KRAS inhibitor compounds

Abstract

The invention provides a KRAS inhibitor compound and application thereof. Specifically disclosed are heterocyclic compounds represented by formula (I-1) or formula (I-2), pharmaceutically acceptable salts thereof, stereoisomers thereof, deuterated derivatives thereof or solvates thereof. The compound is novel in structure and good in activity and selectivity. # imgabs0 #

Description

KRAS inhibitor compounds

[0001] This application claims priority to:

[0002] Application number: CN202210900237X, application date: 2022-07-28;

[0003] Application number: CN2022111939164, application date: 2022-09-28;

[0004] Application number: CN2023100049248, application date: 2023-01-03;

[0005] Application number: CN2023104033982, application date: April 14, 2023;

[0006] Application number: CN2023105900621, application date: 2023-05-23. Technical Field

[0007] The present invention relates to the field of medicine, and in particular to a KRAS inhibitor compound and applications thereof. Background Art

[0008] Mutations in the RAS oncogene are the most common activating mutations in human cancer, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), with 85% of RAS-driven cancers caused by mutations in the KRAS subtype. KRAS mutations are commonly found in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutant tumors, 80% of oncogenic mutations occur at codon 12, with the most common mutations including p.G12D (41%), p.G12V (28%), and p.G12C (14%).

[0009] The full name of the KRAS gene is Kirsten rat sarcoma viral oncogene homolog. KRAS plays a pivotal role in the signaling regulation of cell growth. Upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4, upon receiving external signals, transmit these signals downstream through the RAS protein. When inactive, the KRAS protein binds tightly to GDP (guanine diphosphate). Upon activation by guanine nucleotide exchange factors such as SOS1, it binds to GTP (guanine triphosphate), becoming active as a kinase. Mutations in the KRAS gene can independently transmit growth and proliferation signals to downstream pathways, independent of upstream growth factor receptor signals, leading to uncontrolled cell growth and tumor progression. Furthermore, the presence of KRAS mutations is an important indicator of tumor prognosis. Statistics show that among KRAS subtypes, KRAS G12D is also a common submutation, accounting for 12% of colorectal cancer, 36% of pancreatic cancer, and 4% of non-small cell lung cancer. Therefore, it is very necessary to develop a new KRAS inhibitor, which has great potential to become a new treatment method in the field of tumor treatment. Therefore, it is necessary to develop more effective, safer, and better pharmacokinetic KRAS inhibitors to meet clinical needs.

[0010] Summary of the Invention

[0011] The present invention provides KRAS inhibitor compounds and their uses. Specifically disclosed are heterocyclic compounds represented by Formula I-1 or Formula I-2, their pharmaceutically acceptable salts, stereoisomers, deuterated derivatives, or solvates thereof. The compounds of the present invention have novel structures and exhibit excellent activity and selectivity.

[0012] Wherein, in formula I-1 and formula I-2, Cy1 represents a 6-membered aryl group or a 6-membered heteroaryl group; further, the Cy1 can be arbitrarily replaced by 0-3 selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a Rb 、-NR a C(O)R a 、-NR a R b substituted by a substituent;

[0013] Wherein, in formula I-1, Cy2 represents a 6-membered aryl group or a 6-membered heteroaryl group; further, the Cy2 can be arbitrarily replaced by 0-3 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halo (C1-C6), halo (C1-C6 alkoxy), hydroxy (C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent;

[0014] Among them, X 1 N or CR X1 ;X 2 N or CR X2 ;X 3 N or CR X3 ;

[0015] Among them, R X1 、R X2 、R X3 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)Ra 、-NR a R b ;

[0016] Wherein, L1 and L2 each independently represent absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -, -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-NR a -, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、、-(C1-C6 alkylene)C(O)、-NR a C(O)(C1-C6 alkylene)-, -(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is connected, they form a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S;

[0017] Among them, R 1 、R 2 Each independently represents a 5-16 membered saturated or unsaturated cycloalkyl group or a 5-16 membered saturated or unsaturated heterocycloalkyl group, and the R 1 、R 2 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent;

[0018] Among them, Y 1 、Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenylene, and wherein CR a R b Can be O, NH, -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a - replaced;

[0019] Or, Y 1 、Y 2 Together they form a 5-10 membered saturated or unsaturated ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring;

[0020] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), C3-C6 cycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered ring, which may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0021] In addition, the present invention provides a heterocyclic compound represented by Formula I-1' or Formula I-2', a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated derivative thereof, or a solvate thereof:

[0022] Wherein, in Formula I-1' and Formula I-2',

[0023] M 1 Indicates CR M1 or N; M 2 Indicates CR M2 or N; M 3 Indicates CR M3or N; M 4 Indicates CR M4 or N; M 5 Indicates CR M5 or N; M 6 Indicates CR M6 or N; M 7 Indicates CR M7 or N; M 8 Indicates CR M8 or N; M 9 Indicates CR M9 or N; M 10 Indicates CR M10 or N;

[0024] Among them, R M1 、R M2 、R M3 、R M4 、R M5 、R M6 、R M7 、R M8 、R M9 、R M10 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent;

[0025] Among them, X 1 N or CR X1 ;X 2 N or CR X2 ;X 3 N or CR X3 ;

[0026] Among them, R X1 、R X2 、R X3Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ;

[0027] Wherein, L1 and L2 each independently represent absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -, -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-NR a -、-(C1-C6 alkylene)-、-(C1-C6 alkylene)-O-、-NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、、-(C1-C6 alkylene)C(O)、-NR a C(O)(C1-C6 alkylene)-, -(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is connected, they form a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S;

[0028] Among them, R 1 、R 2 Each independently represents a 5-16 membered saturated or unsaturated cycloalkyl group or a 5-16 membered saturated or unsaturated heterocycloalkyl group, and the R 1 、R 2 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent;

[0029] Among them, Y 1 、Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenylene, and wherein CR a R b Can be O, NH, NR a , -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a - replaced;

[0030] Or, Y 1 、Y 2 Together they form a 5-10 membered saturated or unsaturated ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring;

[0031] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), C3-C6 cycloalkyl; or R a 、R bTogether with the atoms connected thereto, they form a 3-6 membered ring, which may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S. In a preferred embodiment of the present invention, wherein X 2 Indicates CH or N.

[0032] In the preferred technical solution of the present invention, wherein X 3 Indicates CR X3 or N, where R X3 Indicates H, halogen, OR a , CN, NO2, SF5, POMe2, NH2, C1-C6 alkyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl).

[0033] In the preferred technical solution of the present invention, L1 represents absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -, -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-NR a -, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is connected, they form a 3-6 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S.

[0034] In a preferred technical solution of the present invention, L1 represents O-C1-C6 alkylene-.

[0035] In the preferred technical solution of the present invention, wherein L1 represents -O-(C0-C6 alkylene)-(CR T R T′)-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is attached, they form a 3-6 membered saturated or unsaturated ring.

[0036] In the preferred technical solution of the present invention, R 1 represents a 5-16 membered saturated or unsaturated heterocyclic alkyl group, and the R 1 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

[0037] In the preferred technical solution of the present invention, R 1 Has any of the following structures:

[0038] Furthermore, the R 1 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R bsubstituted by a substituent.

[0039] In the preferred technical solution of the present invention, R 1 express:

[0040] Among them, R 1' 、R 2' 、R 3' 、R 4' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ;

[0041] or R 1' With R 2' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 1' With R 2' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0042] or R 3' With R 4' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 3' With R 4' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0043] or R 5' With R 6' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 5' With R 6' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NRa R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0044] or R 7' With R 8' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 7' With R 8' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0045] or R 9' With R 10' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 9' With R 10' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0046] or R 11' With R 12' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 11' With R 12' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0047] or R 2' With R 3' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR aR b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0048] or R 4' 、R 5' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0049] or R 8' 、R 9' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0050] or R 10' 、R 11' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O.

[0051] In the preferred technical solution of the present invention, R 1' 、R 2' 、R 3' 、R 4' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Each independently represents hydrogen, halogen, hydroxyl, carbonyl, C1-C6 alkyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C2-C6 alkenyl, or C2-C6 alkynyl.

[0052] In the preferred technical solution of the present invention, wherein said R 1 Has the following structure:

[0053] Among them, R 1' 、R 2' 、R 5' 、R 6' 、R 7'、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Having any of the above definitions.

[0054] In the preferred technical solution of the present invention, wherein said R 1 Has the following structure:

[0055] Wherein, ring A is a 3-6 membered ring, and said ring A can be arbitrarily replaced by 0-2 selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo (C1-C6 alkyl), halo (C1-C6 alkoxy), hydroxy (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a substituted by a substituent;

[0056] Among them, R 1' 、R 4' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Having any of the above definitions.

[0057] In the preferred technical solution of the present invention, wherein said R 1 Has the following structure:

[0058] Among them, R 1' 、R 2' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' As defined in any one of the above, wherein R L 、RL’ Each independently represents hydrogen, C1-C6 alkyl or halogen.

[0059] In the preferred technical solution of the present invention, R 1' 、R 2' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Each independently represents hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl); R 3' 、R 4' Together with the atoms connected thereto, they form a 3-6 membered ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring is arbitrarily selected from 0-2 selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a Substituted by:

[0060] In the preferred technical solution of the present invention, wherein L2 represents absence, -O-C1-C6 alkylene-, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -NR a -C1-C6 alkylene-, -C1-C6 alkylene-NR a -.

[0061] In a preferred technical solution of the present invention, L2 represents non-existence.

[0062] In the preferred technical solution of the present invention, R 2 It is any one of the following cyclic structures of formula (i), formula (ii) or formula (iii):

[0063] Among them, W 1 Indicates -(CR W1 R W2 ) p -、-(CR W1 R W2 ) p -O-、-O-(CR W1 R W2 ) p -、-NR a -(CR W1 R W2 ) p -、-(CR W1 R W2 ) p -NR a -, -CH=CH- or NR W1 ;

[0064] Among them, R W1 、R W2 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ; or R W1 、R W2 Together with the carbon atoms connected to it, they form a 3-8 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; and the ring may also be arbitrarily replaced by 1-2 groups selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a Rb 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0065] Among them, R 1 "、R 2 "、R 3 "、R 4 "、R 5 "、R 6 "、R 7 "、R 8 "Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ;

[0066] or R 1 "With R 2 "Together with the atoms to which they are commonly attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0067] or R 3 "With R 4 "Together with the atoms to which they are commonly attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0068] or R 5 "With R 6 "Together with the atoms to which they are commonly attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R aor any CH2 in the ring is replaced by C=O;

[0069] or R 7 "With R 8 "Together with the atoms to which they are commonly attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0070] or R 2 "With R 3 "Together with the atoms to which they are attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0071] or R 4 "With R 5"Together with the atoms to which they are attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0072] or R 6 "With R 7 "Together with the atoms to which they are attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to the substitution by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O;

[0073] or R 5 "With R W1Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O.

[0074] In the preferred technical solution of the present invention, R 2 Any of the following ring structures:

[0075] Furthermore, the R 2 It can be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(0)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

[0076] In the preferred technical solution of the present invention, R 2 Any of the following ring structures:

[0077] Furthermore, the R2 It can be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(0)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

[0078] In the preferred technical solution of the present invention, R 2 Any of the following ring structures:

[0079] In the preferred technical solution of the present invention, wherein, M 1 To M 10 Indicates CH or N.

[0080] In the preferred technical solution of the present invention, wherein, M 1 To M 10 Indicates CH.

[0081] In the preferred technical solution of the present invention,

[0082] Y 1 、Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenylene, and wherein CR a R b Can be O, NH, -C(O), -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -P(O)R a - replaced.

[0083] In the preferred technical solution of the present invention, wherein, Y 1 、Y 2 Together they form -(C1-C 10 Alkylene)-NR a -、-O-(C1-C 10 Alkylene)-NRa -、-NR a (C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-C(O)NR a -、-(C1-C 10 Alkylene)-NR a C(O)-、-(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NR a -(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NR a -(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-NR a -、-NR a -(C1-C 10 Alkylene)-, -O-(C1-C 10 Alkylene)-, -C(O)NR a -(C1-C 10 Alkylene)-、-NR a C(O)-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -O-(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-C(O),-(C1-C 10 Alkylene)-C(O)-, -O-(C1-C 10 Alkylene)-C(O)-, -C(O)-(C1-C 10 Alkylene)-, -C(O)-(C1-C 10 Alkylene)-O-, -O-(C1-C 10 Alkylene)-C(O)NR a -、-C(O)NR a -(C1-C 10Alkylene)-O-, -(C1-C 10 Alkylene)-S-, -S-(C1-C 10 alkylene)-.

[0084] In the preferred technical solution of the present invention, wherein, Y 1 、Y 2 Together they form a 5-10 membered saturated or unsaturated ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring.

[0085] In the preferred technical solution of the present invention, wherein, Y 1 、Y 2 Together they form any of the following structures:

[0086] In the preferred technical solution of the present invention, it has the following structure:

[0087] Definition of terms

[0088] It is particularly noted that, herein, when a "compound" having a specific structural formula is mentioned, this generally also encompasses its stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives, as well as its alternative forms of pharmaceutically acceptable salts, solvates, hydrates, and the like. It is well known to those skilled in the art that salts, solvates, and hydrates of a compound are alternative forms of the compound, all of which can be converted into the compound under certain conditions. Therefore, it is particularly noted that, herein, when a compound is mentioned, this generally also encompasses its pharmaceutically acceptable salts, and furthermore, its solvates and hydrates.

[0089] Similarly, reference herein to a compound generally also includes prodrugs, metabolites, and N-oxides thereof.

[0090] The pharmaceutically acceptable salts or pharmaceutically acceptable salts of the present invention may be formed using inorganic or organic acids. The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and are considered to be a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent, as summarized below. For example, the free base can be reacted with a suitable acid. In addition, when the compounds of the present invention have an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (such as sodium or potassium salts) and alkaline earth metal salts (such as calcium or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts formed by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and ammonium cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0091] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.

[0092] The precursors or metabolites described herein may be those known in the art, as long as the precursors or metabolites are converted to compounds through in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention that, within the scope of reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and are considered to have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism or N-demethylation of the compounds of the present invention.

[0093] As used herein, "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution-phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0094] The term "stereoisomerism" as used herein is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism (i.e., optical isomerism). Conformational isomerism refers to a stereoisomerism phenomenon in which the atoms or groups of atoms in an organic molecule with a certain configuration have different spatial arrangements due to the rotation or distortion of carbon-carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations that occur in the structure of cyclohexane. "Stereoisomers" refer to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. The compounds of the present invention may have asymmetric centers, each of which can produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures, as well as pure or partially purified compounds. The compounds of the present invention may exist as tautomers, which have different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds of formula (I) are included within the scope of the present invention.

[0095] The "isotope derivative" of the present invention refers to a molecule in which the compound in this patent is isotopically labeled. The isotopes commonly used as isotope labels are: Hydrogen isotopes: 2 H and 3 H; Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 2 H and carbon 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving a reduction in dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0096] The compound or pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumor injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions.

[0097] The pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents. Examples of carriers employed in the injectable composition of the present invention are water, saline solutions, glucose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents and emulsifiers.

[0098] Other features of the present invention will become apparent as the present invention describes exemplary embodiments, which are given to illustrate the present invention and are not intended to be limiting thereof. The following examples were prepared, isolated, and characterized using the methods disclosed herein.

[0099] Unless otherwise indicated, the following definitions apply to the terms used in this application (including the specification and claims). It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include the plural unless otherwise indicated. Conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. Throughout this application, unless otherwise indicated, the use of "or" or "and" means "and / or."

[0100] In the specification and claims, a given chemical formula or name is intended to encompass all stereo and optical isomers and racemates thereof. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, which can be separated into mixtures of isomers or into separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic form. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free form and the salts of these final products are within the scope of the present invention. If desired, one form of a compound can be converted into another. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; and a mixture of isomeric compounds of the present invention can be separated into its individual isomers. The compounds of the present invention, their free forms, and their salts can exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms that may exist are encompassed by the present invention.

[0101] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other and not related to each other. For example, for a substituent R a (or R b ), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R b ) When a definition is selected in a substituent, it does not mean that the R a (or R b ) has the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a Rb In the case of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R b In, R a (or R b ) must be hydrogen.

[0102] Unless otherwise defined, when a substituent is indicated as "optionally substituted", the substituent is selected, for example, from substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein both amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl , alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonylamino such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or the case where there are two substituents on nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic groups such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclic groups.

[0103] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl.

[0104] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0105] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" group contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

[0106] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0107] The term "carbonyl" refers to an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O).

[0108] The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. Fused aryl groups may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. For example, a dotted line drawn from a ring system indicates that the bond may be attached to any suitable ring atom.

[0109] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl groups refer to C3-C8 cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include cycloalkyl groups of bridged rings, spirocycles or fused rings.

[0110] The term "heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom in the ring is replaced by a heteroatom selected from O, N, S, and Se.

[0111] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to a C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyls include cyclic alkenyls of bridged rings, spirocycles or fused rings.

[0112] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0113] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via an oxygen bridge. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0114] In the present disclosure, when referring to certain substituent groups, the expression Cx1-Cx2 is used, which means that the number of carbon atoms in the substituent group may be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0115] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.

[0116] In the context of the present invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0117] The term "heteroaryl" means a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycle that is fully unsaturated, partially unsaturated, and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups in which any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic radicals described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, the heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1.

[0118] The reagents and raw materials used in the present invention are commercially available.

[0119] The positive effects of this invention include: the compound exhibits excellent cell proliferation inhibition activity against KRAS G12D-mutated gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. It also exhibits good stability in liver microsomes, hepatocytes, plasma, and whole blood, good PK properties, and significant tumor inhibition. DETAILED DESCRIPTION

[0120] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0121] NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.

[0122] MS was determined using an Agilent 1200-G1956A / 1200-6110A / 1200-6140A / 1260-6125B / Prime-6125B / 1260-6120 LC / MS, a SHIMADZU 20A-2010 / 20A-2020 LC / MS, and a Waters ACQ-QDA LC / MS.

[0123] HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.

[0124] SFC analysis was performed using a Waters UPCC with PDA Detector and QDa Detector ultra-high performance convergence chromatograph, a Waters UPC 2 with PDA detector ultra high performance convergence chromatograph, Agilent 1260 with DAD detector high performance liquid chromatograph, Shimadzu LC-20AB with PDA detector high performance liquid chromatograph, Shimadzu LC-20AD with PDA detector high performance liquid chromatograph.

[0125] Preparative HPLC separation was performed using a Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV Detector preparative chromatograph.

[0126] SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, and Prep 350 SFC SYSTEM.

[0127] Flash column chromatography separation was performed using a Biotage IsoleraOne flash preparative chromatograph.

[0128] The thin layer chromatography silica gel plate used was GF254 acrylic adhesive silica gel plate produced by Anhui Liangchen Silicon Source Material Co., Ltd. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.25 mm, and the specification of the thin layer chromatography separation and purification product was 0.5 mm.

[0129] Pressurized hydrogenation reaction hydride bottles and hydrogen cylinders.

[0130] Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.

[0131] The glove box is customized by DELLIX.

[0132] Intermediate 1: tert-Butyl (1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0133] Step 1: A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.50 g, 14.96 mmol) and urea (8.98 g, 149.56 mmol) was stirred at 200 ° C for 2 hours. Cooled to 100 ° C, water (30 mL) was added, stirred for 1 hour, filtered, and the solid product was added with water (25 mL) and stirred at 50 ° C for 1 hour. Filtered, the solid product was added with water (25 mL), stirred at 25 ° C for 12 hours, filtered, and the solid was vacuum dried to obtain a crude compound 7-bromo-8-fluoroquinazoline-2,4 (1H, 3H) -dione (4.40 g) as a gray solid. LCMS (ESI): [M+H] + =258.8.

[0134] Step 2: To a concentrated sulfuric acid solution (35 mL) of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g, 14.96 mmol) was added potassium nitrate (3.43 g, 33.97 mmol) at 0°C. The solution was stirred at 0°C for 1 hour. The mixture was poured into water (35 mL), the solid was filtered out, and vacuum dried to obtain a gray solid compound, 7-bromo-8-fluoro-6-nitroquinazoline-2,4(1H,3H)-dione (3.50 g, 11.51 mol, 77% yield). LCMS (ESI): [M+H] + =303.9. 1 H NMR (400MHz, DMSO-d6) δppm 11.98 (br s, 1H), 11.85 (s, 1H), 8.34 (s, 1H).

[0135] Step 3: At 0 ° C, diisopropylethylamine (2.45 mL, 14.80 mmol) was added to a toluene (22 mL) solution of 7-bromo-8-fluoro-6-nitroquinazoline-2,4 (1H, 3H) -dione (1.50 g, 4.93 mmol) and phosphorus oxychloride (3.67 mL, 39.47 mmol). The mixture was stirred at 100 ° C for 3 hours under nitrogen protection. The mixture was dried, ethyl acetate (30 mL) was added, followed by ice and ice water (30 mL), and extracted with ethyl acetate (20 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a crude compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g) as a gray solid. LCMS (ESI): [M+H] + =341.8.

[0136] Step 4: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g, 4.55 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (965 mg, 4.55 mmol) in dichloromethane (15 mL) was added triethylamine (1.84 mL, 13.20 mmol). The mixture was stirred at 25°C for 2 hours. Water (10 mL) was added and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give a gray solid compound (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (590 mg, 1.14 mmol, yield 25%). LCMS (ESI): [M+H] + =517.7.

[0137] Step 5: To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.14 mmol) in trifluoroethanol (4.4 mL) was added diisopropylethylamine (944 μL, 5.71 mmol). The mixture was stirred at 70°C for 12 hours and then dried by spin drying. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.86 mmol, 75% yield) as a yellow solid. LCMS(ESI):[M+H] + =581.7.

[0138] Step 6: To a solution of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 3.45 mmol) in ethanol (40 mL) and water (20 mL) was added ammonium chloride (1.84 g, 34.46 mmol) and iron powder (0.96 g, 17.23 mmol). The mixture was stirred at 80°C under nitrogen for 2 hours, filtered, and the solid was washed with dichloromethane (60 mL). The filtrate was added with water (100 mL) and extracted with dichloromethane (100 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude compound tert-butyl (1R, 5S)-3-(6-amino-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.95 g) as a brown solid. LCMS (ESI): [M+H] + =551.9.

[0139] Step 7: Under nitrogen protection, tert-butyl (1R, 5S)-3-(6-amino-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.93 g, 3.51 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) were added to the mixture. To a solution of (1-heterocyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.34 g, 4.56 mmol) in 1,4-dioxane (40 mL) were added potassium phosphate (1.5 M, 7.0 mL, 10.52 mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (255.4 mg, 0.35 mmol). The mixture was stirred at 100° C. under nitrogen for 2 hours. Water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain a brown solid compound, tert-butyl (1R, 5S)-3-(6-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 1.64 mmol, 47% yield). LCMS (ESI): [M+H] + =856.5.

[0140] Step 8: To a solution of tert-butyl (1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1370.0 mg, 1.60 mmol) in N,N-dimethylformamide (27 mL) was added cesium fluoride (2431.1 mg, 16.00 mmol). The mixture was stirred at 25°C under nitrogen for 1 hour. Water (90 mL) was added for dilution, and the mixture was extracted with ethyl acetate (90 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give tert-butyl (1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720.0 mg, 1.03 mmol, 64% yield) as a brown solid compound. LCMS (ESI): [M+H] + =700.2.

[0141] Intermediate 2: Methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate

[0142] Step 1: Dissolve 2-amino-4-bromo-3-fluorobenzoic acid (25.0 g, 106.83 mmol) in N,N-dimethylformamide (100 mL), add N-iodosuccinimide (36.0 g, 160.24 mmol), and stir the mixture at 80°C for 2 hours. The mixture is diluted with water (3 L), stirred at room temperature for 1 hour, filtered, and the filter cake is washed with water (300 mL x 3). The filter cake is concentrated to obtain the yellow compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94.47 mmol, 88% yield). LCMS (ESI): [M+H] + =359.9.

[0143] Step 2: Compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.35 mmol) and urea (50.0 g, 833.52 mmol) were added to the reaction flask. The reaction system was heated to 200 ° C and reacted for 4 hours. Cooled to room temperature, water (300 mL) was added to dilute, heated to 80 ° C and stirred for half an hour, filtered while hot, and the filter cake was repeated twice. The filter cake was concentrated under reduced pressure to obtain a yellow compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (26.7 g, 69.36 mmol, yield 83%). LCMS (ESI): [M+H] + =387.0.

