.04(d,J＝16.8Hz,1H),6.87–6.82(m,2H),6.68(s,1H),5.58–5.42(m,3H),5.09(dd,J＝12.9,5.4Hz,1H),4.00–3.73(m,5H),3.49(dd,J＝39.5,14.1Hz,2H),3.33–3.17(m,3H),3.17–3.00(m,4H),2.99–2.74(m,5H),2.64–2.53(m,2H),2.49–2.38(m,1H),2.30(d,J＝8.2Hz,3H),2.25–2.09(m,1H),2.08–1.96(m,1H),1.62–1.38(m,9H),0.78–0.57(m,4H).

Example 90N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) propoxy) -N-methylpropanamide

LC-MS:m/z 875(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.87(d,J＝7.9Hz,1H),7.63–7.49(m,2H),7.06–6.92(m,3H),6.87(s,1H),6.85(s,1H),6.70(s,1H),6.60(dt,J＝34.5,5.9Hz,1H),5.62–5.46(m,3H),5.04(dd,J＝12.9,5.4Hz,1H),3.98–3.75(m,5H),3.54–3.37(m,5H),3.30–3.23(m,2H),3.21–3.13(m,1H),3.07(s,1H),2.96–2.80(m,3H),2.69–2.51(m,4H),2.34(d,J＝6.6Hz,3H),2.09–1.97(m,1H),1.77–1.58(m,2H),1.54(d,J＝7.1Hz,3H),0.75–0.56(m,4H).

Example 91N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -8- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) -N-methyloct-7-ynnamide

LC-MS:m/z 868(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.19–11.12(m,1H),8.00–7.89(m,1H),7.87–7.72(m,3H),7.58(d,J＝15.5Hz,1H),7.02(d,J＝3.2Hz,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.45(m,3H),5.14(dd,J＝12.9,5.4Hz,1H),3.99–3.73(m,5H),3.55–3.44(m,2H),3.06(s,1H),2.98–2.82(m,3H),2.65–2.54(m,2H),2.41–2.19(m,7H),2.10–1.98(m,1H),1.54(d,J＝7.0Hz,3H),1.51–1.43(m,1H),1.43–1.29(m,4H),1.29–1.14(m,1H),0.78–0.56(m,4H).

Example 92N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- ((4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) but-3-yn-1-yl) oxy) -N-methylpropanamide

LC-MS:m/z 870(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.20–11.12(m,1H),7.91–7.73(m,4H),7.58(d,J＝19.2Hz,1H),7.02(s,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.62–5.46(m,3H),5.14(dd,J＝12.9,5.4Hz,1H),3.97–3.73(m,5H),3.57–3.41(m,6H),3.07(s,1H),2.96–2.81(m,3H),2.70–2.52(m,6H),2.33(d,J＝5.4Hz,3H),2.10–1.98(m,1H),1.54(d,J＝7.1Hz,3H),0.75–0.56(m,4H).

Example 93N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) amino) -N-methylheptamide

LC-MS:m/z 874(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.13(s,1H),8.56(d,J＝4.8Hz,1H),7.89(d,J＝7.4Hz,1H),7.57(d,J＝17.4Hz,1H),7.03(d,J＝10.7Hz,1H),6.98–6.88(m,2H),6.88–6.81(m,2H),6.69(s,1H),5.62–5.45(m,3H),5.09(dd,J＝12.8,5.4Hz,1H),3.99–3.72(m,5H),3.60–3.42(m,4H),3.05(s,1H),2.97–2.81(m,3H),2.65–2.52(m,2H),2.33(d,J＝3.5Hz,3H),2.31–2.15(m,2H),2.10–1.98(m,1H),1.53(d,J＝7.0Hz,3H),1.47–1.21(m,4H),1.21–0.91(m,4H),0.78–0.56(m,4H).

Example 94N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethyl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 900(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.90(d,J＝7.7Hz,1H),7.60–7.52(m,2H),7.08–6.98(m,3H),6.89–6.82(m,2H),6.71–6.67(m,2H),5.62–5.45(m,3H),5.07(dd,J＝13.0,5.4Hz,1H),3.99–3.72(m,5H),3.61–3.38(m,3H),3.29–3.21(m,2H),3.14(s,1H),2.97–2.77(m,4H),2.72–2.52(m,5H),2.44–2.38(m,1H),2.34(s,3H),2.06–1.92(m,2H),1.66–1.38(m,6H),1.35–1.23(m,1H),0.78–0.59(m,4H).

Example 95N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) glycyl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 914(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.90(t,J＝9.5Hz,1H),7.63–7.52(m,2H),7.10–7.01(m,4H),6.90–6.83(m,2H),6.70(s,1H),5.62–5.47(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.35–4.01(m,3H),3.98–3.88(m,3H),3.88–3.68(m,2H),3.67–3.56(m,1H),3.48–3.38(m,1H),3.19(s,1H),3.09–2.79(m,5H),2.77–2.65(m,1H),2.65–2.53(m,2H),2.36(s,3H),2.33–2.13(m,1H),2.09–1.96(m,1H),1.55(dd,J＝7.2,2.1Hz,3H),1.52–1.37(m,2H),1.37–1.22(m,2H),0.82–0.57(m,4H).

Example 96 cis-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) cyclohexyl) -N-methylpiperidine-4-carboxamide and trans-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-e- 6-yl) oxy) methyl) cyclopropyl) methyl) -1- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) cyclohexyl) -N-methylpiperidine-4-carboxamide

Isomer 1: LC-MS M/z 954(M + H) ⁺ 。1H NMR(400MHz,DMSO)δ11.11(s,1H),7.93(d,J＝8.0Hz,1H),7.67–7.50(m,2H),7.16(d,J＝8.7Hz,1H),7.10–7.00(m,2H),6.90–6.82(m,2H),6.70(s,1H),6.14(d,J＝8.2Hz,1H),5.66–5.44(m,3H),5.05(dd,J＝12.7,5.5Hz,1H),4.03–3.79(m,5H),3.73(d,J＝10.3Hz,1H),3.59–3.38(m,4H),3.15(s,1H),2.98–2.80(m,4H),2.72–2.54(m,5H),2.35(s,3H),2.10–1.95(m,4H),1.92(s,1H),1.85–1.63(m,2H),1.55(d,J＝7.0Hz,3H),1.51–1.16(m,6H),0.81–0.58(m,4H).

Isomer 2: LC-MS M/z 954(M + H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.93–7.87(m,1H),7.63–7.51(m,2H),7.15(d,J＝8.7Hz,1H),7.09–6.99(m,2H),6.90–6.83(m,2H),6.70(s,1H),6.13(d,J＝8.2Hz,1H),5.68–5.43(m,3H),5.05(dd,J＝12.8,5.4Hz,1H),4.03–3.79(m,5H),3.73(d,J＝10.3Hz,1H),3.59–3.36(m,4H),3.13(s,1H),2.98–2.81(m,4H),2.79–2.66(m,1H),2.65–2.46(m,4H),2.35(s,3H),2.31–2.11(m,2H),2.09–1.94(m,3H),1.88–1.57(m,4H),1.55(d,J＝7.0Hz,3H),1.49–1.17(m,4H),0.82–0.56(m,4H).

