TWI841200B - Heterocyclic compounds, drug compositions and applications thereof - Google Patents

Abstract

The present invention provides a heterocyclic compound, a drug composition and its application. Specifically disclosed are a heterocyclic compound as shown in formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent thereof. The compound of the present invention has a novel structure and good activity and selectivity.

Description

Heterocyclic compounds, drug compositions and applications thereof

This application claims the priority of Chinese patent application No. 2022100698643 with a filing date of 2022/1/21; Chinese patent application No. 2022105001306 with a filing date of 2022/5/6; Chinese patent application No. 202210900237X with a filing date of 2022/7/28; Chinese patent application No. 2022111939164 with a filing date of 2022/9/28; and Chinese patent application No. 2023100101425 with a filing date of 2023/1/4. This application cites the full text of the above Chinese patent applications.

The present invention relates to a heterocyclic compound, a drug composition and applications thereof.

RAS oncogene mutations 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), of which 85% of RAS-driven cancers are caused by KRAS subtype mutations. KRAS mutations are common 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, and the most common mutations include: p.G12D (41%), p.G12V (28%), and p.G12C (14%).

The full name of the KRAS gene is Kirsten rat sarcoma viral oncogene homolog. KRAS plays a pivotal role in the signal regulation of cell growth. After receiving external signals, the upstream cell surface receptors such as EGFR (ErbBl), HER2 (ErbB2), ErbB3 and ErbB4 will transmit the signal to the downstream through the RAS protein. When the KRAS protein is not activated, it is tightly bound to GDP (guanine nucleotide diphosphate). After being activated by guanine nucleotide exchange factors such as SOSl, it binds to GTP (guanine nucleotide triphosphate) and becomes a kinase active state. After the KRAS gene mutates, it can transmit growth and proliferation signals to downstream pathways independently without relying on upstream growth factor receptor signals, causing uncontrolled cell growth and tumor progression. At the same time, whether the KRAS gene has mutations is also an important indicator of tumor prognosis. Statistics show that among the subtypes of KRAS, KRAS G12D is also a common submutation, with colorectal cancer accounting for 12%, pancreatic cancer accounting for 36%, and non-small cell lung cancer accounting for 4%. Therefore, it is very necessary to develop a new KRAS G12D 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 G12D inhibitors to meet clinical needs.

The technical problem to be solved by the present invention is to address the defect that the existing KRAS G12D inhibitor has a relatively single structure, and to provide a heterocyclic compound, a drug composition and its application. The compound of the present invention has a novel structure and good activity and selectivity.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides a heterocyclic compound as shown in Formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvent complex thereof (referring to the aforementioned heterocyclic compound as shown in Formula I-0, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof): wherein Ring K is an aromatic ring or a heteroaromatic ring; ^X1 is N, NRX1 ^' or ^CRX1 ; ^X2 is N or ^CRX2 ; ^RX1 and ^RX2 are each independently H, CN, halogen, _C1 - _C6 alkyl, C1- _C6 alkyl substituted by one or more halogens, _C1 - _C6 alkyl substituted by one or more hydroxyl groups, PO( _C1 - _C6 alkyl) ₂ , _{C3 -C6 cycloalkyl} , C3- _C6 cycloalkenyl, C2- _C6 alkenyl, _{C2 -C6 alkynyl} , _3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 6-14 membered aryl, 5-14 membered heteroaryl, substituted by one or more X ^X1-1 is a 3-6 membered heterocycloalkyl substituted by one or more ^X1-2 , a 5-14 membered heteroaryl substituted by one or more X1-2, _NO2 , a 3-6 membered heterocycloalkenyl substituted by one or more ^X1-3 , ^ORa , _SF5 , C(=O) ^X1-4 , C(=O) ^ORa , ^-NRaC (O) ^Ra , ^NX1-5X1-6 or _SO2X1-7 ; ^X1-1 and ^X1-3 are each independently (C=O) _-C1 - ^C6 alkyl; ^X1-2 is independently _C1 - _C6 alkyl; ^{X1-4 is} independently H, _C3 - _C8 cycloalkyl, 3-8 membered heterocycloalkyl, _C1 - _C6 alkyl, or _C1 - _C6 alkyl substituted by one or _more halogens; X ^X1-5 and ^X1-6 are each independently H, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, _SO2 - _C1 - _C6 alkyl or (C=O) _-C1 - _C6 alkyl, or ^X1-5 and ^X1-6 together with the atoms to which they are connected form a _C3 - _C6 aliphatic carbocyclic ring, a _C3 - _C6 carboolefin ring, a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered carboolefin ring; ^X1-7 is ^ORa or _C1 - _C6 alkyl; ^X3 is N or ^CRX3 , ^RX3 is H, halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C3 - _C6 cycloalkyl, C3- _C6 R ^{a and R b each independently represent hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; or R a} _{and R b together with the atoms to which they are attached form a C 3 -C 6} ^{aliphatic ring , a} C ₃ -C 6 carboolefin ring ^{, a} 3-6 membered aliphatic heterocyclic ring or a _3-6 membered carboolefin ring; or R ^{a and} R ^b together with the ^{atoms to} which they ^are attached form a C ₃ -C ₆ aliphatic ring, a C ₃ -C ₆ carboolefin ring, _a 3-6 membered aliphatic heterocyclic ring or a _{3-6 membered} carboolefin ring ^; or R ^X1 and ^RX3 and the atoms to which they are connected together form a _C5 - _C8 cycloenone structure; or ^RX1' and ^RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups; ^R1 is a _C6 - _C14 aryl, a _C6 - _C14 aryl substituted by one or more ^R1-1 , a 5-14 membered heteroaryl, or a 5-14 membered heteroaryl substituted by one or more ^R1-2 ; ^R1-1 and ^R1-2 are each independently halogen, OH, CN, _NO2 , _C1 - _C6 alkyl, C2- _C6 alkenyl, _C2 - _C6 alkynyl, _C3 -C6 cycloalkyl, _{C3 - C6} substituted by one or more _halogens , C ₁ -C 6 alkyl groups, C 2 -C 8 alkyl groups, or C 3 -C ₈ aliphatic carbocyclic rings or C ₃ -C ₈ aliphatic carbocyclic rings substituted by one or ^more _R ^1-3 ; or, two adjacent R _1-1 groups ^together with the atoms to which ^they are attached form a C ₃ -C ₈ ^{aliphatic carbocyclic} ring or ^a C _{3 -C 8} aliphatic carbocyclic ring substituted by one or more R ^1-3 , and the remaining R ^1-1 groups are independently halogens ^{, OH} , CN, ^NO ₂ , C ¹ -C _{6 alkyl groups} , C ₂ -C C ₂ -C 6 alkenyl, C 3 -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C ₁ -C ₆ alkyl substituted by one or more halogens, C ₁ -C _{6 alkyl} substituted by one or more hydroxyl groups, OR ^a , B(OH) ₂ , O(C=O)- C ₁ -C ₁₀ alkyl, SO ₃ R ^a , NR ^a R ^b , COR ^a , CONR ^a R ^b , C(O)OR ^a , NR ^a COR ^a ; or, two adjacent R ^1-2 together with the atoms to which they are attached form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-4 , and the remaining R ^{R 1-2} are independently halogen, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, C 2 -C 6 alkenyl, C ₂ -C ₆ alkynyl, C _{3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl} , _3-6 membered heterocycloalkyl, _3-6 membered heterocycloalkenyl, C ₁ -C ₆ alkyl substituted with one or more halogens, C ₁ -C ₆ alkyl substituted with one or more hydroxyl groups, OR ^a , B(OH) ₂ , O(C=O)- C ₁ -C ₁₀ alkyl, SO ₃ R ^a , NR ^a R ^b , COR ^a , CONR ^a R ^b , C(O)OR ^a , NR ^a COR ^a ; R ^1-3 and R ^1-4 are independently halogen; or X ¹ is CR ^X1 , wherein X The C atom in ^X1 is connected to the C atom in the aryl or heteroaryl group in ^R1 through -O-( _CH2 ) _{n1- *} , _* -NH-( _CH2 ) _n2- , -C≡C-( _CH2 ) _n3 -C≡C- _* , or -( _CH2 ) _n4 -O-( _CH2 ) _{n5- *} , wherein the * end is connected to the C atom in ^X1 ; n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6; ^R2 is H, halogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _{C2 - C6} alkynyl, C3- _C6 cycloalkyl, _C3 - _C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated ( _C1 - _C6 alkyl), OR ^a , hydroxy(C ₁ -C ₆ alkyl), cyano, nitro, -SO ₃ R ^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 , 5-14 membered heteroaryl, 6-14 membered aryl; L ₂ represents absence, -O-(C ₁ -C ₆ alkylene) or -NR ^a -(C ₁ -C ₆ alkylene); R ³ represents ; wherein R ^1' , R ^2' , R ^3' , R ^4' , R ^5' , R ^6' , R ^7' , R ^8' , R ^9' , R ^10' , R ^11' , and R ^12' each independently represent hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -SO ₃ R ^a , -NR ^a R ^b , -CO(C ₁ -C ₆ alkyl) or -C(O)NR ^a R ^b ; or R ^1' and R ^2' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily substituted with 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3~6 membered heterocycloalkyl, 3~6 membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^3' and R ^4' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C ₈ carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily being substituted by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^5' and R ^6' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C ₃ -C _8- membered aliphatic carbon ring, substituted C ₃ -C _8- membered carbon olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered carbon heteroolefin ring; the substitution refers to arbitrarily 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^7' and R ^8' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to being arbitrarily replaced by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or ^{any CH2} in the ring is substituted by C=O; or ^{R9 '} and R10 ^' together with the atoms connected thereto form a _C3 - _{C8 aliphatic} carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic _ring , a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R R ^11' and R ^12' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or ^{any CH2} in the ring is substituted by C=O; or ^{R2' and} R3 ^' together with the atoms connected thereto form _{a C3} -C8 _aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^4' , R ^5' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C ₈ carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or any _CH2 in the ring is substituted by C= ^O ; or ^{R8' ,} R9 ^' together with the atoms connected thereto form a _C3 -C8 _aliphatic carbocyclic ring, a C3- ^C8 carboolefin ring, a _{3-8 -} membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R R ^10' and R ^11' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or ^any _CH2 in the ring is substituted by C= ^O ; or ^{R3 '} and R4 ^' together with the atoms connected thereto form a _C3 -C8 _aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; and R R ^9' and R ^10' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; R ⁴ is L ₁ -R ⁵ , L ₁ represents absence, CR ^a R ^b or NR ^a ; R ⁵ is any cyclic structure of the following formula (i), formula (ii) or formula (iii): wherein ^W1 represents ^CRW1RW2 or ^NRW1 ; wherein ^{RW1 and RW2 each} independently represent hydrogen, halogen, cyano, nitro, C1- _C6 alkyl, _C2 -C6 alkenyl _{, C2} - _C6 alkynyl, halogenated ( _C1 - _C6 alkyl), hydroxyl ( _C1 - _C6 alkyl), _C3 - _C6 cycloalkyl, C3- _C6 cycloalkenyl, _3-6 ^{membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa, -SO3Ra, NRaRb , C} _{( O} ^{) Ra} , C(O) ^ORa , C(O) ^{NRaRb , NRaC} (O) ^Ra or (C=O) _-OC1 - _C6 alkyleneO-(C=O) _-C1 - _C10alkyl ; or ^RW1 , R ^W2 together with the atoms connected to it form a 3-8 membered aliphatic heterocyclic ring; wherein ^W2 represents CH or N; wherein Y is methyl, ethyl, _C3 alkyl, _C2 - _C3 alkenyl, or ; R ^c and R ^d together with the atoms to which they are connected form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; or R ^d and R ^d' together with the atoms to which they are connected form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; wherein R ^1'' , R ^2'' , R ^3'' , R ^4'' , R ^5'' , R ^6'' , R ^7'' , and R ^8'' each independently represent hydrogen, halogen, cyano, nitro, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C or R _{1'' and R 2''} ^{together with} the atoms ^to which they ^are attached form a C ₃ -C ₈ aliphatic carbocyclic ring, a C 3 -C ₈ carboolefin ^ring , ^{a 3-8} membered ^aliphatic heterocyclic ring, a 3-8 membered carboolefin ring ^{, a} substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C ₈ carboolefin ring ^{, a substituted} C 3 -C 8 aliphatic heterocyclic ring, a substituted C ₃ -C 8 carboolefin ring, a substituted C _{3 -C 8 aliphatic carbocyclic ring, a substituted C 3} -C ₈ aliphatic heterocyclic ring, a substituted C 3 -C 8 aliphatic heterocyclic ring, a substituted C ₃ -C ₈ aliphatic heterocyclic ring, a substituted C ₃ -C _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^{NRaRb , -NRaC} (O)Ra; or any _CH2 in the ring is substituted by C= ^O ; or ^{R5 ''} and R6 ^'' together with the atoms connected thereto form a _C3 - _C8 aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted C3- _{C8 8-} membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^7'' and R ^8'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^ORa , -C(O) ^{NRaRb , -NRaC} (O)Ra; or any _CH2 in the ring is substituted by C= ^O ; or ^{R2'' and R3 ''} together with the atoms connected thereto form a _C3 - _C8 aliphatic carbocyclic ring, a C3-C8 carboolefin ring, a _{3-8 -} membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted C3- _{C8 8-} membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^R4'' , R5 ^'' together with the atoms connected thereto form a _C3 - _C8 aliphatic carbon ring, a _C3 - _C8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted _C3 - _C8 aliphatic carbon ring, a substituted _C3 - _C8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, halogenated ( _C1 - _C6 alkyl), hydroxyl ( _C1 - _C6 alkyl), _C3 - _C6 cycloalkyl, _C3 -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or any _CH2 in the ring is substituted by C= ^O ; or R6 ^{'' and} R7 ^'' together with the atoms connected ^thereto form a _C3 - _C8 aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted C3- _{C8 8-} membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O) ^Ra ; or any _CH2 in the ring is replaced by C=O; and ^{R5 ''} and R6 ^'' together with the atoms connected ^thereto form a _C3 - _C8 aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted C3- _{C8 8-} membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; It satisfies at least one of the following conditions: Condition 1: In R ³ , R ^1' and R ^2' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carbon heteroolefin ring. The substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or ^any _CH2 in the ring is substituted by C= ^O ; or ^{R3 '} and R4 ^' together with the atoms connected thereto form a _C3 -C8 _aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^5' and R ^6' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily substituted with 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or any _CH2 in the ring is substituted by C= ^O ; or ^{R7 '} and R8 ^' together with the atoms connected thereto form a _C3 -C8 _aliphatic carbocyclic ring, a C3- ^C8 carboolefin ring, a _{3-8 -} membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R R ^9' and R ^10' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6 ^- membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O) ^Ra ; or ^any _CH2 in the ring is substituted by C=O; or R11 ^' and R12 ^' together with the atoms connected thereto form a _C3 - _C8 aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^2' , R ^3' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C ₈ carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O)Ra; or ^any _CH2 in the ring is substituted by C= ^O ; or ^{R4 '} and R5 ^' together with the atoms connected thereto form a _C3 -C8 _aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R ^8' , R ^9' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C ₈ carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6 ^- membered heterocycloalkyl, _3-6 -membered heterocycloalkenyl, ^-ORa , -SO3Ra, -NRaRb, ^-C (O) ^Ra , -C(O) ^{ORa ,} -C(O) ^NRaRb , ^-NRaC (O) ^Ra ; or ^any _CH2 in the ring is substituted by C=O; or R10 ^' and R11 ^' together with the atoms connected thereto form a _C3 - _C8 aliphatic carbocyclic ring, a C3- _C8 carboolefin ring, a _3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted _C3 -C8 _aliphatic carbocyclic ring, a substituted _C3 -C8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; or R R ^3' and R ^4' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a C ₃ -C ₈ carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily substituted with 1-2 groups selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C _6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; and R ^9' and R ^10' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbocyclic ring, a C ₃ -C ₈ carboolefin ring, a 3-8-membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C ₃ -C ₈ aliphatic carbocyclic ring, a substituted C ₃ -C 8 _8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogenated (C ₁ -C ₆ alkyl), hydroxyl (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR ^a , -SO ₃ R ^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 CH ₂ in the ring is substituted by C=O; Condition 2: R ⁵ is any cyclic structure of the following formula (i), formula (ii) or formula (iii): wherein, in formula (ii), when ^W2 is N, ^W1 is ^NRW1 , ^RW1 is not H; in formula (iii), when ^W2 is N, ^W1 is ^NRW1 , ^RW1 is H, Y is not ethylidene; Condition 3: ^X1 is ^CRX1 , ^RX1 is _C1 - _C6 alkyl, _C1 - _C6 alkyl substituted by one or more halogens, PO( _C1 - _C6 alkyl) ₂ , _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, 3-6 membered heterocycloalkyl substituted by one or more ^X1-1 , 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heteroaryl substituted by one or more ^X1-2 , _NO2 , _C3 - _C6 cycloalkyl, C3- _{C6 6-} membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 3-6-membered heterocycloalkenyl substituted by one or more X ^1-3 , SF ₅ , C(=O) X ^1-4 , C(=O) OR ^a , -NR ^a C(O)R ^a , NX ^1-5 X ^1-6 or SO ₂ X ^1-7 ; or, ^RX1 and ^RX3 and the atoms to which they are connected together form a C ₅ -C ₈ cycloalkenone structure; or, X ¹ is NR ^X1' , ^RX1' and ^RX3 and the atoms to which they are connected together form a 5-8-membered heteroaromatic ring or a 5-8-membered heteroaromatic ring substituted by one or more hydroxyl groups; or, X ¹ is CR ^X1 , wherein the C atom in X ¹ and R The C atom in the aryl or heteroaryl in ^X1 is connected through -O-(CH ₂ ) _n1 - _* , _* -NH-(CH ₂ ) _n2 -, -C≡C-(CH ₂ ) _n3 -C≡C- _* , or -(CH ₂ ) _n4 -O-(CH ₂ ) _n5 - _* , wherein the * end is connected to the C atom in ^X1 ; Condition 4: ^R1 is a C ₆ ~C ₁₄ aryl substituted by one or more R ^1-1 or a 5-14 membered heteroaryl substituted by one or more R ^1-2 ; When ^R1 is a C ₆ ~C ₁₄ aryl substituted by one or more R ^1-1 , two adjacent R ^1-1s together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C 14 substituted by one or more R ^1-3 ₈ aliphatic carbocyclic rings, the remaining R ^1-1 are independently halogen, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, C 2 -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, _3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C ₁ -C ₆ alkyl substituted with one or more halogens, C ₁ -C ₆ alkyl substituted with one or more hydroxyl groups, OR ^a , B(OH) ₂ , O(C=O)- C ₁ -C ₁₀ alkyl, SO ₃ R ^a , NR ^a R ^b , COR ^a , CONR ^a R ^b , C(O)OR ^a , NR ^a COR ^a ; when R ¹ is substituted with one or more R When the 5- to 14-membered heteroaryl is substituted with ^1-2 substituted 5- to 14-membered heteroaryl, two adjacent R ^1-2 together with the atoms to which they are connected form a C ₃ -C ₈ carbon ring or a C ₃ -C ₈ carbon ring substituted with one or more R ^1-4 , and the remaining R ^1-2 are independently halogen, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, C ₁ -C ₆ alkyl substituted with one or more halogens, C ₁ -C ₆ alkyl substituted with one or more hydroxyl groups, OR ^a , B(OH) ₂ , O(C=O)- C ₁ -C ₁₀ -alkyl, SO ₃ R ^a , NR ^a R ^b , COR ^a , CONR ^a R ^b , C(O)OR ^a , NR ^a COR ^a ; R ^1-3 and R ^1-4 are independently halogen; wherein the types of heteroatoms in the 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carbon heteroalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbon heteroalkene ring, 3-8-membered aliphatic heterocycle and 3-8-membered carbon heteroalkene ring are independently selected from one, two or three of N, O and S; the 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carbon heteroalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbon heteroalkene ring, 3-8-membered heterocyclic ring and 3-8-membered carbon heteroalkene ring are independently selected from one, two or three of N, O and S; The number of heteroatoms in the heterocycloalkyl, 3-6 membered heterocycloalkenyl, 3-8 membered heterocycloalkyl, 3-6 membered aliphatic heterocycle, 3-6 membered carbon heteroalkene ring, 3-8 membered aliphatic heterocycle, 3-8 membered carbon heteroalkene ring, 3-8 membered aliphatic heterocycle and 3-8 membered carbon heteroalkene ring is independently 1, 2 or 3; the number of heteroatoms in the 5-14 membered heteroaryl and 5-8 membered heteroaryl ring is independently 1, 2, 3 or 4.

In one embodiment, ^X1 is N, NR ^X1′ or CR ^X1 .

In one embodiment, ^RX1 is CN, halogen, _C1 - _C6 alkyl _, C1- _C6 alkyl substituted by one or more halogens, PO( _C1 - _C6 alkyl) ₂ , _C3 - _C6 cycloalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more ^X1-1 , 5-14 membered heteroaryl, 5-14 membered heteroaryl substituted by one or more ^X1-2 , _NO2 , 3-6 ^membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more ^X1-3 , SF5, C(=O) _{X1-4 ,} ^NX1-5X1-6 or ^{SO2X1-7 .}

In one embodiment, X ^1-1 and X ^1-3 are each independently (C=O)-C ₁ -C ₆ alkyl.

In one embodiment, X ^1-2 are independently C ₁ -C ₆ alkyl.

In one embodiment, ^X1-4 are independently H, _C3 - _C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1- _C6 alkyl, _{or C1-C6 alkyl substituted with one or more halogens; X1-5 and X1-6 are each independently H, C1-C6 alkyl ,} ^{SO2 -} _{C1 - C6 alkyl ,} or (C=O) _-C1 - _C6 alkyl.