[0144] Step 3: Add 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7 g, 64.17 mmol) to phosphorus oxychloride (300 mL). Add diisopropylethylamine (40.0 mL, 224.59 mmol) at 0°C, and stir at 130°C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was added to ice water (500 mL) and extracted with dichloromethane (500 mL*3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-4% methanol / dichloromethane gradient) to obtain 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (26.7 g, 62.88 mmol, 98% yield). LCMS (ESI): [M+H] + =420.8.

[0145] Step 4: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0 g, 23.71 mmol) in dichloromethane (100 mL) were added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.54 g, 26.08 mmol) and triethylamine (10.0 mL, 71.12 mmol). The reaction mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-36% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.60 g, 5.93 mmol, 25% yield). LCMS(ESI):[M+H] + =597.0.

[0146] Step 5: To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25.4 g, 42.50 mmol) in 2,2,2-trifluoroethanol (193 mL) was added diisopropylethylamine (37.7 mL, 212.51 mmol), and the reaction solution was stirred at 70 ° C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to obtain tert-butyl (1S,5R)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.1 g, 30.6 mmol, yield 72%). LCMS (ESI): [M+H] + =661.3.

[0147] Step 6: At 25°C, the compound tert-butyl (1S,5R)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.51 mmol) was dissolved in dioxane (20.0 mL), and tributyl (1-ethoxyvinyl) stannane (510 mg, 1.41 mmol) was added. Tetrakis(triphenylphosphine)palladium (170 mg, 0.15 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (1R,5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (680 mg, 1.12 mmol, 74% yield) as a white solid. LCMS (ESI): [M+H] + =605.0.

[0148] Step 7: Add tert-butyl (1R,5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.66 mmol) and hydrochloric acid (2M aqueous solution, 1.65 mL, 3.30 mmol) to tetrahydrofuran (8.00 mL) at 25°C. The reaction system was reacted at 20°C for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to 7, and the mixture was extracted with ethyl acetate (4 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.38 mmol, 58% yield) as a white solid. LCMS (ESI): [M+H] + =577.2.

[0149] Step 8: Dissolve tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 3.46 mmol) in dioxane (20 mL) and sodium hydroxide (1.5 M aqueous solution, 18.5 mL, 27.7 mmol). Add bromine (0.53 mL, 10.4 mmol) dropwise slowly at 0°C. The reaction is stirred at 0°C for 3 hours and then at 20°C for 16 hours. Water (50 mL) was added to the reaction solution, and the pH was adjusted to 4 with 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40% gradient ethyl acetate / petroleum ether) to give 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (1.00 g, 1.73 mmol, yield 50%). LCMS (ESI): [M+H] + =581.3.

[0150] Step 9: 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy) Quinazoline-6-carboxylic acid (350 mg, 0.60 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (402 mg, 0.78 mmol) and potassium phosphate (1.5 M aqueous solution, 1.20 mL, 1.81 mmol) were dissolved in dioxane (3.50 mL). Methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (44 mg, 0.06 mmol) was added under a nitrogen atmosphere, and the reaction solution was stirred at 100°C for 16 hours. Four identical batches of the same reaction mixture were combined, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to obtain the compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (650 mg, 0.72 mmol, 30% yield). LCMS (ESI): [M+H] + =885.3.

[0151] Step 10: To a turbid solution of compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (650 mg, 0.72 mmol) and potassium carbonate (329 mg, 2.38 mmol) in dimethylformamide (7 mL) was added iodomethane (224 mg, 1.58 mmol) at 0°C, and the reaction solution was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (600 mg), as a yellow oily liquid. LCMS (ESI): [M+H] + =899.3.

[0152] Step 11: To a solution of the compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (600 mg, 0.66 mmol) in dimethylformamide (6 mL) was added cesium fluoride (1.00 g, 6.60 mmol) and stirred at 20°C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to obtain the compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (400 mg, 0.53 mmol, yield 80%). LCMS (ESI): [M+H] + =743.6.

[0153] Intermediate 3: (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline

[0154] Step 1: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (8.00 g, 23.47 mmol) in dichloromethane (50 mL) at -40°C, add (R)-3-methylpiperidin-3-ol hydrochloride (2.49 g, 16.43 mmol) and diisopropylethylamine (25.0 mL, 140.8 mmol). Stir the solution at -40°C for 4 hours. Add water (50 mL) to the reaction mixture, extract with dichloromethane (50 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-35% gradient of ethyl acetate / petroleum ether) to give (R)-1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (7.50 g, 17.87 mmol, 76% yield) as a yellow solid. LCMS (ESI): [M+H] + =420.9.

[0155] Step 2: To a solution of (R)-1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (7.50 g, 17.87 mmol) in trifluoroethanol (80 mL) was added diisopropylethylamine (12.5 mL, 71.49 mmol) at 20°C. The solution was stirred at 70°C for 3 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid compound (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (6.80 g, 14.07 mmol, yield 78%). LCMS (ESI): [M+H] + =483.0.

[0156] Step 3: To a solution of (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (61 g, 126.24 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (67.94 g, 132.55 mmol), cesium carbonate (123.39 g, 378.71 mmol) in toluene (1000 mL) and water (250 mL) was added methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (18.39 g, 25.25 mmol) at 25°C under a nitrogen atmosphere. The solution was stirred at 100° C. for 16 hours. The solution was concentrated and purified, and then purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound (3R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (90.00 g, 107.24 mmol, 85% yield). LCMS (ESI): [M+H] + =789.5.

[0157] Step 4: To a solution of (3R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (64.00 g, 81.13 mmol) in dimethylformamide (500 mL) was added cesium fluoride (61.62 g, 405.64 mmol) at 25°C and the reaction was stirred at 25°C for 2 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (500 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid compound (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (35.00 g, 55.33 mmol, yield 68%). LCMS (ESI): [M+H] + =633.1.

[0158] Step 5: To a solution of (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (35.00 g, 55.33 mmol) and (2E)-methyl 3-iodoacrylate (17.60 g, 83.00 mmol) in triethylamine (175 mL) and dimethylformamide (260 mL) was added cuprous iodide (1.05 g, 5.53 mmol) and tetrakis(triphenylphosphine)palladium (12.79 g, 11.07 mmol) at 25° C. under nitrogen atmosphere. The reaction was stirred at 50° C. for 2 hours. The reaction mixture was filtered, the filtrate was dried, and the crude product was purified by flash column chromatography (silica gel, 0-35% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound (E)-5-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)pent-2-ene-4-ynoic acid methyl ester (40.00 g, 47.45 mmol, yield 86%). LCMS (ESI): [M+H] + =717.0.

[0159] Step 6: To a solution of methyl (E)-5-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)pent-2-ene-4-ynoate (27.00 g, 37.68 mmol) in methanol (1500 mL) was added platinum dioxide (2.70 g, 11.89 mmol) at 25° C. Under a hydrogen atmosphere of 15 psi, the mixture was stirred at 25° C. for 16 hours. The solution was filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / dichloromethane) to give a red solid compound, methyl 5-(8-(6-amino-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)pentanoate (16.00 g, 23.01 mmol, yield 61%). LCMS (ESI): [M+H] + =693.2.

[0160] Step 7: To a solution of methyl 5-(8-(6-amino-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)pentanoate (17.00 g, 24.54 mmol) in tetrahydrofuran (170 mL) and water (34 mL) was added lithium hydroxide (3.09 g, 73.63 mmol) at 25°C. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with water (200 mL), the pH was adjusted to 4 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (200 mL*3). The combined organic layers were dried, filtered, and the filtrate was concentrated to give a brown solid compound 5-(8-(6-amino-8-fluoro-4-((S)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)pentanoic acid (17.00 g, 22.54 mmol, yield 92%). LCMS (ESI): [M+H] + =679.3.

[0161] Step 8: To a solution of 5-(8-(6-amino-8-fluoro-4-((S)-3-hydroxy-3-methylpiperidin-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)pentanoic acid (17.00 g, 25.05 mmol) and diisopropylethylamine (175 mL, 1002.01 mmol) in dioxane (660 mL) was added tri-n-butyl cyclic phosphoric anhydride (40.91 g, 75.15 mmol) at 25 ° C. and stirred at 60 ° C for 16 hours. The reaction was quenched by adding water (600 mL) and extracted with ethyl acetate (600 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The crude product was purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (13.00 g, 19.68 mmol, yield 79%). LCMS (ESI): [M+H] + =661.3.

[0162] Step 9: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (2.0 g, 3.03 mmol) in dichloromethane (20 mL) were added tert-butyldimethylsilyl trifluoromethanesulfonate (2.28 mL, 18.16 mmol) and diisopropylethylamine (2.0 mL, 12.11 mmol) in portions at 0° C. The mixture was stirred at 20° C. under nitrogen for 3 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether / dichloromethane with a volume ratio of 3:1)) to give a yellow solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (1.92 g, 2.48 mmol, yield 82%). LCMS (ESI): [M+H] + =775.3.

[0163] Step 10: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (600.0 mg, 0.77 mmol) and (1,5-cyclooctadiene)iridium(I) chloride dimer (52.0 mg, 0.08 mmol) in tetrahydrofuran (48 mL) was added phenylsilane (1.91 mL, 15.49 mmol). The mixture was stirred at 25°C under nitrogen for 12 hours and then dried by evaporation. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (3:1 by volume petroleum ether / dichloromethane)) to give (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (430 mg, 0.57 mmol, 73% yield) as a yellow solid. LCMS (ESI): [M+H] + =761.3.

[0164] Intermediate 4: (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline

[0165] Step 1: To a solution of (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (3.9 g, 6.17 mmol), 4-methylbenzenesulfonyl azide (1.95 g, 7.40 mmol), and cuprous iodide (0.12 g, 0.62 mmol) in chloroform (50 mL) and water (0.28 mL, 15.41 mmol) was added triethylamine (1.03 mL, 7.40 mmol). The mixture was stirred at 20° C. under nitrogen protection for 12 hours, diluted with water (50 mL), extracted with ethyl acetate (20 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a crude compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-(p-methylphenylsulfonylacetamide) (5.0 g) as a brown solid. LCMS (ESI): [M+H] + =820.0.

[0166] Step 2: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-p-methylbenzenesulfonylacetamide (5.4 g, 6.59 mmol) in N,N-dimethylformamide (50 mL) were added iodomethane (1.23 mL, 19.76 mmol) and potassium carbonate (2.73 g, 19.76 mmol). The mixture was stirred at 20 ° C for 12 hours. Water (100 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (2.38 g, 2.85 mmol, 43% yield). LCMS (ESI): [M+H] + =834.2.

[0167] Step 3: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (11.5 g, 13.79 mmol) and triethylamine (9.59 mL, 68.96 mmol) in dichloromethane (140 mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (5.20 mL, 41.38 mmol) at 0°C. The mixture was stirred at 20°C for 16 hours. Water (40 mL) was added for dilution, and the mixture was extracted with dichloromethane (40 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / (petroleum ether:dichloromethane=3:1)) to give 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (12.7 g, 13.41 mmol, 97% yield) as a brown solid compound. LCMS (ESI): [M+H] + =948.4.

[0168] Step 4: To a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (12.50 g, 13.19 mmol) in dichloromethane (155 mL) was added 1 M diisobutylaluminum hydride (42.19 mL, 42.19 mmol) at -70°C. The mixture was stirred at -70°C for 1 hour, quenched by the addition of acetic acid (7.25 mL, 126.58 mmol), diluted with water (100 mL), stirred, and allowed to stand for 16 hours. Then, dichloromethane (100 mL * 3) was used for extraction, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether: dichloromethane = 3:1)) to give compound 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)acetaldehyde (7.70 g, 10.08 mmol, yield 76%) as a brown solid. LCMS (ESI): [M+H] + =765.3.

[0169] Step 5: Borane / tetrahydrofuran (1 M, 41 mL, 40.71 mmol) was added to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)acetaldehyde (18.50 g, 24.19 mmol) in tetrahydrofuran (190 mL) at 0°C, and the reaction was stirred at 10°C for 16 hours. The reaction was quenched with methanol at 0°C. The mixture was concentrated under reduced pressure to give a brown solid compound, 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethan-1-ol (18.50 g, 21.71 mmol, yield 90%). LCMS (ESI): [M+H] + =767.8.

[0170] Step 6: Under nitrogen protection, to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethan-1-ol (1.0 g, 1.30 mmol) and rhodium acetate dimer (57.6 mg, 0.13 mmol) in dichloromethane (10.0 mL) was added dropwise ethyl diazoacetate (0.62 mL, 5.87 mmol). The mixture was stirred at 25 ° C. under nitrogen protection for 1 hour. Methanol (5 mL) was added to quench the mixture and the mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether:dichloromethane=10:1)) to give a crude compound, ethyl 2-(2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)acetate (1.20 g), as a brown oil. LCMS (ESI): [M+H] + =853.3.

[0171] Step 7: To a solution of ethyl 2-(2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)acetic acid ethyl ester (1.0 g, 0.28 mmol) in ethyl acetate (40 mL) was added wet palladium on carbon (200.0 mg). The mixture was stirred at 20° C. for 12 hours under hydrogen (45 psi), filtered, and the filtrate was concentrated under reduced pressure to give a crude compound, ethyl 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)acetate (1.0 g), as a brown oil. LCMS (ESI): [M+H] + =823.3.

[0172] Step 8: To a solution of ethyl 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)acetate (1.0 g, 1.22 mmol) in tetrahydrofuran (8.0 mL) and water (2.0 mL) was added lithium hydroxide (153.0 mg, 3.65 mmol). The mixture was stirred at 50° C. for 3 hours and at 25° C. for 12 hours, and the pH was adjusted to 5-6 using 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a yellow solid compound 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)acetic acid (0.8 g, 1.01 mmol, yield 83%). LCMS (ESI): [M+H] + =795.3.

[0173] Step 9: To a solution of 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)acetic acid (3.30 g, 4.15 mmol) and diisopropylethylamine (29 mL, 166.06 mmol) in dioxane (135 mL) was added n-butylphosphonic anhydride (50% ethyl acetate solution, 6.78 g, 12.45 mmol) at 25°C under a nitrogen atmosphere, and the reaction solution was stirred at 60°C for 2 hours. Water (160 mL) was added to the reaction solution, and ethyl acetate (160 mL*3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a brown solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (3.04 g, 3.33 mmol, yield 80%). LCMS (ESI): [M+H] + =777.5.

[0174] Step 10: Dissolve compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (900 mg, 1.2 mmol) and phenylsilane (2.86 mL, 23.2 mmol) in tetrahydrofuran (70 mL), reduce the temperature to 0°C, add bis(1,5-cyclooctadiene)iridium(I) chloride dimer (78 mg, 0.1 mmol) under nitrogen, and stir at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient tetrahydrofuran / (petroleum ether:dichloromethane=3:1)) to give a yellow solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500 mg, 0.7 mmol, yield 56%). LCMS (ESI): [M+H] + =763.3.

[0175] Step 11: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL) was added iodomethane (81.0 uL, 1.32 mmol) and cesium carbonate (235 mg, 0.72 mmol). The mixture was stirred at 25°C for 16 hours. Water (3 mL) was added to dilute the mixture and the mixture was extracted with ethyl acetate (5 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / (3:1 by volume petroleum ether / dichloromethane)) to afford (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol, 90% yield) as a yellow solid. LCMS (ESI): [M+H] + =777.3.

[0176] Intermediate 5: tert-Butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0177] Step 1: Under nitrogen atmosphere, tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.10 g, 5.34 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolato) To a mixed solution of (1-(2-cyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.56 g, 6.94 mmol) in toluene (124 mL) and water (31.0 mL) were added cesium carbonate (5.22 g, 16.03 mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (0.78 g, 1.07 mmol). The mixture was stirred at 100°C for 16 hours. The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient tetrahydrofuran / petroleum ether) to give a brown solid compound, tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.27 g, 3.69 mmol, yield 69%). LCMS (ESI): [M+H] + =886.1.

[0178] Step 2: At 25°C, the compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.00 g, 5.64 mmol) and cesium fluoride (4.29 g, 28.22 mmol) were added to N,N-dimethylformamide (50.0 mL), and the reaction system was reacted at 20°C for 16 hours. The solution was diluted with water (30 mL) and extracted with ethyl acetate (15 mL*3). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate and the residue were purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to obtain a white solid compound, tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 2.03 mmol, 36% yield). LCMS (ESI): [M+H] + =730.0.

[0179] Step 3: At 25 ° C, the compound tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy) quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.41 mmol) and ethyl diazoacetate (56.3 mg, 0.49 mmol) were dissolved in acetonitrile (6.00 mL), and cuprous iodide (7.83 mg, 0.04 mmol) was added, and the reaction solution was stirred at 20 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to obtain a brown oily compound, tert-butyl (1R,5S)-3-(7-(8-(4-ethoxy-4-oxobut-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65% purity, 310 mg, 0.24 mmol, 60% yield). LCMS (ESI): [M+H] + =816.3.

[0180] Step 4: At 25°C, the compound tert-butyl (1R, 5S)-3-(7-(8-(4-ethoxy-4-oxobut-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 65%, 280 mg, 0.22 mmol) was dissolved in ethyl acetate (10.0 mL), and dry palladium on carbon (200 mg) was added. The reaction system was reacted at 15 psi of hydrogen atmosphere at 20°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily compound, tert-butyl (1R,5S)-3-(6-amino-7-(8-(4-ethoxy-4-oxobutyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65% purity, 241 mg, 0.20 mmol, 89% yield). LCMS (ESI): [M+H] + =790.5.

[0181] Step 5: At 25 ° C, the compound tert-butyl (1R, 5S)-3-(6-amino-7-(8-(4-ethoxy-4-oxobutyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65% purity, 230 mg, 0.20 mmol) and lithium hydroxide (73.3 mg, 1.74 mmol) were added to a mixed solvent of tetrahydrofuran (4.60 mL) and water (920 uL), and the reaction system was reacted at 60 ° C for 16 hours. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phase was concentrated under reduced pressure to give a brown solid compound, 4-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)butanoic acid (130 mg, 0.17 mmol, yield 85%). LCMS (ESI): [M+H] + =762.3

[0182] Step 6: To a solution of 4-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)butanoic acid (130 mg, 0.17 mmol) and N-methylmorpholine (66.3 mg, 0.66 mmol) in 1-methyl-2-pyrrolidone (2.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (150 mg, 0.39 mmol) at 25°C, the reaction system was reacted at 20°C for 2 hours, and then the temperature was raised to 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to obtain a brown solid compound, tert-butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 160 mg, 0.17 mmol, yield 99%). LCMS (ESI): [M+H] + =744.1

[0183] Intermediate 6: (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0184] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (200 mg, 0.26 mmol) in acetonitrile (2.00 mL) was added hydrogen chloride (4 M in dioxane, 7.86 mL, 31.46 mmol). The solution was stirred at 25°C for 48 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient methanol / dichloromethane) to give (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (157 mg, 0.26 mmol, yield 99%) as a brown solid. LCMS (ESI): [M+H] + =605.1. 1 H NMR (400MHz, CD3OD) δppm 8.18-7.94(m,1H),7.77(dd,J=6.1,9.0Hz,1H),7.48-7.25(m,2H),7.07-6.93(m,1H),5.18(br d,J=7.8Hz,2H),3.86(br s,1H),3.70-3.53(m,4H),3.53-3.37(m,3H),3.29-3.10(m,2H),2.79- 2.68(m,1H),2.62-2.47(m,1H),2.07-1.96(m,4H),1.46-1.34(m,3H).

[0185] Step 2: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (140 mg, 0.23 mmol) in dichloromethane (1.4 mL) was added diisopropylethylamine (123 uL, 0.69 mmol). Trifluoromethanesulfonic anhydride (39.0 uL, 0.23 mmol) was slowly added dropwise at -78°C, and the solution was stirred at -70°C for 4 hours. After the reaction was complete, the mixture was quenched with water (1 mL) and extracted with dichloromethane (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to give a yellow solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl trifluoromethanesulfonate (49.0 mg, 0.07 mmol, yield 29%). LCMS (ESI): [M+H] + =737.2.

[0186] Step 3: Under nitrogen protection, compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl trifluoromethanesulfonate (45.0 mg, 61.09 umol), palladium acetate (4.11 mg, 18.33 umol) and triphenylphosphine (9.64 mg, 36.65 umol) were added to N,N-dimethylformamide (2.25 mL), and then triethylamine (25.5 uL, 0.18 mmol) and formic acid (6.91 uL, 0.18 mmol) were added, and the solution was stirred at 80 ° C for 30 minutes. After the reaction, the mixture was cooled to room temperature, diluted with water (1 mL), and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to obtain a brown solid compound (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (27.0 mg, 45.87 umol, yield 75%). LCMS (ESI): [M+H] + =589.2. 1 H NMR (400MHz, CDCl3) δppm 7.99(d,J=8.3Hz,1H),7.89(dd,J=6.0,8.9Hz,1H),7.52(t,J=7.2Hz,1H),7.39-7.27(m,3H),4.95-4.75(m,2H),4.36-4.07 (m,3H),4.01-3.86(m,1H),3.62-3.30(m,4H),3.19-3.05(m,2H),2.79-2.57(m,2H),2.12-1.67(m,4H),1.38-1.31(m,3H).

[0187] Intermediate 7: (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0188] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (200 mg, 0.26 mmol) in acetonitrile (2.00 mL) was added hydrogen chloride (4 M in dioxane, 7.86 mL, 31.46 mmol). The solution was stirred at 25°C for 48 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient methanol / dichloromethane) to give (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol (157 mg, 0.26 mmol, yield 99%) as a brown solid. LCMS (ESI): [M+H] + =603.2

[0189] Step 2: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol (140 mg, 0.23 mmol) in dichloromethane (1.4 mL) was added diisopropylethylamine (123 uL, 0.69 mmol). Trifluoromethanesulfonic anhydride (39.0 uL, 0.23 mmol) was slowly added dropwise at -78°C, and the solution was stirred at -70°C for 4 hours. After the reaction was completed, the mixture was quenched with water (1 mL) and extracted with dichloromethane (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to obtain a yellow solid compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-17-yl trifluoromethanesulfonate (49.0 mg, 0.07 mmol, yield 29%). LCMS (ESI): [M+H] + =735.2.

[0190] Step 3: Under nitrogen protection, compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-17-yl trifluoromethanesulfonate (45.0 mg, 61.09 umol), palladium acetate (4.11 mg, 18.33 umol) and triphenylphosphine (9.64 mg, 36.65 umol) were added to N,N-dimethylformamide (2.25 mL), and then triethylamine (25.5 uL, 0.18 mmol) and formic acid (6.91 uL, 0.18 mmol) were added, and the solution was stirred at 80 ° C for 30 minutes. After the reaction, the mixture was cooled to room temperature, diluted with water (1 mL), and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / dichloromethane) to obtain a brown solid compound (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphthyl[1',8':4,5,6][1]azacycloundecane[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (27.0 mg, 45.87 umol, yield 75%). LCMS (ESI): [M+H] + =587.3.

[0191] Intermediate 8: 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0192] Step 1: To a solution of tert-butyl (1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1370.0 mg, 1.60 mmol) in N,N-dimethylformamide (27 mL) was added cesium fluoride (2431.1 mg, 16.00 mmol). The mixture was stirred at 25°C under nitrogen for 1 hour. Water (90 mL) was added for dilution, and the mixture was extracted with ethyl acetate (90 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give tert-butyl (1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720.0 mg, 1.03 mmol, 64% yield) as a brown solid compound. LCMS (ESI): [M+H] + =700.2.

[0193] Step 2: In a glove box, tetrakis(triphenylphosphine)palladium (165.2 mg, 0.14 mmol) and cuprous iodide (13.6 mg, 0.07 mmol) were added to a solution of tert-butyl (1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,22-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500.0 mg, 0.71 mmol) and methyl 3-iodoacrylate (227.2 mg, 1.07 mmol) in N,N-dimethylformamide (3.75 mL) and triethylamine (2.5 mL). The mixture was stirred at 50°C under nitrogen for 2 hours and then dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give tert-butyl (1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-((E)-5-methoxy-5-oxopent-3-en-1-yn-1-yl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530.0 mg, 0.68 mmol, 95% yield) as a brown solid compound. LCMS (ESI): [M+H] + =784.2.