Example 97N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) - [1,3' -diazetidin ] -3-yl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 967(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.06(s,1H),7.88(d,J＝7.9Hz,1H),7.63(d,J＝8.3Hz,1H),7.55(d,J＝16.6Hz,1H),7.03(d,J＝19.8Hz,1H),6.90–6.81(m,2H),6.77(s,1H),6.69(s,1H),6.63(dd,J＝8.4,2.1Hz,1H),5.64–5.44(m,3H),5.05(dd,J＝12.8,5.4Hz,1H),4.00(t,J＝7.9Hz,2H),3.96–3.79(m,5H),3.79–3.69(m,2H),3.61–3.37(m,4H),3.29–3.22(m,2H),3.12(s,1H),2.95–2.86(m,3H),2.86–2.66(m,3H),2.64–2.51(m,4H),2.49–2.36(m,2H),2.34(s,3H),2.08–1.96(m,1H),1.54(d,J＝7.0Hz,3H),1.47–1.20(m,4H),0.81–0.58(m,4H).

Example 98N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) - [1,3' -diazetidin ] -3-yl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 967(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.06(s,1H),7.88(d,J＝7.9Hz,1H),7.59–7.51(m,2H),7.10(d,J＝6.9Hz,1H),7.03(d,J＝19.2Hz,1H),6.89–6.81(m,2H),6.76(dd,J＝8.5,2.8Hz,1H),6.69(s,1H),5.61–5.46(m,3H),5.04(dd,J＝12.8,5.4Hz,1H),4.22–4.08(m,2H),3.97–3.85(m,6H),3.85–3.70(m,1H),3.55–3.35(m,4H),3.30–3.22(m,2H),3.12(s,1H),2.95–2.85(m,3H),2.85–2.65(m,3H),2.65–2.52(m,4H),2.48–2.37(m,2H),2.34(s,3H),2.04–1.96(m,1H),1.54(d,J＝7.0Hz,3H),1.47–1.18(m,4H),0.79–0.57(m,4H).

Example 994- ((7- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) -7-oxoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 845(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.97(d,J＝8.0Hz,1H),7.78(d,J＝22.1Hz,1H),7.62–7.53(m,1H),7.13–7.04(m,2H),7.02(d,J＝7.6Hz,1H),6.88(s,1H),6.86(s,1H),6.70(s,1H),6.57–6.47(m,1H),5.66–5.47(m,3H),5.23–5.09(m,1H),5.09–5.02(m,1H),3.97–3.75(m,3H),3.72–3.52(m,4H),3.49–3.38(m,1H),3.31–3.21(m,1H),2.95–2.82(m,1H),2.65–2.53(m,2H),2.36(s,3H),2.33–2.27(m,2H),2.26–2.18(m,1H),2.16–2.07(m,1H),2.07–1.96(m,1H),1.68–1.44(m,7H),1.44–1.24(m,4H).

Example 1004- ((6- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) -6-oxohexyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 831(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.99(d,J＝8.0Hz,1H),7.78(d,J＝22.5Hz,1H),7.63–7.53(m,1H),7.13–6.98(m,3H),6.88(s,1H),6.85(s,1H),6.70(s,1H),6.57–6.50(m,1H),5.68–5.46(m,3H),5.25–5.09(m,1H),5.09–5.01(m,1H),3.95–3.77(m,3H),3.73–3.52(m,3H),3.48–3.38(m,1H),2.97–2.82(m,1H),2.81–2.72(m,2H),2.64–2.53(m,2H),2.36(s,3H),2.34–2.19(m,3H),2.16–2.08(m,1H),2.07–1.95(m,1H),1.69–1.48(m,7H),1.45–1.31(m,2H).

Example 1014- ((2- (2- (3- ((S) -3- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

LC-MS:m/z 877(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.97(dd,J＝8.0,2.4Hz,1H),7.77(d,J＝19.3Hz,1H),7.61–7.51(m,1H),7.12(dd,J＝8.6,6.9Hz,1H),7.09–7.00(m,2H),6.88(s,1H),6.86(s,1H),6.71(s,1H),6.64–6.55(m,1H),5.69–5.46(m,3H),5.23–5.09(m,1H),5.09–5.01(m,1H),3.86(s,3H),3.72–3.39(m,14H),2.95–2.81(m,1H),2.64–2.43(m,4H),2.36(s,3H),2.29–2.17(m,1H),2.15–2.08(m,1H),2.08–1.98(m,1H),1.60–1.53(m,3H).

Example 102N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) butoxy) -N, 2-dimethylpropionamide

LC-MS:m/z 903(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.88(d,J＝7.9Hz,1H),7.61–7.50(m,2H),7.08–6.95(m,2H),6.89–6.83(m,2H),6.69(s,1H),6.52–6.43(m,1H),5.62–5.49(m,3H),5.05(dd,J＝12.9,5.4Hz,1H),3.99–3.77(m,5H),3.57–3.44(m,2H),3.28–3.21(m,3H),3.21–3.13(m,2H),2.96–2.82(m,1H),2.65–2.52(m,4H),2.34(s,3H),2.07–2.00(m,1H),1.61–1.44(m,7H),1.25(s,6H),0.66(s,4H).

Example 103N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) cyclohexyl) oxy) -N-methylbutanamide

LC-MS:m/z 929(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.88(t,J＝7.9Hz,1H),7.63–7.52(m,2H),7.15–7.01(m,3H),6.88–6.82(m,2H),6.69(s,1H),6.16–6.08(m,1H),5.62–5.44(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),3.98–3.83(m,4H),3.83–3.73(m,1H),3.62–3.36(m,3H),3.15–3.06(m,2H),3.01–2.82(m,5H),2.64–2.52(m,2H),2.38–2.30(m,4H),2.30–2.20(m,1H),2.07–1.99(m,1H),1.93–1.60(m,4H),1.60–1.44(m,5H),1.22–1.01(m,4H),0.77–0.57(m,4H).

Example 104N 1- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -N4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) cyclohexyl) -N1, N4-dimethylsuccinamide

LC-MS:m/z 956(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.12(s,1H),7.90(t,J＝6.9Hz,1H),7.68–7.53(m,2H),7.21–6.97(m,3H),6.93–6.81(m,2H),6.70(s,1H),6.60–6.08(m,1H),5.72–5.43(m,3H),5.14–5.01(m,1H),4.01–3.74(m,5H),3.66–3.37(m,4H),3.13–3.07(m,1H),2.97–2.81(m,3H),2.68–2.53(m,6H),2.53–2.43(m,1H),2.40–2.23(m,5H),2.11–1.91(m,2H),1.89–1.64(m,2H),1.63–1.42(m,4H),1.41–1.14(m,4H),0.82–0.54(m,4H).