In one embodiment, X ^1-5 and X ^1-6 are each independently H, C ₁ -C ₆ alkyl, SO ₂ -C ₁ -C ₆ alkyl or (C=O)-C ₁ -C ₆ alkyl.

In one embodiment, X ^1-7 is OH or C ₁ -C ₆ alkyl.

In one embodiment, ^X2 is N or CR ^X2 , and ^RX2 is CN.

In one embodiment, ^X3 is N or CR ^X3 , and ^RX3 is H or C ₁ -C ₆ alkyl.

In one embodiment, R ^1-1 and R ^1-2 are each independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)C ₁ -C ₆ alkyl, C 2 -C ₆ alkynyl, C _{1 -C 6} alkyl substituted with one or more halogens, B(OH) ₂ or O(C=O)- C ₁ -C ₁₀ alkyl.

In one embodiment, two adjacent R ^1-1 together with the atoms to which they are attached form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-3 , and the remaining R ^1-1 are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens, B(OH) ₂ or O(C=O)- C ₁ -C ₁₀ alkyl.

In one embodiment, two adjacent R ^1-2 together with the atoms to which they are attached form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-4 , and the remaining R ^1-2 are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens, B(OH) ₂ or O(C=O)- C ₁ -C ₁₀ alkyl.

In one embodiment, R ² is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.

In one embodiment, _L2 represents -O-( _C1 - _C6 alkylene).

In one embodiment, ^R3 is the following cyclic structure: wherein R ^1' , R ^2' , R ^3' , R ^4' , R ^5' , R ^6' , R ^7' , R ^8' , R ^9' , R ^10' , R ^11' , and R ^12' independently represent hydrogen or halogen; or R ^3' and R ^4' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R ^9' and R ^10' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R ^3' and R R 4 ^' and R ^5' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; and R 9' and R ^10' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R ^4' and R ^5' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R ^8' and R ^9' together with the atoms connected thereto form a C ₃ -C or R ^2' and R ^3' together with the atoms connected thereto form a C ₃ -C _{8 aliphatic} carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution with 1-2 halogens; or R ^10' and R ^11' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C _{3 -C 8 aliphatic} carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution with 1-2 halogens.

In one embodiment, R ⁴ is L ₁ -R ⁵ , L ₁ is absent or NR ^a , and R ^a is hydrogen or C ₁ -C ₆ alkyl.

In one embodiment, R ⁵ is a cyclic structure of any of the following formulas (i), (ii) or (iii): wherein ^W1 represents ^CRW1RW2 or ^NRW1 ; wherein ^RW1 and ^RW2 each independently represent hydrogen, _C1 - _C6 alkyl, 3-6 membered heterocycloalkyl, ^NRaRb , or (C=O)-O ^- _C1 -C6 ^alkyleneO- (C=O) _-C1 - _C10 alkyl; or ^RW1 and ^RW2 together with the atoms to which _{they are connected form a 3-8 membered aliphatic heterocyclic ring; Ra and Rb each independently represent hydrogen or C1-C6} ^{alkyl ;} _{wherein W2} ^represents CH or N; Y is methylene, ethylene, _C3 alkylene, _C2 - _C3 alkenyl, or ; R ^c and R ^d together with the atoms to which they are connected form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; or R ^d and R ^d' together with the atoms to which they are connected form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; wherein R ^1'' , R ^2'' , R ^3'' , R ^4'' , R ^5'' , R ^6'' , R ^7'' , R ^8'' each independently represents hydrogen or C ₁ -C ₆ alkyl; or R ^2'' , R ^3'' together with the atoms to which they are connected form a C ₃ -C ₈ -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or, R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or, R ^4'' and R ^5'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH 2 in the ring is replaced by C=O. ₂ is replaced by C=O; or, R ^5'' and R ^6'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or, R ^6'' and R ^7'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrary substitution by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; and R ^5'' and R ^6'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrary substitution by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O.

In one embodiment, ring K is an aromatic ring or a heteroaromatic ring; ^X1 is N, NRX1 ^' or ^CRX1 , ^RX1 is CN, halogen _{, C1} - _C6 alkyl, C1- _C6 alkyl substituted by one or more halogens, PO( _C1 - _C6 alkyl) ₂ , _C3 - _C6 cycloalkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more ^X1-1 , 5-14 membered heteroaryl, 5-14 membered heteroaryl substituted by one or more ^X1-2 , _NO2 , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more ^X1-3 , _SF5 , ^C (=O) ^X1-4 , ^{NX1-5X1-6 or} _SO2X1-7 ; ^X1-1 and ^X1-3 are each independently (C=O) _-C1 - _C6 alkyl; ^X1-2 is independently _C1 - _C6 alkyl; ^X1-4 is independently H, _C3 - _C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1- _C6 alkyl, or _{C1 - C6} alkyl substituted with one or more halogens; ^X1-5 and ^X1-6 are each independently H, _C1 - _C6 alkyl, _SO2 - _C1 - _C6 alkyl or (C=O) _-C1 - _C6 alkyl; ^X1-7 is OH or _C1 - _C6 alkyl; ^X2 is N or CR ^X2 , ^RX2 is CN; ^X3 is N or CR ^X3 , R ^X3 is H or C ₁ -C ₆ alkyl; or ^RX1 , ^RX3 and the atoms to which they are connected together form a C ₅ -C ₈ cycloenone structure; or ^RX1' , ^RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted with one or more hydroxyl groups; R ¹ is a C ₆ -C ₁₄ aryl, a C ₆ -C ₁₄ aryl substituted with one or more R ^1-1 , a 5-14 membered heteroaryl or a 5-14 membered heteroaryl substituted with one or more R ^1-2 ; R ^1-1 and R ^1-2 are each independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C 6 -C 14 substituted with one or more halogens; or, two adjacent R ^1-1s together with the atoms to which they are attached form a _{C 3} -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-3 , and the remaining R ^1-1s _are independently _halogen , OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens, B(OH) ₂ or O(C=O)- C _{1 -C 10} alkyl; or, two adjacent R ^1-2s together with the atoms to which they are attached form a C _{3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic} ring substituted by one or more R ^1-4 ; -C ₈ aliphatic carbocyclic ring, the remaining R ^1-2 are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C 2 -C 6 alkynyl, C ₁ -C ₆ alkyl substituted with _one or _more halogens, B(OH) ₂ or O(C=O)- C ₁ -C ₁₀ alkyl; R ^1-3 and R ^1-4 are independently halogen; or X ¹ is CR ^X1 , wherein the C atom in X ¹ and the C atom in the aryl or heteroaryl group in R ¹ are bonded via -O-(CH ₂ ) _n1 - _* , _* -NH-(CH ₂ ) _n2 -, -C≡C-(CH ₂ ) _n3 -C≡C- _* or -(CH ₂ ) _n4 -O-(CH ₂ ) _n5 - _* , wherein the * end is connected to the C atom in ^X1 ; n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6; ^R2 is a halogen, a _C1 - _C6 alkyl or a _C1 - _C6 alkoxy; _L2 represents -O-( _C1 - _C6 alkylene); ^R3 is the following cyclic structure: wherein R ^1' , R ^2' , R ^3' , R ^4' , R ^5' , R ^6' , R ^7' , R ^8' , R ^9' , R ^10' , R ^11' , and R ^12' each independently represent hydrogen or a halogen; or R ^3' and R ^4' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R ^9' and R ^10' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R ^3' and R R 4 ^' and R ^5' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; and R 9' and R ^10' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R ^4' and R ^5' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R ^8' and R ^9' together with the atoms connected thereto form a C ₃ -C R ₄ is L ₁ -R 5 , L 1 is absent or NR a , R ₅ is absent or NR a , R ^{6 is} absent or NR a _{, R 7 is} absent or NR a , R ⁸ is absent or NR a , R ₉ is absent _or NR b , R ¹⁰ _is absent or NR _b , R ¹¹ is absent or ^{NR a} , R ¹² is absent or NR _b , R ₁₃ is absent or NR _b ⁵ is any one of the following cyclic structures of formula (i), formula (ii) or formula (iii): wherein ^W1 represents ^CRW1RW2 or ^NRW1 ; wherein ^RW1 and ^RW2 each independently represent hydrogen, _C1 - _C6 alkyl, 3-6 membered heterocycloalkyl, ^NRaRb , or (C=O)-O ^- _C1 -C6 ^alkyleneO- (C=O) _-C1 - _C10 alkyl; or ^RW1 and ^RW2 together with the atoms to which _{they are connected form a 3-8 membered aliphatic heterocyclic ring; Ra and Rb each independently represent hydrogen or C1-C6} ^{alkyl ;} _{wherein W2} ^represents CH or N; Y is methylene, ethylene, _C3 alkylene, _C2 - _C3 alkenyl, or ; R ^c and R ^d together with the atoms to which they are connected form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; or R ^d and R ^d' together with the atoms to which they are connected form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; wherein R ^1'' , R ^2'' , R ^3'' , R ^4'' , R ^5'' , R ^6'' , R ^7'' , R ^8'' each independently represents hydrogen or C ₁ -C ₆ alkyl; or R ^2'' , R ^3'' together with the atoms to which they are connected form a C ₃ -C ₈ -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or, R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or, R ^4'' and R ^5'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH 2 in the ring is replaced by C=O. ₂ is replaced by C=O; or, R ^5'' and R ^6'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or, R ^6'' and R ^7'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; or R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; and R ^5'' and R ^6'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C ₁ -C ₆ alkyl; or any CH ₂ in the ring is replaced by C=O; it satisfies at least one of the following conditions: Condition 1: in R ³ , R ^3' and R ^4' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, substituted C ₃ -C or R ^9' and R ^10' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C 3 -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or R ^3' and R ^4' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; and R ^9' and R ^10' together with the atoms connected thereto form a C ₃ -C 8 aliphatic carbon ring, a substituted C ₃ -C _{8 aliphatic} carbon ring or a _3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or R ^4' and R ^5' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C 3 -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or, R ^2' and R ^3' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a substituted C ₃ -C ₈ aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or, R ^10' and R ₁₁ ^' together with the atoms connected thereto form a C 3 -C ₈ aliphatic carbon ring, a substituted C _{3 -C} 8 aliphatic carbon ring or a _3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; _8- membered aliphatic carbon ring or 3-8-membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by 1-2 halogens; Condition 2: R ⁵ is any one of the following cyclic structures of formula (i), formula (ii) or formula (iii): wherein, in formula (ii), when ^W2 is N, ^W1 is ^NRW1 , ^RW1 is not H; wherein in formula (iii), when ^W2 is N, ^W1 is ^NRW1 , ^RW1 is H, Y is not ethylidene; Condition 3: ^X1 is ^CRX1 , ^RX1 is _C1 - _C6 alkyl substituted by one or more halogens, PO( _C1 - _C6 alkyl) ₂ , _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _NO2 , _C3 - _C6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkyl substituted by one or more ^X1-1 , 5-14 membered heteroaryl substituted by one or more ^X1-2 , ^1-3 substituted 3-6 membered heterocycloalkenyl, _SF5 , C(=O) ^X1-4 , ^NX1-5X1-6 or _SO2X1-7 ; or, ^RX1 and ^RX3 and the atoms to which they are connected together form a _C5 - _C8 cycloalkenone structure; or, ^X1 is NRX1 ^' , ^RX1' and ^RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring or a ^{5-8 membered} heteroaryl ring substituted with one or more hydroxyl groups; or, ^X1 is ^CRX1 , wherein the C atom in ^X1 and the C atom in the aryl or heteroaryl in ^R1 are bonded to each other through -O-( _CH2 ) _{n1- *} , _* -NH-( _CH2 ) _n2- , -C≡C-( _CH2 ) _n3 -C≡C- _* or -( _CH2 ) _n4 -O-(CH ₂ ) _n5 - _* are connected, wherein the * end is connected to the C atom in X ¹ ; Condition 4: R ¹ is a C ₆ ~C ₁₄ aryl substituted by one or more R ^1-1 or a 5-14 membered heteroaryl substituted by one or more R ^1-2 ; When R ¹ is a C ₆ ~C ₁₄ aryl substituted by one or more R ^1-1 , two adjacent R ^1-1s and the atoms to which they are connected together form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-3 , and the remaining R ^1-1s are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C when R ¹ is a _5-14 membered heteroaryl substituted by one or more R ^1-2 , _two adjacent R ^1-2 together with the atoms to which they are connected form a C _{3 -C 8} aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-4 , and the remaining R ^1-2 are independently halogen, OH, NH 2 , CN, C 1 -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C _{6 alkyl} substituted by one or more _halogen , _B (OH) ₂ or O(C=O)- C _{1 -C 10 alkyl} ; R R ^1-3 and R ^1-4 are independently halogen.

In one embodiment, ^RX1 is CN, halogen, _C1 - _C6 alkyl substituted by one or more halogens, PO( _C1 - _C6 alkyl) ₂ , C3- _C6 cycloalkyl, _C2 - _C6 alkenyl, _C2 - _{C6 alkynyl} , 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more ^X1-1 , 5-14 membered heteroaryl substituted by one or more ^X1-2 , _NO2 , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more ^{X1-3 ,} C( ⁼ O) ^X1-4 , ^NX1-5X1-6 or _SO2X1-7 .

In one embodiment, X ^1-4 are independently C ₁ -C ₆ alkyl.

In one embodiment, X ^1-7 is C ₁ -C ₆ alkyl.

In one embodiment, ^X3 is CR ^X3 and ^RX3 is H.

In one embodiment, RX1 ^' and ^RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring.

In one embodiment, R ¹ is a C ₆ -C ₁₄ aryl substituted by one or more R ^1-1 or a 5-14 membered heteroaryl substituted by one or more R ^1-2 ; R ^1-1 and R ^1-2 are each independently a halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, (C=O)-C ₁ -C 6 alkyl, C 2 -C ₆ alkynyl, a C _{1 -C 6} alkyl substituted by one or more halogens, or B(OH) ₂ ; or, two adjacent R ^1-1s together with the atoms to which they are _connected form a C ₃ -C ₈ aliphatic carbocyclic ring, and the remaining R ^1-1s are independently a halogen, OH, NH ₂ , C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens, or B(OH) ₂ .

In one embodiment, the C atom in ^X1 is connected to the C atom in the aryl or heteroaryl group in ^R1 through -O-( _CH2 ) _{n1- *} or -( _CH2 ) _n4 -O-( _CH2 ) _{n5- *} , wherein the * end is connected to the C atom in ^X1 ; n1, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6.

In one embodiment, ^R2 is halogen.

In one embodiment, ^R3 is , , , , , , , , , , , , , , , , , , , , , , When X is a halogen, Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently a 3-8 membered aliphatic heterocyclic ring, a C ₃ -C ₈ aliphatic carbon ring, or a C ₃ -C ₈ aliphatic carbon ring substituted with one or more halogens; Preferably, Ring A is a 3-8 membered aliphatic heterocyclic ring, a C ₃ -C ₈ aliphatic carbon ring, or a C 3 -C 8 _aliphatic carbon ring substituted with 1 or 2 halogens. _8-membered aliphatic carbon ring; Ring B and Ring C are each independently a 3-8-membered aliphatic heterocyclic ring; Ring D is a 3-8-membered aliphatic heterocyclic ring or a C ₃ -C ₈ aliphatic carbon ring; Ring E is a C ₃ -C ₈ aliphatic carbon ring.

In one embodiment, ^R4 is formula (i), formula (ii) or formula (iii): wherein in formula (i), R ^1'' , R ^2'' , R ^7'' and R ^8'' are each independently hydrogen; R ^3'' and R ^4'' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted with one or more ^Ras ; or any CH ₂ in the ring is replaced by C=O; or, R ^5'' and R ^6'' together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted with one or more ^Ras ; or any CH 2 in the ring is replaced by C=O; or, R ^3'' and R ^4'' together with the atoms to which they are connected form a C ₃ -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted with one or more Ras; or any CH ₂ in the ring is replaced by C=O; _8-membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more ^Ra ; or any _CH2 in the ring is replaced by C=O; and R5 ^'' and R6 ^'' together with the atoms connected thereto form a _C3 - _{C8 aliphatic} carbon ring, 3-8-membered aliphatic heterocyclic ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more ^Ra ; or any _CH2 in the ring is replaced by C=O; ^Ra independently represents hydrogen or _C1 - _C6 alkyl; wherein, in formula (ii), ^W1 represents ^CRW1RW2 or ^NRW1 ; ^W2 represents N; when ^W1 is ^CRW1RW2 , ^{RW1 and RW2} each independently represent H, 3-8 ^- membered heterocycloalkyl or ^RW1 , R ^W2 together with the atoms connected to it form a 3-8 membered aliphatic heterocyclic ring; when ^W1 is NR ^W1 , R ^W1 is H, R ^1'' , R ^2'' , R ^3'' , R ^4'' , R ^7'' and R ^8'' are each independently hydrogen or C ₁ -C ₆ alkyl; or, R ^2'' , R ^3'' together with the atoms connected to it form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more ^Ra ; or any CH ₂ in the ring is replaced by C=O; or R ^6'' , R ^7'' together with the atoms connected to it form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R or any CH ₂ in the ring is substituted by C=O; or R ^5'' and R ^6'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic ^heterocycle or a 3-8 membered aliphatic heterocycle substituted by one or more ^Ra ; or any CH ₂ in the ring is substituted by C=O; or R ^3'' and R ^4'' together with the atoms connected thereto form a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocycle or a 3-8 membered aliphatic heterocycle substituted by one or more ^Ra ; or any CH ₂ in the ring is substituted by C=O; ^Ra independently represents hydrogen or C ₁ -C ₆ alkyl; wherein, in formula (iii), W ¹ represents CR ^W1 R ^W2 or NR ^W1 , R ^W1 , R ^{and W2} each independently represent hydrogen, NR ^a R ^b , C ₁ -C ₆ alkyl or (C=O)-O-CH ₂ -O-(C=O)-C ₁ -C ₁₀ alkyl, ^Ra and R ^b each independently represent hydrogen or C ₁ -C ₆ alkyl; W ² represents CH or N; R ^1'' , R ^2'' , R ^3'' and R ^4'' are hydrogen; Y is methyl, ethyl, C ₃ alkyl, C ₂ -C ₃ alkenyl, or ; R ^c and R ^d together with the atoms to which they are attached form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens; or R ^d and R ^d' together with the atoms to which they are attached form a C ₃ -C ₆ aliphatic carbon ring or a C ₃ -C ₆ aliphatic carbon ring substituted by one or more halogens.

In one embodiment, ^R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , wherein R ^4-1 is H, C ₁ -C ₆ alkyl or (C=O)-O-CH ₂ -O-(C=O)-C ₁ -C ₁₀ alkyl; R ^4-2 is C ₁ -C ₆ alkyl, and the number of R ^4-2 is one or more; R ^4-3 and R ^4-4 are each independently H or a 3-8 membered heterocyclic alkyl, or R ^4-3 and R ^4-4 and the carbon atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F, Ring G, Ring H, Ring I and Ring J are each independently C ₃ -C _8- membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring, 5-8-membered lactamic amide ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more ^Re ; ^Re is C ₁ -C ₆ alkyl; preferably, R ^4-1 is H or C ₁ -C ₆ alkyl; R ^4-2 is C ₁ -C ₆ alkyl, and the number of R ^4-2 is one or more; R ^4-3 and R ^4-4 are each independently H or 3-6-membered heterocyclic alkyl, or R ^4-3 and R ^4-4 and the carbon atom to which they are connected together form a 3-6-membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F and Ring G are each independently C ₃ -C ₈ aliphatic carbocyclic ring; Ring H is a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more ^Re ; Ring I and Ring J are each independently a 3-8 membered aliphatic heterocyclic ring and a 5-8 membered lactam ring; ^Re is a C ₁ -C ₆ alkyl group.

In one embodiment, in ^RX1 , the halogen can independently be F, Cl, Br or I, such as Cl.

In one embodiment, in ^RX1 , the _C1 - _C6 alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

In one embodiment, in ^RX1 , the C ₃ -C ₆ cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

In one embodiment, in ^RX1 , the _C2 - _{C6 alkenyl} group may be a _C2 - _C4 alkenyl group, such as a vinyl group.

In one embodiment, in ^RX1 , the _C2 - _C6 alkynyl group may be a _C2 - _C4 alkynyl group, such as ethynyl.

In one embodiment, in ^RX1 , the type of heteroatoms in the 3-6 membered heterocycloalkyl group can be independently selected from N and O, and the number of heteroatoms can be independently 1; In one embodiment, in ^RX1 , the 3-6 membered heterocycloalkyl group can be independently tetrahydropyrrolyl, oxacyclobutane, tetrahydropyranyl or piperidinyl. For example , , or .

In one embodiment, in ^RX1 , in the 5-14 membered heteroaryl group, the type of heteroatom may be N, and the number of heteroatom may be 2.

In one embodiment, in R ^X1 , the 5-14 membered heteroaryl group may be a 5-6 membered heteroaryl group, such as pyrazolyl or imidazolyl, and more preferably or .

In one embodiment, in ^RX1 , in the 3-6 membered heterocycloalkenyl group, the type of the heteroatom can be independently selected from N and O, and the number of the heteroatom can be independently 1.

In one embodiment, in R ^X1 , the 3-6 membered heterocycloalkenyl group may be independently a 6 membered heterocycloalkenyl group, such as a 6 membered heterocycloalkenyl group containing 1 O atom or a 6 membered heterocycloalkenyl group containing 1 N atom, and more preferably or .

In one embodiment, in ^X1-1 , ^X1-2 , ^X1-3 , ^X1-4 , ^X1-5 , ^X1-6 and ^X1-7 , the _C1 - _C6 alkyl group may independently be a _C1 - _C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

In one embodiment, in X ^1-4 , the C ₃ -C ₈ cycloalkyl group may be a C ₃ -C ₆ cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.