[0194] Step 3: To a solution of tert-butyl (1R, 5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-((E)-5-methoxy-5-oxopent-3-ene-1-yn-1-yl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500.0 mg, 0.64 mmol) in methanol (50 mL) was added platinum dioxide (400.0 mg, 1.76 mmol). The mixture was stirred at 25 ° C. under a hydrogen atmosphere of 15 psi for 2 days. The solid was filtered and washed with methanol (50 mL), and the filtrate was dried by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether). A yellow solid compound, tert-butyl (1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-(5-methoxy-5-oxopentyl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260.0 mg, 0.33 mmol, yield 48%), was obtained. LCMS (ESI): [M+H] + =790.4.

[0195] Step 4: To a solution of tert-butyl (1R,5S)-3-(6-amino-8-fluoro-7-(7-fluoro-8-(5-methoxy-5-oxopentyl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.30 mmol) in tetrahydrofuran (2.4 mL) was added lithium hydroxide (38.3 mg, 0.91 mmol) and water (0.48 mL). The mixture was stirred at 50° C. for 24 hours. Water (5 mL) was added to dilute the mixture, 1 M hydrochloric acid was used to adjust the pH to 5-6, and then ethyl acetate (5 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a crude compound 5-(8-(6-amino-4-((1R, 5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)pentanoic acid (240 mg) as a yellow solid. LCMS (ESI): [M+H] + =776.3.

[0196] Step 5: To a solution of 5-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)pentanoic acid (210 mg, 0.27 mmol) and N-methylmorpholine (273.4 mg, 2.71 mmol) in N-methylpyrrolidone (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (308.8 mg, 0.81 mmol). The mixture was stirred at 25° C. under nitrogen protection for 2 hours and then at 80° C. for 16 hours. Water (30 mL) and saturated sodium bicarbonate solution (30 mL) were added, extracted with ethyl acetate (60 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether). A brown oily crude product (300 mg) was obtained. The crude product (200 mg) was then purified by flash column chromatography (C18, 0-70% gradient of acetonitrile / water). A white solid compound, tert-butyl (1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (72 mg, 0.10 mmol, yield 53%), was obtained. LCMS (ESI): [M+H] + =758.2.

[0197] Step 6: To a solution of tert-butyl (1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.07 mmol) and tris(pentafluorophenyl)borane (33.8 mg, 0.07 mmol) in toluene (2 mL) was added polymethylsiloxane (500 uL). The mixture was stirred at 110°C under nitrogen for 2 days. The mixture was dried by spin drying. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether). A yellow solid compound, tert-butyl (1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.04 mmol, yield 61%), was obtained. LCMS (ESI): [M+H] + =744.3.

[0198] Intermediate 9: (2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0199] Step 1: Dissolve 1-(tert-butyl)-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylate (9.00 g, 33.9 mmol) in tetrahydrofuran (90 mL). The temperature was lowered to -78°C. Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 68.0 mL, 68.0 mmol) was added under nitrogen and stirred at -78°C for 1 hour. 3-Chloro-2-(chloromethyl)prop-1-ene (12.7 g, 102 mmol) was added to the reaction solution, and the reaction solution was stirred at 20°C for 16 hours. The reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-5% gradient tetrahydrofuran / petroleum ether) to give 1-(tert-butyl) 2-methyl 2-(2-(chloromethyl)allyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (8.90 g, 25.2 mmol, 74% yield) as a colorless oil. LCMS (ESI): [M-56+H] + =298.0; 1H NMR (400MHz, CDCl3) δppm5.52-5.38(m,1H),5.11(br s,1H),4.13-3.87(m,3H),3.84-3.63(m,4H),3.46-3.21(m,1H),2.86-2.45(m,3H),1.52-1.43(m,9H).

[0200] Step 2: 1-(tert-Butyl)-2-methyl-2-(2-(chloromethyl)allyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.00 g, 5.65 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (6.30 mL, 84.8 mmol) was added. The reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), and adjusted to alkalinity by adding triethylamine. The mixture was then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% methanol / dichloromethane gradient) to obtain methyl 2,2-difluoro-6-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.50 g, 2.26 mmol, 40% yield) as a yellow oil. LCMS (ESI): [M+H] + =218.1; 1 H NMR (400 MHz, CDCl3) δ ppm 5.01-4.95 (m, 2H), 3.91 (br d, J = 14.6 Hz, 1H), 3.70 (s, 3H), 3.60-3.49 (m, 1H), 3.47-3.34 (m, 2H), 3.00-2.82 (m, 2H), 2.65 (br d, J = 16.4 Hz, 1H), 2.44-2.29 (m, 1H). Lithium tetrahydrogen (2.5 M solution in tetrahydrofuran, 4.00 mL, 10.0 mmol) was dissolved in tetrahydrofuran (4 mL), and methyl 2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (500 mg, 2.26 mmol) was added at 0°C, and the reaction solution was stirred at 60°C for 2 hours. The reaction mixture was quenched by adding water (370 uL), sodium hydroxide (15% aqueous solution, 370 uL), and water (1000 uL), filtered, and the filtrate was concentrated under reduced pressure to give (2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (220 mg, 1.13 mmol, yield 50%). LCMS (ESI): [M+H] + =182.1.

[0201] Intermediate 10: (Hexahydrocyclopropano[b]pyrrolazin-5a(3H)-yl)methanol

[0202] Step 1: To a solution of (3R)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (950 mg, 3.72 mmol) and 1-bromo-3-chloropropane (1.76 g, 11.16 mmol) in tetrahydrofuran (10 mL) was added lithium bistrimethylsilylamide (1 M in tetrahydrofuran, 7.44 mL, 7.44 mmol) under nitrogen at -65°C. The reaction was stirred at 25°C for 16 hours. Saturated ammonium chloride solution (10 mL) was added to the mixture, which was then extracted with ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / dichloromethane) to give 2-tert-butyl 3-ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (630 mg, 1.90 mmol, yield 51%) as a colorless oily compound. LCMS (ESI): [M+Na] + =354.3.

[0203] Step 2: To a solution of 2-tert-butyl 3-ethyl 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (610 mg, 1.84 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4 M in dioxane, 1.38 mL, 5.51 mmol). The reaction was stirred at 25 ° C for 16 hours. The mixture was concentrated in vacuo to give the crude compound 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (60% purity, 690 mg) as a colorless oil. LCMS (ESI): [M+H] + =232.2.

[0204] The third step: to 3- (3- chloropropyl) -2- azabicyclo [3.1.0] hexane -3- carboxylic acid ethyl ester (60% purity, 670mg, 1.73mmol) in ethanol (26mL) solution, potassium iodide (29mg, 0.17mmol) and potassium carbonate (719mg, 5.20mmol). The reaction was stirred at 25 ° C for 16 hours. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethanol / dichloromethane) to give a yellow oily compound hexahydrocyclopropane and [b] pyrrolizine -5a (3H) -carboxylic acid ethyl ester (95% purity, 320mg, 1.56mmol, 90% yield). LCMS (ESI): [M+H] + =196.1.

[0205] Step 4: At 0 ° C, lithium aluminum tetrahydride (72 mg, 1.91 mmol) was added to a solution of hexahydrocyclopropane [b] pyrrolazine-5a (3H) -carboxylic acid ethyl ester (95% purity, 310 mg, 1.50 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at 0 ° C for 1 hour. Water (72 uL) and 15% aqueous sodium hydroxide solution (72 uL) were added to the reaction, followed by water (216 uL). Anhydrous sodium sulfate was added for drying. The filter cake was filtered and washed with tetrahydrofuran (30 mL), and the filtrate was concentrated in vacuo to give a crude compound (hexahydrocyclopropane [b] pyrrolazine-5a (3H) -yl) methanol (230 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + =154.1.

[0206] Intermediate 11: (1-morpholinocyclopropyl)methanol

[0207] Step 1: Dissolve 1-aminocyclopropane-1-carboxylic acid ethyl ester (200 mg, 1.55 mmol) in acetonitrile (2.00 mL). Add potassium carbonate (899 mg, 6.50 mmol) and tetrabutylammonium bromide (74.9 mg, 0.23 mmol). Then, add a solution of 1-bromo-2-(2-bromoethoxy)ethane (431 mg, 1.86 mmol) in acetonitrile dropwise to the reaction mixture. The mixture is stirred at 80°C under nitrogen for 16 hours. The reaction mixture is filtered, the filtrate is dried, and the residue is purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to afford 1-morpholinocyclopropane-1-carboxylic acid ethyl ester (160 mg, 0.81 mmol, 52% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 4.15 (q, J = 7.1Hz, 2H), 3.59 (br s, 4H), 2.96 (br s, 4H), 1.36-1.18 (m, 5H), 0.94 (q, J = 3.7Hz, 2H).

[0208] Second step: at 0 ℃, to tetrahydrofuran (1.50mL) solution of 1-morpholinecyclopropane-1-ethyl formate (160mg, 0.80mmol), lithium aluminum hydroxide (0.64mL, 1.61mmol) is added. The mixture is stirred at 0 ℃ for 1 hour. The reaction adds water (0.64mL) and 15% aqueous sodium hydroxide solution (0.64mL), and then adds water (1.92mL). Anhydrous sodium sulfate drying is added. Filter and wash filter cake with tetrahydrofuran (30mL), filtrate is concentrated in vacuo to obtain crude compound (1-morpholinecyclopropyl) methanol (100mg), which is a colorless oily liquid. 1H NMR (400MHz, CDCl3) δppm 3.68-3.62(m,4H),3.59(s,2H),2.80-2.64(m,4H),0.76-0.70(m,2H),0.56-0.50(m,2H).

[0209] Intermediate 12: (2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol and (2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0210] Step 1: To a solution of potassium tert-butoxide (0.95 g, 8.52 mmol) in N,N-dimethylformamide (11 mL) at -50°C was added a solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (1.0 g, 4.73 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (0.82 g, 4.26 mmol) in N,N-dimethylformamide (5 mL). The mixture was slowly warmed to 25°C under nitrogen and stirred at 25°C for 0.5 h. Saturated ammonium chloride solution (5 mL) and 2M hydrochloric acid (9 mL) were added under an ice bath. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran / petroleum ether) to give ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (250 mg, 1.02 mmol, 22% yield) as a yellow oil. LCMS (ESI): [M+H] + =246.0; 1 H NMR (400MHz, CDCl3) δppm 4.36 (br d, J=14.7Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.75 (br d,J=14.7Hz,1H),3.13(td,J=1.3,15.4Hz,1H),2.90-2.73(m,1H),2.63(ddd,J=2.0,9. 2,13.2Hz,1H),2.55-2.34(m,2H),2.15(td,J=10.1,13.2Hz,1H),1.29(t,J=7.2Hz,3H).

[0211] Step 2: To a solution of lithium aluminum hydride (15.5 mg, 0.41 mmol) in tetrahydrofuran (1 mL) was added a solution of ethyl 2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (100.0 mg, 0.41 mmol) in tetrahydrofuran (1 mL) at 0° C. The mixture was stirred at 65° C. for 5 hours, and lithium aluminum hydride (7.7 mg, 0.20 mmol) was added, and the mixture was stirred at 65° C. for 3 hours. The mixture was cooled to 0°C, and water (23 uL), 15% sodium hydroxide (23 uL), and water (69 uL) were added. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a mixture of the crude compound (2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol and (2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (74.0 mg) as a yellow oil. LCMS (ESI): [M+H] + =190.1;172.1.

[0212] Example 1: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-5,6-dihydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-7(8H)-one

[0213] Step 1: At 25 ° C, tert-butyl (1R, 5S) -3- (3,14-difluoro-16- (methoxymethoxy) -7-oxo-12- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydro-4H-naphtho [1',8': 4,5,6] azepine [2,3-g] quinazolin-10-yl) -3,8-diazabicyclo [3.2.1] octane To a solution of -8-carboxylate (80% purity, 150 mg, 0.16 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (77.1 mg, 0.48 mmol) in tetrahydrofuran (2.00 mL) was added sodium tert-butoxide (79.0 mg, 0.80 mmol), and the reaction system was reacted at 50 ° C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (3 mL), and extracted with ethyl acetate (3 mL*3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-8% gradient of methanol / dichloromethane) to obtain a yellow solid compound, tert-butyl (1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-7-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.05 mmol, 30% yield). LCMS (ESI): [M+H] + =802.9

[0214] Step 2: To a solution of tert-butyl (1R, 5S)-3-(3,14-difluoro-12-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-7-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.05 mmol) in acetonitrile (800 uL) was added hydrogen chloride (4 M dioxane solution, 200 uL, 0.80 mmol) at 25 ° C, and the reaction system was reacted at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to acetonitrile (4 mL). The pH was adjusted to 8 with triethylamine and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a white solid compound, 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-5,6-dihydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-7(8H)-one (7.68 mg, 11.6 umol, yield 26%). LCMS (ESI): [M+H] + =659.3. 1 H NMR (400MHz, CD3OD) δppm 7.80 (s, 1H), 7.70 (dd, J=6.1, 9.0Hz, 1H), 7.32-7.20 (m, 2H), 6.91 (s, 1H), 5.46-5.24 (m, 1H), 4.65 (br d,J=12.3Hz,1H),4.44-4.19(m,3H),3.77(br d,J=12.7Hz,1H),3.71-3.57(m,3H),3.31-3.19(m,3H),3.05(dt,J=6.1,9.3Hz,1H),2.97-2.87(m,1H),2.76(br t,J=12.2Hz,1H),2.46-2.23(m,3H),2.22-2.15(m,1H),2.14-2.08(m,1H),2.08-1.98(m,4H),1.95-1.83(m,4H),1.82-1.74(m,1H).

[0215] Example 2: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-16-ol

[0216] Step 1: Tert-butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.20 mmol), tris(pentafluorophenyl)borane (206 mg, 0.40 mmol) and polymethylsiloxane (2.50 mL, 1.00 mmol) were added to toluene (6.00 mL), and the reaction solution was stirred at 110 ° C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to obtain a brown solid compound, tert-butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.19 mmol, yield 95%). LCMS (ESI): [M+H] + =730.2.

[0217] Step 2: Tert-butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.19 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (91.6 mg, 0.58 mmol) were dissolved in tetrahydrofuran (2.00 mL), and then sodium tert-butoxide (55.3 mg, 0.58 mmol) was added. The reaction solution was stirred at 60°C for 24 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (1 mL) and water (1 mL), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (1 mL * 2), the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(3,14-difluoro-12-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (48.0 mg, 0.06 mmol, yield 32%). LCMS (ESI): [M+H] + =789.5.

[0218] Step 3: Dissolve the compound tert-butyl (1R,5S)-3-(3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (46.0 mg, 0.06 mmol) in acetonitrile (2.00 mL), add hydrogen chloride (4 M solution in dioxane, 292 uL, 1.17 mmol), and stir at 25 ° C for 2 hours. The reaction mixture was concentrated in vacuo, and acetonitrile (1 mL) was added to the residue, neutralized with triethylamine to a pH of >7, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-16-ol (18.4 mg, 0.03 mmol, 49% yield) as a yellow solid. LCMS (ESI): [M+H] + =645.4. 1 H NMR(400MHz,CD3OD)δppm 7.78-7.70(m,1H),7.36-7.24(m,2H),7.08(s,1H),7.04-6.99(m,1H),5.41-5.26(m,1H) ,4.45-4.34(m,2H),4.32-4.26(m,1H),4.24-4.18(m,1H),3.71-3.52(m,4H),3.47-3.38( m,1H),3.28-3.22(m,3H),3.10-2.98(m,1H),2.87-2.75(m,1H),2.61-2.49(m,1H),2.44- 2.13(m,3H),2.07-1.98(m,2H),1.97-1.85(m,6H),1.70-1.53(m,2H),1.41-1.03(m,2H).

[0219] Example 3: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-16-ol

[0220] Step 1: To a solution of tert-butyl (1R, 5S)-3-(3,14-difluoro-16-(methoxymethoxy)-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (27.0 mg, 37.0 umol) in dimethylformamide (200 uL) were added cesium carbonate (13.0 mg, 40.70 umol) and iodomethane (4.59 uL, 74.33 umol) and stirred at 25 ° C for 16 hours. The reaction solution was slowly poured into ice water (100 μL), and ethyl acetate (100 μL) was added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 μL x 2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to obtain tert-butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-methyl-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (22.0 mg, 29.58 μmol, 80% yield). LCMS(ESI):[M+H] + =744.3.

[0221] Step 2: Add tert-butyl (1R, 5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-methyl-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 26.89 umol) and ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (12.8 mg, 80.67 umol) to tetrahydrofuran (400 uL), and then add sodium tert-butoxide (7.75 mg, 80.67 umol) and stir at 60 ° C for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (200 uL) and water (200 uL), the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 uL*2), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a brown oily compound tert-butyl (1R, 5S)-3-(3,14-difluoro-12-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 24.90 umol, yield 93%). LCMS(ESI):[M+H] + =803.5.

[0222] Step 3: Dissolve the compound tert-butyl (1R, 5S)-3-(3,14-difluoro-12-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 24.90 umol) in acetonitrile (400 uL), add hydrogen chloride (4 M dioxane solution, 62.3 uL, 0.25 mmol), and stir at 25 ° C for 2 hours. The reaction mixture was concentrated in vacuo, and acetonitrile (500 μL) was added to the residue, neutralized with triethylamine to a pH of >7, and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative HPLC to obtain 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-methyl-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-16-ol (9.40 mg, 14.19 μmol mmol, 57% yield) as a yellow solid. LCMS (ESI): [M+H] + =659.3. 1 H NMR (400MHz, CD3OD) δppm 7.65 (dd, J=6.0, 9.0Hz, 1H), 7.41 (s, 1H), 7.26-7.18 (m, 2H), 6.94 (d, J=2.4Hz, 1H), 5.41-5.23 (m, 1H), 4.48 (br dd,J=6.3,12.8Hz,1H),4.37(br d,J=15.5Hz,1H),4.32-4.26(m,1H),4.24-4.18(m,1H),3.71-3.54(m,4H),3.32-3.15(m,3H),3.09-2 .96(m,1H),2.95-2.73(m,2H),2.40(s,3H),2.37-2.12(m,4H),2.06-1.83(m,8H),1.52-1.29(m,4H).

[0223] Example 4: 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-8(9H)-one

[0224] Step 1: To a solution of tert-butyl (1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (63.0 mg, 0.40 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (25.4 mg, 0.26 mmol). The mixture was stirred at 50°C under nitrogen for 24 hours. The reaction solution was cooled to 0°C and diluted with water (5 mL). The mixture was extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a crude compound, tert-butyl (1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-8-oxo-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg), which was a brown oily liquid. LCMS (ESI): [M+H] + =817.6.

[0225] Step 2: To a solution of tert-butyl (1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-8-oxo-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.15 mmol) in acetonitrile (2400 uL) was added hydrogen chloride (4 M in dioxane, 550 uL, 2.20 mmol). The solution was stirred at 25°C for 1 hour. The solution was blown dry with nitrogen, and the residue was purified by preparative HPLC to give a white solid compound 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-8(9H)-one (6.76 mg, 0.01 mmol, yield 7%). LCMS (ESI): [M+H] + =673.2. 1 H NMR(400MHz,CD3OD)δppm 7.82(s,1H),7.67(dd,J=5.9,9.0Hz,1H),7.34-7.19(m,2H),6.94(d,J=2.3Hz,1H),5.40-5.23(m,1H), 4.49-4.42(m,2H),4.33-4.18(m,2H),3.83-3.59(m,4H),3.29-3.19(m,3H),3.08-2.98(m,1H),2.75(br s,1H),2.59-2.40(m,2H),2.36-2.20(m,2H),2.13(d,J=9.2Hz,2H),2.06-1.77(m,8H),1.58-1.41(m,3H).

[0226] Example 5: 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0227] Step 1: To a solution of tert-butyl (1R,5S)-3-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15 mg, 0.02 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (9.6 mg, 0.06 mmol) in tetrahydrofuran (0.3 mL) was added sodium tert-butoxide (3.8 mg, 0.04 mmol). The mixture was stirred at 50°C under nitrogen for 24 hours. Water (2 mL) was added to dilute the mixture at 0°C, and the mixture was extracted with ethyl acetate (5 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried in a rotary evaporation reaction to obtain a crude compound, tert-butyl (1R, 5S)-3-(3,15-difluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg), which was a brown oily liquid. LCMS (ESI): [M+H] + =803.4.

[0228] Step 2: To a solution of tert-butyl (1R,5S)-3-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.02 mmol) in acetonitrile (400 uL) was added hydrogen chloride (4 M in dioxane, 75 uL, 0.30 mmol). The solution was stirred at 25°C for 1 hour. The solution was dried with nitrogen. The residue was purified by preparative HPLC to give a white solid compound 11-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol (2.03 mg, 3.0 umol, yield 15%). LCMS (ESI): [M+H]+ =659.3. 1 H NMR(400MHz,CD3OD)δppm 8.56(br s,1H),7.69(dd,J=5.8,9.0Hz,1H),7.31(d,J=2.6Hz,1H),7.25(t,J=9.5Hz,1H),7.06(s,1H),6.94(d,J=2.6Hz,1H),5.43-5.28(m,1H),4.48(br d,J=12.0Hz,1H),4.41-4.23(m,3H),3.78(br s,2H),3.72-3.55(m,3H),3.38(br s,2H),3.18-2.93(m,2H),2.64(br d,J=11.9Hz,1H),2.48-2.26(m,3H),2.19(br d,J=11.5Hz,1H),2.13-1.86(m,8H),1.78-1.49(m,3H),1.46-1.29(m,3H).

[0229] Example 6A: 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecyl[2,3-g]quinazolin-17-ol

[0230] Example 6B: 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecyl[2,3-g]quinazolin-17-ol

[0231] Step 1: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-8(9H)-one (80 mg, 0.12 mmol) and 1,5-cyclooctadiene iridium chloride dimer (8.13 mg, 0.01 mmol) in tetrahydrofuran (12 mL) was added phenylsilane (262.1 mg, 2.42 mmol). The mixture was stirred at 55°C under nitrogen for 10 hours and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-35% gradient of ethyl acetate / petroleum ether) to give (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (24 mg, 0.04 mmol, 31% yield) as a yellow solid. LCMS (ESI): [M+H] + =647.2.

[0232] Step 2: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (43 mg, 0.07 mmol) in N,N-dimethylformamide (1.075 mL) were added cesium carbonate (23.8 mg, 0.07 mmol) and iodomethane (8.2 uL, 0.13 mmol). The mixture was stirred at 25° C. under nitrogen for 16 hours. Water (3 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (5 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a crude compound (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (62 mg). LCMS (ESI): [M+H] + =661.3.

[0233] Step 3: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (60 mg, 0.09 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57.8 mg, 0.36 mmol) in tetrahydrofuran (1.5 mL) was added sodium tert-butoxide (26.2 mg, 0.27 mmol). The mixture was stirred at 60° C. under nitrogen for 12 hours. Water (3 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (3 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a crude compound (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (100 mg) as a brown oily liquid. LCMS (ESI): [M+H] + =720.4.

[0234] Step 4: To a solution of (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (100 mg, 0.09 mmol) in acetonitrile (2000 uL) was added hydrogen chloride (4 M in dioxane, 520 uL, 2.08 mmol). The solution was stirred at 25°C for 1 hour. The solution was dried with nitrogen. The residue was purified by preparative HPLC to give two isomers of compound 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecyl[2,3-g]quinazolin-17-ol.

[0235] Example 6A: LCMS (ESI): [M+H] + =676.4. 1H NMR(400MHz,CD3OD)δppm 7.84(s,1H),7.66(dd,J=5.9,9.0Hz,1H),7.29-7.17(m,2H),6.90(d,J=2.6Hz,1H),5.48-5.26(m,1H),4.47-4.26(m,3H),4.15(br d,J=13.4Hz,1H),3.52-3.35(m,4H),3.21-3.11(m,1H),2.95-2.84(m,1H),2.78(s,3H ),2.69-2.44(m,3H),2.40-2.32(m,1H),2.28-2.05(m,4H),2.03-1.65(m,6H),1.58(br s,1H),1.47-1.18(m,8H).