Example 105N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) ethoxy) -N-methylbutanamide

LC-MS:m/z 875(M+H) ⁺ 。 ¹ H NMR(400MHz,DMSO)δ11.11(s,1H),7.91–7.85(m,1H),7.64–7.51(m,2H),7.10–6.99(m,3H),6.87(s,1H),6.85(s,1H),6.69(s,1H),6.59–6.50(m,1H),5.64–5.46(m,3H),5.10–5.01(m,1H),4.01–3.72(m,5H),3.54–3.34(m,6H),3.19(dt,J＝40.2,6.5Hz,2H),3.03(s,1H),2.96–2.80(m,3H),2.63–2.53(m,2H),2.41–2.31(m,4H),2.31–2.23(m,1H),2.06–1.98(m,1H),1.62–1.49(m,5H),0.75–0.57(m,4H).

Example 106N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) -N-methylbutanamide

LC-MS:m/z 900(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(dd,J＝7.9,4.1Hz,1H),7.70–7.52(m,2H),7.24(dd,J＝17.6,2.3Hz,1H),7.16–7.00(m,2H),6.89(s,1H),6.87(s,1H),6.69(s,1H),5.65–5.42(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),3.98–3.71(m,5H),3.57–3.38(m,2H),3.28–3.20(m,2H),3.20–3.11(m,2H),3.08(s,1H),2.97–2.81(m,3H),2.64–2.53(m,2H),2.38–2.26(m,5H),2.23–2.17(m,2H),2.17–1.99(m,2H),1.98–1.79(m,1H),1.61–1.40(m,5H),0.78–0.58(m,4H).

Example 107N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -5- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) -N-methylpentanamide

LC-MS:m/z 914(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.92(dd,J＝12.3,7.9Hz,1H),7.70–7.51(m,2H),7.29–7.23(m,1H),7.15–7.01(m,2H),6.89–6.83(m,2H),6.66(s,1H),5.64–5.44(m,3H),5.08(dd,J＝12.8,5.4Hz,1H),3.99–3.84(m,4H),3.83–3.74(m,1H),3.51–3.37(m,2H),3.23–3.18(m,2H),3.15–3.11(m,2H),3.09(s,1H),2.99–2.81(m,3H),2.65–2.52(m,2H),2.38–2.29(m,5H),2.26–2.21(m,2H),2.13–1.98(m,5H),1.54(d,J＝5.5Hz,3H),1.35–1.28(m,2H),1.26–1.18(m,1H),1.09–0.95(m,1H),0.79–0.57(m,4H).

Example 108N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) -N-methylpropanamide

LC-MS:m/z 831(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.77(s,1H),7.90(dd,J＝8.2,3.3Hz,1H),7.59(d,J＝18.8Hz,1H),7.04(d,J＝6.0Hz,1H),6.97–6.81(m,4H),6.70(s,1H),6.60(s,1H),6.58(s,1H),5.63(d,J＝7.4Hz,1H),5.60–5.51(m,3H),4.33–4.19(m,1H),3.99–3.86(m,4H),3.86–3.76(m,1H),3.56–3.39(m,2H),3.09(s,1H),2.97–2.87(m,2H),2.86–2.77(m,1H),2.77–2.64(m,2H),2.63–2.52(m,2H),2.48–2.37(m,3H),2.35(s,3H),2.24–1.98(m,2H),1.94–1.71(m,3H),1.64–1.44(m,6H),1.43–1.31(m,1H),0.79–0.57(m,4H).

Example 109N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) piperazin-1-yl) -N-methylacetamide

LC-MS:m/z 955(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(d,J＝7.9Hz,1H),7.66(dd,J＝8.6,2.0Hz,1H),7.58(d,J＝11.9Hz,1H),7.29(dd,J＝4.0,2.2Hz,1H),7.24–7.17(m,1H),7.03(d,J＝8.0Hz,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.45(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.03–3.74(m,6H),3.62–3.47(m,2H),3.10(s,1H),3.09–2.97(m,2H),2.97–2.78(m,5H),2.64–2.52(m,3H),2.43–2.31(m,5H),2.31–2.25(m,2H),2.25–2.13(m,4H),2.05–1.98(m,1H),1.76–1.68(m,1H),1.67–1.58(m,1H),1.54(d,J＝7.0Hz,3H),1.41–1.19(m,2H),0.79–0.60(m,4H).

Example 110N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidine-4-carbonyl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 968(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.91(t,J＝7.9Hz,1H),7.65(d,J＝8.5Hz,1H),7.58(d,J＝27.0Hz,1H),7.30(s,1H),7.25–7.15(m,1H),7.05(d,J＝18.8Hz,1H),6.91–6.82(m,2H),6.70(s,1H),5.67–5.44(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.35–4.15(m,1H),4.08–3.95(m,2H),3.92(s,3H),3.89–3.62(m,3H),3.25–3.15(m,2H),3.11–2.73(m,8H),2.63–2.52(m,3H),2.38–2.32(m,3H),2.26–2.09(m,1H),2.06–1.98(m,1H),1.72–1.44(m,8H),1.44–1.33(m,2H),1.32–1.12(m,1H),0.82–0.57(m,4H).

Example 111N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (9- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) -3, 9-diazaspiro [5.5] undecan-3-yl) -N-methylacetamide

LC-MS:m/z 940(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.90(dd,J＝10.9,7.9Hz,1H),7.71–7.53(m,2H),7.28–7.20(m,1H),7.18–7.00(m,2H),6.91–6.82(m,2H),6.67(d,J＝16.8Hz,1H),5.65–5.42(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.01–3.72(m,5H),3.59–3.39(m,2H),3.27–3.16(m,4H),3.15–3.02(m,3H),2.98–2.82(m,3H),2.65–2.54(m,2H),2.31(d,J＝42.7Hz,3H),2.24–2.10(m,4H),2.07–1.96(m,1H),1.53(dd,J＝7.2,2.2Hz,3H),1.40–1.28(m,4H),1.28–1.13(m,4H),0.81–0.58(m,4H).

Example 112N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) amino) methyl) piperidin-1-yl) -N-methylacetamide

LC-MS:m/z 900(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.90(dd,J＝8.0,3.4Hz,1H),7.62–7.52(m,2H),7.12–6.99(m,3H),6.86(s,1H),6.84(s,1H),6.70(s,1H),6.59–6.53(m,1H),5.62–5.47(m,3H),5.05(dd,J＝12.9,5.4Hz,1H),3.95–3.83(m,4H),3.82–3.73(m,1H),3.60–3.38(m,2H),3.21–3.00(m,5H),2.97–2.81(m,3H),2.79–2.69(m,2H),2.64–2.52(m,2H),2.34(s,3H),2.07–1.99(m,1H),1.97–1.79(m,2H),1.67–1.39(m,6H),1.28–1.09(m,2H),0.77–0.59(m,4H).