In one embodiment, in ^X1-4 , the 3- to 8-membered heterocycloalkyl group may be a 3- to 6-membered heterocycloalkyl group, such as a piperidinyl group, a morpholinyl group or a piperazinyl group.

In one embodiment, when ^RX1 and ^RX3 and the atoms to which they are connected together form a _C5 - _C8 cycloenone structure, the _C5 - _C8 cycloenone may be a _C5 - _C6 cycloenone, such as cyclopentenone. In this case, Can .

In one embodiment, when ^RX1' and ^RX3 and the atoms to which they are connected together form a 5- to 8-membered heteroaryl ring or a 5- to 8-membered heteroaryl ring substituted with one or more hydroxyl groups, the type of heteroatom in the 5- to 8-membered heteroaryl ring may independently be N, and the number of the heteroatom may independently be 2, 3 or 4.

In one embodiment, when ^RX1' and ^RX3 and the atoms to which they are connected together form a 5- to 8-membered heteroaryl ring or a 5- to 8-membered heteroaryl ring substituted with one or more hydroxyl groups, the 5- to 8-membered heteroaryl ring may independently be a 5-membered heteroaryl ring, such as a pyrazole ring, a triazole ring, a tetrazole ring or an oxadiazole ring, in this case, Can , , , , or .

In one embodiment, ^RX1 is CN, Cl, _CF3 , _NH2 , N( _{CH3 ) 2} , _NO2 , _NHSO2CH3 , _NHCOCH3 , PO( _CH3 ) ₂ , _SF5 , C(=O)H, C(=O) _CH3 , C(=O _{) CF3} , C(=O _{)CH2CH3 , SO2CH3} , _SO3 H, cyclopropyl, vinyl, ethynyl, tetrahydropyrrolyl, oxacyclobutane, tetrahydropyranyl, acetyl-substituted piperidinyl, methyl-substituted imidazolyl, methyl-substituted pyrazolyl, 6-membered heterocycloalkenyl containing 1 O atom, 6-membered heterocycloalkenyl containing 1 N atom substituted by acetyl, cyclopropyl-substituted carbonyl, cyclopentyl-substituted carbonyl or cyclohexyl-substituted carbonyl, for example, CN, Cl, CF ₃ , NH ₂ , N(CH ₃ ) ₂ , NO ₂ , NHSO ₂ CH ₃ , NHCOCH ₃ , PO(CH ₃ ) ₂ , SF ₅ , C(═O)H, C(═O)CH ₃ , C(═O)CF ₃ , C(═O)CH ₂ CH ₃ , SO ₂ CH ₃ , SO ₃ H, cyclopropyl, vinyl, ethynyl, , , , , , , , , , or .

In one embodiment, in ^R1 , the _C6 - _C14 aryl group can be independently phenyl or naphthyl, for example , , or .

In one embodiment, in ^R1 , in the 5- to 14-membered heteroaryl group, the type of heteroatom can be independently N, and the number of heteroatom can be independently 1.

In one embodiment, in ^R1 , the 5- to 14-membered heteroaryl group may independently be a 5- to 12-membered heteroaryl group, such as a pyridyl group, a quinolyl group or an isoquinolyl group, and more preferably , or .

In one embodiment, in R ^1-1 , R ^1-2 , R ^1-3 and R ^1-4 , the halogen can independently be F, Cl, Br or I, such as F or Cl.

In one embodiment, in R ^1-1 and R ^1-2 , the C ₁ -C ₆ alkyl group may independently be a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

In one embodiment, in R ^1-1 and R ^1-2 , the C ₁ -C ₁₀ alkyl group may independently be a C ₁ -C ₉ alkyl group, such as n-nonyl.

In one embodiment, n1 is 2.

In one embodiment, n2 is 6.

In one embodiment, n3 is 4.

In one embodiment, n4 is 1.

In one embodiment, n5 is 1.

In one embodiment, R ¹ is naphthyl substituted by one or more R ^1-1 , phenyl substituted by one or more R ^1-1 , pyridyl substituted by one or more R ^1-2 , quinolyl substituted by one or more R ^1-2 , or isoquinolyl substituted by one or more R ^1-2 , for example , , , , , , , , , , , , , , , , , , , , , , , or In one embodiment, in R ² , the halogen may be F, Cl, Br or I, for example, F.

In one embodiment, in R ² , the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In one embodiment, in R ² , the C ₁ -C ₆ alkoxy group may be a C ₁ -C ₄ alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group.

In one embodiment, ^R2 is F.

In one embodiment, in L ₂ , the C ₁ -C ₆ alkylene group may be a C ₁ -C ₃ alkylene group, such as a methylene group, an ethylene group or a propylene group, preferably a methylene group.

In one embodiment, in the definition of R ³ , in the 3-8 membered aliphatic heterocyclic ring, the type of heteroatom can be independently O, and the number of heteroatom can be independently 1.

Herein, "the 3- to 8-membered aliphatic heterocyclic ring in the definition of R ³ " refers to all 3- to 8-membered aliphatic heterocyclic rings described within the above definition of R ³ , such as the 3- to 8-membered aliphatic heterocyclic rings in Ring A, Ring B, Ring C, Ring D and Ring E.

In one embodiment, in the definition of R ³ , the 3-8 membered aliphatic heterocyclic ring can independently be a 4-5 membered aliphatic heterocyclic ring, such as cyclohexane or tetrahydrofuran ring.

In one embodiment, in the definition of ^R3 , the 3- to 8-membered heterocyclic ring can be independently For example, the 3- to 8-membered heterocyclic rings in Ring A, Ring B and Ring C may be independently .

In one embodiment, in the definition of ^R3 , the 3-8 membered heterocyclic ring can be independently For example, in ring D and ring E, the 3- to 8-membered heterocyclic ring may be independently .

In one embodiment, in the definition of R ³ , the C ₃ -C ₈ aliphatic ring can independently be a C ₃ -C ₆ aliphatic ring, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane.

Herein, "the C ₃ -C ₈ aliphatic carbon ring in the definition of R ³ " refers to all C ₃ -C ₈ aliphatic carbon rings described within the above definition of R ³ , for example.

In one embodiment, in the definition of R ³ , the C ₃ -C ₈ aliphatic carbon ring can be independently or For example, in Ring A, Ring B and Ring C, the C ₃ -C ₈ aliphatic carbon ring may be independently or .

In one embodiment, in the definition of R ³ , the C ₃ -C ₈ aliphatic carbon ring can be independently , or For example, in ring D and ring E, the C ₃ -C ₈ aliphatic carbon ring may be independently , or .

In one embodiment, in the definition of R ³ , the halogen may be F, Cl, Br or I, such as F.

Herein, "the halogen in the definition of R ³ " refers to all the halogens within the definition of R ³ , such as the halogens in Ring A, Ring B, Ring C, Ring D and Ring E.

In one embodiment, in R ^4-1 and R ^4-2 , the C ₁ -C ₆ alkyl group may be independently a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably a methyl group.

In one embodiment, in R ^4-1 , the C ₁ -C ₁₀ alkyl group may be a C ₁ -C ₉ alkyl group, such as n-nonyl or isopropyl.

In one embodiment, in R ^W1 , R ^W2 , R ^4-3 and R ^4-4 , the type of heteroatom in the 3- to 8-membered heterocycloalkyl group can be independently selected from N and O, and the number of heteroatom can be independently 1 or 2.

In one embodiment, in R ^W1 , R ^W2 , R ^4-3 and R ^4-4 , the 3- to 8-membered heterocycloalkyl group may be independently a 4- to 6-membered heterocycloalkyl group, such as tetrahydropyrrolyl, morpholinyl or piperidinyl. , or .

In one embodiment, when R ^W1 and R ^W2 and the atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring or when R ^4-3 and R ^4-4 and the carbon atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring, the 3-8 membered aliphatic heterocyclic ring may be a 4-5 membered aliphatic heterocyclic ring, such as N-heterocyclobutane, and more preferably .

In one embodiment, in the definition of R ⁴ , the C ₃ -C ₈ aliphatic ring may independently be a C ₃ -C ₆ aliphatic ring, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane or cyclohexane.

Herein, "the C ₃ -C ₈ aliphatic carbon ring in the definition of R ⁴ " refers to all C ₃ -C ₈ aliphatic carbon rings within the above definition of R ⁴ , such as the C ₃ -C ₈ aliphatic carbon rings in ring F, ring G, ring H, ring I and ring J.

In one embodiment, in the definition of R ⁴ , the C ₃ -C ₈ aliphatic carbon ring can be independently or For example, in ring F and ring H, the C ₃ -C ₈ aliphatic carbon ring may be independently or .

In one embodiment, in the definition of R ⁴ , the C ₃ -C ₈ aliphatic carbon ring can be independently For example, in Ring G, Ring I and Ring J, the C ₃ -C ₈ aliphatic carbon ring may be independently .

In one embodiment, in the definition of R ⁴ , the 3-8 membered aliphatic heterocyclic ring can independently be a 4-5 membered aliphatic heterocyclic ring, such as a tetrahydropyrrole ring or N-heterocyclobutane.

Herein, "the 3- to 8-membered aliphatic heterocyclic ring in the definition of R ⁴ " refers to all 3- to 8-membered aliphatic heterocyclic rings within the above definition of R ⁴ , such as the 3- to 8-membered aliphatic heterocyclic rings in ring F, ring G, ring H, ring I and ring J.

In one embodiment, in the definition of ^R4 , the 3-8 membered heterocyclic ring can be independently For example, in ring F and ring H, the 3- to 8-membered heterocyclic ring may be independently .

In one embodiment, in the definition of R ⁴ , the 3-8 membered heterocyclic ring can be independently For example, in ring G, ring I and ring J, the 3- to 8-membered heterocyclic ring may be independently .

In one embodiment, in ring F, ring G, ring H, ring I and ring J, the 5- to 8-membered lactam rings may independently be 5-membered lactam rings.

In one embodiment, in ring G, ring I and ring J, the 5- to 8-membered lactam rings may be independently .

In one embodiment, in R ^e , the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably a methyl group.

In one embodiment, X may be F, Cl, Br or I, such as F or Br.

In one embodiment, ^R3 is , , , , , , , , , , , , , , , , , , , , , , When, in one embodiment, R ⁴ is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .

In one embodiment, when ^R3 is , , , , , , , , , , , , , , , , , , , , , , When R ⁴ is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .

In one embodiment, when ^R3 is , , , , , , , , , , , , , , , , , , , , , , When ^R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .

In one embodiment, ^R4 is , or R ^4-3 and R ^4-4 are each independently H or a 3- to 8-membered heterocycloalkyl group, wherein the 3- to 8-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group or a piperidinyl group, for example or Ring H is a 3- to 8-membered aliphatic heterocyclic ring or a 3- to 8-membered aliphatic heterocyclic ring substituted by one or more ^Re , preferably a 3- to 8-membered aliphatic heterocyclic ring, such as a tetrahydropyrrole ring, more preferably .

In one embodiment, ^X1 is N; ^R3 is , , , or Ring A is a 3-8 membered aliphatic ring, a C ₃ -C ₈ aliphatic carbon ring, or a C ₃ -C ₈ aliphatic carbon ring substituted with one or more halogens, such as cyclohexane, cyclopropane, or F-substituted cyclopropane, and more preferably , , or Ring D and Ring E are each independently a C ₃ -C ₈ aliphatic carbon ring, such as cyclopropane, more such as , or .

In one embodiment, ^X1 is ^CRX1 ; ^RX1 is CN, _NO2 , halogen, _C1 - _C6 alkyl substituted by one or more halogens, _C3 - _C6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, PO( _C1 - _C6 alkyl) ₂ , 3-6 membered heterocycloalkyl substituted by one or more ^{X1-1 ,} 5-14 membered heteroaryl substituted by one or more ^X1-2 , 3-6 membered ^{heterocycloalkenyl} substituted by one or more ^X1-3 , C(=O) ^X1-4 , ^NX1-5X1-6 or _SO2X1-7 ; The 3-6 membered heterocycloalkyl group is preferably an oxacyclobutane group or a tetrahydropyrrolyl group, for example or The 5- to 14-membered heteroaryl group is preferably pyrazolyl, for example ; R ³ is or Ring A is preferably a C ₃ -C ₈ aliphatic carbon ring substituted with one or more halogens, such as a cyclopropane substituted with F, more preferably .

In one embodiment, R ¹ is a C ₆ -C ₁₄ aryl substituted by one or more R ^1-1 or a 5-14 membered heteroaryl substituted by one or more R ^1-2 ; when R ¹ is a C ₆ -C ₁₄ aryl substituted by one or more R ^1-1 , two adjacent R ^1-1s together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-3 , and the remaining R ^1-1s are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C 1 -C ₆ alkyl, C ₂ -C ₆ alkynyl, C _{1 -C 6} alkyl substituted by one or more halogens, B(OH) ₂ or O(C=O)-C ₁ -C ₁₀ alkyl; when R ¹ is a 5-14 membered heteroaryl substituted by one or more R ^1-2 , two adjacent R ^1-2 together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-4 , and the remaining R ^1-2 are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens, B(OH) ₂ or O(C=O)- C ₁ -C ₁₀ alkyl; R ^1-3 and R ^1-4 are independently halogen.

In one embodiment, the heterocyclic compound as shown in formula I-0 is a heterocyclic compound as shown in formula I: wherein ^X1 is N or CR ^X1 , ^RX1 is CN, halogen, CF ₃ , SO ₂ Me, POMe ₂ or NH ₂ ; ^X2 is N or CR ^X2 , ^RX2 is CN; ^R1 is , , , , , , , , , , , , or , , , , , , or ; R ² is a halogen; R ³ and R ⁴ are defined in any of the following schemes: Scheme 1: R ³ is , , , , , , , , , , , , , , , , , , , , , , When ^R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , ; Option 2: R ³ is , , , , , , , , , , , , , , , , , , , , , , When ^R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .

In certain preferred embodiments of the present invention, certain groups in the heterocyclic compound of formula I, its pharmaceutically acceptable salt, its stereoisomer or its solvate are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present application (referred to as "in a certain embodiment of the present invention" for short), ^X1 is N, C-CN, C-Cl, C- _CF3 , C- _SO2Me , C- _POMe2 or C- _NH2 .

In one embodiment of the present invention, ^X2 is N or C-CN.

In one embodiment of the present invention, ^R2 is F.

In one embodiment, the compound shown in formula I-0 is a compound shown in formula I-1: ; Among them, R ⁴ is or ; J is H or a halogen; it is any one of the following: 1) X ¹ is CR ^{X 1} , RX ¹ is C ₁ -C ₆ alkyl substituted by one or more halogens, PO(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more X ^1-1 , 5-8 membered heteroaryl substituted by one or more X ^1-2 , NO ₂ , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more X ^1-3 , SF ₅ , C(=O) X ^1-4 , NX ^1-5 X ^1-6 or SO ₂ X ^1-7 ; or R ^X1 , ^RX3 and the atoms connected thereto together form a _C5 - _C8 cycloenone structure; the definitions of other substituents are as described in any scheme herein; 2) ^X1 is NRX1 ^' , ^RX1' , ^RX3 and the atoms connected thereto together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted with one or more hydroxyl groups; the definitions of other substituents are as described in any scheme herein; 3) ^X1 is ^CRX1 , wherein the C atom in ^X1 and the C atom in the aryl or heteroaryl group in ^R1 are connected through -O-( _CH2 ) _{n1- *} , _* -NH-( _CH2 ) _n2- , -C≡C-( _CH2 ) _n3 -C≡C- _* or -( _CH2 ) _n4 -O-( _CH2 ) _{n5- *} , wherein the * end is connected to X 1 is connected to the C atom in ¹ ; the definitions of other substituents and n1, n2, n3, n4 and n5 are as described in any scheme herein; 4) R ¹ is a C ₆ ~ C ₁₄ aryl substituted by one or more R ^1-1 or a 5-14 membered heteroaryl substituted by one or more R ^1-2 ; when R ¹ is a C ₆ ~ C ₁₄ aryl substituted by one or more R ^1-1 , two adjacent R ^1-1s together with the atoms to which they are connected form a C ₃ -C ₈ aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-3 , and the remaining R ^1-1s are independently halogen, OH, NH ₂ , CN, C ₁ -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C when R ¹ is a _5-14 membered heteroaryl substituted by one or more R ^1-2 , _two adjacent R ^1-2 together with the atoms to which they are connected form a C _{3 -C 8} aliphatic carbocyclic ring or a C ₃ -C ₈ aliphatic carbocyclic ring substituted by one or more R ^1-4 , and the remaining R ^1-2 are independently halogen, OH, NH 2 , CN, C 1 -C ₆ alkyl, (C=O)-C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₁ -C _{6 alkyl} substituted by one or more _halogen , _B (OH) ₂ or O(C=O)- C _{1 -C 10 alkyl} ; R R ^1-3 and R ^1-4 are independently halogen; the definitions of the remaining substituents are as described in any scheme herein.

In one embodiment, the compound shown in formula I-0 is a compound shown in formula I-2: ; It is any of the following: 1) R ³ is , , , , , , , , , , , , , , , , , , , , , , wherein Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently a 3-8 membered aliphatic heterocyclic ring, a C ₃ -C ₈ aliphatic carbon ring, or a C ₃ -C ₈ aliphatic carbon ring substituted with one or more halogens; R ⁴ is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , wherein R ^4-1 is H, C ₁ -C ₆ alkyl or (C=O)-O-CH ₂ -O-(C=O)-C ₁ -C ₁₀ alkyl; R ^4-2 is C ₁ -C ₆ alkyl, and the number of R ^4-2 is one or more; R ^4-3 and R ^4-4 are each independently H or a 3-8 membered heterocyclic alkyl, or R ^4-3 and R ^4-4 and the carbon atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F, Ring G, Ring H, Ring I and Ring J are each independently C ₃ -C ₈ -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring, 5-8-membered lactamic amide ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more ^Re ; ^Re is C ₁ -C ₆ alkyl; the definitions of the remaining substituents are as described in any of the schemes herein; 2) R ³ is , , , , , , , , , , , , , , , , , , , , , , wherein X is a halogen; Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently a 3-8 membered aliphatic heterocyclic ring, a C ₃ -C ₈ aliphatic carbon ring or a C ₃ -C ₈ aliphatic carbon ring substituted with one or more halogens; R ⁴ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , wherein X is a halogen; R ^4-1 is a C ₁ -C ₆ alkyl group or a (C=O)-O-CH ₂ -O-(C=O)- C ₁ -C ₁₀ alkyl group; R ^4-3 and R ^4-4 are each independently H or a 3-8 membered heterocyclic alkyl group, or R ^4-3 and R ^4-4 together with the carbon atom to which they are connected form a 3-8 membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F, Ring G, Ring H, Ring I and Ring J are each independently a C ₃ -C ₈ aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring, a 5-8 membered lactamic ring or a ring substituted by one or more R ^e -substituted 3- to 8-membered aliphatic heterocyclic ring; ^Re is a C ₁ -C ₆ alkyl group; and the definitions of the remaining substituents are as described in any of the schemes herein.

The present invention also provides a heterocyclic compound as shown below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvent combination thereof (referring to the aforementioned heterocyclic compound as shown below, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof): . .

In a preferred embodiment, the pharmaceutically acceptable salt of the heterocyclic compound is as follows: , , , , , , , , , , , , , , , , , , , , , , or .

The present invention also provides a heterocyclic compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent complex thereof (referring to the aforementioned heterocyclic compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof) as shown below: A compound having a retention time of 0.660 min under the following conditions, which is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Keep 50% of Phase B for 5 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.147 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Keep 50% of Phase B for 5 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.311 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, keep 40% Phase B for 2.5 minutes, keep 5% Phase B for 1.5 minutes, flow rate: 2.8 ml/min; The compound with a retention time of 3.397 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, keep 40% Phase B for 2.5 minutes, keep 5% Phase B for 1.5 minutes, flow rate: 2.8 ml/min; The compound with a retention time of 4.236 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IE 100*4.6mm 3um; Mobile phase: Phase A is 0.1% diethylamine/n-heptane, Phase B is isopropanol; Gradient: A/B = 60/40, Flow rate: 1 ml/min; Under the following conditions, the compound with a retention time of 1.942 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes, flow rate: 4 ml/min; The compound with a retention time of 2.343 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 3.004 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.414 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: 40% Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 3.344 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: 40% Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.150 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.203 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.696 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes; Flow rate: 4 ml/min; The compound with a retention time of 2.137 min under the following conditions is A stereoisomer in: Chromatography column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes; Flow rate: 4 ml/min.

The compound with a retention time of 1.787 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.089 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 0.797 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.514 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.943 min is A stereoisomer in: Chromatographic column: ChiralPak AD-3, 150 * 4.6 mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 3.400 min is A stereoisomer in: Chromatographic column: ChiralPak AD-3, 150 * 4.6 mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the retention time of the compound is 1.729 min and 1.951 min, which is The mixture of two stereoisomers in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; The compound with a retention time of 6.088 min under the following conditions is A stereoisomer mixture in: Chromatographic column: Chiralpak IG-3 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 8.998 min is A stereoisomer mixture in: Chromatographic column: Chiralpak IG-3 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.374 min is The mixture of two stereoisomers in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; The compound with a retention time of 2.812 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 6.215 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 0.438 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50 *4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.251 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50 *4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 0.369 min is The mixture of two stereoisomers in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Keep Phase B at 40%; Flow rate: 4 ml/min; The compound with a retention time of 0.752 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Keep Phase B at 40%; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.937 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Keep Phase B at 40%; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 3.692 min is One of the stereoisomers in the mixture: Chromatography column: Chiralpak AD-3, 150mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 2.5 ml/min.