[0236] Example 6B: LCMS (ESI): [M+H] + =676.4. 1 H NMR (400MHz, CD3OD) δppm 7.80 (s, 1H), 7.66 (dd, J= 5.9,9.0Hz,1H),7.29-7.17(m,2H),6.90(d,J=2.6Hz,1H),5.49-5.26(m,1H),4.45-4.38(m,1H),4.33(d,J =11.3Hz,2H),4.18(d,J=13.3Hz,1H),3.47-3.36(m,4H),3.28(d,J=3.3Hz,1H),3.19-3.10(m,1H),2.91(br t,J=10.1Hz,1H),2.80(s,3H),2.59(br d,J=6.4Hz,2H),2.39-2.31(m,1H),2.27-2.15(m,2H),2.15-2.03(m,2H),2.01-1.64(m,6H),1.54(br s,1H),1.43-1.24(m,8H).

[0237] Example 7: (R)-1-(3,15-difluoro-13-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0238] Step 1: To a solution of (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (32 mg, 0.05 mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (30.8 mg, 0.22 mmol) in tetrahydrofuran (0.8 mL) was added sodium tert-butoxide (15.7 mg, 0.16 mmol). The mixture was stirred at 60°C under nitrogen for 30 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by preparative HPLC to give a yellow solid compound (R)-1-(3,15-difluoro-13-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (5.81 mg, 9.2 umol, yield 14%). LCMS (ESI): [M+H] + =628.2. 1 H NMR (400MHz, CD3OD) δppm 8.06 (d, J=8.1Hz, 1H), 7.94 (dd, J=6.0, 9.0Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.50-7.29 (m, 3H), 4.38 (br s, 2H), 4.24 (br d,J=13.3Hz,1H),4.17-4.06(m,1H),3.83-3.70(m,1H),3.45-3.38(m,1H),3.29(br s,1H),3.06-2.85(m,3H),2.77-2.65(m,1H),2.48(br d,J=5.5Hz,1H),2.16(br dd,J=6.4,12.4Hz,3H),2.09-1.93(m,4H),1.92-1.71(m,7H),1.59(br d,J=8.1Hz,2H),1.43(br s,2H),1.32(br d,J=3.1Hz,4H),1.02(br s,1H).

[0239] Example 8: 12-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-18-ol

[0240] Step 1: To a solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.41 mmol) and 4-tert-butyldimethylsilyloxybutyne (424 uL, 2.06 mmol) in toluene / diisopropylamine (v / v = 1:1, 4.5 mL) was slowly added cuprous iodide (7.80 mg, 0.04 mmol), iodine (313 mg, 1.23 mmol) and dichlorobis(triphenylphosphine)palladium(II) (28.8 mg, 0.04 mmol) at 25°C. The reaction was stirred at 25°C for 16 hours. Saturated aqueous sodium sulfite solution (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL*2). The organic phase was washed with water (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl (1R,5S)-3-(7-(8-(6-((tert-butyldimethylsilyl)oxy)hex-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy))naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (364 mg, 0.40 mmol, yield 97%) as a brown solid. LCMS (ESI): [M+H] + =912.4.

[0241] Step 2: At 25° C. and under nitrogen protection, platinum dioxide (100 mg) was added to a methanol (1 mL) solution of the compound tert-butyl (1R, 5S) -3- (7- (8- (6- ((tert-butyldimethylsilyl) oxy) hexa-1,3-diyn-1-yl) -7-fluoro-3- (methoxymethoxy)) naphthalen-1-yl) -8-fluoro-6-nitro-2- (2,2,2-trifluoroethoxy) quinazolin-4-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.11 mmol). The solution was replaced with hydrogen and stirred at 20° C. for 16 hours under a hydrogen atmosphere of 15 psi. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude compound, tert-butyl (1R,5S)-3-(6-amino-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg), as a brown solid. LCMS (ESI): [M+H] + =890.4.

[0242] Step 3: To a solution of tert-butyl (1R,5S)-3-(6-amino-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.34 mmol) in tetrahydrofuran (4 mL) at 0°C was added sodium bicarbonate (56.6 mg, 0.67 mmol). The solution was stirred at 0°C for 5 minutes. Benzyl chloroformate (95.0 uL, 0.67 mmol) was added to the reaction solution, maintaining the temperature at 0°C. The reaction was stirred at 25°C for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, tert-butyl (1R, 5S)-3-(6-((benzyloxy)carbonyl)amino)-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg), as a brown solid. LCMS (ESI): [M+H] + =1024.5.

[0243] Step 4: Dissolve tert-butyl (1R,5S)-3-(6-((benzyloxy)carbonyl)amino)-7-(8-(6-((tert-butyldimethylsilyl)oxy)hexyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.39 mmol) in tetrabutylammonium fluoride (1 M in tetrahydrofuran, 8.0 mL, 8.0 mmol) at 20°C. Stir the reaction at 20°C for 1 hour. Add water (5 mL) to the reaction mixture, extract with ethyl acetate (5 mL*3), and dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl (1R, 5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-8-(6-hydroxyhexyl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.26 mmol, 68% yield) as a light yellow solid compound. LCMS (ESI): [M+H] + =910.4.

[0244] Step 5: To a solution of tert-butyl (1R,5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-8-(6-hydroxyhexyl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.26 mmol) in tetrahydrofuran (8 mL) at 20°C under a nitrogen atmosphere, triphenylphosphine (553 mg, 2.11 mmol) and diisopropyl azodicarboxylate (780 μL, 3.96 mmol) were slowly added. The reaction was stirred at 65°C for 1 hour. Water (8 mL) was added to the reaction mixture, which was extracted with ethyl acetate (6 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-18-(methoxymethoxy)-14-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazoline-10-carboxylate (purity 40%, 200 mg, 0.09 mmol, yield 34%) as a pink oily compound. LCMS (ESI): [M+H] + =892.5.

[0245] Step 6: At 0°C, the compound benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-18-(methoxymethoxy)-14-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2 To a solution of [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]quinazoline-10-carboxylate (180 mg, 0.08 mmol) in tetrahydrofuran (3 mL) were added 4A molecular sieves (180 mg), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (102 mg, 0.65 mmol), and sodium tert-butoxide (62.0 mg, 0.65 mmol), and the reaction was stirred at 25°C for 2 hours. The reaction solution was diluted with water (4 mL) and extracted with ethyl acetate (3 mL*3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to give benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazoline-10-carboxylate (60.0 mg, 0.06 mmol, 78% yield) as a yellow oily compound. LCMS (ESI): [M+H] + =951.7.

[0246] Step 7: To a solution of benzyl 12-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazoline-10-carboxylate (55.0 mg, 0.06 mmol) in ethyl acetate (2 mL) was added wet palladium on carbon (55.0 mg) at 25° C. under nitrogen protection. The solution was stirred at 20° C. under a 15 psi hydrogen atmosphere for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid compound, tert-butyl (1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.05 mmol, yield 85%). LCMS (ESI): [M+H] + =817.2.

[0247] Step 8: To a solution of tert-butyl (1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.04 mmol) in acetonitrile (1 mL) was added hydrogen chloride (4 M in dioxane, 214.0 uL, 0.86 mmol) at 25°C. The solution was stirred at 20°C for 1 hour. The solution was quenched with triethylamine (200 uL) and concentrated. The residue was purified by preparative HPLC to give a yellow solid compound 12-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-18-ol (formate salt, 4.59 mg, 6.55 umol, yield 15%). LCMS (ESI): [M+H] + =673.2. 1 H NMR (400MHz, CD3OD) δppm 8.52 (br s, 1H), 7.65 (dd, J=8.9, 5.9Hz, 1H), 7.33-7.18 (m, 2H), 6.94 (br s, 2H), 5.48-5.29 (m, 1H), 4.50 (br d,J=12.6Hz,1H),4.46-4.32(m,3H),3.95(br s,2H),3.73-3.59(m,3H),3.54(br s,3H),3.22(br d,J=11.74Hz,1H),2.76-2.63(m,1H),2.52-1.92(m,12H),1.77(br s,1H),1.56-1.39(m,3H),1.27-1.16(m,3H),1.07(br d,J=6.6Hz,1H).

[0248] Example 9A and Example 9B: 12-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecyl[2,3-g]quinazolin-9(10H)-one

[0249] Step 1: To a solution of tert-butyl (1R,5S)-3-(6-((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-8-(6-hydroxyhexyl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700.0 mg, 0.77 mmol) in dichloromethane (7.00 mL) was slowly added Dess-Martin periodinane (652.0 mg, 1.53 mmol) under nitrogen at 20°C. The reaction was stirred at 20°C for 3 hours. The reaction mixture was added with saturated sodium bicarbonate solution (4 mL) and water (6 mL), extracted with ethyl acetate (5 mL * 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude compound tert-butyl (1R, 5S)-3-(6-(((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(6-oxohexyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g), which was a yellow oily liquid. LCMS (ESI): [M+H] + =908.3.

[0250] Step 2: To a solution of tert-butyl (1R,5S)-3-(6-((benzyloxy)carbonyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(6-oxohexyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.10 mmol) in tert-butanol (6.00 mL) and water (3.00 mL) at 0°C were slowly added 2-methyl-2-butene (2.33 mL, 22.03 mmol), sodium dihydrogen phosphate (0.66 g, 5.51 mmol) and sodium chlorite (0.50 g, 5.51 mmol), and the reaction was stirred at 20°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated sodium bicarbonate (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to give 6-(8-(6-((benzyloxy)carbonyl)amino)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)hexanoic acid (620.0 mg, 0.67 mmol, 60% yield) as a yellow solid. LCMS (ESI): [M+H] + =924.3.

[0251] Step 3: To a solution of 6-(8-(6-((benzyloxy)carbonyl)amino)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)hexanoic acid (620.0 mg, 0.67 mmol) in ethyl acetate (5.00 mL) was added dry palladium on carbon (620.0 mg) at 20° C. The solution was stirred at 20° C. under a 15 psi hydrogen atmosphere for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)hexanoic acid (500.0 mg, 0.63 mmol, yield 94%). LCMS (ESI): [M+H] +=790.3.

[0252] Step 4: To a solution of 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)hexanoic acid (500.0 mg, 0.63 mmol) and 4A powdered molecular sieves (500.0 mg) in tetrahydrofuran (7.00 mL) were slowly added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (806.2 mg, 5.06 mmol) and sodium tert-butoxide (365.0 mg, 3.79 mmol) at 20° C. The solution was stirred at 80° C. for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 6-(8-(6-amino-4-((1R, 5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)hexanoic acid (1.00 g), which was a brown oily liquid. LCMS (ESI): [M+H] + =849.4.

[0253] Step 5: To a solution of 6-(8-(6-amino-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)hexanoic acid (1.00 g, 1.17 umol) in dioxane (40.0 mL) were slowly added diisopropylethylamine (8.39 mL, 47.12 mmol) and tri-n-butyl cyclophosphoric anhydride (50% ethyl acetate solution, 3.50 mL, 5.88 mmol) at 20° C. The solution was stirred at 100° C. for 2 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (20 mL*2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid compound, tert-butyl (1R, 5S)-3-(3,16-difluoro-14-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-9-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecyl[2,3-g]quinazolin-12-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (0.80 g, 0.96 umol, yield 82%). LCMS (ESI): [M+H] + =831.4.

[0254] Step 6: To a solution of tert-butyl (1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-9-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-12-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (0.80 g, 0.96 umol) in acetonitrile (10.0 mL) was added hydrogen chloride (4 M in dioxane, 4.81 mL, 19.2 mmol) at 20° C. The solution was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure, and dimethyl sulfoxide (3 mL) was added to the residue and neutralized with triethylamine (200 uL). The mixture was purified by preparative HPLC to obtain a yellow solid compound 12-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6][1]azacyclododecano[2,3-g]quinazolin-9(10H)-one (Example 10) (43.03 mg, 0.06 umol, yield 6%). LCMS (ESI): [M+H] + =687.2. 1 H NMR(400MHz,CH3OD)δppm 8.94-7.75(m,1H),7.68(dd,J=9.0,5.8Hz,1H),7.34-7.19(m,2H),6.91(br s,1H),5.38-5.18(m,1H),4.66-4.39(m,2H),4.29-4.14(m,2H),3.66(br s,4H),3.19(br d,J=19.1Hz,3H),3.06-2.74(m,3H),2.39-2.05(m,4H),2.03-1.81(m,9H),1.52-0.71(m,5H).

[0255] In Example 9, two stereoisomers were obtained by SFC separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / isopropanol; phase B is maintained at 60%; flow rate: 80 ml / min).

[0256] Example 9A: LCMS (ESI): [M+H] +=687.2; SFC analysis (column: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol; gradient: maintain 40% phase B; flow rate: 4 ml / min): chiral column peak position at 1.861 min; 1 H NMR(400MHz,CD3OD)δppm 9.15-7.90(m,1H),7.68(dd,J=8.9,5.9Hz,1H),7.35-7.19(m,2H),6.91( s,1H),5.35-5.21(m,1H),4.60-4.39(m,2H),4.31-4.12(m,2H),3.65(br s,4H),3.23-3.12(m,3H),3.05-2.76(m,3H),2.39-2.06(m,4H),2.04-1.75(m,9H),1.52-1.23(m,5H).

[0257] Example 9B: LCMS (ESI): [M+H] + =687.2; SFC analysis (column: Chiralpak IG-3 ID, 3 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / isopropanol; gradient: maintain 40% phase B; flow rate: 4 ml / min); the peak position of the chiral column is 5.520 min; 1 H NMR(400MHz,CD3OD)δppm 9.10-7.98(m,1H),7.67(dd,J=9.11,5.93Hz,1H),7.35-7.19(m,2H),6.90(s,1H),5.35-5.20(m,1H),4.67-4.36(m,2H),4.29- 4.11(m,2H),3.75-3.47(m,4H),3.23-3.14(m,3H),3.04-2.75(m,3H),2.40-2.07(m,4H),2.01-1.76(m,9H),1.50-1.28(m,5H).

[0258] Example 10: 15-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-hydroxy-4,5,6,7,8,9,10,11-octahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-12(13H)-one

[0259] Step 1: To a solution of tert-butyl (1R,5S)-3-(6-amino-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.29 mmol), hept-6-ynoic acid (180.3 mg, 1.43 mmol) and N-methylmorpholine (144.4 mg, 1.43 mmol) in N,N-dimethylacetamide (4 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (326 mg, 0.86 mmol). The mixture was stirred at 25°C under nitrogen for 1 hour and then at 60°C for 16 hours. The mixture was concentrated under pressure, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to obtain tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-(hept-6-ynamido)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (150 mg, 0.19 mmol, 65% yield). LCMS (ESI): [M+H] + =808.2.

[0260] Step 2: To a solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-(hept-6-ynamido)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.10 mmol), bis(triphenylphosphine)palladium dichloride (3.5 mg, 5.0 umol) and cuprous iodide (1.9 mg, 10.0 umol) in toluene / diisopropylamine (volume ratio 1:1, 90 mL) was added iodine (75.4 mg, 0.30 mmol). The mixture was stirred at 80°C for 2 hours, saturated sodium sulfite solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to obtain a yellow solid ring-closed compound (42.0 mg, 0.05 mmol, yield 53%). LCMS (ESI): [M+H] + =806.3.

[0261] Step 3: To a methanol (50 mL) solution of the ring-closed compound (58.0 mg, 0.07 mmol) obtained above, dry palladium carbon (100.0 mg) was added. The mixture was stirred at 25 ° C for 16 hours under a hydrogen atmosphere of 15 psi. Filter, wash the solid with methanol (100 mL), and the filtrate was dried. The crude compound tert-butyl (1R, 5S) -3- (3, 19-difluoro-21- (methoxymethoxy) -12-oxo-17- (2, 2, 2-trifluoroethoxy) -4, 5, 6, 7, 8, 9, 10, 11, 12, 13- decahydronaphtho[1', 8': 4, 5, 6][1] azacyclopentadecano[2, 3-g] quinazolin-15-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (56.0 mg) was obtained as a brown solid. LCMS(ESI):[M+H] + =814.4.

[0262] Step 4: To a solution of tert-butyl (1R,5S)-3-(3,19-difluoro-21-(methoxymethoxy)-12-oxo-17-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (56 mg, 0.07 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.8 mg, 0.28 mmol) in tetrahydrofuran (1.1 mL) was added sodium tert-butoxide (19.8 mg, 0.21 mmol). The mixture was stirred at 50°C under nitrogen for 16 hours. Water (2 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a crude compound, tert-butyl (1R, 5S)-3-(3,19-difluoro-17-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-(methoxymethoxy)-12-oxo-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg), which was a brown oily liquid. LCMS(ESI):[M+H] + =873.7.

[0263] Step 5: To a solution of tert-butyl (1R,5S)-3-(3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-(methoxymethoxy)-12-oxo-4,5,6,7,8,9,10,11,12,13-decahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-15-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.07 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 429 uL, 1.72 mmol). The solution was stirred at 25°C for 1 hour. The solution was dried with nitrogen. The residue was purified by preparative HPLC to give a white solid compound 15-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,19-difluoro-17-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-21-hydroxy-4,5,6,7,8,9,10,11-octahydronaphtho[1',8':4,5,6][1]azacyclopentadecano[2,3-g]quinazolin-12(13H)-one (formate salt, 8.90 mg, 0.01 mmol, yield 11%). LCMS (ESI): [M+H] + =729.2. 1 H NMR(400MHz,CD3OD)δppm 9.18(s,1H),8.55(s,1H),7.73(dd,J=5.9,9.0Hz,1H),7.37(d,J=2.5Hz,1H ),7.29(t,J=9.4Hz,1H),6.98(d,J=2.6Hz,1H),5.49-5.21(m,1H),4.65(br d,J=12.9Hz,1H),4.49(br d,J=13.1Hz,1H),4.40-4.27(m,2H),3.89(br s,2H),3.74(br d,J=13.9Hz,1H),3.59(br d,J=13.5Hz,1H),3.52-3.35(m,3H),3.12(dt,J=5.4,9.7Hz,1H),2.90-2.7 2(m,1H),2.58-2.36(m,2H),2.35-2.28(m,2H),2.20-1.95(m,10H),1.49(br s,1H),1.36-1.12(m,10H).

[0264] Example 11: 16-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,20-difluoro-18-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-22-hydroxy-5,6,7,8,9,10,11,12-octahydro-4H-naphtho[1',8':4,5,6][1]azacyclohexadecano[2,3-g]quinazolin-13(14H)-one

[0265] Example 11 was prepared by a similar synthetic route according to Example 10: LCMS (ESI): [M+H] + =743.3; 1 H NMR(400MHz,CD3OD)δppm 9.24(s,1H),7.71(dd,J=5.8,9.1Hz,1H),7.35(d,J=2.6Hz,1H),7.27(t,J=9.6Hz,1H),7.00(d,J=2.6Hz,1H),5.36-5.22(m,1H),4.53(br dd,J=8.3,12.4Hz,2H),4.26(d,J=10.6Hz,1H),4.18(dd,J=2.3,10.2Hz,1H),3.72-3.53(m,4H),3.30-3.11(m,4H),3.00(br d,J=5.1Hz,1H),2.78-2.62(m,1H),2.38-2.33(m,2H),2.25-2.18(m,1H),2.15-2.10(m,1H),2.05(br d,J=4.0Hz,2H),2.02-1.87(m,8H),1.85-1.76(m,2H),1.58(br s,1H),1.45(br d,J=6.2Hz,1H),1.37-1.27(m,2H),1.23-1.15(m,6H).

[0266] Example 12: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-8-one

[0267] Example 13: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-ethyl-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-8-one

[0268] Step 1: Dissolve the compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (150 mg, 0.2 mmol), dibenzylamine (159 mg, 0.8 mmol) and formaldehyde (37% aqueous solution, 48 uL, 0.6 mmol) in dimethyl sulfoxide (0.4 mL), add cuprous iodide (8 mg, 0.04 mmol) under nitrogen, and stir at 60°C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*2). The organic phases were combined, washed with saturated brine (5 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol / dichloromethane) to give a yellow solid compound, methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-(3-(benzhydrylamino)prop-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (120 mg, 0.12 mmol, yield 62%). LCMS (ESI): [M+H] + =953.1.

[0269] Step 2: Compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(benzhydrylamino)prop-1-yn-1-yl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (120 mg, 0.12 mmol) was dissolved in ethyl acetate (6 mL), and dry palladium carbon (containing 10% palladium, <1% water, 100 mg) was added under nitrogen, and the hydrogen atmosphere was replaced three times. The reaction was stirred at 20°C and 15 psi of hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a mixture of a crude compound, methyl 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate and methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (80 mg), as a yellow oily liquid. LCMS(ESI):[M+H] + =776.1;804.3.

[0270] Step 3: Compounds methyl 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate and methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2. A mixture of 1]oct-3-yl)-7-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (80 mg, 0.10 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL), and lithium hydroxide (26 mg, 0.60 mmol) was added at 0°C, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was adjusted to pH 4 with 1 M dilute hydrochloric acid and lyophilized to obtain a mixture of 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid and 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (60 mg). LCMS (ESI): [M+H] + =762.5;790.3.

[0271] Step 4: Compound 7-(8-(3-aminopropyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid and 4-((1R,5S)-8-(tert-butoxycarbonyl)-3 To a solution of a mixture of 2-(8-(3-(ethylamino)propyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (60 mg, 0.08 mmol) and N-methylmorpholine (40 mg, 0.39 mmol) in methylpyrrolidone (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (90 mg, 0.24 mmol), and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 2). The organic phases were combined, washed with saturated brine (5 mL * 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude compound of tert-butyl (1R, 5S)-3-(3,14-difluoro-16-(methoxymethoxy)-8-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-10-yl)-3, A mixture of 8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-ethyl-3,14-difluoro-16-(methoxymethoxy)-8-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg) was obtained as a yellow oily liquid. LCMS (ESI): [M+H] + =744.2;772.2.

[0272] Step 5: Compounds tert-butyl (1R, 5S) -3- (3,14-difluoro-16- (methoxymethoxy) -8-oxo-12- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydro-4H-naphtho [1', 8': 5,6,7] azepine [3,4-g] quinazolin-10-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate and tert-butyl (1R, 5S) -3- (7-ethyl-3,14-difluoro-16- (methoxymethoxy) -8-oxo-12- (2,2,2-trifluoroethoxy) -5,6,7,8-tetrahydro-4H-naphtho [1', 8': 5,6,7] azepine [3,4-g] quinazolin-10-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (18 mg, 0.11 mmol) in tetrahydrofuran (0.4 mL) were added sodium tert-butoxide (10 mg, 0.10 mmol), and the reaction solution was stirred at 20°C for 1 hour. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*2). The organic phases were combined, washed with saturated brine (5 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, tert-butyl (1R, 5S)-3-(3,14-difluoro-12-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-10-yl)-3,8 A mixture of -diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-ethyl-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]azepino[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg) was obtained as a yellow oily liquid. LCMS (ESI): [M+H] + =804.1;832.2.

[0273] Step 6: Compound tert-butyl (1R, 5S)-3-(3,14-difluoro-12-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R, 5S)-3-(7-ethyl-3,14-difluoro-12-(( A mixture of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-16-(methoxymethoxy)-8-oxo-5,6,7,8-tetrahydro-4H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylates (30 mg, 37 μmol) was dissolved in acetonitrile (0.1 mL), and hydrogen chloride (4 M in dioxane, 0.18 mL, 0.74 mmol) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and acetonitrile (500 μL) was added to the residue. Triethylamine was added to adjust the pH to 8, and the residue was purified by preparative HPLC to obtain the two target compounds.

[0274] Example 12: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-8-one (4.66 mg, 6 umol, yield 16%) was obtained as a white solid. LCMS (ESI): [M+H] + =659.2; 1H NMR (400MHz, CD3OD) δppm 7.61-7.50 (m, 2H), 7.18-7.06 (m, 2H), 6.83 (d, J = 2.5Hz, 1H), 5.32-5.11 (m, 1H), 4.26-3.90 (m, 3H), 3.74 (br d,J=12.6Hz,1H),3.60-3.46(m,2H),3.39(br d,J=12.9Hz,1H),3.30-3.23(m,1H),3.19-3.05(m,4H),2.97-2.75(m,2H),2.46-2.35(m,1H), 2.31-2.02(m,3H),1.94-1.83(m,3H),1.83-1.64(m,5H),1.61-1.50(m,1H),1.31-1.15(m,1H).