Example 113N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -7- ((1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-4-yl) amino) -N-methylheptamide

LC-MS:m/z 874(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.06(s,1H),7.90(t,J＝6.8Hz,1H),7.58(d,J＝19.9Hz,1H),7.03(d,J＝11.5Hz,1H),6.90–6.83(m,3H),6.69(s,1H),6.49(d,J＝7.9Hz,1H),6.35(dd,J＝14.5,8.2Hz,1H),5.62–5.46(m,3H),5.28(dd,J＝12.7,5.3Hz,1H),4.88(dt,J＝19.4,5.6Hz,1H),3.96–3.84(m,4H),3.84–3.73(m,1H),3.59(s,3H),3.56–3.37(m,2H),3.06(s,1H),2.96–2.80(m,5H),2.75–2.57(m,2H),2.33(d,J＝3.8Hz,3H),2.25(dt,J＝33.6,7.5Hz,2H),2.05–1.91(m,1H),1.53(dd,J＝7.2,1.9Hz,3H),1.49–1.20(m,5H),1.19–1.07(m,2H),1.03–0.96(m,1H),0.78–0.57(m,4H).

Example 114N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) methyl) piperidin-1-yl) -N-methylacetamide

LC-MS:m/z 969(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(dd,J＝7.9,5.1Hz,1H),7.68(d,J＝8.5Hz,1H),7.58(d,J＝11.6Hz,1H),7.32(s,1H),7.23(dd,J＝8.7,2.3Hz,1H),7.04(d,J＝13.8Hz,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.60–5.51(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),3.92–3.86(m,4H),3.81–3.74(m,1H),3.59–3.47(m,1H),3.43–3.35(m,4H),3.12(s,1H),3.08–2.99(m,2H),2.96–2.82(m,3H),2.74–2.52(m,4H),2.44–2.27(m,7H),2.11–1.97(m,3H),1.92–1.73(m,2H),1.61–1.43(m,5H),1.39–1.22(m,2H),1.12–0.90(m,2H),0.74–0.63(m,4H).

Example 115 cis-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) -N-methylcyclohexane-1-carboxamide and trans-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-e Lin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) -N-methylcyclohexane-1-carboxamide

Isomer 1: LC-MS M/z 940(M + H) +. 1H NMR (400MHz, DMSO) δ 11.09(s,1H),7.92(t, J ═ 9.0Hz,1H),7.68(dd, J ═ 8.6,4.9Hz,1H),7.57(d, J ═ 27.8Hz,1H),7.33(dd, J ═ 8.6,2.1Hz,1H),7.25(dd, J ═ 8.3,2.5Hz,1H),7.07(d, J ═ 39.5, 1H), 6.90-6.81 (m,2H),6.70(s,1H), 5.63-5.45 (m,3H),5.08(dd, 09, J ═ 12.6,5.1Hz,1H),3.94(d, J ═ 19.5, 3H),3.80(dd, 3.80, 3.7 (m,3H), 3.97 (H), 3.44, 3.47H), 2.7.7.7.7 (d, J ═ 2H, 3.06H), 2H, 3.7.7.7 (dd, 2H, 6H), 6, 5H, 5.65 (m,2H), 6H, 6.7.7.7.7.44 (m,2H),6, 2H), 6(m,2H, 3.47H, 2H), 6.7.7.7.6 (m,2H),6, 2H),6.6, 2H),6 (d, 2H),6, 6.47 (m, 6, 2H), 6.6.6.6, 2H),6, 2.7.7.6.7.7.6, 2H), 6(m,2H), 6, 2H), 1H) 1.64-1.36 (m,7H), 1.34-1.13 (m,2H), 0.83-0.59 (m,4H).

Isomer 2: LC-MS M/z 940(M + H) +. 1H NMR (400MHz, DMSO) δ 11.09(s,1H),7.95(s,1H),7.67(dd, J ═ 8.5,5.1Hz,1H),7.57(d, J ═ 21.9Hz,1H),7.37 to 7.18(m,2H),7.04(d, J ═ 10.0Hz,1H),6.88 to 6.82(m,2H),6.68(d, J ═ 14.0Hz,1H),5.63 to 5.45(m,3H),5.11 to 5.02(m,1H),4.00 to 3.61(m,5H),3.49 to 3.36(m,2H),3.34 to 3.22(m,2H),3.17 to 3.01(m,3H),2.97 to 2.75(m, 3.65 (m,2H), 2.49 to 3.36(m,2H),3.34 to 3.22(m,2H),3.17 to 3.01(m,3H),2.97 to 2.75(m, 2H), 2.65(m, 6.50 to 3.28.28.28.28, 6.6.0 (m,1H), 2H) 0.79-0.59 (m,4H).

Example 116N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) piperazin-1-yl) methyl) piperidin-1-yl) -N-methylacetamide

LC-MS:m/z 987(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.12(s,1H),7.91(dd,J＝8.0,4.5Hz,1H),7.73(d,J＝11.4Hz,1H),7.58(d,J＝12.3Hz,1H),7.43(dd,J＝7.5,3.0Hz,1H),7.04(d,J＝14.4Hz,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.62–5.45(m,3H),5.11(dd,J＝12.8,5.4Hz,1H),3.98–3.73(m,5H),3.61–3.37(m,2H),3.25–3.14(m,4H),3.14–2.99(m,3H),2.97–2.81(m,3H),2.75–2.65(m,2H),2.65–2.54(m,2H),2.45–2.37(m,3H),2.34(d,J＝5.6Hz,3H),2.14–1.95(m,3H),1.95–1.83(m,1H),1.82–1.70(m,1H),1.64–1.42(m,5H),1.40–1.22(m,1H),1.09–0.90(m,2H),0.78–0.60(m,4H).

Example 117 cis-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) cyclohexyl) (methyl) amino) -N-methylbutanamide and trans-N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) amino) -yl) oxy) methyl) cyclopropyl) methyl) -4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) cyclohexyl) (methyl) amino) -N-methylbutanamide

Isomer 1: LC-MS M/z 942(M + H) ⁺ 。1H NMR(400MHz,DMSO)δ11.11(s,1H),8.04–7.85(m,1H),7.67–7.51(m,2H),7.18–6.98(m,4H),6.88–6.80(m,1H),6.69(s,1H),6.17–6.06(m,1H),5.68–5.46(m,3H),5.06(dd,J＝13.1,5.4Hz,1H),3.98–3.71(m,5H),3.61–3.48(m,2H),3.12–2.99(m,1H),2.96–2.80(m,3H),2.71–2.55(m,2H),2.40–2.25(m,5H),2.25–2.12(m,3H),2.09–1.82(m,7H),1.76–1.49(m,5H),1.49–1.36(m,4H),1.34–1.20(m,2H),1.17–1.03(m,2H),0.77–0.57(m,4H).