The compound with a retention time of 3.586 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The compound with a retention time of 3.607 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The compound with a retention time of 3.539 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The compound with a retention time of 3.539 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The peak position is 3.565 min; The compound with a retention time of 3.754 min under the following conditions is A stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 3.131 min is A stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 1.653 min is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; 2 min from 5% phase B to 40% phase B, keep 40% phase B for 1.2 min, and then keep 5% phase B for 0.8 min; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.763 min is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; 2 min from 5% phase B to 40% phase B, keep 40% phase B for 1.2 min, and then keep 5% phase B for 0.8 min; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.343 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.527 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.739 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 2.203 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 3.304 min is A stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/methanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 4.369 min is A stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/methanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 4.500 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 5.555 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 2.676 min is A stereoisomer in: chromatography column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 3.176 min is A stereoisomer in: chromatography column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 0.634 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.129 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 4 ml/min; The above retention time test conditions are not limitations on the compounds. As long as the above test conditions are used for measurement, the retention time obtained is the same as the above record or within the error range, and the compound is a stereoisomer in the compounds defined by the retention time above, it falls within the protection scope of the present invention.

The present invention also provides a pharmaceutical composition comprising: (1) a heterocyclic compound as described in any of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, and (2) a pharmaceutical adjuvant.

The present invention also provides a use of a substance A or the drug composition in the preparation of a KRAS G12D inhibitor, wherein the substance A is a heterocyclic compound as described in any of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof.

In the application, the KRAS G12D inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in this field to provide rapid detection of KRAS G12D inhibitory effects.

The present invention also provides a use of a substance A or the drug composition in the preparation of a drug, wherein the substance A is a heterocyclic compound as described in any of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, and the drug is used to treat cancer, such as colorectal cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer, etc.

Unless otherwise specified, the terms used in the present invention have the following meanings: Technical personnel in the field can understand that, according to the conventions used in the field, the " " used in the structural formula of the group described in the present invention means that the corresponding group is connected to other fragments and groups in the compound through this site.

The term "pharmaceutically acceptable" means that salts, solvents, adjuvants, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively alkaline functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentianic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, bis(hydroxynaphthoic acid)), amino acids (e.g., glutamine, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

The term "solvent" refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvent may exist in an ordered or unordered arrangement. The solvent includes but is not limited to: water, methanol, ethanol, etc.

The terms "compound", "pharmaceutically acceptable salt", "solvent complex" and "pharmaceutically acceptable salt solvent complex" may exist as a single stereoisomer or a mixture thereof (e.g., a racemate) if stereoisomers exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotational chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral separation by bonding (chemical bonding, etc.) or salification (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention is not less than 95% relative to all stereoisomers of the compound.

The terms "compound", "pharmaceutically acceptable salt", "solvent complex" and "pharmaceutically acceptable salt solvent complex" may exist in the form of a single tautomer or a mixture thereof if tautomers exist, preferably in the form of a more stable tautomer as the main component.

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

The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₁ to C ₆ ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₃ to C ₆₎ . Cycloalkyl groups include, but are not limited to: , , , wait.

The term "cycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₃ to C ₆ ), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp ² double bonds, is monocyclic, and is not aromatic. (Monocyclic) cycloalkenyl groups include, but are not limited to: , wait.

The term "carbene ring" has the same definition as the term "cycloalkenyl" if any of the following conditions are met: 1. It is attached to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., _C2 - _C6 ) and having one or more (e.g., 1, 2, or 3) carbon-carbon ^sp2 double bonds. Alkenyl groups include, but are not limited to, vinyl, , wait.

The term "alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C ₂ to C ₆ ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp ³ triple bonds. Alkynyl groups include, but are not limited to, ethynyl and the like.

The term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group with a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), preferably a monocyclic ring. The heterocycloalkyl is attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to: , , or wait.

The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between the monocyclic rings, and each ring is aromatic. Heteroaryl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heteroaryl includes, but is not limited to: , , , or wait.

The term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon radical with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon ^sp2 double bonds, is monocyclic, and is not aromatic. Heterocycloalkenyl is linked to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyls include, but are not limited to: or wait.

The term "carboheteroalkene" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocycloalkenyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

Examples of the term "cycloketones" include, but are not limited to .

The term "heteroaryl" satisfies any of the following conditions, and the rest of the definition is the same as the term "heteroaryl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

The term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C ₆ ~C ₁₄ ), which is monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic, the monocyclic rings share two atoms and one bond, and (at least one ring/each ring) is aromatic. The aryl group is connected to the rest of the molecule through the carbon atoms in the aromatic ring. Aryl groups include, but are not limited to, phenyl or naphthyl.

The term "aromatic ring" meets any of the following conditions, and the rest of the definition is the same as the term "aryl group": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

The term "aliphatic heterocyclic" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

The term "aliphatic ring" satisfies any of the following conditions, and the rest of the definition is the same as the term "cycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

The term "alkoxy" refers to the group R ^X -O-, where R ^X is defined the same as the term "alkyl". Alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

The positive and progressive effects of the present invention are: the compound of the present invention has good cell proliferation inhibition activity on KRAS G12D mutated gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. It has good stability in liver microsomes, liver cells, plasma and whole blood, good PK properties, and significant tumor inhibition effect.

Specific implementation methods

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

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

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

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

SFC analysis was performed using Waters UPCC with PDA Detector and QDa Detector, Waters UPC2 with PDA detector, Agilent 1260 with DAD detector, Shimadzu LC-20AB with PDA detector, and Shimadzu LC-20AD with PDA detector.

Preparative HPLC separation was performed using 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.

SFC separation was performed using 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.

Rapid column separation was performed using the Biotage IsoleraOne rapid preparative chromatogram.

The thin layer chromatography silica plate uses the GF254 acrylic adhesive silica plate of Anhui Liangchen Silicon Source Material Co., Ltd. The specification of the silica plate used in thin layer chromatography (TLC) is 0.25mm, and the specification of the thin layer chromatography separation and purification product is 0.5mm.

Pressurized hydrogenation reaction hydrogenation bottles and hydrogen cylinders.

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

The glove box used was a DELLIX custom glove box. Intermediate A1 : 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

Step 1: Slowly add N-bromosuccinimide (145 g, 815 mmol) and silver nitrate (12.6 g, 74.2 mmol) to a solution of ethynyltriisopropylsilane (135 g, 742 mmol) in acetone (2000 mL), and then stir the reaction solution at 25 ^° C for 16 hours. The reaction solution is concentrated, the residue is stirred with petroleum ether (1500 mL) for 0.5 hours, filtered, and the filtrate is rotary dried to obtain the crude product compound (bromoethynyl)triisopropylsilane (171 g), which is a yellow oily liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.13-0.84 (m, 21H).

Step 2: Dissolve 2-(4-fluorophenyl)acetic acid (200 g, 1.30 mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (205 g, 1.42 mol) and 4-dimethylaminopyridine (14 g, 114 mmol) in acetonitrile (600 mL), cool to 0 ^o C, slowly add diisopropylethylamine (485 mL), and stir at 0 ^o C for 15 minutes. Control the reaction temperature below 30 ^o C, slowly add trivaleryl chloride (175 mL) to the reaction solution, stir at room temperature for 30 minutes, and then raise to 50 ^o C and stir for 16 hours. The reaction temperature was lowered to 0 ^° C, and dilute hydrochloric acid (1 M, 2000 mL) was slowly added, and then the reaction was stirred at 0 ^° C for 2 hours. A large amount of yellow solid was generated. Filtered, the filter cake was washed with a mixture of acetonitrile and water (volume ratio of 1/4, 6000 mL), and vacuum dried to obtain the crude product compound 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (364 g) as a white solid. LCMS (ESI): [MH] ^- = 278.9; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.36 (dd, J = 5.6, 8.5 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 4.36 (s, 2H), 3.75 (s, 1H)1.69 (s, 6H)

Step 3: Dissolve 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (362 g, 1.29 mol) in tert-butyl alcohol (930 mL), heat to 90 ^° C and stir for 2 hours. The reaction solution was rotary dried to obtain the crude product compound tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (280 g) as a yellow solid. LCMS (ESI): [MH] ^- = 250.9; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.23-7.19 (m, 2H), 7.17-7.11 (m, 2H), 3.86 (s, 2H), 3.54 (s, 2H), 1.40 (s, 9H).

Step 4: tert-Butyl 4-(4-fluorophenyl)-3-oxobutanoate (278 g, 1.10 mol) was dissolved in dichloromethane (2480 mL), trifluoroacetic acid (575 mL, 7.50 mol) was added at 0 ^° C, and the reaction was stirred at 25 ^° C for 16 hours. After the reaction was completed, the crude product compound 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g) was obtained as a white solid by vacuum concentration. LCMS (ESI): [MH] ^- = 194.8; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.26-7.15 (m, 2H), 7.11-7.01 (m, 2H), 3.85 (s, 2H), 3.56 (s, 2H)

Step 5: Dissolve 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g, 1.18 mol) in trifluoromethanesulfonic acid (1230 mL, 13.9 mol) and stir at 25 ^° C for 24 hours. Slowly add 0 ^° C ice water (10 L), and extract the reaction solution with ethyl acetate (5 L * 3). Wash the combined organic phase with water (2 L) and saturated salt water (2 L), dry with sodium sulfate, filter, and rotate the filtrate under reduced pressure to dry. The residue is purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain compound 7-fluoronaphthalene-1,3-diol (89 g, 0.5 mol, 4-step yield: 38%), which is a red oily liquid. LCMS (ESI): [M+H] ⁺ = 179.1; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.26 (s, 1H), 9.55 (s, 1H), 7.67-7.51 (m, 2H), 7.27-7.17 (m, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 1.8 Hz, 1H).

Step 6: 7-fluoronaphthalene-1,3-diol (88 g, 494 mmol), (bromoethynyl)triisopropylsilane (155 g, 592 mmol) and potassium acetate (98 g, 1.0 mol) were mixed in dioxane (640 mL), and dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (30.2 g, 49.6 mmol) was added under nitrogen. The reaction solution was stirred at 110 ^° C for 2 hours. Filter, the filtrate was rotary dried, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123 g, 343 mmol, yield: 69%). LCMS (ESI): [MH] ^- = 357.0; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 10.06 (s, 1H), 9.18 (s, 1H), 7.60 (dd, J = 5.6, 9.2 Hz, 1H), 7.22-7.13 (m, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 1.23-1.16 (m, 21H).

Step 7: Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123 g, 343 mmol) in dichloromethane (1230 mL), cool to 0 ^° C, slowly add diisopropylethylamine (180 mL, 1030 mmol) and chloromethyl methyl ether (36.5 g, 454 mmol) to the reaction solution, and stir the reaction at 20 ^° C for 16 hours. After the reaction, the mixture was quenched with water (1000 mL), and then extracted with dichloromethane (500 mL *2). The organic phases were combined and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (48 g, 119 mmol, yield: 35%). LCMS (ESI): [MH] ^- = 401.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.19-9.08 (m, 1H), 7.71-7.63 (m, 1H), 7.24-7.16 (m, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 5.27 (s, 2H), 3.52 (s, 3H), 1.22-1.19 (m, 21H).

Step 8: Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (48.0 g, 119 mmol), diisopropylethylamine (62 mL, 357 mmol), and 4-dimethylaminopyridine (3.00 g, 24.5 mmol) in dichloromethane (480 mL), slowly add trivaleryl chloride (29 mL, 238 mmol) at 0 ^o C, and stir the reaction solution at 20 ^o C for 2 hours. Add dichloromethane (360 mL) and water (360 mL) to the reaction solution, separate the liquids, extract the aqueous phase with dichloromethane (200 mL * 2), combine the organic phases, dry with sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give compound 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl pivalate (50 g, 102 mmol, yield 86%) as a yellow oily liquid. ¹ HNMR (400 MHz, CDCl ₃ ) δ ppm 7.60 (dd, J = 5.5, 9.1 Hz, 1H), 7.22-7.20 (m, 1H), 7.19-7.13 (m, 1H), 6.76 (d, J = 2.3 Hz, 1H), 5.18 (s, 2H), 3.45 (s, 3H), 1.39 (s, 9H), 1.11-1.05 (m, 21H).

Step 9 : Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl pivalate (50 g, 102 mmol) in N,N-dimethylformamide (916 mL), add cesium fluoride (167 g, 1099 mmol), and stir at 20 ^° C for 3 hours. After the reaction, reduce the pressure and concentrate to remove the solvent. Dissolve the crude product in ethyl acetate (1000 mL) and water (2000 mL), separate the organic phase, and extract the aqueous phase with ethyl acetate (1000 mL * 2). The organic phases were combined and washed with saturated brine (1000 mL), dried over sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain compound 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (19 g, 57.5 mmol, yield 56%) as a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 331.1; ¹ HNMR (400 MHz, CDCl ₃ ) δ ppm 7.66 (dd, J = 5.6, 9.1 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.20-7.16 (m, 1H), 6.79 (d, J = 2.1 Hz, 1H), 5.19 (s, 2H), 3.50 (s, 1H), 3.43 (s, 3H), 0.99 (s, 9H).

Step 10: Dissolve 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (19 g, 57.5 mmol) in methanol (200 mL), add palladium carbon (content 10%, 2.00 g) under nitrogen, and replace the reaction solution with hydrogen three times. The reaction solution is hydrogenated with a hydrogen balloon at 20 ^o C for 2 hours. After the reaction is completed, filter and the filtrate is rotary dried to obtain the crude product compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (16 g). LCMS (ESI): [M+H] ⁺ =335.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.51 (dd, J = 5.6, 9.0 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.16-7.09 (m, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.18 (s, 2H), 3.43 (s, 3H), 3.04 (q, J = 7.5 Hz, 2H), 1.38 (s, 9H), 1.18-1.12 (m, 3H).

Step 11: Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl pivalate (16 g, 47.8 mmol) in methanol (250 mL), add potassium hydroxide (8.50 g, 151 mmol), and stir the reaction at 20 ^° C for 2 hours. After the reaction is completed, the reaction solution is adjusted to pH 6 with dilute hydrochloric acid (1 M) at 0 ^° C, extracted with ethyl acetate (200 mL*3), the organic phases are combined, washed with saturated brine (100 ml), dried over sodium sulfate, filtered, the filtrate is rotary dried, and the residue is purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (11 g, 43.9 mmol, yield 92%) as a yellow solid. LCMS (ESI): [M+H] ⁺ = 251.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.50 (dd, J = 5.6, 8.9 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 5.55-5.45 (m, 1H), 5.30-5.24 (m, 2H), 3.58-3.48 (m, 3H), 3.35 (dd, J = 3.0, 7.3 Hz, 2H), 1.35-1.26 (m, 3H).

Step 12: Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (11 g, 43.9 mmol) and diisopropylethylamine (23 mL, 132 mmol) in dichloromethane (220 mL), slowly add trifluoromethanesulfonic anhydride (11 mL, 67.1 mmol) at -40 ^° C, and stir at -40 ^° C for 2 hours. After the reaction is completed, quench the reaction with ice water (200 mL) and extract with dichloromethane (200 mL * 2). Combine the organic phases, wash with saturated brine (100 mL), dry with sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (15 g, 39.2 mmol, yield 89%) as a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 382.9; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.64 (dd, J = 5.6, 8.9 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.34-7.27 (m, 1H), 5.30 (s, 2H), 3.59-3.47 (m, 3H), 3.27 (dq, J = 2.8, 7.4 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H).

Step 13: 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (15 g, 39.2 mmol), bis(xanaphthene) boronate (20 g, 78.7 mmol), potassium acetate (12 g, 122 mmol) were mixed in toluene (380 mL), and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane (3.20 g, 3.92 mmol) was added under nitrogen. The reaction temperature was raised to 130 ^° C and stirred for 16 hours. The reaction solution was filtered and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give a yellow oily crude product. The crude product was purified by flash column chromatography (C18, 0-100% gradient of acetonitrile/pure water) to give compound 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.20 g, 6.11 mmol, yield: 16%) as a yellow solid. LCMS (ESI): [M+H] ⁺ = 361.0; ¹ HNMR (400 MHz, CDCl ₃ ) δ ppm 7.49 (dd, J = 5.9, 8.9 Hz, 1H), 7.38-7.27 (m, 2H), 7.12 (t, J = 9.3 Hz, 1H), 5.24-5.16 (m, 2H), 3.49-3.38 (m, 3H), 3.11-2.97 (m, 2H), 1.42-1.33 (m, 12H), 1.19 (t, J = 7.5 Hz, 3H). Intermediate A2 : ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

^Step 1: Add trifluoromethanesulfonic anhydride (5.19 g, 18.4 mmol) to a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4.93 g, 12.2 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) in dichloromethane (75 mL) at -40 ° C. Stir the solution at -40 ^° C for 1 hour and concentrate the solution. The residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to give a yellow oily compound 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (purity 90%, 6 g, 10.1 mmol, yield 82%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.10 (dd, J = 5.7, 9.2 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.63 (t, J = 9.0 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 5.36 (s, 2H), 3.43-3.41 (m, 3H), 1.15-1.04 (m, 21H).

Step 2: Potassium acetate (3.31 g, 33.7 ^mmol ) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.92 g, 1.13 mmol) were added to a toluene (60 mL) solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate) (purity 90%, 6 g, 10.1 mmol) and bispinacol borate (5.70 g, 22.4 mmol) at 25 °C under nitrogen atmosphere. The suspension was stirred at 130 ^° C for 3 hours. The suspension was filtered and concentrated to obtain a black crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give a white solid compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.10 g, 4.10 mmol, yield 41%). LCMS (ESI): [M+H] ⁺ = 513.0. Intermediate A3 : ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

Step 1: Dissolve the compound 7-fluoro-1-tetralone (18.0 g, 109 mmol) in acetic acid (300 mL) and hydrobromic acid (33% acetic acid solution, 2.5 mL), add liquid bromine (19.2 g, 120 mmol) dissolved in acetic acid (20 mL) at 0 ^o C. Stir the reaction at 25 ^o C for 3 hours. Dilute the reaction solution with dichloromethane (300 mL), wash with water (70 mL*3), dry with sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is dissolved in dimethylformamide (200 mL), lithium bromide (16.2 g, 186 mmol) and lithium carbonate (13.7 g, 186 mmol) are added, and the reaction is stirred at 160 ^o C for 3.5 hours. The reaction solution was diluted with ethyl acetate (500 mL), dried with industrial brine (500 mL*2), sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of ethyl acetate/petroleum ether) to obtain yellow solid 7-fluoronaphthalene-1-ol (14.3 g, 88 mmol, yield 80%). LCMS (ESI): [M+H] ⁺ =163.1. 1H NMR (400MHz, CDCl ₃ ) δ ppm 7.89-7.76 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.34-7.24 (m, 2H), 6.86 (d, J = 7.5 Hz, 1H), 5.41-5.30 (m, 1H).

Step 2 : Dissolve 7-fluoronaphthalene-1-ol (14.3 g, 88.2 mmol), (bromoethynyl)triisopropylsilane (27.6 g, 105 mmol), sodium acetate (1.45 g, 17.6 mmol) and potassium carbonate (12.2 g, 88.2 mmol) in dichloroethane (192 mL), add dichloro(p-methylisopropylphenyl)ruthenium (II) dimer (8.10 g, 13.2 mmol) under nitrogen, and stir the reaction solution at 50 ^° C for 16 hours. After the reaction, filter and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-2% gradient of ethyl acetate/petroleum ether) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (28.5 g, 83.2 mmol, 94% yield). LCMS (ESI): [M+H] ⁺ =343.3. 1H NMR (400MHz, CDCl ₃ ) δ ppm 9.11 (s, 1H), 7.80 (dd, J = 5.8, 9.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.24 (t, J = 8.8 Hz, 1H), 7.08-7.01 (m, 1H), 1.24-1.18 (m, 21H).

Step 3: Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (28.5 g, 83.2 mmol) and diisopropylethylamine (59.0 mL, 338 mmol) in dichloromethane (500 mL), slowly add trifluoromethanesulfonic anhydride (35.8 g, 127 mmol) at -40 ^o C, and stir for 2 hours at -40 ^o C. After the reaction, quench with ice water (500 mL) and extract with DCM (200 mL*2). The combined organic phases are washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (33 g, 69.6 mmol, 84% yield) as a yellow oil. 1H NMR (400MHz, CDCl ₃ ) δ ppm 7.92-7.77 (m, 2H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 1H), 7.39 (t, J=8.8 Hz, 1H), 1.28-1.16 (m, 21H).