[0275] Example 13: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-ethyl-3,14-difluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-16-hydroxy-4,5,6,7-tetrahydro-8H-naphtho[1',8':5,6,7]azepine[3,4-g]quinazolin-8-one (6.41 mg, 8 umol, yield 23%) was obtained as a white solid. LCMS (ESI): [M+H] + =687.4; 1 H NMR (400MHz, CD3OD) δppm7.61-7.49(m,2H),7.19-7.07(m,2H),6.80(d,J=2.5Hz,1H),5.32-5.10(m,1H),4.25-4.05(m,3H),3.74(br d,J=12.5Hz,1H),3.67-3.44(m,3H),3.37(br d,J=12.9Hz,1H),3.17-3.06(m,3H),3.02-2.88(m,2H),2.87-2.72(m,2H),2.50(br t,J=11.8Hz,1H),2.31-1.66(m,12H),1.61-1.47(m,1H),1.28-1.14(m,1H),0.50(t,J=7.1Hz,3H).

[0276] Example 14: 12-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-10-one

[0277] Step 1: Dissolve tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 3.46 mmol) in dioxane (20 mL) and sodium hydroxide (1.5 M aqueous solution, 18.5 mL, 27.7 mmol). Add bromine (0.53 mL, 10.4 mmol) dropwise slowly at 0°C. The reaction is stirred at 0°C for 3 hours and then at 20°C for 16 hours. Water (50 mL) was added to the reaction solution, and the pH was adjusted to 4 with 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40% gradient ethyl acetate / petroleum ether) to give 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (1.00 g, 1.73 mmol, yield 50%). LCMS (ESI): [M+H] + =581.3.

[0278] Step 2: 7-bromo-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (350 mg, 0.60 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl) )ethynyl)triisopropylsilane (402 mg, 0.78 mmol) and potassium phosphate (1.5 M aqueous solution, 1.20 mL, 1.81 mmol) were dissolved in dioxane (3.50 mL), and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (44 mg, 0.06 mmol) was added under a nitrogen atmosphere, and the reaction solution was stirred at 100 ° C for 16 hours. Four identical batches of the same reaction mixture were combined, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate / petroleum ether) to obtain the compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (650 mg, 0.72 mmol, 30% yield). LCMS (ESI): [M+H] + =885.3.

[0279] Step 3: To a turbid solution of compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (650 mg, 0.72 mmol) and potassium carbonate (329 mg, 2.38 mmol) in dimethylformamide (7 mL) was added iodomethane (224 mg, 1.58 mmol) at 0°C, and the reaction solution was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (600 mg), as a yellow oily liquid. LCMS (ESI): [M+H] + =899.3.

[0280] Step 4: To a solution of the compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (600 mg, 0.66 mmol) in dimethylformamide (6 mL) was added cesium fluoride (1.00 g, 6.60 mmol) and stirred at 20°C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (400 mg, 0.53 mmol, 80% yield). LCMS (ESI): [M+H] + =743.6.

[0281] Step 5: Compound methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (150 mg, 0.2 mmol), benzylprop-2-yn-1-carbamate (77 mg, 0.4 mmol) and elemental iodine (154 mg, 0.6 mmol) were dissolved in toluene (1.5 mL) and diisopropylamine (1.5 mL), and cuprous iodide (4 mg, 0.02 mmol) and dichlorobis(triphenylmethane) were added under nitrogen. The reaction mixture was stirred at 20°C for 16 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give methyl 7-(8-(5-(((benzyloxy)carbonyl)amino)penta-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (100 mg, 0.10 mmol, yield 53%). LCMS (ESI): [M+H] + =930.6.

[0282] Step 6: The compound methyl 7-(8-(5-(((benzyloxy)carbonyl)amino)penta-1,3-diyn-1-yl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (100 mg, 0.1 mmol) was dissolved in ethyl acetate (6 mL), and dry palladium carbon (containing 10% palladium, <1% water, 50 mg) and dry palladium hydroxide on carbon (containing 20% ​​palladium hydroxide, <1% water, 50 mg) were added under nitrogen. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at 20°C and 15 psi of hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude compound, methyl 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (68 mg), as a yellow oily liquid. LCMS (ESI): [M+H] + =804.4.

[0283] Step 7: The compound methyl 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylate (68 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL), and lithium hydroxide (22 mg, 0.50 mmol) was added at 0°C, and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was adjusted to pH 4 with 1 M dilute hydrochloric acid and lyophilized to obtain the compound 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (45 mg, 0.05 mmol). LCMS (ESI): [M+H] + =790.4.

[0284] Step 8: To a solution of compound 7-(8-(5-aminopentyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazoline-6-carboxylic acid (45 mg, 0.05 mmol) and N-methylmorpholine (28 mg, 0.28 mmol) in methylpyrrolidone (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (65 mg, 0.17 mmol), and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 2), the organic phases were combined, washed with saturated brine (5 mL * 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude compound tert-butyl (1R, 5S) -3- (3,16-difluoro-18- (methoxymethoxy) -10-oxo-14- (2,2,2-trifluoroethoxy) -5,6,7,8,9,10-hexahydro-4H-naphtho [1',8': 5,6,7][1] azacyclododecano [3,4-g] quinazolin-12-yl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] + =772.2.

[0285] Step 9: To a solution of compound tert-butyl (1R,5S)-3-(3,16-difluoro-18-(methoxymethoxy)-10-oxo-14-(2,2,2-trifluoroethoxy)-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.05 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (18 mg, 0.11 mmol) in tetrahydrofuran (0.4 mL) was added sodium tert-butoxide (10 mg, 0.10 mmol), and the reaction solution was stirred at 20°C for 1 hour. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*2). The organic phases were combined, washed with saturated brine (5 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude compound, tert-butyl (1R, 5S)-3-(3,16-difluoro-14-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-10-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] + =831.3.

[0286] Step 10: Dissolve the compound tert-butyl (1R,5S)-3-(3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-(methoxymethoxy)-10-oxo-5,6,7,8,9,10-hexahydro-4H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-12-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30 umol) in acetonitrile (0.1 mL), add hydrogen chloride (4 M in dioxane, 0.15 mL, 0.6 mmol), and the reaction solution is stirred at 4 ℃ for 2 h. The mixture was stirred at 20°C for 2 hours, concentrated under reduced pressure, and the residue was added to acetonitrile (500uL). Triethylamine was added to adjust the pH to 8, and the residue was purified by preparative HPLC to give a white solid compound 12-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,16-difluoro-14-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-18-hydroxy-4,5,6,7,8,9-hexahydro-10H-naphtho[1',8':5,6,7][1]azacyclododecano[3,4-g]quinazolin-10-one (2.36 mg, 3umol, yield 11%). LCMS (ESI): [M+H] + =687.5; 1 H NMR (400MHz, CD3OD) δppm 7.72(s,1H),7.61-7.51(m,1H),7.25-7.01(m,3H),5.28-5.11(m,1H),4.29(br d,J=6.6Hz,1H),4.22-4.07(m,2H),3.68(br d,J=7.1Hz,1H),3.59-3.44(m,3H),3.16-2.85(m,6H),2.67(br d,J=13.1Hz,1H),2.47(br s,1H),2.30-1.99(m,4H),1.96-1.64(m,8H),1.27-1.01(m,5H).

[0287] Example 15: 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-16-hydroxy-12-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-7(8H)-one

[0288] Step 1: At 25°C, tert-butyl (1R,5S)-3-(3,14-difluoro-16-(methoxymethoxy)-7-oxo-12-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.07 mmol) was dissolved in acetonitrile (1.00 mL) and hydrogen chloride (4 M solution in dioxane, 336 uL), and the reaction system was reacted at 25°C for 3 hours. The mixture was diluted with acetonitrile (3 mL), triethylamine was added at 0°C to adjust the pH to 8, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain a yellow solid compound 10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,14-difluoro-16-hydroxy-12-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-naphtho[1',8':4,5,6]azepine[2,3-g]quinazolin-7(8H)-one (8.72 mg, 14.5 umol, yield 21%). LCMS (ESI): [M+H] + =600.4; 1 H NMR (400MHz, CD3OD) δppm 7.86 (s, 1H), 7.71 (dd, J=5.9, 9.0Hz, 1H), 7.32-7.21 (m, 2H), 6.91 (d, J=2.6Hz, 1H), 5.03 (q, J=8.8Hz, 2H), 4.72 (br d,J=13.2Hz,1H),4.48(br d,J=12.2Hz,1H),3.88(br s,1H),3.84(br s,1H),3.70(br d,J=13.2Hz,1H),2.99-2.87(m,1H),2.83-2.71(m,1H),2.47-2.34(m,1H),2.21-1.82(m,8H).

[0289] Example 16: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphthol[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0290] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (60 mg, 0.09 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (59 mg, 0.37 mmol) in tetrahydrofuran (600 uL) were added 4A molecular sieves (60 mg) and sodium tert-butoxide (27 mg, 0.28 mmol). The solution was stirred at 60°C for 16 hours. The reaction solution was diluted with water (1 mL) and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy))-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (100 mg, 85.01 umol, yield 92%). LCMS (ESI): [M+H] + =706.4

[0291] Step 2: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (100 mg, 0.14 mmol) in acetonitrile (1000 uL) was added hydrogen chloride (4 M in dioxane, 355 uL, 1.42 mmol) at 25°C and the reaction was stirred at 25°C for 1 hour. The solution was concentrated, dichloromethane (3 mL) was added and the pH was adjusted to 8 with triethylamine. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol (12.54 mg, 18.94 umol, yield 13%). LCMS (ESI): [M+H] + =662.2; 1 H NMR (400MHz, CD3OD) δ = 7.69 (dd, J = 5.8, 8.9Hz, 1H), 7.48-7.37 (m, 1H), 7.33-7.22 ( m,2H),6.94(dd,J=2.6,5.4Hz,1H),5.52-5.29(m,1H),4.52-4.35(m,2H),4.26(br d,J=12.5Hz,1H),4.15(br dd,J=7.3,12.9Hz,1H),3.85-3.71(m,1H),3.69-3.41(m,4H),3.24-3.16(m,1H),3.01(br t,J=13.6Hz,1H),2.66-1.74(m,14H),1.66-1.52(m,2H),1.42(br d,J=7.0Hz,2H),1.32(d,J=3.5Hz,3H),1.05(br s,1H)

[0292] Example 17A and Example 17B: Two Stereoisomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0293] Example 17A was prepared by a similar synthetic route to Example 16: the compound with a shorter retention time in HPLC was a yellow solid (17.47 mg). LCMS (ESI): [M+H] + =603.3; 1 H NMR (400MHz, CD3OD) δppm 7.66 (dd, J=5.9, 8.8Hz, 1H), 7.36 (br s,1H),7.28(d,J=2.2Hz,1H),7.22(t,J=9.5Hz,1H),6.93(d,J=2.2Hz,1H),4.97-4.89(m,2H),4.24-4.04(m,2H),3.74(br d,J=15.0Hz,1H),3.44-3.33(m,2H),2.98(br t,J=13.3Hz,1H),2.69-2.56(m,1H),2.38(br d,J=7.7Hz,1H),2.18(br d,J=9.9Hz,1H),1.89-1.72(m,4H),1.68-1.49(m,2H),1.47-1.34(m,2H),1.30(s,3H),1.08-0.94(m,1H).

[0294] Example 17B was prepared by a similar synthetic route to Example 16: the compound with a longer retention time in HPLC was a yellow solid (20.64 mg). LCMS (ESI): [M+H] + =603.1; 1 H NMR(400MHz,CD3OD)δppm 7.67(dd,J=5.8,8.9Hz,1H),7.45(s,1H),7.29(d,J=2.4Hz,1H),7.23(t,J=9. 6Hz,1H),6.92(d,J=2.2Hz,1H),4.98-4.90(m,2H),4.27-4.06(m,2H),3.77(br d,J=15.4Hz,1H),3.35(br d,J=13.4Hz,2H),2.98(br t,J=13.4Hz,1H),2.62(br s,1H),2.37(br s,1H),2.16(br d,J=10.6Hz,1H),1.91-1.72(m,4H),1.58(br s,2H),1.39(br s,2H),1.29(s,3H),1.01(br d,J=6.6Hz,1H).

[0295] Example 18A and Example 18B: Two isomers of (R)-13-((2-oxabicyclo[2.2.2]octan-1-yl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0296] Example 18A was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =645.3; 1 H NMR (400MHz, CD3OD) δppm 7.70-7.63(m,1H),7.35-7.20(m,3H),6.88(br d,J=4.0Hz,1H),4.24-4.08(m,3H),4.06-3.88(m,3H),3.72(br d,J=14.8Hz,1H),3.45-3.34(m,2H),2.96(br t,J=13.0Hz,1H),2.71-2.57(m,1H),2.37(br s,1H),2.16(br d,J=10.3Hz,1H),2.07-1.95(m,2H),1.91-1.69(m,11H),1.65-1.34(m,4H),1.31(s,3H),1.01(br d,J=7.9Hz,1H).

[0297] Example 18B was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =645.3; 1 H NMR (400MHz, CD3OD) δppm 7.73-7.62(m,1H),7.41(s,1H),7.32-7.16(m,2H),6.92(d,J=2.1Hz,1H),4.24-4.11(m,3H),4.06(br d,J=13.0Hz,1H),3.97-3.88(m,2H),3.75(br d,J=14.9Hz,1H),3.35(br s,2H),2.96(br t,J=13.4Hz,1H),2.64(br d,J=12.2Hz,1H),2.37(br s,1H),2.14(br d,J=9.0Hz,1H),2.00(br s,2H),1.91-1.72(m,11H),1.57(br s,4H),1.29(s,3H),0.99(br s,1H).

[0298] Example 19: (R)-13-((2-oxabicyclo[2.2.2]oct-4-yl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0299] Example 19 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =645.3; 1 H NMR (400MHz, CD3OD) δppm 7.68(dd,J=5.9,8.9Hz,1H),7.47-7.33(m,1H),7.30(d,J=2.6Hz,1H),7.24(t,J=9.5Hz,1H),6.99-6.88(m,1H),4.18(br d,J=12.8Hz,1H),4.13-3.98(m,3H),3.87(s,2H),3.82-3.68(m,2H),3.44-3.37(m,1H),2.98(br t,J=13.1Hz,1H),2.72-2.57(m,1H),2.38(br s,1H),2.18(br d,J=9.8Hz,1H),2.10-1.97(m,2H),1.87-1.65(m,11H),1.64-1.52(m,2H),1.41(br d,J=4.8Hz,2H),1.32(d,J=5.3Hz,3H),1.01(br d,J=6.7Hz,1H).

[0300] Example 20A and Example 20B: Two isomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((4-methoxybicyclo[2.2.2]octan-1-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0301] Example 20A was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =673.5; 1H NMR (400MHz, CD3OD) δppm 7.71-7.60(m,1H),7.36-7.31(m,1H),7.31-7.27(m,1H),7.27-7.19(m,1H),6.95-6.86(m,1H),4.19(br s,3H),3.73-3.69(m,1H),3.43-3.36(m,1H),3.17(d,J=3.7Hz,3H),3.04-2.90(m,1H),2.72-2.56(m,1H),2.45-2.28(m,1H),2.16(br d,J=12.6Hz,2H),1.82-1.63(m,15H),1.63-1.54(m,4H),1.51-1.35(m,2H),1.31(s,3H),1.12-0.85(m,1H).

[0302] Example 20B was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =673.4; 1 H NMR(400MHz,CD3OD)δppm 7.74-7.64(m,1H),7.47-7.40(m,1H),7.32-7.28(m,1H),7.28-7.21(m,1H),6.94(d,J= 2.6Hz,1H),4.59-4.51(m,1H),4.19-4.06(m,3H),3.85-3.67(m,1H),3.41-3.34(m,1H) ,3.21-3.17(m,3H),3.08-2.88(m,1H),2.73-2.60(m,1H),2.46-2.32(m,1H),2.21-2.0 3(m,1H),1.91-1.58(m,19H),1.49-1.34(m,2H),1.34-1.26(m,3H),1.13-0.90(m,1H).

[0303] Example 21A and Example 21B: Two isomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0304] Example 21A was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =644.3;1 H NMR(400MHz,CD3OD)δppm 8.55(s,1H),7.68(dd,J=5.7,9.0Hz,1H),7.38(s,1H),7.30(d,J=2.6Hz,1H),7.24(t,J=9. 5Hz,1H),6.93(d,J=2.6Hz,1H),4.50(d,J=4.6Hz,2H),4.27(td,J=4.7,9.1Hz,1H),4.15(br d,J=13.4Hz,1H),3.82-3.70(m,1H),3.53-3.33(m,5H),3.16-2.94(m,3H),2.69-2.55(m,1H),2.45-2.33(m,1H) ),2.27-2.08(m,5H),2.04-1.93(m,4H),1.88-1.73(m,4H),1.64-1.50(m,2H),1.45-1.35(m,2H),1.31(s,3H).

[0305] Example 21B was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =644.2; 1 H NMR(400MHz,CD3OD)δppm 8.55(br s,1H),7.73-7.65(m,1H),7.46(s,1H),7.30(d,J=2.6Hz,1H),7.24(t,J=9 .7Hz,1H),6.92(d,J=2.6Hz,1H),4.50(s,2H),4.34-4.23(m,1H),4.16(br d,J=13.0Hz,1H),3.77(br d,J=15.2Hz,1H),3.58-3.33(m,5H),3.11(br dd,J=5.6,11.6Hz,2H),3.00(br t,J=13.0Hz,1H),2.69-2.56(m,1H),2.44-2.31(m,1H),2.30-2.10(m,5H),2.05-1 .97(m,4H),1.88-1.74(m,4H),1.64-1.51(m,2H),1.48-1.36(m,2H),1.30(s,3H).

[0306] Example 22A and Example 22B: Two Stereoisomers of 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0307] Step 1: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150.00 mg, 0.23 mmol) in N,N-dimethylformamide (1.50 mL) was added cesium carbonate (83.14 mg, 0.26 mmol) and iodomethane (0.03 mL, 0.47 mmol). The mixture was stirred at 25°C under nitrogen for 16 hours. Water (3 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (5 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a crude compound (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150 mg). LCMS (ESI): [M+H] + =661.2.

[0308] Step 2: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (140 mg, 0.21 mmol) and (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (129.87 mg, 0.85 mmol) in tetrahydrofuran (1.50 mL) were added 4A molecular sieves (150 mg) and sodium tert-butoxide (41.6 mg, 0.42 mmolecular weight). ol). The solution was stirred at 60°C for 4 hours. The reaction solution was diluted with water (2 mL), extracted with ethyl acetate (1 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow crude compound (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150 mg). LCMS(ESI):[M+H] + =714.4

[0309] Step 3: To a solution of (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (150 mg, 0.21 mmol) in acetonitrile (1.5 mL) was added hydrogen chloride (4 M in dioxane, 1.05 mL, 4.20 mmol) at 25°C and the reaction was stirred at 25°C for 1 hour. The solution was concentrated, acetonitrile (3 mL) was added and the pH was adjusted to 8 with triethylamine. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give two stereoisomers of the compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol.

[0310] Example 22A: LCMS (ESI): [M+H] + =670.3; 1H NMR (400MHz, CD3OD) δppm 7.83-7.72(m,1H),7.63(dd,J=6.0,9.0Hz,1H),7.28-7.15(m,2H),6.88(d,J=2.5Hz,1H),5.00(br s,2H),4.31-4.25(m,2H),4.13(br d,J=13.1Hz,1H),3.79(br d,J=14.4Hz,1H),3.44-3.33(m,3H),3.29-3.17(m,2H),2.93-2.79(m,2H),2.78 -2.75(m,3H),2.64-2.44(m,3H),2.25-2.10(m,2H),2.09-1.58(m,8H),1.55(br s,1H),1.43-1.19(m,8H).

[0311] Example 22B: LCMS (ESI): [M+H] + =670.4; 1 H NMR (400MHz, CD3OD) δppm 7.80 (s, 1H), 7.63 (dd, J=5.9, 9.0Hz, 1H), 7.27-7.13 (m, 2H), 6.88 (d, J=2.5Hz, 1H), 5.00 (br s, 2H), 4.28 (br d,J=7.0Hz,2H),4.09(br d,J=13.1Hz,1H),3.79(br d,J=14.3Hz,1H),3.47-3.32(m,3H),3.28-3.10(m,2H),2.89-2.78(m,2H),2.75(s,3H),2.6 3-2.45(m,3H),2.23-2.09(m,2H),2.07-1.61(m,8H),1.59-1.50(m,1H),1.44-1.21(m,8H).

[0312] Example 23: 13-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0313] Example 23 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =670.3; 1H NMR (400MHz, CD3OD) δppm 8.56 (br s, 1H), 7.69 (br dd, J = 5.8, 8.9Hz, 1H), 7.51-7.36 (m, 1H), 7.31 (br d, J = 2.3Hz, 1H), 7.26 (br t, J = 9.5Hz, 1H), 6.95 (br s,1H),4.61(br s,2H),4.35-4.14(m,2H),3.77(br d,J=14.5Hz,1H),3.55(br s,1H),3.48-3.25(m,3H),3.28(br s,1H),3.18-2.94(m,2H),2.64(br s,1H),2.47-2.02(m,8H),1.94-1.70(m,4H),1.59(br d,J=8.2Hz,2H),1.42(br s,2H),1.32(br d,J=2.7Hz,3H),1.07(br s,1H),0.89-0.54(m,4H).

[0314] Example 24A and Example 24B: Two isomers of 13-((1s,7a's)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0315] Example 24A was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =706.5; 1H NMR(400MHz,CD3OD)δppm 7.67(dd,J=5.9,8.9Hz,1H),7.33(s,1H),7.30-7.27(m,1H),7.23(t,J=9.6H z,1H),6.93(d,J=2.5Hz,1H),4.74-4.50(m,1H),4.41-4.24(m,2H),4.18(br d,J=12.5Hz,1H),4.10-3.98(m,1H),3.72(br d,J=14.6Hz,1H),3.49-3.32(m,3H),3.25-3.15(m,1H),3.02-2.83(m,2H),2.78-2.57(m,2H),2.38(br d,J=6.5Hz,1H),2.29(br dd,J=6.1,13.6Hz,1H),2.22-2.11(m,2H),2.03(s,1H),1.97-1.91(m,1H),1.87 -1.73(m,5H),1.64-1.50(m,2H),1.49-1.33(m,4H),1.32-1.27(m,3H),1.00(br d,J=7.3Hz,1H).

[0316] Example 24B was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =706.8; 1H NMR (400MHz, CD3OD) δppm 7.69(dd,J=5.8,9.1Hz,1H),7.43(s,1H),7.31(d,J=2.6Hz,1H),7.25(t,J=9.6Hz,1H),6.94(d,J=2.6Hz,1H),4.63(br s,1H),4.41-4.28(m,2H),4.20(br d,J=12.5Hz,1H),4.10(br d,J=13.3Hz,1H),3.77(br d,J=14.9Hz,1H),3.41-3.34(m,2H),3.30(br s,1H),3.24-3.14(m,1H),2.99(br t,J=13.2Hz,1H),2.89(br d,J=12.0Hz,1H),2.78-2.59(m,2H),2.44-2.25(m,2H),2.23-2.10(m,2H),2.04(br d,J=13.5Hz,1H),1.98-1.92(m,1H),1.89-1.75(m,5H),1.60(br d,J=8.4Hz,2H),1.52-1.36(m,4H),1.31(s,3H),1.02(br s,1H).

[0317] Example 25: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0318] Example 25 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =656.1; 1H NMR (400MHz, CD3OD) δppm 8.56 (br s, 1H), 7.70 (dd, J=5.9, 8.8Hz, 1H), 7.49-7.30 (m, 2H), 7.26 (t, J=9.5Hz, 1H), 6.95 (br s, 1H), 5.19 (br d,J=6.2Hz,2H),4.70-4.47(m,2H),4.29(br d,J=13.0Hz,1H),4.16(br d,J=13.4Hz,2H),3.83-3.68(m,2H),3.56(br s,1H),3.46-3.34(m,2H),3.16-2.91(m,3H),2.78-2.59(m,2H),2.48-2.26(m,2H),2. 25-1.98(m,4H),1.91-1.71(m,4H),1.67-1.38(m,4H),1.32(d,J=3.1Hz,3H),1.06(br s,1H).