Isomer 2: LC-MS M/z 942(M + H) ⁺ 。1H NMR(400MHz,DMSO)δ11.13(s,1H),7.89(d,J＝7.8Hz,1H),7.66–7.51(m,2H),7.11–6.99(m,3H),6.91–6.82(m,2H),6.69(s,1H),6.39(t,J＝8.7Hz,1H),5.64–5.43(m,3H),5.13–5.02(m,1H),3.97–3.68(m,5H),3.54–3.39(m,2H),3.12–2.98(m,1H),2.96–2.79(m,3H),2.69–2.54(m,2H),2.38–2.25(m,5H),2.25–2.13(m,3H),2.12–1.87(m,7H),1.74–1.56(m,4H),1.53(d,J＝7.0Hz,3H),1.50–1.36(m,5H),1.35–1.19(m,3H),0.77–0.56(m,4H).

Example 118N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1'- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) -N-methyl- [1,4' -bipiperidine ] -4-carboxamide

LC-MS:m/z 940(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.90(dd,J＝8.1,3.7Hz,1H),7.66(dd,J＝8.5,3.5Hz,1H),7.55(d,J＝19.8Hz,1H),7.31(s,1H),7.22(dd,J＝8.8,2.4Hz,1H),7.05(d,J＝31.1Hz,1H),6.91–6.80(m,2H),6.69(s,1H),5.63–5.45(m,3H),5.07(dd,J＝13.0,5.3Hz,1H),4.07–3.99(m,2H),3.97–3.70(m,5H),3.53–3.38(m,2H),3.12(s,1H),2.97–2.80(m,5H),2.80–2.67(m,1H),2.66–2.53(m,4H),2.33(d,J＝4.1Hz,3H),2.19–1.95(m,2H),1.79–1.57(m,4H),1.56–1.50(m,3H),1.48–1.18(m,6H),0.81–0.57(m,4H).

Example 119N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) oxy) piperidin-1-yl) -N-methylacetamide

LC-MS:m/z 970(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.15(s,1H),8.01–7.94(m,1H),7.72(d,J＝8.5Hz,1H),7.64(d,J＝14.2Hz,1H),7.38(d,J＝2.3Hz,1H),7.29(dd,J＝8.7,2.3Hz,1H),7.10(d,J＝14.5Hz,1H),6.92(s,1H),6.90(s,1H),6.75(s,1H),5.68–5.53(m,3H),5.13(dd,J＝12.9,5.4Hz,1H),4.05–3.90(m,4H),3.90–3.74(m,2H),3.69–3.51(m,3H),3.38–3.29(m,2H),3.29–3.19(m,2H),3.18–3.04(m,3H),3.02–2.88(m,3H),2.72–2.57(m,4H),2.40(d,J＝6.1Hz,3H),2.15–1.94(m,3H),1.91–1.66(m,4H),1.60(d,J＝7.0Hz,3H),1.54–1.25(m,4H),0.84–0.65(m,4H).

Example 120N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) azetidin-3-yl) piperazin-1-yl) -N-methylacetamide

LC-MS:m/z 927(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.91(d,J＝7.9Hz,1H),7.65(d,J＝8.3Hz,1H),7.58(d,J＝15.6Hz,1H),7.04(d,J＝8.8Hz,1H),6.87(s,1H),6.85(s,1H),6.75(dd,J＝14.9,2.1Hz,1H),6.69(d,J＝5.0Hz,1H),6.65–6.54(m,1H),5.63–5.48(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.01(t,J＝7.9Hz,1H),3.95–3.83(m,5H),3.81–3.73(m,2H),3.67–3.49(m,2H),3.46–3.36(m,2H),3.28–3.18(m,1H),3.15–3.00(m,4H),2.96–2.81(m,3H),2.64–2.50(m,4H),2.35(d,J＝15.0Hz,3H),2.32–2.18(m,4H),2.14–1.95(m,1H),1.54(d,J＝7.0Hz,3H),0.78–0.60(m,4H).

Example 121N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) amino) -N-methylcyclohexyl-1-carboxamide

LC-MS:m/z 954(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.91(d,J＝8.1Hz,1H),7.65(d,J＝8.5Hz,1H),7.56(d,J＝20.3Hz,1H),7.31(s,1H),7.22(d,J＝8.4Hz,1H),7.03(d,J＝9.7Hz,1H),6.90–6.82(m,2H),6.70(s,1H),5.66–5.45(m,3H),5.07(dd,J＝12.9,5.5Hz,1H),4.06–3.69(m,7H),3.53–3.43(m,2H),3.14(s,1H),3.07–2.95(m,2H),2.94–2.83(m,3H),2.64–2.51(m,4H),2.34(d,J＝2.7Hz,3H),2.05–1.97(m,1H),1.92–1.75(m,3H),1.70–1.43(m,6H),1.42–1.12(m,7H),0.81–0.48(m,4H).

Example 122N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (2- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) ethyl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 969(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.91(dd,J＝7.9,5.1Hz,1H),7.67(d,J＝8.5Hz,1H),7.56(d,J＝20.0Hz,1H),7.34–7.30(m,1H),7.23(dt,J＝8.7,2.6Hz,1H),7.04(d,J＝23.5Hz,1H),6.90–6.80(m,2H),6.69(d,J＝5.7Hz,1H),5.64–5.46(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),4.01–3.68(m,5H),3.57–3.42(m,2H),3.41–3.30(m,8H),3.13(s,1H),2.96–2.78(m,3H),2.72–2.52(m,4H),2.49–2.38(m,4H),2.38–2.21(m,5H),2.07–1.91(m,2H),1.54(dd,J＝7.1,3.0Hz,3H),1.48–1.17(m,4H),0.80–0.59(m,4H).

Example 123N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) -N-methylbutanamide

LC-MS:m/z 845(M+H)+。1H NMR(400MHz,DMSO)δ10.80(s,1H),7.95(s,1H),7.60(d,J＝25.5Hz,1H),7.06(d,J＝17.2Hz,1H),6.97–6.78(m,4H),6.70(s,1H),6.66–6.52(m,2H),5.69(s,1H),5.64–5.42(m,3H),4.34–4.20(m,1H),4.05–3.69(m,5H),3.60–3.41(m,2H),3.08(s,1H),2.96–2.84(m,3H),2.83–2.66(m,2H),2.65–2.52(m,2H),2.34(s,3H),2.27–2.04(m,4H),2.02–1.66(m,4H),1.63–1.35(m,9H),0.81–0.51(m,4H).