Step 4 : Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5.20 g, 10.9 mmol), bis(triisopropylsilyl)ethynyl)naphthalen-1-yl borate (4.17 g, 16.4 mmol), and potassium acetate (6.18 g, 21.9 mmol) in toluene (100 mL). Add [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium in dichloromethane (0.89 g, 1.10 mmol) under nitrogen, and stir at 130 ^° C for 3 hours. After the reaction, filter and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran/petroleum ether) to give yellow solid ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.77 g, 3.91 mmol, 35% yield). LCMS (ESI): [M+H] ⁺ =453.3. 1H NMR (400MHz, CDCl ₃ ) δ ppm 7.89-7.74 (m, 3H), 7.44 (dd, J = 7.0, 8.1 Hz, 1H), 7.28-7.25 (m, 1H), 1.46 (s, 12H), 1.25-1.12 (m, 21H). Intermediate A4 : (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : Add diisopropylethylamine (4 mL, 23.77 mmol), dichloromethane solution (140 mL) and ( ^1R ,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.87 g, 18.22 mmol) solution to 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.00 g, 15.84 mmol) at -40 °C and stir at -40 ^° C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was concentrated under reduced pressure to give yellow solid (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (purity 80%, 8 g, 14.94 mmol, yield 94%). LCMS (ESI): [M+H] ⁺ = 428.1. ¹ H NMR (400 MHz, CDCl ₃ - d 4) δ = 8.78 (s, 1H), 4.52-4.27 (m, 4H), 3.60 (dt, J = 6.6, 13.3 Hz, 2H), 1.98-1.82 (m, 4H), 1.47-1.43 (m, 9H)

Step 2 : Add ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol (0.56 g, 3.50 mmol) to the compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (purity 80%, 1.50 g, 2.80 mmol), and add diisopropylethylamine (2 mL, 10.51 mmol) and dioxane (15 mL) at 25 ^° 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 concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 0-10% dichloromethane/methanol) to obtain a yellow solid compound (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 60%, 620 mg, 0.68 mmol, yield 19%). LCMS (ESI): [M+H] ⁺ = 551.2. ¹ H NMR (400 MHz, CDCl ₃ - d 4) δ = 8.65 (s, 1H), 4.25-4.20 (m, 1H), 3.96 (d, J = 13.0 Hz, 1H), 3.69-3.65 (m, 1H), 3.55-3.48 (m, 2H), 3.45-3.35 (m, 1H), 3.19-3.09 (m, 2H), 2.99-2.91 (m, 1H), 2.66-2.49 (m, 1H), 2.31-2.19 (m, 3H), 1.93-1.84 (m, 4H), 1.78 (td, J = 3.2, 6.7 Hz, 2H), 1.62 (br d, J = 7.8 Hz, 3H), 1.49-1.47 (m, 1H), 1.45 (s, 9H) Intermediate A5 : tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (5.00 g, 19.8 mmol) and diisopropylethylamine (4.2 mL, 23.7 mmol) in dichloromethane (140 mL) was added a solution of ( ^1R ,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.20 g, 19.8 mmol) at -40 °C and stirred at -40 ^° C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL * 3). The organic phase was concentrated under reduced pressure to give a crude product, compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.50 g), as a yellow solid. LCMS (ESI): [M+H] ⁺ = 428.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.87 (s, 1H), 4.67-4.30 (m, 4H), 3.93-3.59 (m, 2H), 2.08-1.94 (m, 2H), 1.69 (m, 2H), 1.54 (s, 9H).

Step 2 : Add diisopropylethylamine (5 mL, 28.0 mmol) to a mixture of (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.00 g, 18.6 mmol) and 2,2,2-trifluoroethanol (18.6 g, 186.7 mmol). 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 concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00 g, 18.3 mmol, yield 98%). LCMS (ESI): [M+H] ⁺ = 492.0.

Step 3 : Under nitrogen protection, caesium carbonate solution (1.5 M aqueous solution, 43% HCl) was added to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00 g, 18.3 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10.7 g, 20.9 mmol) in dioxane (200 mL). mL) and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (1.40 g, 2.09 mmol). The mixture was stirred at 80 ^° C for 3 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2 g) as a brown solid. LCMS (ESI): [M+H] ⁺ = 842.5. Intermediate A6 : tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : Add cesium fluoride (21.6 g, 142.5 mmol) to a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2 g, 22.9 mmol) in dimethylformamide (250 mL). Stir the mixture at 25 ^° C for 2 hours. Filter the reaction solution, collect the filtrate, wash the filter cake with dimethylformamide (3 mL *50), and concentrate the filtrate in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate/petroleum ether) to give a brown oily compound tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 95%, 8.50 g, 11.7 mmol, yield 51%). LCMS (ESI): [M+H] ⁺ = 686.3.

Step 2 : Under nitrogen protection, palladium carbon (5%, 4.00 g) was added to a solution of tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 11.6 mmol) in ethyl acetate (200 mL), and the reaction system was replaced with hydrogen. The mixture was stirred at 25 ^° C for 16 hours. The reaction solution was filtered and the filtrate was concentrated to obtain a yellow oily crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to give a brown solid compound tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 95%, 4.20 g, 5.79 mmol, yield 50%). LCMS (ESI): [M+H] ⁺ = 689.9. Intermediate A7 : tert-butyl (1R,5S)-3-(7-bromo-6-iodo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : Compound 2-amino-4-bromo-3-fluorobenzoic acid (25.0 g, 107 mmol) was dissolved in N,N-dimethylformamide (100 mL), N-iodosuccinimide (36.0 g, 160 mmol) was added, and the mixture was stirred at 80 ^° C for 2 hours. The reaction solution was cooled to room temperature and added to water (3 L), slurried at room temperature for 1 hour, filtered and washed with water (300 mL * 3), and the filter cake was vacuum dried to obtain compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94 mmol, yield 88%). LCMS (ESI): [M+H] ⁺ = 361.9.

Step 2 : Compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.3 mmol) and urea (50.0 g, 833 mmol) were added to the reaction bottle. The reaction system was heated to 200 ^o C for 4 hours. After cooling to room temperature, water (300 mL) was added and the temperature was raised to 80 ^o C for slurrying and stirring for half an hour. The mixture was filtered while hot, and the filter cake was slurried and filtered twice. The filter cake was vacuum dried to obtain 7-bromo-8-fluoro-6-iodoquinazoline-2,4-dihydroxy (26.7 g, 69.3 mmol, yield 83%). LCMS (ESI): [M+H] ⁺ = 387.0.

Step 3 : Add compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7 g, 64.1 mmol) to phosphorus oxychloride (300 mL), add diisopropylethylamine (40 mL, 224 mmol) at 0 ^° C, and stir at 130 ^° C for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was added to ice water (500 mL), extracted with dichloromethane (500 mL * 3), the organic phase was dried with anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-4% gradient methanol/dichloromethane) to obtain compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (26.7 g, 62 mmol, yield 98%). LCMS (ESI): [M+H] ⁺ = 420.8.

Step 4 : To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0 g, 23.7 mmol) in dichloromethane (100 mL) were added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.54 g, 26.1 mmol) and triethylamine (10 mL, 71 mmol). The reaction solution was stirred at 20 ^° C for 2 hours. The reaction solution 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 the compound 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, yield 25%). LCMS (ESI): [M+H] ⁺ = 599.0.

Step 5 : Add the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00 g, 5.00 mmol) to trifluoroethanol (15 mL), add diisopropylethylamine (1560 uL, 8.94 mmol), and stir the reaction solution at 50 ^o C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient of methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.69 g, 2.55 mmol, yield 51%). LCMS (ESI): [M+H] ⁺ = 662.2. Intermediate A8 : tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : 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 (3.00 g, 5.02 mmol) in N,N-dimethylacetamide (30 mL) were added cuprous cyanide (4.50 g, 50.2 mmol) and zinc powder (0.72 g, 11.0 mmol) under nitrogen atmosphere, and the reaction solution was stirred at 100 ^° C for 16 hours. The reaction solution 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 the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.70 g, 3.41 mmol, yield 68%). LCMS (ESI): [M+H] ⁺ = 498.2.

Step 2 : Add the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.48 g, 2.98 mmol) to trifluoroethanol (15 mL), add diisopropylethylamine (1560 uL, 8.94 mmol), and stir the reaction solution at 50 ^o C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient of methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 0.90 g, 1.28 mmol, yield 43%). LCMS (ESI): [M+H] ⁺ = 562.0. Intermediate A9 : tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : Dissolve 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (0.50 g, 1.51 mmol) in dichloromethane (10 mL), add (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.32 g, 1.51 mmol) and triethylamine (630 uL, 4.54 mmol), and stir at 20 ^° C for 16 hours. The reaction solution was added to saturated brine (10 mL), extracted with dichloromethane (10 mL), and the organic phase was concentrated under reduced pressure to obtain the compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 0.83 g, 1.48 mmol, yield 98%). LCMS (ESI): [M+H] ⁺ = 507.2.

Step 2 : Compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 550 mg, 0.98 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (173 mg, 1.09 mmol) were added to N,N-dimethylformamide (5 mL) and tetrahydrofuran (5 mL), and cesium carbonate (1.06 g, 3.26 mmol) and triethylenediamine (24 mg, 0.22 mmol) were added. The reaction system was stirred at 20 ^° C for 16 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phase was concentrated under reduced pressure to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 490 mg, 0.62 mmol, yield 63%). LCMS (ESI): [M+H] ⁺ = 629.9. Intermediate A10 : 8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine

Step 1 : Dissolve the compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00 g, 11.88 mmol) and trifluoroethanol (1.43 g, 14.2 mmol) in toluene (60 mL), add sodium tert-butoxide (1.14 g, 11.8 mmol) at 0 ^o C, and stir the mixture at 0 ^o C for 2 hours. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate (30 mL * 3), the filtrate is washed with saturated salt water (50 mL * 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (3.76 g). LCMS (ESI): [M+H] ⁺ = 315.8.

Step 2 : Add 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70% purity, 1.00 g, 2.21 mmol) to a suspension of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.71 g, 4.43 mmol), diisopropylethylamine (0.79 mL, 4.43 mmol) and 4A molecular sieve (1 g) in 2-methyltetrahydrofuran (10 mL) at 0 ^° C. The reaction system was heated to 25 ^° C for 1 hour. Three batches of equal volume were combined, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain yellow oily 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 3.00 g, 5.10 mmol, yield 77%). LCMS (ESI): [M+H] ⁺ = 439.0.

Step 3 : Compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 2.75 g, 4.69 mmol) was added to dioxane (60 mL), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21 g, 6.27 mmol) and cesium carbonate (1.5 M aqueous solution, 12.5 mL, 18.80 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (419 mg, 0.63 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 80 ^° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane). The crude product was purified by preparative HPLC to give a yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.90 mmol, yield 40%). LCMS (ESI): [M+H] ⁺ = 789.3. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 9.27 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 5.6, 8.9 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.57-5.38 (m, 1H), 5.36-5.29 (m, 2H), 5.27-5.17 (m, 1H), 5.11-4.92 (m, 1H), 4.87-4.51 (m, 2H), 3.85 (br s, 2H), 3.54 (s, 3H), 3.49-3.33 (m, 1H), 3.18 (br s, 1H), 2.66-2.10 (m, 6H), 0.91-0.82 (m, 18H), 0.54 (dtd, J = 3.8, 7.4, 14.8 Hz, 3H). Intermediate A11 : (Dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)-methanol

Step 1: Add diisopropylethylamine (21 mL, 126 mmol) to a solution of L-proline methyl ester hydrochloride (7.00 g, 42.2 mmol) and (3-(bromomethyl)cyclohexyl-3-yl)methanol (10 g, 55.2 mmol) in N,N-dimethylacetamide (80 mL). Heat the mixture to 50 ^° C and stir for 12 hours under nitrogen. Rotate the reaction mixture to dryness. The residue is purified by flash column chromatography (silica gel, 0-70% gradient of tetrahydrofuran/petroleum ether) to obtain the crude product compound ((3-(hydroxymethyl)cyclohexyl-3-yl)methyl)-L-proline methyl ester (3 g) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 230.2;

Step 2 ^: To a solution of ((3-(hydroxymethyl)oxacyclobutane-3-yl)methyl)-L-proline methyl ester (1.00 g, 4.36 mmol) and carbon tetrabromide (1.88 g, 5.67 mmol) in dichloromethane (25 mL) at 0 ° C, triphenylphosphine (1831 mg, 6.98 mmol) was added in three batches, and then the mixture was stirred at 25 ^° C for 3 hours under nitrogen protection. The reaction mixture was rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless liquid compound ((3-(bromomethyl)oxacyclobutane-3-yl)methyl)-L-proline methyl ester (400 mg, 1.37 mmol, yield 31%). LCMS (ESI): [M+H] ⁺ =294.0.

Step 3 : Under nitrogen protection, a solution of ((3-(bromomethyl)oxacyclobutane-3-yl)methyl)-L-proline methyl ester (200 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL) and tetrahydrofuran (1 mL) was cooled to -70 ^° C, and potassium hexamethyldisilazide (1 M tetrahydrofuran solution, 958 uL, 0.96 mmol) was added at -60 ^° C to -70 ^° C, and then the mixture was stirred at -60 ^° C to -70 ^° C for 30 minutes. Water (10 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-60% gradient of tetrahydrofuran/petroleum ether) to give dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (20 mg, 0.09 mmol, yield 14%) as a colorless liquid compound. LCMS (ESI): [M+H] ⁺ = 212.1. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 4.69-4.52 (m, 4H), 3.69 (s, 3H), 3.60 (d, J = 9.9 Hz, 1H), 3.10 (td, J = 6.5, 10.8 Hz, 1H), 2.86-2.75 (m, 2H), 2.73-2.63 (m, 1H), 2.22 (td, J = 7.2, 12.7 Hz, 1H), 1.88-1.78 (m, 3H), 1.77-1.67 (m, 1H).

Step 4 ^: Under nitrogen protection, to a solution of dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (150 mg, 0.71 mmol) in tetrahydrofuran (3 mL) was added lithium tetrahydroaluminum (81 mg, 2.13 mmol) at -10 °C, and the mixture was stirred at -10 ^° C for 30 minutes. Water (81 uL), sodium hydroxide (15% aqueous solution, 81 uL), and then water (243 uL) were added to the reaction mixture. The mixture was filtered, the solid was washed with tetrahydrofuran, and the filtrate was rotary dried to obtain a colorless liquid compound (dihydro-1'H, 3'H-spiro[cyclohexane-3,2'-pyrrolizine]-7a'(5'H)-yl)-methanol (120 mg, 0.66 mmol, yield 92%). LCMS (ESI): [M+H] ⁺ = 184.1. Intermediate A12 : ( dihydro -1'H, 3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H) -yl ) methanol

Step 1 : To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.00 g, 33.16 mmol) and potassium carbonate (9.16 g, 66.3 mmol) in dimethylformamide (80 ^mL ) was slowly added iodomethane (11.7 g, 82.8 mmol) at 0 ° C. The solution was stirred at 0 ^° C for 1 hour, and then the solution was stirred at 25 ^° C for 12 hours. The reaction mixture was quenched with sodium sulfite solution and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless oily compound 5-(tert-butyl) 6-methyl (S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (8.10 g, 30.1 mmol, yield 91%). LCMS (ESI): [M+Na] ⁺ = 278.1.

Step 2 : At -78 ^o C and nitrogen protection, add 5-(tert-butyl) 6-methyl (S)-5-azaspiro [2.4] heptane-5,6-dicarboxylate (8.00 g, 29.8 mmol) to a solution of lithium diisopropylamide (2 M tetrahydrofuran n-heptane mixed solution, 16 mL, 32 mmol) in tetrahydrofuran (80 mL) and stir for 1 hour, then add 1-bromo-3-chloropropane (3 mL, 31.3 mmol) at -78 ^o C and stir for 2 hours, then stir at 25 ^o C for 12 hours. The solution was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a crude product which was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to give a colorless oily compound 5-(tert-butyl)-6-methyl-6-(3-chloropropyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.80 g, 17.4 mmol, yield 58%). LCMS (ESI): [M+Na] ⁺ = 354.0.

Step 3 : At 25 ^° C, hydrogen chloride (4 M in dioxane, 3 mL, 12 mmol) was added to a solution of 5-(tert-butyl)-6-methyl (S)-6-(3-chloropropyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.80 g, 17.4 mmol) in dichloromethane (12 mL). The solution was stirred at 25 ^° C for 16 hours. The solution was concentrated under reduced pressure to obtain a yellow oily compound 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (purity 85%, 4.67 g, 17.1 mmol, yield 98%). LCMS (ESI): [M+H] ⁺ = 232.1.

Step 4 : Potassium iodide (340 mg, ^2.06 mmol) and potassium carbonate (8.53 g, 61.7 mmol) were added to a solution of methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylate (purity 85%, 4.67 g, 17.1 mmol) in methanol (100 mL) at 25 ° C. The solution was stirred at 25 ^° C for 16 hours. The solution was filtered and concentrated to obtain a brown oily compound, dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (purity 85%, 3.90 g, 17.0 mmol, yield 99%). LCMS (ESI): [M+H] ⁺ = 196.1.

Step 5 : Under nitrogen atmosphere at 0 ^° C, a solution of lithium aluminum hydroxide (0.58 g, 15.3 mmol) in tetrahydrofuran (10 mL) was added with a solution of dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (purity 85%, 2.00 g, 8.72 mmol) in tetrahydrofuran (0.50 mL), and the mixture was stirred at 60 ^° C for 4 hours. After cooling to room temperature, the mixture was quenched with water (600 uL), 15% sodium hydroxide (600 uL) and water (1800 uL) in sequence. The suspension was filtered and concentrated to give a brown oily compound (dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methanol (1.20 g, 7.19 mmol, yield 82%). LCMS (ESI): [M+H] ⁺ = 168.1. Intermediates A13-1 and A13-2 : cis-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-yl)methanol A 13-1 and trans-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-yl)methanol A 13-2

Step 1 : Add di-tert-butyl dicarbonate (31.7 mL, 137 mmol) to a solution of 3-azabicyclo[3.1.0]hexane hydrochloride (15 g, 125 mmol) and triethylamine (35 mL, 250 mmol) in dichloromethane (150 mL) at 20 ^° C. The reaction was stirred at 20 ^° C for 16 hours. Saturated ammonium chloride solution (200 mL) was added to the reaction solution, and then extracted with dichloromethane (300 mL * 2). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a white oily compound 3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (20 g, 109 mmol, yield 78%). LCMS (ESI): [M-56+H] ⁺ = 128.1.

Step 2 : Dissolve the compound tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (20 g, 108 mmol) and tetramethylethylenediamine (9150 uL, 61.3 mmol) in tetrahydrofuran (150 mL), add sec-butyl lithium (1.3 M in n-hexane, 63 mL, 81.9 mmol) at -65 ^o C under nitrogen protection. Stir the reaction at -65 ^o C for 3 hours. Replace the nitrogen with carbon dioxide and stir the reaction solution at -65 ^o C under a carbon dioxide balloon for 1 hour. Add 20% potassium bisulfate solution (300 mL) (pH = 7) and water (200 mL) to the reaction solution. Warm the reaction solution to room temperature and remove THF by decompression and concentration. The residue was extracted with ethyl acetate (300 mL * 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure to obtain a brown oily compound 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (purity 80%, 12 g, 42.2 mmol, yield 43%). LCMS (ESI): [M-56+H] ⁺ = 172.1.

Step 3 : Add iodomethane (5.2 ^mL , 84.4 mmol) to a suspension of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (purity 80%, 12 g, 42.2 mmol) and potassium carbonate (17.6 g, 126 mmol) in acetone (150 mL) at 20 ° C. The reaction was stirred at 20 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to give a yellow oily compound 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5 g, 20.7 mmol, yield 36%). LCMS (ESI): [M+Na] ⁺ = 264.1.

Step 4 : Dissolve the compound 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5 g, 20.7 mmol) and 1-bromo-3-chloropropane (1.2 mL, 12.4 mmol) in tetrahydrofuran (100 mL), add bis(trimethylsilyl)amide lithium (1.0 M tetrahydrofuran solution, 41.4 mL, 41.4 mmol) at -65 ^o C under nitrogen atmosphere. Stir the reaction at -65 ^o C for 2 hours and then raise the temperature to 0 ^o C, add saturated ammonium chloride solution (200 mL), and then extract with ethyl acetate (100 mL * 2), dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate the organic layer under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give a yellow oily compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70 g, 6.81 mmol, yield 33%). LCMS (ESI): [M+Na] ⁺ = 340.1.

Step 5 : Compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70 g, 6.81 mmol) was dissolved in dichloromethane (60 mL), and hydrogen chloride (4 M dioxane solution, 15 mL, 60 mmol) was added at 20 ^° C. The reaction was stirred at 25 ^° C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 218.1.

Step 6 : Compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g, 6.81 mmol) was dissolved in methanol (50 mL), and potassium carbonate (8.57 g, 62.0 mmol) and potassium iodide (0.34 g, 2.07 mmol) were added at 20 ^° C. The reaction was stirred at 20 ^° C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain two intermediates. The slightly polar yellow oily liquid was assumed to be trans-hexahydrocyclopropane[a]pyrrolizine-6a(4H)-carboxylic acid methyl ester (110 mg, 0.61 mmol, 8.9% yield). LCMS (ESI): [M+H] ⁺ = 182.1; The more polar yellow oily liquid was assumed to be cis-hexahydrocyclopropane[a]pyrrolizine-6a(4H)-carboxylic acid methyl ester (250 mg, 1.38 mmol, 20% yield). LCMS (ESI): [M+H] ⁺ = 182.1.

Step 7 : Dissolve lithium aluminum tetrahydrate (35 mg, 0.91 mmol) in tetrahydrofuran (6 mL), add a solution of trans-hexahydrocyclopropyl[a]pyrrolizine-6a(4H)-carboxylic acid methyl ester (110 mg, 0.61 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at -40 ^° C. Stir the reaction at -10 ^° C for 1 hour. Add water (110 uL) and 15% sodium hydroxide aqueous solution (110 uL) to the reaction solution at ^{0 °} C, and then add water (330 uL). Anhydrous sodium sulfate was added and stirred, and the filtrate was filtered and concentrated under reduced pressure to obtain a yellow oily compound trans-(hexahydrocyclopropane[a]pyrrolizine-6a(4H)-yl)methanol ( intermediate A13-1 , 90 mg, 0.59 mmol, yield 96%). LCMS (ESI): [M+H] ⁺ = 154.1.

cis-(hexahydrocyclopropane[a]pyrrolazine-6a(4H)-yl)methanol intermediate A13-2 was prepared in the seventh step using cis-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-carboxylic acid methyl ester as a raw material under similar reaction conditions. LCMS (ESI): [M+H] ⁺ = 154.2. Intermediate A14 : (hexahydro-2H-furan[2,3-b]pyrrolazine-7a(5H)-yl)methanol

Step 1 : To a solution of sodium ethoxide (44.2 g, 650 mmol) in ethanol (1000 mL) were added furan-2-carboxaldehyde (50 g, 520 mmol) and ethyl azidoacetate (80.6 g, 624 mmol) at 0 ^° C. The reaction mixture was stirred at 25 ^° C for 16 hours. The mixture was diluted with saturated ammonium chloride (1 L) and extracted with ethyl acetate (1 L * 3). The organic phase was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-30% dichloromethane/petroleum ether) to obtain a yellow oily compound ethyl 2-azido-3-(furan-2-yl)acrylate (25 g, 120 mmol, yield 23%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.51 (d, J = 1.5 Hz, 1H), 7.12 (d, J = 3.5 Hz, 1H), 6.89 (s, 1H), 6.55 (dd, J = 1.8, 3.5 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

Step 2 : Stir the toluene solution of ethyl 2-azido-3-(furan-2-yl)acrylate (24 g, 115 mmol) at 115 ^° C for 3 hours. A large amount of gas is released during the reaction. After the reaction is completed, vacuum concentrate to obtain ethyl 4H-furan[3,2-b]pyrrole-5-carboxylate (16 g, 89.3 mmol, yield 77%) as a brown solid compound. LCMS (ESI): [M+H] ⁺ = 180.1.