[0319] Example 26: (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((1-(morpholinomethyl)cyclopropyl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0320] Example 26 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =674.3; 1 H NMR(400MHz,CD3OD)δppm 7.69(dd,J=8.9,5.9Hz,1H),7.43(s,1H),7.33-7.21(m,2H),6.97-6.92(m,1H),4. 44-4.34(m,2H),4.22-4.00(m,2H),3.79-3.64(m,5H),3.46-3.35(m,2H),2.98(br t,J=13.0Hz,1H),2.80-2.57(m,7H),2.38(br s,1H),2.17(br s,1H),1.91-1.74(m,4H),1.72-1.24(m,8H),1.00(br s,1H),0.82-0.70(m,2H),0.56(s,2H).

[0321] Example 27: (R)-13-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecyl[2,3-g]quinazolin-17-ol

[0322] Example 27 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =632.3; 1 H NMR(400MHz,CD3OD)δppm 8.56(br s,1H),7.70(dd,J=5.9,9.0Hz,1H),7.50-7.38(m,1H),7.32(d,J=2.6Hz,1H),7.26(t,J=9.6Hz,1H),6.98-6.88(m,1H),4.64(br s,2H),4.43-4.29(m,2H),4.25(br d,J=13.2Hz,1H),4.18-4.05(m,1H),3.75(br d,J=14.7Hz,1H),3.44-3.37(m,1H),3.00(br s,2H),2.72(br s,6H),2.38(br s,1H),2.19(br s,1H),1.92-1.74(m,4H),1.60(br s,2H),1.50-1.34(m,3H),1.32(d,J=4.2Hz,3H),1.02(br s,1H),0.88(s,2H),0.73(br s,2H).

[0323] Example 28A and Example 28B: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0324] Example 28A was prepared by a similar synthetic route to Example 16: a peak with a shorter retention time on HPLC, 0.94 mg, yellow solid. LCMS (ESI): [M+H] + =618.2; 1H NMR (400MHz, CD3OD) δppm 7.67 (dd, J=8.9, 5.7Hz, 1H), 7.39-7.17 (m, 3H), 6.93 (d, J=2.4Hz, 1H), 4.65-4.44 (m, 3H), 4.27-4.01 (m, 2H), 3.73 (br d,J=15.2Hz,1H),3.41(br d,J=13.0Hz,1H),2.98(br t,J=13.3Hz,1H),2.74-2.59(m,5H),2.46-2.08(m,3H),2.04-1.70(m,8H),1.65-1.24(m,8H),1.02(br s,1H).

[0325] Example 28B was prepared by a similar synthetic route to Example 16: the peak with the longest retention time on HPLC, 1.04 mg, yellow solid. LCMS (ESI): [M+H] + =618.2; 1 H NMR (400MHz, CD3OD) δppm 7.74-7.61(m,1H),7.48-7.37(m,1H),7.33-7.18(m,2H),6.92(br s,1H),4.65-4.38(m,3H),4.35-4.04(m,2H),3.82-3.65(m,1H),3.42-3.38(m,2H),3.05-2.90(m,1H),2.78(s,3H),2.61(br s,2H),2.43-2.06(m,3H),2.05-1.69(m,7H),1.67-1.16(m,8H),1.02(br s,1H).

[0326] Example 29 and Example 30: 13-((2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazole Quinazolin-17-ol and 3,15-difluoro-13-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0327] Example 29 was prepared by a similar synthetic route to Example 16: (1.5 mg, 2.17 μmol, yield 1%), as a yellow solid. LCMS (ESI): [M+H] + =692.4; 1 H NMR(400MHz,CD3OD)δppm 7.69(br dd,J=5.8,9.0Hz,1H),7.45(s,1H),7.34-7.20(m,2H),6.94(d,J=2.5Hz,1H),4.50-4.29(m,2H),4.26-4.09(m,2H),4.02-3.59(m,4H),3.38(br s,1H),3.07-2.84(m,3H),2.71-2.56(m,2H),2.39(br s,1H),2.26-1.94(m,5H),1.91-1.73(m,5H),1.60(br s,2H),1.41(br s,2H),1.31(s,3H),1.02(br s,1H).

[0328] Example 30 was prepared by a similar synthetic route to Example 16: (8.0 mg, 11.89 μmol, yield 7%), as a yellow solid. LCMS (ESI): [M+H] + =674.4; 1 H NMR(400MHz,CD3OD)δppm 7.74-7.65(m,1H),7.47-7.18(m,3H),6.95(br s,1H),6.93-6.53(m,1H),4.53-4.00(m,4H),3.96-3.53(m,2H),3.48-3.36(m,2H),3.32-3.1 7(m,1H),3.05-2.52(m,5H),2.45-1.91(m,6H),1.90-1.72(m,4H),1.64-1.36(m,5H),1.32(br d,J=3.7Hz,3H),1.03(br s,1H).

[0329] Example 31: (R)-13-((2,6-dimethylene-tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0330] Example 31 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =668.3; 1 H NMR (400MHz, CD3OD) δppm 7.59 (dd, J=5.9, 9.1Hz, 2H), 7.22 (d, J=2.6Hz, 1H), 7.18-7.12 (m, 1H), 6.84 (d, J=2.6Hz, 1H), 5.22 (br s, 4H), 4.61 (br d,J=13.8Hz,1H),4.37(br d,J=14.8Hz,2H),3.86(br d,J=15.5Hz,2H),3.69(br d,J=14.9Hz,1H),3.52(br d,J=13.5Hz,1H),3.08-2.95(m,3H),2.84-2.73(m,2H),2.61-2.51(m,1H), 2.27-2.05(m,3H),1.85-1.64(m,4H),1.54-1.34(m,3H),1.32-1.03(m,8H).

[0331] Example 32: (Z)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0332] Example 32 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =654.5; 1 H NMR (400MHz, CD3OD) δppm 7.81(dd,J=5.7,9.0Hz,1H),7.38-7.27(m,2H),7.09-6.98(m,1H),6.88(br d,J=8.7Hz,1H),5.69-5.59(m,1H),5.14(br s,3H),4.78-4.37(m,2H),4.32-3.95(m,3H),3.69-3.52(m,2H),3.51-3.36(m,2H),3.05-2.53(m,4H),2.40-1.69(m,12H),1.61(br s,1H),1.32(d,J=3.8Hz,3H).

[0333] Examples 33A and 33B: Two isomers of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-((1-morpholinocyclopropyl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0334] Example 33A was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =660.3; 1 H NMR (400MHz, CD3OD) δppm 7.67 (dd, J=6.2, 8.6Hz, 1H), 7.41-7.09 (m, 3H), 6.93 (s, 1H), 4.51 (br d, J=3.0Hz, 3H), 4.17-4.10 (m, 1H), 4.02 (br d,J=12.5Hz,1H),3.72(br d,J=13.9Hz,1H),3.59(br d,J=3.9Hz,4H),3.40(br d,J=13.4Hz,2H),2.88(br d,J=4.3Hz,4H),2.67-2.62(m,1H),2.43-2.33(m,1H),2.23-2.13(m,1H),1.87-1.68( m,4H),1.64-1.50(m,2H),1.45-1.35(m,2H),1.31(s,3H),1.05-0.95(m,1H),0.75(br d,J=9.9Hz,4H).

[0335] Example 33B was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =660.2; 1H NMR (400MHz, CD3OD)δppm 7.67(dd,J=5.7,8.9Hz,1H),7.42(s,1H),7.31-7.19(m,2H),6.92(d,J=2.1Hz,1H),4.51(d,J=6.8Hz,3H),4.18-4.04(m,2H),3.75(br d,J=14.0Hz,1H),3.63-3.55(m,4H),3.36(br s,2H),2.91-2.83(m,4H),2.68-2.62(m,1H),2.42-2.30(m,1H),2.20-2.10(m,1H),1.88-1.71(m,4H),1.64-1.53(m,2H),1.39(br d,J=6.9Hz,2H),1.30(s,3H),1.04-0.94(m,1H),0.76(br d,J=10.0Hz,4H).

[0336] Example 34: 13-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0337] Example 34 was prepared by a similar synthetic route with reference to Example 16: 1 H NMR (400MHz, CD3OD) δppm 7.69 (dd, J=6.1, 8.8Hz, 1H), 7.49-7.17 (m, 3H), 6.94 (br s, 1H), 4.63 (br s,2H),4.57-4.44(m,2H),4.23-4.03(m,2H),3.84-3.70(m,1H),3.47-3.36(m,2H),3.12-2 .94(m,2H),2.82-2.62(m,2H),2.50(s,3H),2.44-2.15(m,3H),1.94-1.71(m,4H),1.60(br s,2H),1.40(br s,2H),1.32(d,J=4.4Hz,3H),1.02(br s,1H).

[0338] Example 35: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0339] Example 35 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =632.4; 1 H NMR(400MHz,CD3OD)δppm 8.56(br s,1H),7.69(dd,J=8.9,5.9Hz,1H),7.45-7.36(m,1H),7.31(d,J=2.6Hz,1H),7 .25(t,J=9.5Hz,1H),6.99-6.87(m,1H),5.35-5.27(m,1H),4.29-4.02(m,3H),3 .82-3.72(m,1H),3.48-3.37(m,3H),3.07-2.96(m,1H),2.92-2.78(m,5H),2.72 -2.60(m,1H),2.44-2.11(m,4H),2.07-1.96(m,2H),1.91-1.74(m,6H),1.59(br d,J=6.5Hz,2H),1.45(br d,J=6.1Hz,3H),1.32(d,J=3.4Hz,3H).

[0340] Example 36: 13-(2,2-difluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0341] Example 36 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =680.3; 1H NMR (400MHz, CD3OD) δppm 7.69 (dd, J=8.7, 5.9Hz, 1H), 7.44-7.34 (m, 1H), 7.32-7.21 (m, 2H), 6.95 (br s,1H),4.29-4.16(m,3H),4.13-4.03(m,1H),3.81-3.71(m,1H),3.54-3.37(m,3H),3 .22-3.09(m,2H),3.04-2.84(m,2H),2.72-2.59(m,2H),2.46-1.70(m,12H),1.59(br s,2H),1.40(br d,J=5.5Hz,2H),1.32(br d, J = 4.6 Hz, 3H).

[0342] Example 37: 3,15-difluoro-13-((hexahydrocyclopropano[b]pyrrolazin-5a(3H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0343] Example 37 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =656.1; 1 H NMR(400MHz,CD3OD)δppm 7.67(dd,J=5.9,8.9Hz,1H),7.45-7.31(m,1H),7.30-7.18(m,2H),7.02-6. 84(m,1H),4.32-3.94(m,5H),3.77-3.69(m,1H),3.44-3.34(m,2H),3.17(br s,4H),2.67-2.58(m,1H),2.42-2.34(m,1H),2.26-2.10(m,4H),1.98(br d,J=4.4Hz,3H),1.81-1.69(m,4H),1.62-1.51(m,2H),1.44-1.34(m,2H),1.29(d,J=4.0Hz,3H),1.07-0.92(m,1H),0.88-0.55(m,2H).

[0344] Example 38: 13-((2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0345] Example 38 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =692.7; 1 H NMR (400MHz, CD3OD) δppm 7.61-7.53(m,1H),7.28-7.07(m,3H),6.83(d,J=2.6Hz,1H),4.92(br d,J=3.8Hz,2H),4.23-4.06(m,3H),3.97(br d,J=13.1Hz,1H),3.65(br t,J=14.6Hz,2H),3.41-3.32(m,2H),3.30-3.24(m,1H),3.10-2.98(m,1H),2.93-2.81(m,1H),2.75-2.67(m,1H),2.60-2.46( m,3H),2.31(q,J=14.4Hz,2H),2.14-2.00(m,1H),1.80-1.60(m,4H),1.55-1.38(m,2H),1.35-1.16(m,6H),0.95-0.84(m,1H).

[0346] Example 39: (R)-13-(3-(dimethylamino)azetidinyl)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0347] Example 39 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =603.1. 1H NMR (400MHz, CD3OD) δppm 7.73-7.63(m,1H),7.41-7.14(m,3H),6.92(dd,J=2.8,4.7Hz,1H),4.22(br s,2H),4.13-3.85(m,4H),3.69(br s,1H),3.37(br s,2H),3.29-3.25(m,1H),2.93(s,1H),2.67(br d,J=4.5Hz,1H),2.44-2.34(m,1H),2.26(s,6H),2.15-2.04(m,1H),1.87-1.68(m,4H),1.56(br s,2H),1.36(br s,2H),1.30(d,J=5.4Hz,3H),1.01-0.87(m,1H).

[0348] Example 40: (3R)-1-(17-amino-3,15-difluoro-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0349] Step 1: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (1.00 g, 1.51 mmol) in acetonitrile (20.0 mL) was added hydrogen chloride (4 M in dioxane, 5.68 mL, 22.71 mmol) at 0° C. The solution was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude compound (R)-3,15-difluoro-17-hydroxy-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (1.00 g) as a brown solid. LCMS (ESI): [M+H] + =617.1.

[0350] Step 2: To a solution of (R)-3,15-difluoro-17-hydroxy-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (crude, 920 mg, 1.49 mmol) in dichloromethane (20.0 mL) was added triethylamine (1.04 mL, 7.46 mmol) at 0°C. Trifluoromethanesulfonic anhydride (276 uL, 1.64 mmol) was slowly added dropwise at 0°C, and the solution was stirred at 0°C for 4 hours. After the reaction was complete, the mixture was quenched with ice water (10 mL) and extracted with dichloromethane (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl trifluoromethanesulfonate (510 mg, 0.68 mmol, yield 46%) as a brown solid. LCMS (ESI): [M+H] + =749.1.

[0351] Step 3: Under nitrogen atmosphere, to a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl trifluoromethanesulfonate (500 mg, 0.67 mmol) in tetrahydrofuran (5.00 mL) were added tert-butyl carbamate (110 mg, 0.94 mmol), cesium carbonate (653 mg, 2.00 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (38.6 mg, 0.07 mmol) and tris(dibenzylideneacetone)dipalladium (61.2 mg, 0.07 mmol). The mixture was stirred at 70°C for 2 hours. It was cooled naturally to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-60% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound (R)-(3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamic acid tert-butyl ester (110 mg, 0.15 mmol, yield 23%). LCMS (ESI): [M+H] + =716.5.

[0352] Step 4: Compound (R)-tert-butyl (3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (110 mg, 0.15 mmol) and phenylsilane (166 mg, 1.54 mmol) were dissolved in tetrahydrofuran (5.0 mL), and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (10.3 mg, 15.37 umol) was added, and the reaction was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give tert-butyl (R)-(3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (53.0 mg, 75.51 umol, 49% yield) as a yellow solid. LCMS (ESI): [M+H] + =702.1.

[0353] Step 5: Dissolve (R)-tert-butyl (3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (50.0 mg, 71.25 umol), 4A molecular sieves (20.0 mg) and sodium tert-butoxide (34.2 mg, 0.36 mmol) in tetrahydrofuran (500 uL), add (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (54.0 mg, 0.36 mmol), and stir the reaction at 60 ° C for 16 hours. The mixture was diluted with water (300 uL) and extracted with ethyl acetate (300 uL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound, tert-butyl (3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (28.0 mg, 37.05 umol, yield 52%). LCMS (ESI): [M+H]+ =755.4.

[0354] Step 6: Dissolve the compound tert-butyl (3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-yl)carbamate (30.0 mg, 39.74 umol) in trifluoroacetic acid / dichloromethane (volume ratio of 1:4, 300 uL) and stir at 25°C for 2 hours. The reaction solution was concentrated in vacuo, and the residue was added to dichloromethane (300 uL) and neutralized with triethylamine (until pH>7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound (3R)-1-(17-amino-3,15-difluoro-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (1.09 mg, 1.59 umol, yield 4%). LCMS (ESI): [M+H] + =655.3; 1 H NMR (400MHz, CD3OD) δppm 7.60 (dd, J=6.3, 8.7Hz, 1H), 7.52-7.41 (m, 1H), 7.37-7.33 (m, 1H), 7.19 (br s, 1H), 6.86 (s, 1H), 5.04 (br s, 2H), 4.41- 4.26(m,2H),4.25-4.15(m,1H),4.14-4.04(m,1H),3.89-3.82(m,1H),3.80-3.70(m,1H),3.48-3.38(m,2H),3.07-2.92(m,1H),2.88-2 .79(m,2H),2.69-2.48(m,2H),2.42-2.28(m,1H),2.24-2.16(m,3H),2.09-1.96(m,3H),1.92-1.74(m,6H),1.67-1.51(m,4H),1.35(br s,3H).

[0355] Example 41: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteriomethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one

[0356] Step 1: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (100 mg, 0.15 mmol) and cesium carbonate (54.3 mg, 0.17 mmol) in N,N-dimethylformamide (2.0 mL) was added deuterated iodomethane (19 uL, 0.30 mmol). The solution was stirred at 25°C for 16 hours. Water (6 mL) was added and the mixture was extracted with ethyl acetate (6 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. A crude brown oily compound (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteriomethyl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (120 mg) was obtained. LCMS (ESI): [M+H] + =678.1.

[0357] Step 2: To a solution of (R)-3,15-difluoro-11-(3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteriomethyl)-13-(2,2,2-trifluoroethoxy)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (115 mg, 0.17 mmol), 4A molecular sieves (115 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (81 mg, 0.51 mmol) in tetrahydrofuran (2.0 mL) was added sodium tert-butoxide (32.6 mg, 0.34 mmol). The mixture was stirred at 60°C for 16 hours. Water (2 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (3 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a crude yellow oily compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteriomethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (200 mg). LCMS (ESI): [M+H] + =737.5.

[0358] Step 3: To a solution of 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-9-(trideuteriomethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (200 mg, 0.27 mmol) in acetonitrile (4.0 mL) was added hydrogen chloride (4 M in dioxane, 1018 uL, 4.07 mmol). The mixture was stirred at 25°C for 1 hour. The reaction solution was dried with nitrogen. The residue was purified by preparative HPLC to give a yellow solid compound, 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteriomethyl)-4,5,6,7-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-8(9H)-one (17.49 mg, 0.03 mmol, yield 9%). LCMS (ESI): [M+H] +=693.3. 1 H NMR (400MHz, CD3OD) δppm 8.11(d,J=9.8Hz,1H),7.70(dd,J=5.9,8.9Hz,1H),7.37-7.23(m,2H),7.10-6.98(m,1H),5.47-5.30(m,1H),4.49-4.39(m, 2H),4.38-4.30(m,1H),4.23-4.13(m,1H),3.60-3.49(m,2H),3.48-3.36(m,4H),3.21-3.10(m,1H),2.76(br d,J=4.5Hz,1H),2.66-2.55(m,1H),2.48(br dd,J=6.7,13.6Hz,1H),2.39-2.31(m,1H),2.24-2.08(m,5H),2.01-1.92(m,1H),1.85(br s,1H),1.82-1.73(m,2H),1.53(br d,J=6.6Hz,2H),1.41-1.33(m,1H),1.31-1.25(m,3H),1.15(br s,1H).

[0359] Example 42: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-17-ol

[0360] Step 1: To a solution of (R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol and (2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (20.0 mg, 0.03 mmol) in tetrahydrofuran (0.4 mL) was added sodium tert-butoxide (9.0 mg, 0.09 mmol). The mixture was stirred at 60°C under nitrogen for 16 hours. Water (2 mL) was added to dilute the mixture at 0°C and the mixture was extracted with ethyl acetate (2 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane:methanol=10:1) to give a yellow solid compound (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (10 mg, 0.01 mmol, yield 46%). LCMS (ESI): [M+H] + =702.4.

[0361] Step 2: To a solution of (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (10 mg, 0.01 mmol) in acetonitrile (200 uL) was added hydrogen chloride (4 M in dioxane, 53 uL, 0.21 mmol). The solution was heated at 25°C. The mixture was stirred for 1 hour. The solution was blown dry with nitrogen, and the residue was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-17-ol (2.22 mg, 3.38 umol, yield 24%). LCMS (ESI): [M+H] + =658.4; 1H NMR (400MHz, CD3OD) δppm 7.77(br s,1H),7.62-7.50(m,1H),7.40-7.25(m,2H),6.97(br s,1H),5.13(br s,2H),4.53-4.40(m,2H),4.29(br d,J=12.5Hz,1H),4.22-3.99(m,2H),3.85(br d,J=8.2Hz,1H),3.69-3.53(m,4H),3.49-3.36(m,3H),3.17-2.92(m,2H),2 .72-2.57(m,3H),2.34-1.93(m,5H),1.92-1.71(m,3H),1.40-1.25(m,5H).

[0362] Examples 42A to 42D: Four Isomers of 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-(((S)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0363] 3,15-Difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecyl[5,6-g]quinazolin-17-ol was separated by SFC (column: DAICELCHIRALPAK IG (250mm*30mm,10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water / ethanol; phase B is maintained at 60%; flow rate: 80 ml / min) to obtain its corresponding four isomers.

[0364] Example 42A: LCMS (ESI): [M+H] + = 658.3; SFC analysis (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position at 0.846 min; 1H NMR (400MHz, CD3OD) δppm 7.77-7.73 (dd, J=6.0, 9.0Hz, 1H), 7.52 (s, 1H), 7.34-7.24 (m, 2H), 6.95 (d, J=2.6Hz, 1H), 5.14 (br s,2H),4.50-4.40(m,2H),4.28(br d,J=14.1Hz,1H),4.13-4.02(m,2H),3.85-3.82(m,1H),3.65-3.57(m,4H),3.45-3.33(m,3H),3.28-3.22(m,1H), 3.19-3.06(m,1H),3.02-2.88(m,2H),2.70-2.58(m,3H),2.29-1.96(m,5H),1.88-1.71(m,3H),1.31-1.26(m,3H).

[0365] Example 42B: LCMS (ESI): [M+H] + =658.3; SFC analysis (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position at 2.271 min; 1 H NMR (400MHz, CD3OD) δppm 7.77-7.70 (dd, J=6.0, 9.0Hz, 1H), 7.49 (s, 1H), 7.34-7.24 (m, 2H), 6.95 (d, J=2.6Hz, 1H), 5.14 (br s,2H),4.59-4.40(m,2H),4.26(br d,J=14.1Hz,1H),4.17-4.14(m,1H),4.08-4.05(m,1H),3.91-3.78(m,1H),3.66-3.52(m,4H),3.50-3.3 0(m,4H),3.25-2.88(m,3H),2.65-2.58(m,3H),2.29-1.96(m,5H),1.88-1.71(m,3H),1.31-1.26(m,3H).

[0366] Example 42C: LCMS (ESI): [M+H] += 658.3; SFC analysis (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position at 0.893 min; 1 H NMR (400MHz, CD3OD) δppm 7.76 (dd, J=6.2, 9.0Hz, 1H), 7.53 (s, 1H), 7.38-7.26 (m, 2H), 6.95 (d, J=2.4Hz, 1H), 5.12 (br s,2H),4.51-4.31(m,2H),4.31-4.19(m,1H),4.18-4.07(m,1H),3.97(m,1H),3.84(m,1H),3.65-3.49( m,4H),3.48-3.30(m,4H),3.18-2.78(m,3H),2.72-2.51(m,3H),2.25-1.69(m,8H),1.32-1.23(m,3H).

[0367] Example 42D: LCMS (ESI): [M+H] + = 658.3; SFC analysis (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: maintain 40% phase B; flow rate: 4 mL / min): chiral column peak position at 3.209 min; 1 H NMR (400MHz, CD3OD) δppm 7.74 (dd, J=6.2, 9.0Hz, 1H), 7.57-7.53 (m, 1H), 7.38-7.27 (m, 2H), 6.95 (m, 1H), 5.16 (br s,2H),4.55-4.45(m,2H),4.35-4.24(m,1H),4.18-4.06(m,2H),3.92-3.81(m,1H),3.65-3.52(m,5 H),3.44-3.30(m,3H),3.16-2.88(m,3H),2.72-2.57(m,3H),2.32-1.75(m,8H),1.32-1.23(m,3H).

[0368] Example 43A and Example 43B: Two Stereoisomers of 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0369] Example 43A was prepared by a similar synthetic route with reference to Example 42: LCMS (ESI): [M+H] + =664.2; 1 H NMR(400MHz,CD3OD)δppm 7.74(dd,J=5.9,9.1Hz,1H),7.51(s,1H),7.35-7.22(m,2H),6.94(d,J=2. 6Hz,1H),5.41-5.18(m,1H),4.31-4.25(m,1H),4.24-4.14(m,2H),4.09(br d,J=13.1Hz,1H),3.83(td,J=6.3,12.5Hz,1H),3.64-3.51(m,3H),3.42(br d,J=12.8Hz,1H),3.34(br s,1H),3.30-2.93(m,6H),2.63(br d,J=3.0Hz,2H),2.39-2.09(m,4H),2.04-1.71(m,6H),1.29(s,3H).