Example 124N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) piperazin-1-yl) methyl) piperidin-1-yl) -N-methylacetamide

LC-MS:m/z 955(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.95(s,1H),7.95–7.88(m,1H),7.59(d,J＝13.0Hz,1H),7.52(d,J＝8.8Hz,1H),7.08–7.00(m,3H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.47(m,3H),5.05(dd,J＝13.3,5.1Hz,1H),4.27(dd,J＝50.0,17.5Hz,2H),3.95–3.83(m,4H),3.83–3.76(m,1H),3.59–3.51(m,2H),3.45–3.36(m,2H),3.27–3.18(m,4H),3.16–3.01(m,3H),2.97–2.83(m,3H),2.77–2.65(m,2H),2.64–2.54(m,2H),2.44–2.36(m,4H),2.34(d,J＝9.9Hz,3H),2.09–2.01(m,2H),2.00–1.93(m,1H),1.88–1.75(m,1H),1.64–1.41(m,5H),1.10–0.92(m,2H),0.78–0.60(m,4H).

Example 125N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-4-yl) amino) methyl) piperidin-1-yl) -N-methylpropanamide

LC-MS:m/z 914(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.89(dd,J＝8.0,4.0Hz,1H),7.62–7.53(m,2H),7.08(dd,J＝8.7,5.3Hz,1H),7.05–6.99(m,2H),6.88–6.83(m,2H),6.69(s,1H),6.58–6.48(m,1H),5.63–5.45(m,3H),5.11–5.01(m,1H),3.94–3.84(m,4H),3.81–3.77(m,1H),3.46(d,J＝9.2Hz,2H),3.18–3.04(m,3H),2.96–2.82(m,3H),2.75–2.68(m,1H),2.65–2.52(m,3H),2.48–2.41(m,1H),2.41–2.25(m,6H),2.11–1.98(m,1H),1.80–1.61(m,2H),1.60–1.38(m,6H),1.21–0.97(m,2H),0.76–0.58(m,4H).

Example 126N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperidin-4-yl) oxy) -N-methylcyclohexyl-1-carboxamide

LC-MS:m/z 955(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.95–7.87(m,1H),7.64(dd,J＝8.5,3.5Hz,1H),7.57(d,J＝20.3Hz,1H),7.29(s,1H),7.25–7.14(m,1H),7.03(d,J＝11.5Hz,1H),6.90–6.82(m,2H),6.69(s,1H),5.63–5.45(m,3H),5.11–5.02(m,1H),3.98–3.80(m,4H),3.79–3.58(m,3H),3.57–3.39(m,4H),3.26–3.06(m,3H),2.98–2.80(m,3H),2.71–2.52(m,2H),2.34(d,J＝8.6Hz,3H),2.05–1.97(m,1H),1.83–1.62(m,3H),1.61–1.46(m,6H),1.46–1.29(m,3H),1.28–1.17(m,1H),1.16–0.85(m,2H),0.78–0.58(m,4H).

Example 127N- ((1- (((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (2- (4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) piperazin-1-yl) ethoxy) -N-methylacetamide

LC-MS:m/z 916(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.96–7.89(m,1H),7.71–7.52(m,2H),7.29–7.22(m,1H),7.14–7.02(m,2H),6.89–6.83(m,2H),6.69–6.65(m,1H),5.65–5.45(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),4.14(d,J＝47.0Hz,2H),4.01–3.86(m,4H),3.86–3.76(m,1H),3.59–3.38(m,2H),3.29–3.09(m,6H),3.03(s,1H),2.98–2.80(m,3H),2.67–2.52(m,2H),2.41–2.29(m,5H),2.29–2.18(m,4H),2.06–1.99(m,1H),1.53(d,J＝7.0Hz,3H),0.80–0.60(m,4H).

Example 128(R) -N- ((1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) -N-methylpiperidine-4-carboxamide

LC-MS:m/z 789(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.25(s,1H),7.95–7.86(m,1H),7.58(d,J＝25.0Hz,1H),7.14–7.05(m,2H),7.03(d,J＝3.5Hz,1H),6.90–6.75(m,4H),6.70(s,1H),5.64–5.47(m,3H),3.98–3.87(m,2H),3.87–3.75(m,3H),3.74–3.64(m,2H),3.64–3.55(m,1H),3.54–3.39(m,3H),3.18(s,1H),2.92(s,2H),2.89–2.79(m,1H),2.76–2.61(m,3H),2.36(s,3H),2.33–2.21(m,1H),1.62–1.43(m,6H),1.42–1.30(m,1H),0.81–0.58(m,4H).

Example 129(R) -N- ((1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -2- (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) -N-methylacetamide

LC-MS:m/z 803(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.26(s,1H),8.06–7.86(m,1H),7.61(d,J＝10.0Hz,1H),7.19–7.01(m,3H),6.90–6.83(m,3H),6.77–6.72(m,1H),6.71–6.66(m,1H),5.66–5.44(m,3H),4.00–3.84(m,4H),3.84–3.77(m,1H),3.75–3.65(m,2H),3.65–3.36(m,2H),3.24–3.16(m,2H),3.15–3.09(m,2H),3.09–3.01(m,2H),2.99–2.83(m,3H),2.75–2.62(m,3H),2.49–2.39(m,4H),2.36(d,J＝3.7Hz,3H),1.53(dd,J＝12.5,7.0Hz,3H),0.81–0.60(m,4H).

Example 130(R) -N- ((1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -3- (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) -N-methylpropanamide

LC-MS:m/z 818(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.27(s,1H),7.91(t,J＝7.5Hz,1H),7.59(d,J＝23.8Hz,1H),7.15–7.08(m,2H),7.05(d,J＝15.3Hz,1H),6.90–6.81(m,3H),6.77(d,J＝8.9Hz,1H),6.69(s,1H),5.62–5.46(m,3H),4.00–3.86(m,4H),3.86–3.76(m,1H),3.69(t,J＝6.7Hz,2H),3.57–3.47(m,2H),3.47–3.39(m,2H),3.10(s,1H),3.04–2.97(m,2H),2.91(s,2H),2.88–2.80(m,2H),2.73–2.64(m,2H),2.50–2.37(m,5H),2.36(s,3H),2.29–2.17(m,2H),1.54(dd,J＝7.1,4.5Hz,3H),0.81–0.57(m,4H).

Example 131(R) -N- ((1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -4- (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) -N-methylbutanamide

LC-MS:m/z 831(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.26(s,1H),7.93(d,J＝7.8Hz,1H),7.59(d,J＝21.5Hz,1H),7.17–7.10(m,2H),7.05(d,J＝12.5Hz,1H),6.90–6.79(m,4H),6.70(s,1H),5.64–5.45(m,3H),3.98–3.86(m,4H),3.85–3.76(m,1H),3.70(t,J＝6.6Hz,2H),3.47(d,J＝10.8Hz,2H),3.32–3.25(m,1H),3.08(s,1H),3.03–2.84(m,6H),2.69(t,J＝6.7Hz,2H),2.34(d,J＝7.0Hz,3H),2.32–2.14(m,6H),2.13–2.03(m,1H),2.00–1.84(m,1H),1.54(dd,J＝7.1,1.7Hz,3H),1.52–1.43(m,2H),0.79–0.59(m,4H).