Step 3 : At 0 ^° C, 4-dimethylaminopyridine (1.07 g, 8.75 mmol) and di-tert-butyl dicarbonate (27.7 g, 127 mmol) were added to a solution of ethyl 4H-furano[3,2-b]pyrrole-5-carboxylate (16.5 g, 92.1 mmol) in acetonitrile (160 mL). The reaction was stirred at 25 ^° C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to obtain a brown oily compound 4-(tert-butyl) 5-ethyl 4H-furano[3,2-b]pyrrole-4,5-dicarboxylate (24 g, 85.9 mmol, yield 93%). LCMS (ESI): [M-56+H] ⁺ = 224.1.

Step 4 : Palladium on carbon (10% purity, 6.10 g, 5.73 mmol) was added to a solution of 4-(tert-butyl)5-ethyl 4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (8 g, 28.6 mmol) in ethanol (200 mL). The reaction was stirred at 60 ^° C and 50 psi hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum to obtain a yellow oily compound 4-(tert-butyl)5-ethyl hexahydro-4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (7.86 g, 27.5 mmol, yield 96%). LCMS (ESI): [M+Na] ⁺ = 308.1.

Step 5 : To ^a solution of 4-(tert-butyl) 5-ethylhexahydro-4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (2 g, 7.01 mmol) and 1-bromo-3-chloropropane (3.31 g, 21.0 mmol) in tetrahydrofuran (20 mL) was added bis(trimethylsilyl)amide lithium (1M tetrahydrofuran solution, 14.0 mL, 14.0 mmol) at -65 °C under nitrogen atmosphere. The reaction was stirred at 25 ^° C for 16 hours. The mixture was added to a saturated aqueous ammonium chloride solution (15 mL). It was then extracted with ethyl acetate (15 mL * 3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran/petroleum ether) to give a colorless oily compound 4-(tert-butyl) 5-ethyl 5-(3-chloropropyl) hexahydro-4H-furano[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol, yield 64%). LCMS (ESI): [M-Na] ⁺ = 384.2.

Step 6 : Add trifluoroacetic acid (4 mL) to ^a solution of 4-(tert-butyl)-5-ethyl-5-(3-chloropropyl)hexahydro-4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol) in dichloromethane (16 mL) at 0 °C. Stir the reaction at 20 ^° C for 2 hours. Concentrate the mixture in vacuo to obtain the crude product compound 5-(3-chloropropyl)hexahydro-2H-furan[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.10 g) as a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 262.1.

Step 7 : Potassium carbonate (1.74 g, 12.6 mmol) and potassium iodide (0.07 g, 0.42 mmol) were added to a solution of 5-(3-chloropropyl)hexahydro-2H-furano[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.10 g, 4.21 mmol) in ethanol (50 mL). The mixture was stirred at 25 ^° C for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethanol/dichloromethane) to obtain a yellow oily compound hexahydro-2H-furano[2,3-b]pyrrolazine-7a(5H)-carboxylic acid ethyl ester (0.86 g, 3.82 mmol, yield 91%). LCMS (ESI): [M+H] ⁺ = 226.1.

Step 8 : Add tetrahydrolithium aluminum (156 mg, 4.12 mmol) to a solution of ethyl hexahydro-2H-furano[2,3-b]pyrrolizine-7a(5H)-carboxylate (0.86 g, 3.82 mmol) in tetrahydrofuran (9.00 mL) at ^-40 °C. Stir the mixture at -10 ^° C for 1 hour. Slowly add water (160 uL) to the mixture, then add 15% sodium hydroxide solution (160 uL) and water (480 uL), add anhydrous sodium sulfate, stir, filter and wash the filter cake with tetrahydrofuran. The filtrate was concentrated in vacuo to obtain a brown oily compound (hexahydro-2H-furano[2,3-b]pyrrolizin-7a(5H)-yl)methanol (510 mg, 2.78 mmol, yield 72%). LCMS (ESI): [M+H] ⁺ = 184.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.52-4.48 (m, 1H), 3.98 (q, J = 8.1 Hz, 1H), 3.82 (dt, J = 4.6, 7.6 Hz, 1H), 3.56-3.48 (m, 1H), 3.33 (td, J = 1.4, 3.1 Hz, 2H), 3.00-2.91 (m, 1H), 2.87-2.77 (m, 1H), 2.19 (d, J = 14.3 Hz, 1H), 2.00-1.94 (m, 2H), 1.91-1.82 (m, 3H), 1.81-1.70 (m, 1H), 1.67-1.55 (m, 1H). Intermediate A15 : (hexahydrocyclopropyl[b]pyrrolizine-5a(3H)-yl)methanol

Step 1 : Under nitrogen atmosphere at -65 ^° C, add lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 7.44 mL, 7.44 mmol) 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, 11.1 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 25 ^° C for 16 hours. Saturated ammonium chloride solution (10 mL) was added to the mixture, and then extracted with ethyl acetate (10 mL * 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, 51% yield) as a colorless oil. LCMS (ESI): [M+Na] ⁺ = 354.3.

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 product 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.

Step 3 : Potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (719 mg, 5.20 mmol) were added to a solution of 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (60% purity, 670 mg, 1.73 mmol) in ethanol (26 mL). 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 ethanol/dichloromethane) to obtain a yellow oily compound hexahydrocyclopropyl[b]pyrrolazine-5a(3H)-carboxylic acid ethyl ester (95% purity, 320 mg, 1.56 mmol, 90% yield). LCMS (ESI): [M+H] ⁺ = 196.1.

Step 4 : Add lithium aluminum tetrahydrate (72 mg, 1.91 mmol) to a solution of ethyl hexahydrocyclopropyl[b]pyrrolizine-5a(3H)-carboxylate (95% purity, 310 mg, 1.50 mmol) in tetrahydrofuran (3 mL) at -40 ^o C. Stir the mixture at -10 ^o C for 1 hour. Add water (72 uL) and 15% aqueous sodium hydroxide solution (72 uL) to the reaction, then add water (216 uL). Add anhydrous sodium sulfate to dry. The filter cake was filtered and washed with tetrahydrofuran (30 mL), and the filtrate was concentrated in vacuo to give a crude product compound (hexahydrocyclopropane [b] pyrrolizine-5a (3H) -yl) methanol (230 mg) as a yellow oily liquid. LCMS (ESI): [M + H] ⁺ = 154.1. Intermediates A16-1 and A16-2 : cis-2,2-difluorodihydro-1'H, 3'H-spiro [cyclopropane-1,2'-pyrrolizine] -7a'(5'H) -yl) methanol A16-1 and trans-2,2-difluorodihydro-1'H, 3'H-spiro [cyclopropane-1,2'-pyrrolizine] -7a'(5'H) -yl) methanol A16-2

Step 1 : Dissolve 1-(tert-butyl) 2-methyl (S)-4-methylpyrrolidine-1,2-dicarboxylate (2.80 g, 11.6 mmol) and trimethyl(trifluoromethyl)silane (4.12 g, 29.0 mmol) in tetrahydrofuran (100 mL), and add sodium iodide (0.87 g, 5.81 mmol) under nitrogen. The reaction was stirred at 60 ^° C for 16 hours. Cool to room temperature, add saturated ammonium chloride (50 mL) to quench, extract the reaction solution with ethyl acetate (100 mL*2), combine the organic phases, wash with saturated sodium sulfite (50 mL) and saturated brine (50 mL) in sequence, dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oily compound 5-(tert-butyl) 6-methyl (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00 g, 11.0 mmol, yield 95%). LCMS (ESI): [M+Na] ⁺ = 313.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.58-4.35 (m, 1H), 3.77 (m, 3H), 3.75-3.65 (m, 1H), 3.59-3.44 (m, 1H), 2.57 (m, 1H), 2.13-1.93 (m, 1H), 1.50-1.43 (m, 9H), 1.41-1.30 (m, 2H).

Step 2 : Dissolve the compound 5-(tert-butyl)6-methyl (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00 g, 11.0 mmol) in tetrahydrofuran (65 mL) and cool to -70 ^o C. Add lithium diisopropylamide (2 M tetrahydrofuran n-heptane mixed solution, 10.3 mL, 20.6 mmol) under nitrogen and stir at -70 ^o C for 1 hour. Add 1-bromo-3-chloropropane (4.32 g, 27.4 mmol) and stir at -70 ^o C for 2 hours, then raise to 25 ^o C and react for 16 hours. The reaction solution was quenched with saturated ammonium chloride (30 mL), extracted with ethyl acetate (50 mL * 2), the organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain two stereoisomers. The less polar colorless oily liquid isomer was separated and confirmed to be of cis configuration by 2D-NMR: cis-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20 g, 3.26 mmol, yield 30%). LCMS (ESI): [M+Na] ⁺ = 390.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.91 (m, 1H), 3.80-3.71 (m, 3H), 3.65-3.44 (m, 3H), 2.48-2.00 (m, 4H), 1.94-1.74 (m, 2H), 1.50-1.42 (m, 9H), 1.41-1.29 (m, 2H); the more polar isomer was separated and confirmed to be in trans configuration by 2D-NMR: trans-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 0.70 g, 1.52 mmol, yield 14%). LCMS (ESI): [M-100+H] ⁺ = 268.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.80-3.73 (m, 3H), 3.71 (m, 1H), 3.67-3.42 (m, 3H), 2.46-2.17 (m, 3H), 2.16-1.73 (m, 3H), 1.50-1.42 (m, 9H), 1.39-1.23 (m, 2H).

Step 3 : Compound cis-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20 g, 3.26 mmol) was dissolved in dichloromethane (4 mL), and hydrogen chloride (4 M dioxane solution, 2 mL, 9.78 mmol) was added at 20 ^° C. The reaction solution was stirred at 20 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (0.83 g) as a white solid. LCMS (ESI): [M+H] ⁺ = 268.1

Step 4 : Dissolve the compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (0.83 g, 3.11 mmol) in methanol (2 mL), add potassium iodide (62 mg, 0.37 mmol) and potassium carbonate (1.55 g, 11.21 mmol) at 25 ^° C. The reaction was stirred at 25 ^° C 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 obtain a colorless oily compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (0.25 g, 1.08 mmol, two-step yield: 33%). LCMS (ESI): [M+H] ⁺ = 232.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.68 (s, 3H), 3.31 (d, J = 10.9 Hz, 1H), 3.19-3.10 (m, 1H), 2.75-2.64 (m, 2H), 2.43 (d, J = 13.4 Hz, 1H), 2.37-2.30 (m, 1H), 1.91-1.74 (m, 4H), 1.30-1.22 (m, 2H)

Step 5 : Dissolve the compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (0.25 g, 1.08 mmol) in tetrahydrofuran (4 mL), and add lithium aluminum tetrahydrogen (61 mg, 1.62 mmol) at 0 ^o C. The reaction was stirred at 60 ^o C for 2 hours. Water (61 uL), sodium hydroxide (15% aqueous solution, 61 uL), water (183 uL), anhydrous magnesium sulfate (1 g) were added to the reaction solution and stirred for 30 minutes. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain colorless oily cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1 ( 0.20 g, 0.96 mmol, yield 89%). LCMS (ESI): [M+H] ⁺ = 204.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.35-3.28 (m, 2H), 3.23 (d, J = 11.0 Hz, 1H), 3.06 (td, J = 6.2, 10.7 Hz, 1H), 2.82-2.73 (m, 2H), 2.04 (d, J = 13.1 Hz, 1H), 1.98-1.69 (m, 5H), 1.36-1.27 (m, 2H).

Trans -2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2 was prepared by referring to the synthesis method of intermediate A16-1 , and trans-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate was prepared under similar reaction conditions. LCMS (ESI): [M+H] ⁺ = 204.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.43-3.28 (m, 2H), 3.16-3.04 (m, 2H), 2.81 (d, J = 12.3 Hz, 1H), 2.70-2.60 (m, 1H), 2.02-1.94 (m, 1H), 1.92-1.64 (m, 5H), 1.38-1.18 (m, 2H). Intermediates A16-1A , A16-1B , A16-2A, and A16-2B : ( (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1A ; (1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1B ; (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2A and (1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2B

Step 1 : To a solution of (S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (90 g, 396 mmol) in dimethylformamide (1.8 L) was added cesium carbonate (168 g, 514 mmol) and ^benzyl bromide (88 g, 514 mmol) at 0 ° C. The suspension was stirred at 25 ^° C for 16 hours. The reaction solution was diluted with water (1.8 L), extracted with ethyl acetate (1 L * 3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless oily compound 2-benzyl 1-(tert-butyl) (S)-4-methylpyrrolidine-1,2-dicarboxylate (120 g, 378 mmol, yield 95%). LCMS (ESI): [M-100+H] ⁺ = 218.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.35 (m, 5H), 5.29-5.06 (m, 2H), 5.04-4.93 (m, 2H), 4.62-4.41 (m, 1H), 4.16-4.02 (m, 2H), 3.07-2.88 (m, 1H), 2.69-2.56 (m, 1H), 1.55-1.29 (m, 9H).

Step 2 : Sodium iodide (1.89 g, 12.6 mmol) was added to a solution of 2-benzyl 1-(tert-butyl)(S)-4-methylpyrrolidine-1,2-dicarboxylate (8.00 g, 25.2 mmol) and trimethyl(trifluoromethyl)silane (8.96 g, 63.0 mmol) in tetrahydrofuran (300 mL) under nitrogen, and the mixture was stirred at 60 ^° C for 16 hours. The mixture was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with saturated sodium sulfite (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran/petroleum ether) to obtain two isomers. The less polar yellow oily liquid product was confirmed by 2D-NMR to be 6-benzyl 5-(tert-butyl) (3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.70 g, 13.2 mmol, yield 48%). LCMS (ESI): [M+Na] ⁺ = 390.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.36 (m, 5H), 5.33-5.05 (m, 2H), 4.62-4.39 (m, 1H), 3.80-3.64 (m, 1H), 3.55-3.37 (m, 1H), 2.65-2.49 (m, 1H), 2.01-1.81 (m, 1H), 1.51-1.23 (m, 10H), 1.23-1.08 (m, 1H). The highly polar yellow oily liquid product was confirmed by 2D-NMR to be 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.70 g, 7.35 mmol, yield 27%). LCMS (ESI): [M+Na] ⁺ = 390.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.41-7.28 (m, 5H), 5.35-5.01 (m, 2H), 4.61-4.34 (m, 1H), 3.79-3.60 (m, 1H), 3.53-3.38 (m, 1H), 2.50-2.32 (m, 1H), 2.17-2.03 (m, 1H), 1.51-1.28 (m, 11H).

Step 3 : To a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (15 g, 40.8 mmol) in tetrahydrofuran (150 ^mL ) was added potassium bis(trimethylsilyl)amide (2M in tetrahydrofuran, 41 mL, 82 mmol) at -78 °C under nitrogen atmosphere. The reaction solution was stirred at -78 ^° C for 1 hour. 1-Bromo-3-chloropropane (13 g, 81.6 mmol) was added to the solution and the solution was stirred at -78 ^° C for 1 hour. Then stirred at 25 ^° C for 14 hours. The solution was quenched with water (150 mL), extracted with ethyl acetate (150 mL * 3) and concentrated to give a crude product compound 6-benzyl 5-(tert-butyl) (3R, 6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (20 g, containing a small amount of 6-benzyl 5-(tert-butyl) (3R, 6R)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate) as a brown oily liquid. LCMS (ESI): [M-56+H] ⁺ = 388.1.

Step 4 : Add hydrogen chloride (4M in dioxane, 100 ^mL , 400 mmol) to a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (6 g, 18.1 mmol) in dichloromethane (200 mL) at 25 °C. Stir the reaction mixture at 25 ^° C for 16 hours. Concentrate the solution to obtain the crude product (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (17 g) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 344.1.

Step 5 : Potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) were added to a solution of (3R, ^6S )-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid benzyl ester (16 g, 46.5 mmol) in methanol (500 mL) at 25 ° C. The solution was stirred at 25 ^° C for 16 hours. The solution was concentrated and purified by preparative HPLC to obtain a brown oily compound benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol, yield 2%), and its configuration was confirmed by 2D-NMR. LCMS (ESI): [M+H] ⁺ = 308.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.43-7.29 (m, 5H), 5.31-5.09 (m, 2H), 3.41 (d, J = 10.9 Hz, 1H), 3.32-3.19 (m, 1H), 2.89-2.71 (m, 2H), 2.59 (d, J = 13.4 Hz, 1H), 2.46-2.31 (m, 1H), 1.97-1.81 (m, 4H), 1.39-1.27 (m, 2H).

Step 6 : Add lithium aluminum tetrahydrate (259 mg, 6.83 mmol) to a solution of ^benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol) in tetrahydrofuran (4 mL) at 0 o C. Stir the suspension at 60 ^o C for 2 hours. Quench the suspension with water (260 uL), 15% sodium hydroxide solution (260 uL) and water (780 uL) in sequence. Then, anhydrous sodium sulfate was added to the suspension, stirred, filtered, and the filtrate was concentrated to obtain a yellow oily compound ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1A ( purity 60%, 300 mg, 0.89 mmol, yield 78%). LCMS (ESI): [M+H] ⁺ = 204.1.

Intermediate A16-1B, A16-2A, A16-2B were prepared by referring to the synthetic route of intermediate A16-1A . Intermediate A17: 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

Step 1: To a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10.0 g, 34.40 mmol) in dichloromethane (50 mL) at 0 ^° C, add hydrogen chloride (4 M in dioxane, 172 mL, 688 mmol) and stir at 20 ^° C for 16 hours. The mixture was rotary dried to give the crude product compound 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g) as a white solid. LCMS (ESI): [M+H] ⁺ = 191.0.

Step 2: Dissolve 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g, 34.40 mmol) in phosphorus oxychloride (50 mL) and stir the mixture at 90 ^° C for 2 hours under nitrogen. Rotate to dry. The crude product compound 4-amino-6-chloro-5-fluoronicotinic acid chloride (10.0 g) is obtained as a brown solid. The methyl ester is quenched with methanol for detection. LCMS (ESI): [M+H] ⁺ = 205.1.

Step 3: Add ammonium thiocyanate (11.8 g, 155.02 mmol) to a solution of 4-amino-6-chloro-5-fluoronicotinoyl chloride (10.0 g, 34.40 mmol) in tetrahydrofuran (100 mL), and then stir the mixture at 20 ^° C for 12 hours under nitrogen protection. Add water (100 mL), extract with ethyl acetate (100 mL * 3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and spin dry. The residue was slurried with petroleum ether/ethyl acetate (volume ratio of 1/3, 20 mL) to obtain a white solid compound 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol, yield 70%). LCMS (ESI): [M+H] ⁺ = 232.0.

Step 4: To a solution of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol) in N,N-dimethylformamide (56 mL), sodium methanolate (1.44 g, 26.59 mmol) and iodomethane (3.26 g, 22.97 mmol) were added. The mixture was stirred at 20 ^° C for 2 hours under nitrogen protection. The reaction solution was poured into water (180 mL), the solid was filtered out, and vacuum dried to obtain a white solid compound 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (5.10 g, 20.76 mmol, yield 86%). LCMS (ESI): [M+H] ⁺ = 246.0.

Step 5: Dissolve 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.10 g, 4.48 mmol) in phosphorus oxychloride (10.0 mL) and add diisopropylethylamine (2.23 mL, 13.43 mmol). Stir the mixture at 95 ^° C for 16 hours under nitrogen protection. Rotate the mixture to dryness, add ethyl acetate (30 mL) and then ice water (30 mL) and separate the layers. Extract the aqueous phase with ethyl acetate (30 mL * 3). Combine all organic phases, dry over anhydrous sodium sulfate, filter, and rotate to dryness. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.10 g, 4.17 mmol, yield 93%). LCMS (ESI): [M+H] ⁺ = 264.0. Example 1 : 4-(4-((1R,5S,8S)-8- amino -3- azabicyclo [3.2.1] octan -3- yl )-8- fluoro -2-(( tetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -7- yl )-5- ethyl -6- fluoronaphthalen -2- ol carboxylate

Step 1 : To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (500 mg, 1.68 mmol) and diisopropylethylamine (350 uL, 2.02 mmol) in dichloromethane (5 mL) was added tert-butyl (( ^1R ,5S,8S)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (381 mg, 1.68 mmol) at -40 o C. The solution was stirred at -40 ^o C for 1 hour. Add water (8 mL) and extract with ethyl acetate (5 mL * 2), combine the organic phases, dry with magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow solid compound tert-butyl ((1R, 5S, 8S)-3-(2,7-dichloro-8-fluoropyrido [4,3-d] pyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl) carbamate (800 mg, 2.30 mmol, yield 86%). LCMS (ESI): [M+H] ⁺ = 442.1

^Step 2: To a solution of tert-butyl ((1R,5S,8S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (800 mg, 2.30 mmol) in dioxane (9 mL) was added (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (459 mg, 3.26 mmol) and diisopropylethylamine (850 mL, 4.88 mmol) at 25 ° C. The solution was stirred at 80 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (440 mg, 0.80 mmol, yield 35%). LCMS (ESI): [M+H] ⁺ = 547.3.