[0370] Example 43B was prepared by a similar synthetic route with reference to Example 42: LCMS (ESI): [M+H] + =664.2; 1H NMR(400MHz,CD3OD)δppm 7.74(dd,J=5.9,9.1Hz,1H),7.48(s,1H),7.35-7.23(m,2H),6.94(d,J=2. 6Hz,1H),5.41-5.19(m,1H),4.30-4.26(m,1H),4.25-4.16(m,2H),4.06(br d,J=13.4Hz,1H),3.89-3.80(m,1H),3.66-3.54(m,3H),3.46-3.40(m,1H),3.38-3.33(m,1H),3.29-2.96(m,6H),2.65(br d,J=3.0Hz,2H),2.39-2.10(m,4H),2.03-1.71(m,6H),1.27(s,3H).

[0371] Example 44: 1-(3,15-difluoro-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethan-1-one

[0372] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (60.0 mg, 0.09 mmol) and (2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (57.0 mg, 0.37 mmol) in tetrahydrofuran (800.0 uL) were added 4A molecular sieves (60.0 mg) and sodium tert-butoxide (55.0 mg, 0.55 mmol). The solution was stirred at 60°C for 16 hours. The reaction solution was diluted with water (1 mL) and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid compound 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (50.0 mg, 0.06 mmol, yield 66%). LCMS (ESI): [M+H] + =814.4.

[0373] Step 2: To a solution of 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (30.0 mg, 0.04 mmol) in dichloromethane (400.0 uL) was added acetyl chloride (2.60 uL, 0.04 mmol) and triethylamine (15.0 uL, 0.11 mmol) at 0°C. The solution was stirred at 20°C for 2 hours. The reaction solution was diluted with water (1 mL) and extracted with dichloromethane (1 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-80% gradient of ethyl acetate / petroleum ether) to obtain a yellow solid compound 1-(11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)yl)ethan-1-one (25.0 mg, 0.03 mmol, yield 79%). LCMS (ESI): [M+H] + =856.4.

[0374] Step 3: To a solution of 1-(11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)yl)ethan-1-one (20.0 mg, 0.02 mmol) in tetrahydrofuran (400.0 uL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 187.0 uL, 0.18 mmol). The solution was stirred at 20°C for 2 hours. The reaction solution was diluted with water (1 mL) and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude compound 1-(3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethan-1-one (20.0 mg, 0.03 mmol) was obtained as a yellow solid. LCMS (ESI): [M+H] + =742.3.

[0375] Step 4: To a solution of 1-(3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethan-1-one (14 mg, 0.02 mmol) in acetonitrile (200.0 uL) was added hydrogen chloride (4 M in dioxane, 19 uL, 0.07 mmol) and the reaction was stirred at 20°C for 2 hours. The solution was concentrated, dimethyl sulfoxide (1 mL) was added and the pH was adjusted to 8 with triethylamine. The mixture was purified by preparative HPLC to give compound 1-(3,15-difluoro-17-hydroxy-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-9(4H)-yl)ethan-1-one (1.05 mg, 1.47 umol, yield 8%). LCMS (ESI): [M+H] + =698.2; 1H NMR (400MHz, CD3OD) δppm 8.17-7.92(m,1H),7.74-7.62(m,1H),7.32-7.24(m,2H),7.24-6.84(m,1H),5.07(br d,J=7.09Hz,2H),4.52-4.33(m, 3H),4.15(br d,J=12.96Hz,1H),4.00-3.58(m,2H),3.56-3.44(m,2H),2.99-2.73(m,4H),2 .62-2.32(m,2H),2.20(s,5H),2.12-1.51(m,8H),1.42-1.18(m,8H),0.92(br d, J = 17.36 Hz, 1H).

[0376] Example 45: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(methylsulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0377] Step 1: To a solution of 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (50 mg, 0.06 mmol) and pyridine (4 uL, 0.03 mmol) in dichloromethane (600 uL) was added methanesulfonic anhydride (43 mg, 0.25 mmol) at 25°C under nitrogen atmosphere. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (1 mL), extracted with dichloromethane (1 mL*3), and the combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated to give a brown solid compound 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-9-(methylsulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (50 mg, 44.8 umol, yield 73%). LCMS (ESI): [M+H] + =892.5.

[0378] Step 2: To a solution of 11-((R)-3-(tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-9-(methylsulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazoline (48 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 538 uL, 0.538 mmol) under nitrogen at 25°C, and the reaction solution was stirred at 25°C for 2 hours. Water (1 mL) was added to the solution, and the mixture was extracted with ethyl acetate (1 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a brown solid crude compound (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9-(methylsulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (37 mg, 47.6 umol, yield 88%). LCMS (ESI): [M+H] + =778.4.

[0379] Step 3: To a solution of (3R)-1-(3,15-difluoro-17-(methoxymethoxy)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(methylsulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (36 mg, 0.05 mmol) in dichloromethane (500 uL) was added pyridine hydrofluoride (500 uL, 0.01 mmol) at 25°C under nitrogen atmosphere. The reaction was stirred at 25°C for 16 hours. The reaction was quenched with triethylamine until neutral, filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-13-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(methylsulfonyl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol (1.68 mg, 2.3 umol, yield 5%). LCMS (ESI): [M+H] + =734.4; 1H NMR (400MHz, CD3OD) δppm 8.41 (s, 1H), 7.69 (dd, J=5.9, 8.9Hz, 1H), 7.42 (d, J=2.5Hz, 1H), 7.30-7.21 (m, 2H), 5.16 (br s,2H),4.53-4.45(m,2H),4.33-4.05(m,3H),3.76-3.64(m,2H),3.58-3.48(m,1H),3.45-3.36(m,2H),3.03(br s,1H),2.98-2.93(m,1H),2.90(s,3H),2.79(br d,J=14.1Hz,1H),2.71-2.61(m,1H),2.41-2.25(m,2H),2.19-2.00(m,4H),1.89-1.71(m,4H),1.45(br s,1H),1.38-1.28(m,4H),1.22-1.08(m,2H),1.06-0.90(m,2H).

[0380] Example 46: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteriomethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0381] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.13 mmol) in N,N-dimethylformamide (1.00 mL) was added deuterated iodomethane (16.6 uL, 0.26 mmol) and cesium carbonate (47.0 mg, 0.14 mmol). The mixture was stirred at 25°C for 4 hours. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-(trideuteriomethyl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.13 mmol, yield 98%) as a yellow solid. LCMS (ESI): [M+H] + =780.3.

[0382] Step 2: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-(trideuteriomethyl)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.13 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (40.8 mg, 0.27 mmol) in tetrahydrofuran (1.00 mL) were added sodium tert-butoxide (123 mg, 1.28 mmol) and 4A molecular sieves (50 mg). The mixture was stirred at 60°C for 16 hours. Water (1 mL) was added for dilution, and the mixture was extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give a brown solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-(trideuteriomethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.12 mmol, yield 93%). LCMS (ESI): [M+H] + =839.4.

[0383] Step 3: To a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-9-(trideuteriomethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (100 mg, 0.12 mmol) in acetonitrile (1.00 mL) was added hydrogen chloride (4 M in dioxane, 1.79 mL, 7.15 mmol). The solution was stirred at 25° C. for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was added to acetonitrile (1 mL) and neutralized with triethylamine (until pH>7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound, 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-(trideuteriomethyl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (42.1 mg, 0.06 mmol, yield 52%). LCMS (ESI): [M+H] + =681.4. 1 H NMR (400MHz, CD3OD) δppm 7.87(d,J=9.5Hz,1H),7.70(dd,J=6.0,9.0Hz,1H),7.32-7.20(m,2H),6.89(d,J=2.6Hz,1H),5.36(br s,1H),4.33-4.23(m,2H),4.20(d,J=10.5Hz,1H),4.10(br t,J=14.6Hz,1H),3.66-3.52(m,2H),3.50-3.32(m,4H),3.29-3.13(m,3H),3.12-2.95(m,3H),2. 84-2.66(m,2H),2.39-2.09(m,4H),2.03-1.82(m,4H),1.81-1.70(m,2H),1.29(d,J=6.3Hz,3H).

[0384] Example 47: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0385] Example 47 was prepared by a similar synthetic route with reference to Example 46: LCMS (ESI): [M+H] + =678.2. 1 H NMR(400MHz,CD3OD)δppm 7.90(s,1H),7.70(dd,J=6.1,8.9Hz,1H),7.30-7.21(m,2H),6.89(d,J= 2.6Hz,1H),5.39-5.20(m,1H),4.35-4.07(m,4H),3.64-3.54(m,2H),3. 47-3.33(m,4H),3.29-3.13(m,3H),3.12-2.94(m,3H),2.86-2.67(m,5H ),2.39-2.10(m,4H),2.03-1.94(m,2H),1.92-1.69(m,4H),1.30(s,3H).

[0386] Example 48: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0387] Example 48 was prepared by a similar synthetic route with reference to Example 46: LCMS (ESI): [M+H] + =672.3. 1H NMR (400MHz, CD3OD) δppm 8.56 (br s, 1H), 7.92 (d, J = 13.33Hz, 1H), 7.73 (dd, J = 9.05, 6.11Hz, 1H), 7.36-7.21 (m, 2H), 6.91 (s, 1H), 5.17 (br s,2H),4.66-4.34(m,3H),4.27-4.05(m,2H),3.70-3.57(m,2H),3.55-3.36(m,6H),3.18-2.91(m,4H),2.77(br d,J=10.03Hz,5H),2.68(br d,J=15.41Hz,1H),2.33-2.01(m,5H),1.94-1.73(m,3H),1.32(d,J=6.85Hz,3H).

[0388] Example 49: 3,15-difluoro-13-(((2R,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0389] Example 49 was prepared by a similar synthetic route with reference to Example 46: LCMS (ESI): [M+H] + =690.3. 1 H NMR (400MHz, CD3OD) δppm 8.47 (br s, 1H), 7.91 (br d, J=12.1Hz, 1H), 7.73 (dd, J=9.1, 6.2Hz, 1H), 7.34-7.22 (m, 2H), 6.90 (br s,1H),5.54-5.32(m,1H),5.08(br s,2H),4.49-4.30(m,3H),4.23-4.08(m,2H),4.02(br d,J=13.8 Hz,1H),3.78(br d,J=13.7Hz,1H),3.68-3.58(m,3H),3.50-3.43(m,2H),3.18-2.95(m,3H),2.86(br s,1H),2.76(br d,J=11.7Hz,5H),2.62-2.11(m,5H),1.89-1.76(m,3H),1.31(d,J=6.7Hz,3H).

[0390] Example 50: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ylmethylcarbamate

[0391] Step 1: To a solution of 3,15-difluoro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (13 mg, 0.02 mmol) in dichloromethane (1300 uL) was added triethylamine (14 uL, 0.10 mmol) and methylcarbamoyl chloride (2.20 mg, 0.02 mmol) at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with water (1 mL) and extracted with dichloromethane (1 mL*3). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ylmethylcarbamate (3.43 mg, 4.76 umol, yield 24%). LCMS (ESI): [M+H] + =721.3. 1H NMR (400MHz, CD3OD) δppm 7.94 (dd, J=6.1, 8.9Hz, 1H), 7.85-7.77 (m, 1H), 7.52 (s, 1H), 7.41 (br t,J=9.6Hz,1H),7.22-7.13(m,1H),5.41-5.20(m,1H),4.37-4.28(m,1H),4.26-4.17(m,2H),4.09(br d,J=13.3Hz,1H),3.87-3.73(m,1H),3.64-3.51(m,3H),3.47-3.35(m,4H),3.29-3.21(m,2H),3.14-3.01(m,2H),2.80(s,3H),2.67(br s,2H),2.43-1.71(m,10H),1.29(s,3H).

[0392] Example 51: 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yldecanoate

[0393] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500.0 mg, 0.68 mmol) and (S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (209.0 mg, 1.36 mmol) in tetrahydrofuran (6.00 mL) was added 4A molecular sieves (600.0 mg) and sodium tert-butoxide (401.0 mg, 4.09 mmol). The solution was stirred at 60°C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (4 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of methanol / dichloromethane) to obtain a yellow solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (400.0 mg, 0.48 mmol, yield 70%). LCMS (ESI): [M+H] + =830.5.

[0394] Step 2: To a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (150 mg, 0.18 mmol) in acetonitrile (2.00 mL) was added hydrogen chloride (4 M in dioxane, 4.06 mL, 16.2 mmol) and the reaction was stirred at 20°C for 16 hours. The solution was concentrated to give compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (150.0 mg, 0.22 mmol, yield 123%). LCMS (ESI): [M+H] + =672.3.

[0395] Step 3: To a solution of 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (150 mg, 0.22 mmol) in dichloromethane (2.00 mL) was added diisopropylethylamine (116.0 uL, 0.66 mmol) and n-decanoyl chloride (57.0 uL, 0.29 mmol) at -40°C. The solution was stirred at 20°C for 0.5 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (1.5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-80% gradient of ethyl acetate / petroleum ether) to obtain a yellow solid compound (30.0 mg, 85% purity). The obtained compound was purified by preparative HPLC to give a yellow solid compound 3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yldecanoate (17.19 mg, 20.8 umol, yield 9%). LCMS (ESI): [M+H] + =826.5. 1 H NMR (400MHz, CDCl3) δppm 7.78 (dd, J=8.6, 6.3Hz, 1H), 7.65 (t, J=2.6Hz, 1H), 7.59 (br d,J=16.5Hz,1H),7.34-7.29(m,1H),7.06(dd,J=6.0,2.5Hz,1H),4.95(br s,2H),4.35-4.14(m,4H),3.84-3.55(m,3H),3.50-3.21(m,6H),3.20-3.04(m,3H),2.94-2.73(m,6H),2.70-2.54(m,5H),2.41(br d,J=15.9Hz,1H),2.18(td,J=12.0,5.5Hz,1H),2.07-1.87(m,7H),1.80-1.71(m,5H),1.69-1.57(m,2H),1.44-1.33(m,7H),0.88(br t,J=6.7Hz,3H).

[0396] Example 52: (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0397] Step 1: To a solution of (R)-1-(3,15-difluoro-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (20.0 mg, 0.03 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (10.8 mg, 0.07 mmol) in tetrahydrofuran (0.30 mL) was added sodium tert-butoxide (39.2 mg, 0.41 mmol). The mixture was stirred at 60°C for 16 hours. The mixture was cooled to room temperature and diluted with water (0.5 mL). The mixture was extracted with ethyl acetate (0.5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC to obtain two stereoisomers of the compound (R)-1-(3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol. Isomer 1, Example 05-546A-100: The peak with the shorter retention time on HPLC was a yellow solid (1.99 mg, 3.07 umol, 9% yield). LCMS(ESI):[M+H] + =648.2.

[0398] Example 52A: LCMS (ESI): [M+H] + =648.3. 1H NMR(400MHz,CD3OD)δppm 8.09(d,J=7.2Hz,1H),8.01(dd,J=9.0,6.1Hz,1H),7.63-7.51(m,2H),7.46-7.31(m,2H),5.48-5.28(m,1H),4.45-4.21(m,3H),4.17- 4.07(m,1H),3.91-3.79(m,1H),3.68-3.34(m,8H),3.29-3.32(m,1H),3.20-3.03(m,2H),2.71(br s,2H),2.50-2.05(m,6H),2.02-1.71(m,4H),1.32-1.25(m,3H).

[0399] Example 52B: LCMS (ESI): [M+H] + =648.3. 1 H NMR(400MHz,CD3OD)δppm 8.09(d,J=7.3Hz,1H),8.01(dd,J=9.0,6.2Hz,1H),7.64-7.52(m,2H),7.47-7.33(m,2H),5.44-5.24(m,1H),4.38-4.18(m,3H),4.12(br d,J=13.1Hz,1H),3.85(dt,J=12.6,6.3Hz,1H),3.66-3.34(m,8H),3.29-3.22(m,1H),3.15-3.01(m,2H),2.71(br d,J=3.9Hz,2H),2.44-1.69(m,10H),1.40-1.25(m,3H).

[0400] Example 53: (R)-1-(3,15-difluoro-13-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0401] Example 53 was prepared by a similar synthetic route with reference to Example 52: LCMS (ESI): [M+H] + =642.3. 1H NMR (400MHz, CD3OD) δppm 8.02(m,2H),7.84-7.69(m,1H),7.61-7.55(m,1H),7.44-7.34(m,2H),5.10(br s,2H),4.48-4.06(m,3H),4.03-3.71(m,2H),3.69-3.37(m,6H),3.32-3.03 (m,3H),2.98-2.85(m,1H),2.81-2.47(m,3H),2.35-1.63(m,10H),1.30(br d,J=8.7Hz,3H).

[0402] Example 54: (R)-1-(3,15-difluoro-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0403] Example 54 was prepared by a similar synthetic route with reference to Example 52: LCMS (ESI): [M+H] + =656.3. 1 H NMR (400MHz, CD3OD) δppm 8.08-7.83(m,3H),7.50(br t,J=7.7Hz,1H),7.37(br t,J=9.6Hz,1H),7.29(br d,J=6.9Hz,1H),5.06(br s,2H),4.48-4.24(m,3H),4.20-4.10(m,1H),3.91(br d,J=12.8Hz,1H),3.72-3.35(m,7H),3.09-2.98(m,2H),2.92-2.77(m,3H),2.74-2.66(m,3H),2.65-2.51(m,1H),2.33-1.54(m,10H),1.30(br d,J=6.5Hz,3H).

[0404] Example 55: 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol

[0405] Step 1: To a solution of (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (3.9 g, 6.17 mmol), 4-methylbenzenesulfonyl azide (1.95 g, 7.40 mmol), and cuprous iodide (0.12 g, 0.62 mmol) in chloroform (50 mL) and water (0.28 mL, 15.41 mmol) was added triethylamine (1.03 mL, 7.40 mmol). The mixture was stirred at 20° C. under nitrogen protection for 12 hours, diluted with water (50 mL), extracted with ethyl acetate (20 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a crude compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-(p-methylphenylsulfonylacetamide) (5.0 g) as a brown solid. LCMS (ESI): [M+H] + =820.0.

[0406] Step 2: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-p-methylbenzenesulfonylacetamide (5.4 g, 6.59 mmol) in N,N-dimethylformamide (50 mL) were added iodomethane (1.23 mL, 19.76 mmol) and potassium carbonate (2.73 g, 19.76 mmol). The mixture was stirred at 20 ° C for 12 hours. Water (100 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran / petroleum ether) to give a brown solid compound 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (2.38 g, 2.85 mmol, 43% yield). LCMS (ESI): [M+H] + =834.2.

[0407] Step 3: To a solution of 2-(2-fluoro-8-(8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (11.5 g, 13.79 mmol) and triethylamine (9.59 mL, 68.96 mmol) in dichloromethane (140 mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (5.20 mL, 41.38 mmol) at 0°C. The mixture was stirred at 20°C for 16 hours. Water (40 mL) was added to dilute the mixture, and the mixture was extracted with dichloromethane (40 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / (petroleum ether:dichloromethane=3:1)) to give 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (12.7 g, 13.41 mmol, 97% yield) as a brown solid compound. LCMS (ESI): [M+H] + =948.4.

[0408] Step 4: To a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)-N-methyl-N-p-toluenesulfonylacetamide (12.50 g, 13.19 mmol) in dichloromethane (155 mL) was added 1 M diisobutylaluminum hydride (42.19 mL, 42.19 mmol) at -70°C. The mixture was stirred at -70°C for 1 hour, quenched by the addition of acetic acid (7.25 mL, 126.58 mmol), diluted with water (100 mL), stirred, and allowed to stand for 16 hours. Then, dichloromethane (100 mL * 3) was used for extraction, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / (petroleum ether: dichloromethane = 3:1)) to give compound 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)acetaldehyde (7.70 g, 10.08 mmol, yield 76%) as a brown solid. LCMS (ESI): [M+H] + =765.3.

[0409] Step 5: Borane / tetrahydrofuran (1 M, 41 mL, 40.71 mmol) was added to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)acetaldehyde (18.50 g, 24.19 mmol) in tetrahydrofuran (190 mL) at 0°C, and the reaction was stirred at 10°C for 16 hours. The reaction was quenched with methanol at 0°C. The mixture was concentrated under reduced pressure to give a brown solid compound, 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethan-1-ol (18.50 g, 21.71 mmol, yield 90%). LCMS (ESI): [M+H] + =767.8.

[0410] Step 6: Under nitrogen protection, to a solution of 2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethan-1-ol (1.00 g, 1.30 mmol) and rhodium acetate dimer (28.8 mg, 0.07 mmol) in dichloromethane (10.0 mL) was added dropwise ethyl 2-diazopropionate (752 mg, 5.87 mmol). The mixture was stirred at 25 ° C. for 1 hour under nitrogen protection. Methanol (5 mL) was added to quench the mixture and the mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / petroleum ether) to give a crude yellow oily compound, ethyl 2-(2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)propanoate (800 mg, 0.92 mmol, 71% yield). LCMS (ESI): [M+H] + =867.3.

[0411] Step 7: To a solution of ethyl 2-(2-(8-(4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)propanoate (1.34 g, 1.55 mmol) in ethyl acetate (60 mL) was added dry palladium on carbon (300 mg). The mixture was stirred at 20° C. under a hydrogen atmosphere (45 psi) for 16 hours, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)propanoate (1.28 g, 1.53 mmol, yield 99%) as a yellow oily compound. LCMS (ESI): [M+H] + =837.3.

[0412] Step 8: To a solution of ethyl 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)propanoate (1.28 g, 1.53 mmol) in tetrahydrofuran (25.0 mL) and water (2.5 mL) was added lithium hydroxide (385 mg, 9.18 mmol). The mixture was stirred at 60° C. for 5 hours and the pH was adjusted to 5-6 using 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (10 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give a yellow solid compound 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)propanoic acid (1.23 g, 1.52 mmol, yield 99%). LCMS (ESI): [M+H] + =809.3.

[0413] Step 9: To a solution of 2-(2-(8-(6-amino-4-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)propanoic acid (1.23 g, 1.52 mmol) and diisopropylethylamine (10.6 mL, 60.82 mmol) in dioxane (49.0 mL) was added n-butylphosphonic anhydride (50% solution in ethyl acetate, 3.29 g, 4.56 mmol), and the reaction solution was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a brown solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (1.2 g, 1.52 mmol, yield 100%). LCMS (ESI): [M+H] + =791.3.

[0414] Step 10: Compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5-dihydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-8(9H)-one (1.2 g, 1.52 mmol) and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (102 mg, 0.15 mmol) were dissolved in tetrahydrofuran (84 mL), and phenylsilane (3.74 mL, 30.35 mmol) was added under nitrogen, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran / (petroleum ether:dichloromethane=3:1)) to give 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (520 mg, 0.67 mmol, yield 44%) as a yellow solid. LCMS (ESI): [M+H] + =777.3.

[0415] Step 11: To a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-7-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol), 4A molecular sieves, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (160 mg, 1.01 mmol) in tetrahydrofuran (5.00 mL) was added sodium tert-butoxide (569 mg, 5.92 mmol). The mixture was stirred at 60°C for 16 hours. The mixture was cooled to room temperature, diluted with water (3 mL), extracted with ethyl acetate (3 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol / dichloromethane) to give a brown solid compound 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (380 mg, 0.59 mmol, yield 77%). LCMS(ESI):[M+H] + =836.7.

[0416] Step 12: To a solution of 11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-17-(methoxymethoxy)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (380 mg, 0.45 mmol) in acetonitrile (3.00 mL) was added hydrogen chloride (2M in dioxane, 27.3 mL, 54.54 mmol). The solution was stirred at 25°C for 16 hours. The reaction solution was concentrated in vacuo, and the residue was added to acetonitrile (1 mL) and neutralized with triethylamine (until pH>7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound, 3,15-difluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-7-methyl-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (60.0 mg, 0.09 mmol, yield 19%). LCMS (ESI): [M+H] + =678.2. 1 H NMR(400MHz,CD3OD)δppm 7.76(dd,J=6.2,8.7Hz,1H),7.59-7.39(m,1H),7.36-7.22(m,2H),7.05-6. 90(m,1H),5.42-5.24(m,1H),4.43-3.99(m,4H),3.92-3.80(m,1H),3.73(br s,1H),3.64-3.34(m,3H),3.31-3.23(m,3H),3.09-3.03(m,1H),2.93-2.52(m,4H),2. 43-2.10(m,4H),2.07-1.84(m,4H),1.83-1.70(m,2H),1.31(s,3H),1.10-0.91(m,3H).