Example 132(R) -N- ((1- (((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) methyl) cyclopropyl) methyl) -5- (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) -N-methylpentanamide

LC-MS:m/z 845(M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.27(s,1H),7.94(d,J＝7.6Hz,1H),7.58(d,J＝25.2Hz,1H),7.17–7.11(m,2H),7.06(d,J＝18.0Hz,1H),6.89–6.79(m,4H),6.69(s,1H),5.63–5.46(m,3H),3.97–3.85(m,4H),3.85–3.73(m,1H),3.70(t,J＝6.7Hz,2H),3.55(dd,J＝14.3,8.5Hz,1H),3.45–3.36(m,2H),3.08(s,1H),3.01–2.81(m,6H),2.69(t,J＝6.7Hz,2H),2.40–2.27(m,6H),2.27–2.20(m,1H),2.20–1.97(m,4H),1.53(d,J＝7.0Hz,3H),1.40–1.18(m,3H),1.12–0.98(m,1H),0.79–0.57(m,4H).

Example 133 evaluation of biological tests

The following biological test examples further illustrate the present invention, but these examples are not meant to limit the scope of the present invention.

Compound pair KRAS ^G12C Inhibition assay for binding to SOS 1.

Experimental procedure

(1) Gradient dilution of test compound: 10mM stock solution (dissolved in 100% DMSO) was added to 384 well assay plates to a final DMSO content of 0.25%.

(2) 5ul of Tag1-SOS1 solution was added to the test plate and 5ul of dilution buffer was added to the control.

(4) 5ul of Tag2-KRAS was added to the test plate ^G12C And (3) solution.

(4) 10ul of Anti-Tag1-Tb3+ and Anti-Tag2-XL665 test solution were added to the test plate. Centrifuged at 1000rpm for 1min and incubated at room temperature for 2 hr.

(5) Reading board

(6) Finally, IC of the compound was calculated using GraphPad Prism software ₅₀ And (5) obtaining values, and drawing a fitting curve.

KRAS-Compound pairs of examples of the invention ^G12C The inhibitory activity of the enzyme in combination with SOS1 is shown in Table 1.

Table 1 inhibitory activity of compounds of examples of the present invention

Inhibition assay of H358 cell proliferation by Compounds

Experimental procedure

1. Cell culture

(a) Resuscitating the cells in a T75 cell culture flask:

TABLE 2 culture of H358 cells

Number of	Cell lines	Culture Medium (Medium)	Passage # T75
				1	NCI-H358	RPMI 1640+10％FBS+1％PS	2～3x10 ⁶

(b) When the cell fusion degree reaches 80-90%, the cells are passaged.

2. Cell proliferation assay

Experimental procedure

Diluted test compounds are added to 384 well cell culture plates using a nanoliter pipetting system, and multiple wells are set. Adding an equal volume of culture medium into the positive control group; the negative control group was centrifuged at 1000rpm for 1min at room temperature with the addition of an equal volume of DMSO.

Cells were seeded into a)384 plates, equal volumes of cells were added to the negative control group and equal volumes of medium were added to the positive control group. Centrifugation was carried out at 1000rpm for 1min at room temperature, the final compound was 0.5% DMSO final concentration, and the mixture was incubated in a 5% CO2 incubator at 37 ℃ for 7 days.

Adding 20. mu.L/well

3D to b) 384-well cell culture plates, shake for 20min at 320rpm in the absence of light, incubate for 2hrs at room temperature in the absence of light.

The luminescence value was read with an Envision multifunctional microplate reader.

3. Data analysis

The Inhibition Rate (IR) of the test compound was calculated by the following formula: IR (%) ═ 100% (1- (RLU compound-RLU blank)/(RLU vehicle control-RLU blank)). The inhibition of the compounds at different concentrations was calculated in Excel and then G was usedMaking a suppression curve graph and calculating related parameters including minimum suppression rate, maximum suppression rate and IC by using raphPad Prism software ₅₀ . The results of the experiment are shown in table 3.

TABLE 3 cell proliferation inhibitory Activity of compound H358 which is an example of the present invention

Compound regulation experiment on SOS1 proteolysis.

Experimental procedure

(1) Inoculating tumor cells (such as H358, 5X 105-1X 06) and culturing in a culture dish (2D, P100 mm dish) for 2-4 days until 70-80% saturation;

(2) after replacing 10ml of fresh culture medium, the incubator was allowed to incubate overnight, and then the same concentrations of the PROTAC candidate of the present invention and SOSi of the control pair were added, and mixed by gentle shaking.

(3) The cells are cultured for 1-24 hours, and time curves (1, 2,4, 6, 8, 24) at the same concentration (0.1 or 1uM) or dose curves (0.0001, 0.001, 0.01, 0.1, 1, 10uM) at 6 and 24 hours are made.

(4) At the end of the time or concentration envisaged, the culture is discarded, the dish is transferred to ice, washed 3 times with 50 ml of ice cold PBS, the remaining liquid is aspirated as dry as possible, and then the ice cold lysate (containing detergens such as triton, NP40 etc.) and proteolytic enzyme inhibitors are added.

(5) The cells were scraped off on ice with a cell scraper and then transferred to a 1.5 ml centrifuge tube, centrifuged at 4 ℃ for 20 minutes, and the supernatant was taken and transferred to a new tube. After protein content is measured, mixing the protein supernatant with 4X glue solution, heating (100 ℃ for 5-10 minutes), cooling, adding 10X antioxidant to obtain a final glue sample, and storing at-20 ℃.

(6) The sample is subjected to Western-blot electrophoresis by using SDS-PAGE gel, the sample can be loaded with 10-50 micrograms of total protein, and after the total protein is electrically converted into a nitrocellulose membrane, the strip and the respective antibody are cut and incubated. Then using the mark 2 to resist temperature and hatch, and then making self-luminous color development and taking a picture.

(7) Finally, IC of the compound was calculated using GraphPad Prism software ₅₀ And (5) obtaining values, and drawing a fitting curve.

The experimental results show that the compound of example 26 (fig. 1) of the present invention has the effect of targeted degradation of SOS1 protein.

Pharmacokinetic testing evaluation

Male SD rats, weighing around 220g, were fasted overnight before SC or IP administration of a solution of the compound of the invention [ DMSO/PEG/physiological saline as vehicle ]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 post administration of the compound of the invention, respectively, and the concentration of the compound of the invention in plasma was determined by LC/MS/MS.

Experimental results show that the compound has good pharmacokinetic characteristics through SC or IP injection administration, and has small toxic and side effects.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula:

ULM represents a small molecule ligand moiety that can bind to E3 ligase;

PTM represents a small molecule ligand moiety that can bind to SOS 1;

l may be a bond or a linking group that may link the PTM and ULM.

2. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein:

the PTM is selected from PTM1 or PTM 2.

3. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein:

PTM1 is preferably selected from:

in the formula:

the dotted line indicates the link to L;

w is selected from the group consisting of substituted or unsubstituted: bond, C ₁ -C ₁₈ Alkylene radical, C ₃ -C ₂₀ Cycloalkylene, 4-20 membered heterocyclylene, OR ¹¹ 、NR ¹¹ R ¹² 、SO ₂ 、NR ¹² SO ₂ CO or NR ¹² CO；R ¹¹ Independently selected from the group consisting of substituted or unsubstituted: c ₃ -C ₂₀ Cycloalkylene, 4-20 membered heterocyclylene, C ₃ -C ₂₀ Cycloalkylene radical C ₁ -C ₁₈ Alkylene, or 4-20 membered heterocyclylene C ₁ -C ₁₈ An alkylene group; r ¹² Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C ₁ -C ₆ Alkyl or C ₃ -C ₆ A cycloalkyl group;

R ¹ 、R ² each independently selected from the group consisting of: bond, hydrogen, deuterium, halogen, cyano, - (CH) ₂ ) _m R ⁸ 、-(CH ₂ ) _m O(CH ₂ ) _p R ⁸ 、-(CH ₂ ) _m SR ⁸ 、-(CH ₂ ) _m COR ⁸ 、-(CH ₂ ) _m C(O)OR ⁸ 、-(CH ₂ ) _m S(O) _q R ⁸ 、-(CH ₂ ) _m NR ⁸ R ⁹ 、-(CH ₂ ) _m C(O)NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)R ⁹ 、-(CH ₂ ) _m NR ⁸ C(O)NR ⁹ R ¹⁰ 、-(CH ₂ ) _m S(O) _q NR ⁸ R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q R ⁹ 、-(CH ₂ ) _m NR ⁸ S(O) _q NR ⁹ R ¹⁰ In which CH ₂ H in (a) may be optionally substituted; r ⁸ 、R ⁹ 、R ¹⁰ Independently selected from the group consisting of substituted or unsubstituted: a bond,Hydrogen, C ₁ -C ₁₈ Alkyl radical, C ₃ -C ₂₀ Cycloalkyl or 4-20 membered heterocyclyl;

wherein the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

m, n are each independently 0, 1, 2,3, 4 or 5;

p is 0, 1, 2,3, 4 or 5;

q is 1 or 2.

4. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, characterized in that PTM1 is selected from the group consisting of:

5. the compound having the structure of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, according to claim 2,

PTM2 is:

in the formula:

the dashed line represents a connection to L;

z' is selected from the following substituted or unsubstituted groups: bond, C ₁ -C ₁₈ Alkylene, deuterated C ₁ -C ₁₈ Alkylene, or halogeno C ₁ -C ₁₈ An alkylene group;

R ^2’ the same or different, each independently selected from the group consisting of: - (CH) ₂ ) _p R ^7’ 、-(CH ₂ ) _m O(CH ₂ ) _p R ^7’ 、-(CH ₂ ) _m SR ^7’ 、-(CH ₂ ) _m COR ^7’ 、-(CH ₂ ) _m C(O)OR ^7’ 、-(CH ₂ ) _m S(O) _q R ^7’ 、-(CH ₂ ) _m NR ^7’ R ^8’ 、-(CH ₂ ) _m C(O)NR ^7’ R ^8’ 、-(CH ₂ ) _m NR ^7’ C(O)R ^8’ 、-(CH ₂ ) _m NR ^7’ C(O)NR ^8’ R ^9’ 、-(CH ₂ ) _m S(O) _q NR ^7’ R ^8’ 、-(CH ₂ ) _m NR ^7’ S(O) _q R ^8’ 、-(CH ₂ ) _m NR ^7’ S(O) _q NR ^8’ R ^9’ In which CH ₂ H in (a) may be optionally substituted; r ^7’ 、R ^8’ And R ^9’ Each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C ₁ -C ₁₈ Alkyl, substituted or unsubstituted C ₃ -C ₂₀ Cycloalkyl, substituted or unsubstituted 4-20 membered heterocyclyl and substituted or unsubstituted C ₁ -C ₁₈ An alkoxy group; or in- (CH) ₂ ) _m NR ^7’ R ^8’ 、-(CH ₂ ) _m C(O)NR ^7’ R ^8’ 、-(CH ₂ ) _m S(O) _q NR ^7’ R ^8’ In, R ^7’ And R ^8’ And the N atom to which it is attached, to form a substituted or unsubstituted 4-20 membered heterocyclic group; or in- (CH) ₂ ) _m NR ^7’ C(O)R ^8’ 、-(CH ₂ ) _m NR ^7’ C(O)NR ^8’ R ^9’ 、-(CH ₂ ) _m NR ^7’ S(O) _q R ^8’ 、-(CH ₂ ) _m NR ^7’ S(O) _q NR ^8’ R ^9’ In, R ^8’ And R ^9’ Is cyclized with the N atom to which it is attached to form a substituted or unsubstituted 4-20 membered heterocyclic group, or R ^7’ And R ^8’ Ring-closing with its adjacent atom to form a substituted or unsubstituted 4-20 membered heterocyclic group; r is ^3’ Selected from the group consisting of substituted or unsubstituted: c ₃ -C ₁₈ Cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl;

Wherein the above substitution means substitution with one or more groups selected from the group consisting of: deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or urea;

m' is 1, 2,3, 4 or 5;

n' is 1, 2,3, 4 or 5;

p' is 0, 1, 2,3, 4 or 5;

q' is 1 or 2.

6. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 2, wherein:

PTM2 is selected from the group consisting of:

7. a compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof according to claim 1, wherein:

ULM is selected from the group consisting of small molecule VLM, CLM, MLM or ILM ligand moieties that can bind to a ligase such as VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2(Mouse double-minute homolog2), or IAP.

8. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, wherein:

l is:

l is optionally through R ^L1 Terminal or R ^L6 The end is connected with PTM or ULM;

The substitution refers to substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl radical, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

each p ^L1 -p ^L6 Independently selected from 0, 1, 2,3, 4, 5, or 6.

9. A compound having the structure of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof according to claim 1, wherein:

l is a substituted or unsubstituted group selected from:

in the formulae (II) to (III) ₂ CH may independently be optionally substituted; and said substitution means substitution by one or more groups selected from the group consisting of: hydrogen, deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkoxy, deuterated C ₁ -C ₁₈ Alkoxy, halo C ₁ -C ₁₈ Alkoxy radical, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea; NH may independently optionally be deuterium, C ₁ -C ₁₈ Alkyl, deuterated C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl, halo C ₁ -C ₁₈ Alkyl hydroxy, C ₃ -C ₂₀ Cycloalkyl, C ₁ -C ₁₈ Alkyl acyl, sulfonyl substitution; and is

In L, each R ^L1 -R ^L6 Two adjacent groups among the groups may be each independently bonded to each other through C, N, O or an S atom or the like.

10. Use of a compound having a structure of general formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to any one of claims 1 to 9, or a pharmaceutical composition comprising same, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with an activity or an amount of expression of SOS 1.