Step 3 : In a nitrogen atmosphere, tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (304 mg, 0.56 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (200 mg, 0.56 mmol), potassium phosphate (1.5 M aqueous solution, 1120 uL, 1.68 mmol) in dioxane (4 To the 2% 4-nitropropene (2-amino-1,1-biphenyl-2-yl)palladium methanesulfonate (41 mg, 60 umol) solution was added [n-butyldi(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (41 mg, 60 umol), and the mixture was stirred at 100 ^° C for 3 hours. The suspension was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give a brown solid compound tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (85% purity, 120 mg, 0.14 mmol, 25% yield). LCMS (ESI): [M+H] ⁺ = 745.6. Step 4: A solution of tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (110 mg, 0.15 mmol) in dichloromethane/trifluoroacetic acid (v/v= 4/1, 1000 uL) was stirred at 25 ^o C for 1 hour. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC using a mobile phase containing a formic acid system to give a white solid compound 4-(4-((1R,5S,8S)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (formate salt, 2.06 mg, 3.4 umol, yield 2%). LCMS (ESI): [M+H] ⁺ = 601.0; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.08 (s, 1H), 8.55 (br s, 1H), 7.68 (dd, J = 5.8, 9.1 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J = 2.5 Hz, 1H), 4.78 (m, J = 10.6 Hz, 2H), 4.48 (s, 2H), 3.69 (br dd, J = 7.3, 12.6 Hz, 2H), 3.41 (s, 3H), 3.08-2.96 (m, 2H), 2.84 (br dd, J = 7.3, 13.1 Hz, 1H), 2.34 (br s, 2H), 2.28-1.89 (m, 11H), 1.60 (br d, J = 9.0 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H)

The following examples were prepared by the synthetic route of Example 1 : Example 2 : 4-(4-((8-azabicyclo[3.2.1]oct-3-yl)amino)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 601.5; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.28 (s, 1H), 7.69 (dd, J = 5.9, 9.2 Hz, 1H), 7.36-7.21 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 4.53 (br s, 1H), 4.05 (br s, 2H), 3.51 (br s, 2H), 3.20-3.08 (m, 2H), 2.56-1.92 (m, 20H), 0.79 (t, J = 7.3 Hz, 3H). Example 3 : 4-(4-(2,5-diazabicyclo[4.1.0]hept-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 573.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.78-9.71 (m, 1H), 7.63-7.55 (m, 1H), 7.22 (br d, J = 2.5 Hz, 1H), 7.19-7.18 (m, 1H), 6.97 (br s, 1H), 4.41 (br s, 2H), 3.31 (m, 1H), 3.13-2.96 (m, 5H), 2.42-2.34 (m, 1H), 2.25-1.91 (m, 12H), 1.53-1.47 (m, 1H), 0.97-0.88 (m, 1H), 0.80 (br t, J = 6.8 Hz, 1H), 0.74-0.67 (m, 3H). Example 4 : 5-ethyl-6-fluoro-4-(8-fluoro-4-(octahydroquinoxaline-1(2H)-yl)-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 615.3 ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.16-8.98 (m, 1H), 8.53-8.36 (m, 2H), 7.76-7.18 (m, 2H), 7.10-7.00 (m, 1H), 4.72-4.42 (m, 5H), 4.23-4.06 (m, 1H), 3.97-3.61 (m, 2H), 3.28-3.22 (m, 2H), 2.59-1.99 (m, 13H), 1.86 (br s, 3H), 1.51 (br s, 4H), 0.87-0.66 (m, 3H). Example 5 : 5-Ethyl-6-fluoro-4-(8-fluoro-4-(5,8-diazaspiro[3.5]nonan-8-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 601.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.19 (s, 1H), 7.73-7.66 (m, 1H), 7.36-7.21 (m, 2H), 7.09 (s, 1H), 4.69-4.68 (m, 2H), 4.28-4.04 (m, 4H), 3.76-3.65 (m, 3H), 3.10-3.04 (m, 2H), 2.52-2.44 (m, 1H), 2.37-2.29 (m, 2H), 2.26-2.05 (m, 12H), 1.97-1.86 (m, 2H), 0.84-0.74 (m, 3H) Example 6 : 4-(4-(3,9-diazabicyclo[3.3.1]nonane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 601.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.25-9.19 (m, 1H), 8.58-8.46 (m, 1H), 7.75-7.68 (m, 1H), 7.36-7.33 (m, 1H), 7.29 (t, J = 9.4 Hz, 1H), 7.10-7.06 (m, 1H), 4.99 (br s, 2H), 4.72-4.70 (m, 2H), 4.10-3.92 (m, 3H), 3.78-3.66 (m, 3H), 3.61 (br s, 2H), 2.54-2.46 (m, 1H), 2.40-2.32 (m, 2H), 2.29-2.04 (m, 11H), 2.00-1.92 (m, 1H), 1.71-1.61 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H) Example 7 : (S)-5-Ethyl-6-fluoro-4-(8-fluoro-4-(2-methylpiperazin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol dicarboxylate

LCMS (ESI): [M+H] ⁺ = 575.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.12 (s, 1H), 8.46 (br s, 2H), 7.71 (dd, J = 5.9, 9.0 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.28 (t, J = 9.4 Hz, 1H), 7.12-7.01 (m, 1H), 5.13 (br s, 1H), 4.69 (s, 2H), 4.67-4.71 (m, 2H), 3.90 (br s, 1H), 3.80-3.74 (m, 2H), 3.38 (br s, 2H), 3.31-3.21 (m, 3H), 2.49 (br d, J = 6.5 Hz, 1H), 2.42-2.31 (m, 2H), 2.28-2.09 (m, 7H), 1.67 (d, J = 7.0 Hz, 3H), 0.90-0.75 (m, 3H). Example 8 : 5-Ethyl-6-fluoro-4-(8-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]yl-3-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 601.3; ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.14 (s, 1H), 8.44 (br s, 1H), 7.69 (dd, J = 6.0, 9.0 Hz, 1H), 7.35-7.21 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 4.68-4.64 (m, 4H), 3.85 (br t, J = 14.3 Hz, 2H), 3.70 (br d, J = 7.5 Hz, 2H), 3.54 (br s, 2H), 3.29-3.24 (m, 1H), 3.29-3.24 (m, 1H), 3H), 2.54-2.42 (m, 4H), 2.34 (br dd, J = 6.8, 10.8 Hz, 2H), 2.26-2.08 (m, 9H), 1.77 (br d, J = 8.0 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). Example 9 : 5-Ethyl-6-fluoro-4-(8-fluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 601.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.10 (s, 1H), 7.69 (dd, J = 9.17, 5.75 Hz, 1H), 7.39-7.18 (m, 2H), 7.05 (d, J = 2.45 Hz, 1H), 4.68 (s, 2H), 4.09-4.02 (m, 6H), 3.70 (br d, J = 3.79 Hz, 2H), 3.48 (br s, 2H), 2.57-2.28 (m, 4H), 2.26-2.07 (m, 12H), 1.33-1.23 (m, 3H). Example 10: 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin)-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate

Step 1 : Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 0.19 mmol) and diisopropylethylamine (113 uL, 0.65 mmol) were added to dimethyl sulfoxide (1.2 mL), and 4-(pyrrolidin-1-yl)piperidine (30 mg, 0.19 mmol) was added, and stirred at 90 ^o C for 3 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (130 mg). LCMS (ESI): [M+H] ⁺ = 843.5.

Step 2 : Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (130 mg, 0.15 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (234 mg, 1.54 mmol) was added and stirred at 20 ^° C for 1 hour. The reaction mixture was diluted with water (1500 uL) and extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100 mg). LCMS (ESI): [M+H] ⁺ = 687.4.

Step 3 : Compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100 mg, 0.13 mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5 mL) and stirred at 20 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (formate, 21.1 mg, 32 umol, yield 25%). LCMS (ESI): [M+H] ⁺ = 643.0; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.04 (s, 1H), 8.54 (br s, 1H), 7.89 (dd, J = 5.6, 9.2 Hz, 1H), 7.44-7.31 (m, 2H), 7.25 (s, 1H), 5.50-5.30 (m, 1H), 4.78 (br d, J = 13.1 Hz, 2H), 4.48-4.34 (m, 2H), 3.55-3.37 (m, 6H), 3.26-3.11 (m, 6H), 2.49-2.20 (m, 5H), 2.14-1.87 (m, 9H).

The following examples were prepared by the synthetic route of Example 10 : Example 11: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 659.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.06 (s, 1H), 8.45 (br s, 1H), 7.89 (dd, J =5.7, 9.1 Hz, 1H), 7.45-7.31 (m, 2H), 7.26 (s, 1H), 5.65-5.41 (m, 1H), 4.78 (br d, J =13.0 Hz, 2H), 4.63 (br s, 2H), 3.96-3.71 (m, 7H), 3.55-3.35 (m, 4H), 2.90-2.71 (m, 5H), 2.66-2.10 (m, 8H), 1.80 (br s, 2H). Example 12 : 4-(4-([1,4'-piperidinyl]-1'-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 657.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.00 (s, 1H), 7.88 (dd, J =5.8, 9.1 Hz, 1H), 7.40-7.28 (m, 2H), 7.27-7.18 (m, 1H), 5.41-5.22 (m, 1H), 4.77 (br d, J =13.3 Hz, 2H), 4.35-4.22 (m, 2H), 3.47-3.38 (m, 3H), 3.29-3.18 (m, 3H), 3.06-2.97 (m, 1H), 2.80-2.73 (m, 1H), 2.67 (br s, 4H), 2.28-2.21 (m, 1H), 2.14 (br d, J =10.6 Hz, 3H), 2.05-1.89 (m, 3H), 1.84-1.74 (m, 2H), 1.67 (br d, J =4.5 Hz, 5H), 1.53 (br d, J =3.9 Hz, 2H). Example 13 : 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-olcarboxylate

LCMS (ESI): [M+H] ⁺ = 601.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.25 (s, 1H), 8.49 (br s, 1H), 7.89 (dd, J =5.8, 9.0 Hz, 1H), 7.41-7.29 (m, 2H), 7.24 (d, J =2.0 Hz, 1H), 5.59-5.37 (m, 1H), 4.61-4.50 (m, 2H), 4.38 (br s, 2H), 4.25-4.10 (m, 2H), 3.85-3.57 (m, 5H), 3.47-3.36 (m, 5H), 3.28 (br s, 1H), 2.66-2.41 (m, 2H), 2.37-2.29 (m, 1H), 2.28-2.17 (m, 2H), 2.15-2.05 (m, 1H). Example 14 : 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((3aR,6aS))-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 615.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.25 (s, 1H), 8.58-8.26 (m, 1H), 7.99-7.78 (m, 1H), 7.42-7.30 (m, 2H), 7.26-7.15 (m, 1H), 5.66-5.35 (m, 1H), 4.66-4.54 (m, 2H), 4.44-4.33 (m, 2H), 4.26-4.14 (m, 2H), 3.91-3.67 (m, 3H), 3.44-3.41 (m, 1H), 3.41-3.34 (m, 3H), 3.18 (br s, 4H), 2.73-2.65 (m, 3H), 2.64-2.47 (m, 2H), 2.41-2.33 (m, 1H), 2.32-2.22 (m, 2H), 2.18-2.02 (m, 1H). Example 15 : 11-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7,11-triazabispiro[3.0.4 ⁵ .3 ⁴ ]dodecane-6-monocarboxylate

LCMS (ESI): [M+H] ⁺ = 669.9; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.24 (br s, 1H), 8.47 (br s, 1H), 7.87 (dd, J = 9.07, 5.82Hz, 1H), 7.38-7.34 (m, 2H), 7.21 (d, J = 2.13Hz, 1H), 5.60-5.32 (m, 1H), 4.67-4.44 (m, 5H), 4.29-4.09 (m, 4H), 3.79 (br d, J = 13.13Hz, 1H), 3.72-3.81 (m, 2H), 3.80-3.91 (m, 2H), 3.40-3.35 (m, 1H), 2.70-1.93 (m, 10H). Example 16 : 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1 : Add trifluoroacetic acid (8 mL) to a solution of (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (2.00 g, 6.08 mmol) in dichloromethane (32 mL), and stir at 50 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (32 mL), washed with ethyl acetate (32 mL*2), and the aqueous phase was freeze-dried to obtain a crude product compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (3.7 g), which was a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 111.2;

Step 2: Add benzoyl chloride (1.65 mL, 14.2 mmol) to a solution of (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 3.55 mmol) and diisopropylethylamine (5.8 mL, 35.5 mmol) in dichloromethane (12 mL) and stir the reaction at 25 ^° C for 16 hours. The reaction solution was quenched with water (40 mL) at 0 ^o C, extracted with dichloromethane (20 mL * 3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran/petroleum ether) to obtain a white solid compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (0.60 g, 1.18 mmol, yield 53%). LCMS (ESI): [M+H] ⁺ = 319.0;

Step 3: Dissolve the compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (400 mg, 1.25 mmol) and tetrabutylammonium bromide (40 mg, 0.13 mmol) in toluene (5 mL). Add (bromodifluoromethyl)trimethylsilane (5.10 g, 25.1 mmol) under nitrogen protection and stir the reaction at 110 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 50% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow oily compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200 mg, 0.54 mmol, yield 43%). LCMS (ESI): [M+H] ⁺ = 369.3;

Step 4: Dissolve the compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200 mg, 0.25 mmol) in 6M hydrochloric acid (2 mL) and stir at 100 ^° C for 16 hours. The reaction solution was washed with EtOAc (2 mL * 3) and the aqueous phase was freeze-dried to obtain the crude product compound (1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (dihydrochloride, 120 mg) as a white solid. ¹ H NMR (400 MHz, D ₂ O) δ ppm 4.53 (d, J = 2.0 Hz, 2H), 3.66-3.47 (m, 4H), 2.71 (dd, J = 0.9, 11.9 Hz, 2H).

Step 5: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.66 mmol), (1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (dihydrochloride, 0.43 mmol) and diisopropylethylamine (748 uL, 4.29 mmol) were dissolved in dimethylacetamide (1.0 mL), ^0. Benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (280 mg, 0.63 mmol) was added at 50°C and the reaction was stirred at 50 ^° C for 2 hours. After cooling to 0 ^o C, the reaction mixture was quenched with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product compound (1R, 2R, 4S, 5S)-3,3-difluoro-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (200 mg), which is a yellow oily liquid. LCMS (ESI): [M/2+H] ⁺ = 425.0;

Step 6: Compound (1R,2R,4S,5S)-3,3-difluoro-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (200 mg, 0.22 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (343 mg, 2.20 mmol) was added, and stirred at 20 ^° C for 1 hour. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated under reduced pressure to obtain a crude product compound (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (250 mg). LCMS (ESI): [M+H] ⁺ = 693.2.

Step 7: To a solution of (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (250 mg, 0.36 mmol) in acetonitrile (0.5 mL) was added hydrogen chloride (4 M in dioxane, 340 uL) and the reaction was stirred at 20 ^° C for 1 hour. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (4.71 mg, 18 umol, yield 5%). LCMS (ESI): [M+H] ⁺ = 648.8. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.07 (s, 1H), 7.88 (dd, J = 5.8, 9.3 Hz, 1H), 7.42-7.30 (m, 2H), 7.21 (d, J = 2.5 Hz, 1H), 5.45-5.26 (m, 1H), 4.85-4.68 (m, 4H), 4.41-4.28 (m, 2H), 3.92-3.77 (m, 4H), 3.44 (m, 2H), 3.15-3.04 (m, 1H), 2.45-2.16 (m, 5H), 2.10-1.92 (m, 3H). Example 17 ：5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]non-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

Step 1: Add trifluoroacetic acid (4 mL) to a solution of (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (1.00 g, 3.04 mmol) in dichloromethane (16 mL), and stir at 50 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (16 mL), washed with ethyl acetate (16 mL*2), and the aqueous phase was freeze-dried to obtain a crude product compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (2.80 g) as a yellow oil. LCMS (ESI): [M+H] ⁺ = 111.2. ¹ H NMR (500 MHz, D ₂ O) δ ppm 6.37 (s, 2H), 3.48 (dd, J = 1.5, 14.3 Hz, 2H), 3.38-3.29 (m, 2H).

Step 2: Add di-tert-butyl dicarbonate (5.00 mL, 23.1 mmol) to a solution of (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 1.31 mmol) and diisopropylethylamine (5.36 mL, 38.4 mmol) in dichloromethane (12 mL) and stir the mixture at 25 ^° C for 16 hours. The reaction solution was quenched with water (40 mL) at 0 ^o C, extracted with dichloromethane (20 mL * 3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain a white solid compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-dicarboxylic acid di-tert-butyl ester (0.35 g, 1.12 mmol, yield 86%). LCMS (ESI): [M+Na] ⁺ = 333.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.18 (br s, 2H), 4.56 (br s, 2H), 3.78 (br d, J = 12.8 Hz, 1H), 3.64 (br d, J = 12.8 Hz, 1H), 3.26-3.02 (m, 2H), 1.50-1.44 (m, 18H).

Step 3: Dissolve (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-dicarboxylic acid di-tert-butyl ester (200 mg, 0.61 mmol) and (trimethylsilyl)diazomethane (2M in n-hexane, 3.00 mL, 6.10 mmol) in dichloromethane (4 mL). Add sodium acetate (27.0 mg, 0.12 mmol) under nitrogen protection and stir the reaction 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, 10% gradient methanol/dichloromethane) to obtain a yellow oily compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane-7,9-dicarboxylic acid di-tert-butyl ester (130 mg, 0.32 mmol, yield 53%). LCMS (ESI): [M+Na] ⁺ = 419.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.10 (br d, J = 19.0 Hz, 1H), 4.01-3.90 (m, 2H), 3.82 (br d, J = 12.6 Hz, 1H), 3.20-2.95 (m, 2H), 1.50 (m, 18H), 1.18 (br t, J = 5.4 Hz, 1H), 1.11-1.05 (m, 1H), 0.04 -0.05 (m, 9H), -0.50 (t, J = 4.8 Hz, 1H).

Step 4: Dissolve the compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane-7,9-dicarboxylic acid di-tert-butyl ester (100 mg, 0.25 mmol) in dichloromethane (1 mL), add hydrogen chloride (4 M dioxane solution, 630 uL) at 0 ^o C, and stir the reaction at 20 ^o C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (dihydrochloride, 65 mg), which is a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 197.1.

Step 5: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (170 mg, 0.24 mmol), (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazotricyclo[3.3.1.0 ^2,4 ]nonane (dihydrochloride, 65 mg, 0.24 mmol) and diisopropylethylamine (420 uL, 2.41 mmol) were dissolved in dimethylacetamide (1.7 mL), ^0. Benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (160 mg, 0.36 mmol) was added at 50 °C and the reaction was stirred at 50 ^° C for 2 hours. The mixture was quenched with saturated sodium bicarbonate (10 mL) at 0 ^° C, extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product compound (1R, 2R, 4S, 5S)-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (200 mg), which is a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 885.6;

Step 6: Compound (1R,2R,4S,5S)-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (200 mg, 0.22 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (343 mg, 2.20 mmol) was added, and stirred at 20 ^° C for 1 hour. The reaction solution was diluted with water (2 mL), extracted with ethyl acetate (3 mL * 3), the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (100 mg, 0.22 mmol, yield 60%). LCMS (ESI): [M+H] ⁺ = 728.8.

Step 7: To a solution of (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]nonane (100 mg, 0.14 mmol) in acetonitrile was added hydrogen chloride (4 M in dioxane, 630 uL) and the reaction was stirred at 20 ^° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (500 uL). Triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 ^2,4 ]non-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (4.30 mg, 6 umol, yield 4%). LCMS (ESI): [M+H] ⁺ = 685.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.19 (br s, 1H), 9.14 (s, 1H), 7.98 (dd, J = 6.0, 8.9 Hz, 1H), 7.47 (br t, J = 9.1 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.17 (s, 1H), 5.40-5.20 (m, 1H), 4.42 (br s, 2H), 4.20-4.11 (m, 1H), 4.03 (br d, J = 10.5 Hz, 1H), 3.94 (br s, 1H), 3.67 (br s, 2H), 3.24 (br d, J = 9.9 Hz, 2H), 3.18-3.08 (m, 2H), 3.03 (br s, 1H), 2.85 (br d, J = 5.7 Hz, 1H), 2.14-1.76 (m, 6H), 1.32-1.09 (m, 2H), -0.06 (s, 9H), -0.20 (m, 1H). Example 18 : 4-(4-((1R, 5S)-8-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol carboxylate

Step 1: In a glove box, potassium phosphate (1.5 M in water, 3.16 mL, 4.73 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (69 mg, 0.09 mmol) were added to a solution of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500 mg, 1.89 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (825 mg, 2.46 mmol) in 1,4-dioxane (15 mL). The mixture was stirred at 50 ^° C for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was diluted with water (2 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1S, 5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (530 mg, 1.21 mmol, yield 64%). LCMS (ESI): [M+H] ⁺ = 437.1.