[0417] Example 56: (R)-1-(17-amino-3,15-difluoro-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol

[0418] Step 1: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (500 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL) was added iodomethane (81.0 uL, 1.32 mmol) and cesium carbonate (235 mg, 0.72 mmol). The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / (3:1 by volume petroleum ether / dichloromethane)) to afford (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol, 90% yield) as a yellow solid. LCMS (ESI): [M+H] + =777.3.

[0419] Step 2: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-17-(methoxymethoxy)-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline (460 mg, 0.59 mmol) in acetonitrile (8.00 mL) was added hydrogen chloride (4 M in dioxane, 1.04 mL, 4.14 mmol). The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a brown solid compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (430 mg, 0.59 mmol, yield 99%). LCMS (ESI): [M+H] +=733.2.

[0420] Step 3: To a solution of (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-ol (135 mg, 0.18 mmol) in dichloromethane (1.35 mL) was added diisopropylethylamine (98 uL, 0.55 mmol). Trifluoromethanesulfonic anhydride (46.5 uL, 0.28 mmol) was slowly added dropwise at -78°C, and the solution was stirred at -70°C for 4 hours. After the reaction was completed, the mixture was quenched with water (1 mL) and extracted with dichloromethane (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a yellow solid crude compound (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl trifluoromethanesulfonate (195 mg). LCMS (ESI): [M+H] + =865.2.

[0421] Step 4: Under nitrogen atmosphere, add (R)-11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazoline-17- To a solution of 1,5-difluoromethanesulfonate (180 mg, 0.21 mmol) in tetrahydrofuran (1.80 mL) were added tert-butyl carbamate (34.1 mg, 0.29 mmol), cesium carbonate (203 mg, 0.62 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.0 mg, 0.02 mmol), and tris(dibenzylideneacetone)dipalladium (19.1 mg, 0.02 mmol). The mixture was stirred at 70°C for 2 hours. After cooling naturally to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran / (3:1 by volume petroleum ether / dichloromethane)) to give a green solid compound, tert-butyl (R)-(11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (144 mg, 0.17 mmol, 83% yield). LCMS (ESI): [M+H] + =832.4.

[0422] Step 5: To a solution of tert-butyl (R)-(11-(3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-(2,2,2-trifluoroethoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (70.0 mg, 0.08 mmol) and (S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (21.9 mg, 0.14 mmol) in tetrahydrofuran (1.00 mL) were added 4A molecular sieves (50 mg) and sodium tert-butoxide (66.1 mg, 0.67 mmol). The mixture was stirred at 60° C. for 16 hours. The mixture was cooled naturally to room temperature, diluted with water (1 mL) and extracted with ethyl acetate (1 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol / dichloromethane) to give a brown solid compound tert-butyl (11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (20.0 mg, 0.02 mmol, yield 27%). LCMS(ESI):[M+H] + =885.5.

[0423] Step 6: To a solution of tert-butyl (11-((R)-3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-3,15-difluoro-9-methyl-13-((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-17-yl)carbamate (20.0 mg, 0.02 mmol) in dichloromethane (200 uL) was added hydrogen chloride (4 M in dioxane, 339 uL, 1.36 mmol). The solution was stirred at 25°C for 16 hours. The reaction solution was concentrated in vacuo, and the residue was added to dichloromethane (1 mL) and neutralized with triethylamine (until pH>7). The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to give a yellow solid compound (R)-1-(17-amino-3,15-difluoro-9-methyl-13-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,8,9-tetrahydro-7H-naphtho[1',8':7,8,9][1]oxa[4]azacycloundecano[5,6-g]quinazolin-11-yl)-3-methylpiperidin-3-ol (formate salt, 7.58 mg, 11.30 umol, yield 50%). LCMS (ESI): [M+H] + =671.2. 1H NMR (400MHz, CD3OD) δppm 8.54 (s, 1H), 7.85 (d, J = 9.2Hz, 1H), 7.62 (dd, J = 6.1, 9.0Hz, 1H), 7.35-7.08 (m, 2H), 6.84 (d, J = 2.3Hz, 1H), 5.11 (br s,2H),4.61-4.26(m,3H),4.15(br t,J=14.1Hz,1H),4.00(br d,J=13.6Hz,1H),3.72-3.47(m,4H),3.46-3.35(m,4H),3.18-3.07(m,1H),3.05-2.85(m,3H),2.84-2.66(m,5H),2.61(br d,J=16.3Hz,1H),2.28-1.72(m,8H),1.30(d,J=5.1Hz,3H).

[0424] Example 57: 13-((2,2-difluoro-6-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-3,15-difluoro-11-((R)-3-hydroxy-3-methylpiperidin-1-yl)-4,5,6,7,8,9-hexahydronaphtho[1',8':4,5,6][1]azacycloundecano[2,3-g]quinazolin-17-ol

[0425] Example 57 was prepared by a similar synthetic route with reference to Example 16: LCMS (ESI): [M+H] + =692.7. 1 H NMR (400MHz, CD3OD) δppm 7.61-7.53(m,1H),7.28-7.07(m,3H),6.83(d,J=2.6Hz,1H),4.92(br d,J=3.8Hz, 2H),4.23-4.06(m,3H),3.97(br d,J=13.1Hz,1H),3.65(br t,J=14.6Hz,2H),3.41-3.32(m,2H),3.30-3.24(m,1H),3.10-2.98(m,1H),2.93-2.81(m,1H),2.75-2.67(m,1H),2.60-2.46( m,3H),2.31(q,J=14.4Hz,2H),2.14-2.00(m,1H),1.80-1.60(m,4H),1.55-1.38(m,2H),1.35-1.16(m,6H),0.95-0.84(m,1H).

[0426] Effect Example 1: AlphaLISA compound screening experiment

[0427] Experimental methods:

[0428] 1. Prepare assay buffer:

[0429] Buffer 1 composition and final concentrations: 25 mM HEPES pH 7.5, 10 mM MgCl2, 0.01% Triton X-100.

[0430] Buffer 2 composition and final concentrations: 25 mM HEPES pH 7.5, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT.

[0431] 2. Experimental Design and Compound Preparation:

[0432] 1> Prepare compounds using an ECHO555 automated plate reader. Test concentrations: The highest detectable concentration of the compound is 10 uM or 1 uM, with 3-fold dilutions, 10 concentrations, 2 replicates per concentration, and 0.5% DMSO.

[0433] 2> High signal control group (High control): 30 replicates, 0.5% DMSO, KRAS protein participates in the reaction, which is regarded as 0% inhibition.

[0434] 3> Low signal control group (Low control): 30 replicates, 0.5% DMSO, no KRAS protein involved in the reaction, regarded as 100% inhibition.

[0435] 3. Experimental steps:

[0436] a. KRAS-GDP protein experimental steps

[0437] 1> Add 5 μl of KRAS solution prepared in buffer 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low signal control group. The final concentration of KRAS reaction is 5 nM (initially 40 nM, after optimization, 5 nM). Incubate at room temperature for 1 hour.

[0438] 2> Add 5 μl of the mixed solution of SOS1 and GTP prepared in buffer 2 to each well of the test plate. The final reaction concentrations are 50 nM and 125 μM (initially 250 nM and 625 μM), respectively. Incubate at room temperature for 1 hour.

[0439] 3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, with the final reaction concentrations of 50 nM and 20 μg / ml, respectively, and incubate at room temperature for 1 hour.

[0440] 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared in buffer 2 to each well of the test plate to a final concentration of 20 μg / ml and incubate at room temperature for 1 hour.

[0441] 5> Use EnVision microplate reader to read the test plate signal value, the excitation light wavelength is 680nm, and the emission light wavelength is 615nm.

[0442] b. KRAS-GTP protein experimental steps

[0443] 1> Mix the prepared protein solution with SOS1-GTP mixed solution (the concentration is the same as GDP protein) at a volume ratio of 1:1 and pre-incubate at room temperature for 1 hour.

[0444] 2> Add 10 μl of the mixed solution from step 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 and 5 μl of the mixed solution of SOS1 and GTP to each well of the low signal control group and incubate at room temperature for 1 hour.

[0445] 3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, with the final reaction concentrations of 50 nM and 20 μg / ml, respectively, and incubate at room temperature for 1 hour.

[0446] 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared in buffer 2 to each well of the test plate to a final concentration of 20 μg / ml and incubate at room temperature for 1 hour.

[0447] 5> Use EnVision microplate reader to read the test plate signal value, the excitation light wavelength is 680nm, and the emission light wavelength is 615nm.

[0448] c. KRAS-GCP protein experimental steps

[0449] 1> Add 5 μl of KRAS solution prepared in buffer 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low signal control group. The final concentration of KRAS reaction is 5 nM. Incubate at room temperature for 1 hour.

[0450] 2> Add 5 μl of buffer 2 to each well of the test plate and incubate at room temperature for 1 hour.

[0451] 3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, with the final reaction concentrations of 50 nM and 20 μg / ml, respectively, and incubate at room temperature for 1 hour.

[0452] 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared in buffer 2 to each well of the test plate to a final concentration of 20 μg / ml and incubate at room temperature for 1 hour.

[0453] 5> Use EnVision microplate reader to read the test plate signal value, the excitation light wavelength is 680nm, and the emission light wavelength is 615nm.

[0454] 4. Experimental Data Analysis:

[0455] 1> Calculate the high control average and low control average based on the original data.

[0456] 2> Calculate the inhibition rate of the compound sample well (Sample signal) using the following formula: (High control average-Sample signal / High control average-Low control average)*100%

[0457] 3> Using the four-parameter fitting mode (log (inhibitor) vs. response--Variable slope (four parameters)) in Graphpad Prism software, the concentration response curve was fitted for the compound and its inhibition rate on the experimental signal at different concentrations to calculate the IC of the compound. 50 value.

[0458] Experimental Materials:

[0459] Experimental instruments:

[0460] Experimental results:

[0461] The inhibitory effects of the compounds of the present invention on GDP, GTP, and GCP proteins of KRAS G12D are shown in Table 1.

[0462] Effect Example 2: ERK phosphorylation cell experiment

[0463] AGS_ERK protein phosphorylation detection

[0464] Day 1: AGS cells were seeded into 384-well cell culture plates and cultured overnight in a 37°C, 5% carbon dioxide cell culture incubator.

[0465] The next day, the compound was added to the plate using Echo550 and incubated for another 3 hours in a 37°C, 5% CO2 incubator. Finally, the cell culture plate was fixed with paraformaldehyde, permeabilized with methanol, and blocked with blocking buffer. A mixture of primary antibodies (rabbit anti-pERK, mouse anti-GAPDH) was added and incubated overnight at 4°C.

[0466] Day 3: Discard the primary antibody and add a secondary antibody cocktail (goat anti-rabbit 800CW, goat anti-mouse 680RD). Incubate at room temperature in the dark. Finally, wash three times with PBST and centrifuge the cell culture plate upside down for 1 minute. Fluorescence signal was read using an Odyssey CLx.

[0467] ERK phosphorylation was calculated according to the following formula:

[0468] Relative expression: (fluorescence signal ratio of compound – average value of positive control) / (average value of negative control – average value of positive control)

[0469] Negative control: DMSO

[0470] Positive control: 10μM Reference

[0471] XLFit 5.0 calculates IC by fitting parameter formula 50 Value: Y=Bottom+(Top–Bottom) / (1+10^((Log IC 50 –X)×HillSlope))

[0472] X: log value of compound concentration

[0473] Y: Average relative expression level of p-ERK among duplicate wells

[0474] The inhibitory effects of the compounds of the present invention on pERK in AGS and AsPC-1 cells are shown in Table 2

[0475] NT: Not tested

[0476] Effect Example 3: 3D Cell Proliferation Experiment

[0477] 3D proliferation assay of AGS and AsPC-1 cells

[0478] The diluted test compound was added to a 384-well low-adsorption cell culture plate using a nanoliter pipetting system (LABCYTE, P-0200). After the cells were plated, the culture plate was placed in a 37°C, 5% CO2 constant temperature incubator. After the compound and cells were incubated for 5 days, the 3D reagent, using Envision multifunctional microplate reader to read the luminescence value (the light signal is proportional to the amount of ATP in the system, and the ATP content directly represents the number of living cells in the system). Finally, the IC value of the compound is obtained using XLFIT software using a nonlinear fitting formula. 50 (half inhibitory concentration). Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0479] X: log value of compound concentration

[0480] Y: inhibition rate (%)

[0481] Inhibition rate (%) = 100 × (negative control average value - compound reading) / (negative control average value - positive control average value)

[0482] Negative control: DMSO

[0483] Positive control: Medium only

[0484] The inhibitory effects of the compounds of the present invention on 3D proliferation of AGS and AsPC-1 cells are shown in Table 3

Claims

1. A heterocyclic compound represented by Formula I-1 or Formula I-2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated derivative thereof, or a solvate thereof: in, In formula I-1 and formula I-2, Cy1 represents a 6-membered aryl group or a 6-membered heteroaryl group; further, the Cy1 can be arbitrarily replaced by 0-3 selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent; Wherein, in formula I-1, Cy2 represents a 6-membered aryl group or a 6-membered heteroaryl group; further, the Cy2 can be arbitrarily replaced by 0-3 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, halogen, halo (C1-C6), halo (C1-C6 alkoxy), hydroxy (C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent; Among them, X 1 N or CR X1 ;X 2 N or CR X2 ;X 3 N or CR X3 ; Among them, R X1 、R X2 、R X3 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ; Wherein, L1 and L2 each independently represent absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-NR a -, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、、-(C1-C6 alkylene)C(O)、-NR a C(O)(C1-C6 alkylene)-, -(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is connected, they form a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; Among them, R 1 、R 2 Each independently represents a 5-16 membered saturated or unsaturated cycloalkyl group or a 5-16 membered saturated or unsaturated heterocycloalkyl group, and the R 1 、R 2 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent; Among them, Y 1 、Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenylene, and wherein CR a R b Can be O, NH, NR a , -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a - replaced; Or, Y 1 、Y 2 Together they form a 5-10 membered saturated or unsaturated ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring; Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), C3-C6 cycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered ring, which may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

2. A heterocyclic compound represented by Formula I-1' or Formula I-2', a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated derivative thereof, or a solvate thereof: in, In Formula I-1' and Formula I-2', M 1 Indicates CR M1 or N; M 2 Indicates CR M2 or N; M 3 Indicates CR M3 or N; M 4 Indicates CR M4 or N; M 5 Indicates CR M5 or N; M 6 Indicates CR M6 or N; M 7 Indicates CR M7 or N; M 8 Indicates CR M8 or N; M 9 Indicates CR M9 or N; M 10 Indicates CR M10 or N; Among them, R M1 、R M2 、R M3 、R M4 、R M5 、R M6 、R M7 、R M8 、R M9 、R M10 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent; Among them, X 1 N or CR X1 ;X 2 N or CR X2 ;X 3 N or CR X3 ; Among them, R X1 、R X2 、R X3 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ; Wherein, L1 and L2 each independently represent absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-NR a -, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、、-(C1-C6 alkylene)C(O)、-NR a C(O)(C1-C6 alkylene)-, -(C1-C6 alkylene)C(O)NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is connected, they form a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; Among them, R 1 、R 2 Each independently represents a 5-16 membered saturated or unsaturated cycloalkyl group or a 5-16 membered saturated or unsaturated heterocycloalkyl group, and the R 1 、R 2 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent; Among them, Y 1 、Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenylene, and wherein CR a R b Can be O, NH, NR a , -C(O), -OC(O)-, -C(O)O-, -CONR a -、-NR a CO-, -N(S(O)2CH3)-, -N(C(O)CH3)-, -S(O)-, -S(O)2-, -P(O)R a - replaced; Or, Y 1 、Y 2 Together they form a 5-10 membered saturated or unsaturated ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring; Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, halo(C1-C6 alkyl), C3-C6 cycloalkyl; or R a 、R b Together with the atoms to which they are attached, they form a 3-6 membered ring, which may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S.

3. The heterocyclic compound represented by formula I-1' or formula I-2' according to claim 2, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: X 2 Indicates CH or N.

4. The heterocyclic compound represented by formula I-1' or formula I-2' according to claim 2 or 3, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: X 3 Indicates CR X3 or N, where R X3 Indicates H, halogen, OR a , CN, NO2, SF5, POMe2, NH2, C1-C6 alkyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl).

5. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: L1 represents absence, -O-(C1-C6 alkylene)-, -O-(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -O-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-, -NR a -(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-(C3-C6 cycloalkyl)-(C0-C6 alkylene)-NR a -、-(C0-C6 alkylene)-(3-6 membered heterocycloalkyl)-(C0-C6 alkylene)-NR a -, -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -NR a -(C1-C6 alkylene)-, -(C1-C6 alkylene)-NR a -、-O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is connected, they form a 3-6 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S.

6. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: L1 represents an O-C1-C6 alkylene group.

7. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 6, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: L1 represents -O-(C0-C6 alkylene)-(CR T R T′ )-(C0-C6 alkylene)-, wherein R T 、R T′ Together with the carbon atom to which it is attached, they form a 3-6 membered saturated or unsaturated ring.

8. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: R 1 represents a 5-16 membered saturated or unsaturated heterocyclic alkyl group, and the R 1 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

9. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: R 1 Has any of the following structures: Furthermore, the R 1 It can also be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), hydroxy(C2-C6 alkenyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

10. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 9, its pharmaceutically acceptable salt, stereoisomer, deuterated derivative or solvate thereof, wherein: R 1 express: Among them, R 1' 、R 2' 、R 3' 、R 4' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ; or R 1' With R 2' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 1' With R 2' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 3' With R 4' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 3' With R 4' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 5' With R 6' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 5' With R 6' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 7' With R 8' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 7' With R 8' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 9' With R 10' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 9' With R 10' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 11' With R 12' Together with the carbon atom to which it is attached, they form a double bond (C=) or C=O; or R 11' With R 12' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 2' With R 3' Together with the atoms to which they are attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the The ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 4' 、R 5' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 8' 、R 9' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 10' 、R 11' Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be arbitrarily replaced by 0-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O.

11. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof, wherein: R 1' 、R 2' 、R 3' 、R 4' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Each independently represents hydrogen, halogen, hydroxyl, carbonyl, C1-C6 alkyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C2-C6 alkenyl, or C2-C6 alkynyl.

12. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 11, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: The R 1 Has the following structure: Among them, R 1' 、R 2' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' As defined in any one of claims 1 to 11.

13. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 12, its pharmaceutically acceptable salt, stereoisomer, deuterated derivative or solvate thereof, wherein: The R 1 Has the following structure: Wherein, ring A is a 3-6 membered ring, and said ring A can be arbitrarily substituted by 0-2 selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo (C1-C6 alkyl), halo (C1-C6 alkoxy), hydroxy (C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 3-6 membered heterocycloalkyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a substituted by a substituent; Among them, R 1' 、R 4' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' As defined in any one of claims 1 to 12.

14. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 13, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: The R 1 Has the following structure: Among them, R 1' 、R 2' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' As defined in any one of claims 1 to 12, wherein R L 、R L’ Each independently represents hydrogen, C1-C6 alkyl or halogen.

15. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 14, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: R 1' 、R 2' 、R 5' 、R 6' 、R 7' 、R 8' 、R 9' 、R 10' 、R 11' 、R 12' Each independently represents hydrogen, halogen, hydroxy, C1-C6 alkyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl); R 3' 、R 4' Together with the atoms connected thereto, they form a 3-6 membered ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring is arbitrarily selected from 0-2 selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a Substituted by:

16. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof, wherein: L2 represents absence, -O-C1-C6 alkylene-, -C1-C6 alkylene-, -C1-C6 alkylene-O-, -NR a -C1-C6 alkylene-, -C1-C6 alkylene-NR a -.

17. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 16, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: L2 means not present.

18. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 17, its pharmaceutically acceptable salt, stereoisomer, deuterated derivative or solvate thereof, wherein: R 2 It is any one of the following cyclic structures of formula (i), formula (ii) or formula (iii): Among them, W 1 Indicates -(CR W1 R W2 ) p -、-(CR W1 R W2 ) p -O-、-O-(CR W1 R W2 ) p -、-NR a -(CR W1 R W2 ) p -、-(CR W1 R W2 ) p -NR a -, -CH=CH- or NR W1 ; Among them, R W1 、R W2 Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ; or R W1 、R W2 Together with the carbon atoms connected to it, they form a 3-8 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; and the ring may also be arbitrarily replaced by 1-2 groups selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; Among them, R 1" 、R 2" 、R 3" 、R 4" 、R 5" 、R 6" 、R 7" 、R 8" Each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b ; or R 1" With R 2" Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 3" With R 4" Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 5" With R 6" Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 7" With R 8" Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 2" With R 3" Together with the atoms to which they are attached, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 4" With R 5" Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 heteroatoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), C3- C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 6" With R 7" Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O; or R 5" With R W1 Together with the atoms connected thereto, they form a substituted or unsubstituted 3-10 membered saturated or unsaturated ring, and the ring may arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, and S; the substitution refers to arbitrarily being replaced by 1-2 atoms selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxyl(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a 、-SO3R a 、-NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-NR a C(O)R a or any CH2 in the ring is replaced by C=O.

19. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 18, its pharmaceutically acceptable salt, stereoisomer, deuterated derivative or solvate thereof, wherein: R 2 Any of the following ring structures: Furthermore, the R 2 It can be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(0)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

20. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 19, its pharmaceutically acceptable salt, stereoisomer, deuterated derivative or solvate thereof, wherein: R 2 Any of the following ring structures: Furthermore, the R 2 It can be arbitrarily replaced by 0-4 groups selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogen, halo(C1-C6 alkyl), halo(C1-C6 alkoxy), hydroxy(C1-C6 alkyl), -OR a 、-C(0)R a 、-OC(O)R a 、-C(O)OR a 、-NO2、-SF5、-SO3R a 、-S(O)2R a , cyano, -C(O)NR a R b 、-NR a C(O)R a 、-NR a R b substituted by a substituent.

21. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof, wherein: R 2 Any of the following ring structures:

22. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 21, its pharmaceutically acceptable salt, stereoisomer, deuterated derivative or solvate thereof, wherein: M 1 To M 10 Indicates CH or N.

23. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 22, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: M 1 To M 10 Indicates CH.

24. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 23, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated derivative thereof, or a solvate thereof, wherein: Y 1 、Y 2 Together they form C1-C 10 Alkylene or C2-C 10 alkenylene, and wherein CR a R b Can be O, NH, -C(O), -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -P(O)R a - replaced.

25. The heterocyclic compound represented by formula I-1' or formula I-2' according to claim 24, its pharmaceutically acceptable salt, its stereoisomer or its solvate, wherein: Y 1 、Y 2 Together they form -(C1-C 10 Alkylene)-NR a -、-O-(C1-C 10 Alkylene)-NR a -、-NR a (C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-C(O)NR a -、-(C1-C 10 Alkylene)-NR a C(O)-、-(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NR a -(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NR a -(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-NR a -、-NR a -(C1-C 10 Alkylene)-, -O-(C1-C 10 Alkylene)-, -C(O)NR a -(C1-C 10 Alkylene)-、-NR a C(O)-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -O-(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-C(O),-(C1-C 10 Alkylene)-C(O)-, -O-(C1-C 10 Alkylene)-C(O)-, -C(O)-(C1-C 10 Alkylene)-, -C(O)-(C1-C 10 Alkylene)-O-, -O-(C1-C 10 Alkylene)-C(O)NR a -、-C(O)NR a -(C1-C 10 Alkylene)-O-, -(C1-C 10 Alkylene)-S-, -S-(C1-C 10 alkylene)-.

26. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 24, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated derivative thereof, or a solvate thereof, wherein: Y 1 、Y 2 Together they form a 5-10 membered saturated or unsaturated ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring.

27. The heterocyclic compound represented by formula I-1' or formula I-2' according to any one of claims 1 to 26, its pharmaceutically acceptable salt, its stereoisomer, deuterated derivative or solvate thereof, wherein: Y 1 、Y 2 Together they form any of the following structures:

28. A compound, a pharmaceutically acceptable salt, a stereoisomer, a deuterated derivative, or a solvate thereof, having the following structure:

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