Step 2: To a solution of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct- ² -ene-8-carboxylate (2.00 g, 4.58 mmol) in dichloromethane (120 mL) was added triethylsilane (4.40 mL, 27.46 mmol) and trifluoroacetic acid (6.80 mL, 91.55 mmol) at -15 ° C. The mixture was stirred at 25 ^° C for 16 hours under nitrogen protection. The reaction mixture was rotary dried to give the crude product 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00 g) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 339.0.

Step 3: Add triethylamine (1.97 mL, 14.17 mmol) and di-tert-butyl dicarbonate (2.03 mL, 8.85 mmol) to a solution of 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00 g, 4.58 mmol) in dichloromethane (20 mL). Stir the mixture at 20 ^° C for 16 hours under nitrogen protection and then spin dry. Add water (5 mL) and extract with ethyl acetate (10 mL * 3). Dry the organic phase with anhydrous magnesium sulfate, filter, and spin dry. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran/petroleum ether) to give a white solid compound tert-butyl (1R, 3s, 5S)-3-(7-chloro-8-fluoro-2-(methylthio) pyrido [4, 3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylate (1.01 g, 2.30 mmol, yield 50%). LCMS (ESI): [M+H] ⁺ = 439.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.04 (s, 1H), 4.60-4.23 (m, 2H), 4.15-3.90 (m, 1H), 2.67 (s, 3H), 2.40-2.25 (m, 2H), 2.22-2.10 (m, 2H), 1.95-1.83 (m, 2H), 1.74 (br dd, J = 1.7, 13.8 Hz, 2H), 1.51 (s, 9H).

Step 4: In a glove box, tert-butyl (1R, 3s, 5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.14 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (701 mg, 1.37 mmol) and cesium carbonate (1113 mg, 3.42 mmol) in dioxane (10 mL) and water (2 mL) solution, add chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (14.7 mg, 0.02 mmol). The mixture was stirred at 100 ^° C for 3 hours under nitrogen protection. The reaction solution was filtered, diluted with water (4 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 3s, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (750 mg, 0.95 mmol, yield 83%). LCMS (ESI): [M+H] ⁺ = 789.4.

Step 5: To a solution of tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.51 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (85% content, 257 mg, 1.27 mmol). The mixture was stirred at 25 ^° C for 2 hours under nitrogen protection. Water (3 mL) was added, and the mixture was extracted with dichloromethane (5 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain the crude product compound tert-butyl (1R, 3s, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg) as a yellow solid. LCMS (ESI): [M-56+H] ⁺ = 765.1.

^Step 6: To a solution of tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.73 mmol) and diisopropylethylamine (510 uL, 3.65 mmol) in dioxane (6.00 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (357 mg, 2.24 mmol) at 25 °C and the mixture was stirred at 80 ^° C for 4 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give brown oily compound tert-butyl (1R, 3s, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 0.38 mmol, 52% yield). LCMS (ESI): [M+H] ⁺ = 900.3.

Step 7: CsF (726 mg, ^{4.78 mmol} ) was added to a solution of tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 0.48 mmol) in dimethylformamide (5.00 mL) at 25 ° C. The solution was stirred at 25 ^° C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound tert-butyl (1R, 3s, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.39 mmol, yield 81%). LCMS (ESI): [M+H] ⁺ = 744.2.

^Step 8: Dissolve tert-butyl (1R,3s,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.48 mmol) in trifluoroacetic acid/dichloromethane (1/4 by volume, 4.00 mL) at 25 °C and stir for 2 hours. The solution was neutralized with triethylamine (1 mL) and diluted with water (5 mL), and extracted with dichloromethane (5 mL * 3). The organic layer was dried and concentrated, and the crude product was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 5.58 mg, 9.68 umol, yield 2%). LCMS (ESI): [M+H] ⁺ = 600.2; ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.47 (s, 1H), 8.47 (s, 1H), 7.89 (dd, J = 5.7, 9.1 Hz, 1H), 7.43-7.30 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 5.48-5.26 (m, 1H), 4.51-4.44 (m, 1H), 4.24 (br s, 2H), 3.37 (br s, 5H), 3.22-3.17 (m, 1H), 3.15-3.08 (m, 1H), 2.61-1.93 (m, 14H). Example 19 : (Isobutyryloxy)methyl (1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Step 1 : At 20 ^o C, add compound 4-nitrophenol (5.00 g, 35.94 mmol) to tetrahydrofuran (65.0 mL), add chloromethyl chloroformate (5.10 g, 39.54 mmol), then slowly add N,N-diisopropylethylamine (6.91 mL, 39.54 mmol), and stir the reaction at 20 ^o C for 2 hours. Dissolve the mixture in ethyl acetate (50.0 mL) and wash with saturated sodium bicarbonate solution (50.0 mL*2) and brine (50.0 mL*2), dry with anhydrous magnesium sulfate, filter and concentrate to obtain a yellow solid compound (4-nitrophenyl) chloromethyl carbonate (8.10 g, 34.98 mmol, yield 97%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.39-8.32 (m, 2H), 7.48-7.43 (m, 2H), 5.87 (s, 2H).

Step 2 : Add the compound (4-nitrophenyl) chloromethyl carbonate (5.00 g, 21.59 mmol) to acetone (100 mL), add sodium iodide (9.71 g, 64.77 mmol) and 4A molecular sieve (5.00 g) at 20 ^° C, and stir the reaction at 40 ^° C for 16 hours. Cool the reaction solution to room temperature and filter through diatomaceous earth. The filtrate was depressurized to remove volatiles and the residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL), respectively. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a yellow oily compound iodomethyl (4-nitrophenyl) carbonate (6.76 g, 20.94 mmol, yield 97%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.36-8.30 (m, 2H), 7.49-7.42 (m, 2H), 6.09 (s, 2H).

Step 3 : Add isobutyric acid (5.00 g, 56.75 mmol) to acetonitrile (200 mL), add silver oxide (4.76 g, 34.05 mmol) at 20 ^° C, and stir at 70 ^° C for 6 hours in the dark. The mixture was cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was vacuum-filtered to remove volatiles to obtain a brown solid compound, silver isobutyrate (1.00 g, 5.12 mmol, 9% yield).

Step 4 : Add iodomethyl (4-nitrophenyl) carbonate (414 mg, 1.28 mmol) to toluene (7.00 mL), add silver isobutyrate (500 mg, 2.56 mmol), and stir at 55 ^° C for 16 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was washed with 10% potassium carbonate solution (3 mL*2) and brine (3 mL*2), respectively. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound (((4-nitrophenoxy)carbonyl)oxy)isobutyric acid methyl ester (220 mg, 0.78 mmol, yield 61%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.36-8.30 (m, 2H), 7.48-7.41 (m, 2H), 5.91 (s, 2H), 2.69 (m, 1H), 1.29-1.22 (m, 6H).

Step 5 : To ^a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.59 mmol) in tetrahydrofuran (5.00 mL) at 25 °C was added ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (121 mg, 0.59 mmol) and sodium tert-butoxide (115 mg, 0.89 mmol), and the solution was stirred at 25 ^° C. for 2 hours. The reaction solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.37 mmol, yield 62%). LCMS (ESI): [M+Na] ⁺ = 967.4.

Step 6 : To ^a solution of tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.37 mmol) in dimethylformamide (3.50 mL) was added cesium fluoride (562 mg, 3.70 mmol) at 25°C and the solution was stirred at 25 ^° C for 2 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 0.37 umol, yield 99%). LCMS (ESI): [M+H] ⁺ = 788.8.

Step 7 : To ^a solution of tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.06 mmol) in acetonitrile (1.00 mL) at 25 °C was added hydrogen chloride (4 M in dioxane, 317 uL, 1.27 mmol) and the solution was stirred at 20 ^° C for 2 hours. The reaction solution was adjusted to pH 7 with triethylamine, and the solvent was removed by concentration under reduced pressure to obtain a crude product, compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (purity 50%, 80.0 mg), which was a brown solid. LCMS (ESI): [M+H] ⁺ = 644.9.

Step 8 ^: To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50% purity, 50.0 mg, 0.04 mmol) in dimethylformamide (1.00 mL) was added methyl (((4-nitrophenoxy)carbonyl)oxy)isobutyrate (19.8 mg, 0.07 mmol) at 20°C and the solution was stirred at 20 ^° C for 2 hours. The mixture was purified by preparative HPLC to give a white solid compound (isobutyryloxy)methyl (1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.26 mg, 0.02 mmol, yield 50%). LCMS (ESI): [M+H] ⁺ = 789.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.12-9.00 (m, 1H), 7.88 (dd, J = 5.6, 9.1 Hz, 1H), 7.44-7.29 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 5.97-5.77 (m, 2H), 4.73 (br s, 2H), 4.58-4.46 (m, 2H), 4.36-4.20 (m, 2H), 3.92-3.69 (m, 2H), 3.40-3.37 (m, 1H), 3.29-3.23 (m, 1H), 3.20-3.09 (m, 1H), 2.96-2.80 (m, 3H), 2.73-2.59 (m, 1H), 2.40-2.28 (m, 1H), 2.17-1.84 (m, 9H), 1.56-1.42 (m, 2H), 1.32-1.15 (m, 6H). Example 20 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol

Step 1 : Under nitrogen, add bis-pinacol borate (681 g, 2.68 mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride in dichloromethane (273 mg, 0.37 mmol), potassium 2-ethylhexanoate (610 mg, 3.35 mmol) to a solution of 4-bromoquinolin-2-ol (500 mg, 2.23 mmol) in dioxane (25 mL). Stir the resulting mixture at 80 ^° C for 1.5 hours. The suspension was filtered and concentrated to give a crude product, which was purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give a brown solid compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol (220 mg, 0.56 mmol, yield 25%). LCMS (ESI): [M+H] ⁺ = 272.1.

Step 2: To a solution of (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.27 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol (74 mg, 0.27 mmol) in dioxane (2000 uL) was added potassium phosphate solution (549 uL, 0.82 mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (20 mg, 0.03 mmol). The suspension was stirred at 100 ^° C for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(2-hydroxyquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.16 mmol, 58% yield) as a brown solid compound. LCMS (ESI): [M+H] ⁺ = 660.3.

Step 3: A solution of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(2-hydroxyquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.17 mmol) in trifluoroacetic acid/dichloromethane (2200 uL) was stirred at 25 ^o C for 2 hours. The solution was alkalized with triethylamine (450 uL) and extracted with dichloromethane (2 mL*3). The combined organic layers were dried and concentrated. Purification by preparative HPLC gave a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol (12.9 mg, 22 umol, yield 14%). LCMS (ESI): [M+H] ⁺ = 560.3. ¹ H NMR (400 MHz, CD ₃ OD- d ₄ ) δ = 9.20 (s, 1H), 7.69-7.57 (m, 1H), 7.52-7.39 (m, 2H), 7.27-7.19 (m, 1H), 6.77 (s, 1H), 5.60-5.40 (m, 1H), 4.81 (br s, 2H), 4.64-4.53 (m, 2H), 4.08 (br s, 2H), 3.91 (br d, J = 11.0 Hz, 2H), 3.84-3.61 (m, 3H), 3.39-3.33 (m, 1H), 2.69-1.91 (m, 10H) Example 21 : 7a'-(((4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan -3 -yl ) -7- (8- ethynyl- 7- fluoronaphthalen -1 -yl )-8 -fluoropyrido [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) tetrahydro -1'H,3'H- spiro [ oxacyclobutane -3,2'- pyrrolizine ]

Step 1 : Add 1.5 M potassium phosphate solution (696 μL, 1.04 μL) to a solution of tert-butyl (1R,5S)-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.35 mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189 mg, 0.42 mmol) in dioxane (4 mL) in a glove box. mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (23 mg, 0.03 mmol) were added, and the mixture was stirred at 100 degrees for 3 hours under nitrogen protection. The reaction mixture was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give a white solid compound tert-butyl (1R,5S)-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.27 mmol, yield 76%). LCMS (ESI): [M+H] ⁺ =865.6.

Step 2 : Add trifluoroacetic acid/dichloromethane = 1:4 (4.4 mL) to tert-butyl (1R,5S)-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.25 mmol). The mixture was stirred at 25 degrees for 1 hour under nitrogen protection. Then it was quickly blown dry with nitrogen and then dried by oil pump rotation. The brown oily compound 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine] (200 mg, 0.25 mmol, crude product) was obtained. LCMS (ESI): [M+H] ⁺ =765.4.

Step 3 : Add cesium fluoride (4468 mg, 26.1 mmol) to a solution of 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine] (200 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at 25 degrees for 2 hours under nitrogen protection. Then filtered. The residue was purified by preparative HPLC to give yellow solid compound 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine] (55 mg, 0.09 mmol, yield 35%). LCMS (ESI): [M+H] ⁺ = 609.3. ¹ H NMR (400MHz, CD ₃ OD) δ ppm 9.04 (s, 1H), 8.23 - 8.05 (m, 2H), 7.77 - 7.58 (m, 2H), 7.46 (t, J = 9.0 Hz, 1H), 4.73 (br d, J = 6.1 Hz, 2H), 4.68 - 4.60 (m, 4H), 4.28 - 4.08 (m, 2H), 3.81 - 3.62 (m, 4H), 3.53 (d, J = 10.4 Hz, 1H), 3.45 (d, J = 9.0 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.97 (br d, J = 10.3 Hz, 1H), 2.78 (td, J = 5.2, 10.6 Hz, 1H), 2.56 (dd, J = 1.8, 13.3 Hz, 1H), 2.07 - 1.93 (m, 3H), 1.93 - 1.76 (m, 6H). Example 22 : 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile

Step 1 : To a solution of 6-bromo-4-methylpyridin-2-amine (1.00 g, 5.35 mmol) in N,N-dimethylformamide (17 mL) at 0 ^o C, add 60% sodium hydrogen (1.10 g, 27.5 mmol), stir at 25 ^o C for 1 hour, then add 1-(chloromethyl)-4-methoxybenzene (1.90 g, 12.1 mmol) at 0 ^o C, and stir the mixture at 25 ^o C for 2 hours under nitrogen protection. Quench with saturated ammonium chloride solution (17 mL) at 0 ^o C, extract five times with ethyl acetate (25 mL), combine the organic phases, wash with brine (50 mL), dry over anhydrous sodium sulfate, filter and spin dry. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2.00 g, 4.68 mmol, yield 79%). LCMS (ESI): [M+H] ⁺ = 427.1.

Step 2 : To a solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2.00 g, 4.68 mmol), tricyclohexylphosphine (0.26 g, 0.94 mmol) and lithium chloride (0.99 g, 23.4 mmol) in 1,4-dioxane (13 mL), hexabutyl ditin (8.14 g, 14.04 mmol) and tris(dibenzylacetone) dipalladium (0) (0.43 g, 9.47 mmol) were added. The mixture was stirred at 110 ^° C for 5 hours under nitrogen protection and then rotary dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) three times to obtain a colorless oily compound N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)pyridin-2-amine (1.80 g, 2.82 mmol, yield 60%). LCMS (ESI): [M+H] ⁺ = 639.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.24-7.15 (m, 4H), 6.92-6.81 (m, 4H), 6.65-6.43 (m, 1H), 6.17 (s, 1H), 4.71 (s, 4H), 3.81 (s, 6H), 2.24-2.13 (m, 3H), 1.73-1.46 (m, 6H), 1.43-1.24 (m, 6H), 1.20-0.95 (m, 6H), 0.89-0.85 (m, 9H).

Step 3 : In a glove box, to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (615 mg, 1.10 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylmethanyl)pyridin-2-amine (1.40 g, 2.2 mmol), cuprous iodide (63 mg, 0.33 mmol) and lithium chloride (116 mg, 2.75 mmol) in 1,4-dioxane (18 mL) was added tetrakis(triphenylphosphine)palladium (254 mg, 0.22 mmol). The mixture was stirred at 120 ^° C for 16 hours under nitrogen protection. Filtered, water (10 mL) was added, and extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether). The crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg) was obtained as a yellow solid. LCMS (ESI): [M+H] ⁺ = 828.3.

Step 4 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (780 mg, 0.94 mmol) in acetonitrile (16 mL) was added N-iodosuccinimide (1060 mg, 4.71 mmol) and p-toluenesulfonic acid (6 mg, 0.04 mmol). The mixture was stirred at 25 ^° C for 5 hours under nitrogen protection. The mixture was rotary dried, brine (10 mL) was added, and ethyl acetate (20 mL) was used for extraction three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (710 mg, 0.74 mmol, yield 79%) was obtained. LCMS (ESI): [M+H] ⁺ = 954.4.

Step 5 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.73 mmol) in N,N-dimethylacetamide (17.5 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3525 mg, 18.3 mmol) and cuprous iodide (1677 mg, 8.81 mmol). The mixture was stirred at 90 ^° C for 12 hours under nitrogen protection. The mixture was filtered, the filtrate was rotary dried, brine (10 mL) was added, and ethyl acetate (10 mL) was used for extraction three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.31 mmol, yield 43%) was obtained. LCMS (ESI): [M+H] ⁺ = 897.3.

Step 6 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.17 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (70 mg, 0.44 mmol) in tetrahydrofuran (3 mL) was added sodium tert-butoxide (24 mg, 0.25 mmol). The mixture was stirred at 25 ^° C for 2 hours under nitrogen. Water (3 mL) was added, and the mixture was extracted three times with ethyl acetate (3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg) was obtained as a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 955.7.

Step 7 : Dissolve tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.16 mmol) in trifluoroacetic acid (3 mL), and stir the mixture at 50 ^° C for 2 hours under nitrogen. Then rotate to dryness. Add dichloromethane (2 mL), adjust pH to 7 with triethylamine, and rotate to dryness. The residue was purified by preparative HPLC to give a white solid compound 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (28.5 mg, 0.05 mmol, yield 20%). LCMS (ESI): [M+H] ⁺ = 615.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.25 (s, 1H), 6.64 (s, 1H), 5.43-5.21 (m, 1H), 4.53 (q, J = 10.4 Hz, 2H), 4.33-4.18 (m, 2H), 3.77-3.60 (m, 4H), 3.31-3.13 (m, 3H), 3.02 (dt, J = 5.6, 9.3 Hz, 1H), 2.48 (d, J = 1.3 Hz, 3H), 2.40-2.09 (m, 3H), 2.05-1.95 (m, 2H), 1.94-1.70 (m, 5H). Example 23 : (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid

Step 1 : Under nitrogen protection, potassium phosphate (1.5 M aqueous solution, 1.09 mL, 1.63 mmol) was added to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-2-ol (176 mg, 0.65 mmol) in dioxane (5.00 mL). mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, (36.4 mg, 0.05 mmol), and the mixture was stirred at 80 ^° C for 2 hours. The reaction solution was diluted with water (2 mL) and extracted with dichloromethane (2 mL * 3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50% petroleum ether/tetrahydrofuran, then 0-10% dichloromethane/methanol) to obtain a brown oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.53 mmol, yield 98%). LCMS (ESI): [M+H] ⁺ = 659.3.

Step 2 : The compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.46 mmol) was slowly added to pyridine (3 mL), trifluoromethanesulfonic anhydride (82.0 uL, 0.50 mmol) was added at 0 ^o C, and the mixture was stirred at 0 ^o C for 1 hour. The reaction solution was diluted with water (1 mL) and extracted with toluene (1 mL * 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% dichloromethane/methanol) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.35 mmol, yield 78%). LCMS (ESI): [M+H] ⁺ = 791.4.

Step 3 : Tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin- ^7a (5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol), boronic acid (17.0 mg, 0.19 mmol), triphenylphosphine (2 mg, 7.6 umol) and diisopropylethylamine (67.0 uL, 0.38 mmol) in isopropanol (1000 μL, 4% d-butyl)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol), boronic acid (17.0 mg, 0.19 mmol), triphenylphosphine (2 mg, 7.6 umol) and diisopropylethylamine (67.0 μL, 0.38 mmol) were added to the mixture at 25 °C under nitrogen. uL) solution was added with [1,3-bis(diphenylphosphino)propane]nickel chloride (3.00 mg, 3.8 umol), and the mixture was stirred at 80 ^° C for 16 hours. The reaction solution was filtered and concentrated to obtain a crude product compound (4-(4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]octane)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (110 mg) as a brown solid. LCMS (ESI): [M+H] ⁺ = 687.4

Step 4 : To ^a solution of (4-(4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (76.0 mg, 0.11 mmol) in acetonitrile (1600 uL) at 25 °C was added hydrogen chloride (4 M in dioxane, 277 uL, 1.11 mmol). The solution was stirred at 25 ^° C for 1 hour. The solution was quenched with triethylamine (155 uL, 1.11 mmol), then concentrated and purified by preparative HPLC to give a white solid compound (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (formate, 11.19 mg, 18.7 umol, yield 17%). LCMS (ESI): [M+H] ⁺ = 587.2 ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.16 (s, 1H), 8.46 (br s, 1H), 8.42 (br s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.67 (br d, J = 8.3 Hz, 1H), 7.59-7.43 (m, 2H), 5.57-5.35 (m, 1H), 4.78 (br s, 2H), 4.60-4.47 (m, 2H), 4.02 (br s, 2H), 3.88 (br dd, J = 5.6, 13.0 Hz, 2H), 3.77-3.51 (m, 3H), 3.29-3.24 (m, 1H), 2.62-2.36 (m, 2H), 2.36-2.13 (m, 3H), 2.12-1.91 (m, 5H). Example 24 : 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-quinazoline-6-carbonitrile

Example 24 was prepared by the synthetic route of Example 22 , using the intermediate to tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate and the intermediate (1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2A

LCMS (ESI): [M+H] ⁺ =659.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.26 (s, 1H), 6.65 (s, 1H), 4.62-4.47 (m, 2H), 4.43-4.29 (m, 2H), 3.79-3.56 (m, 4H), 3.32-3.25 (m, 1H), 3.22-3.10 (m, 1H), 2.85 (d, J = 12.2 Hz, 1H), 2.78-2.64 (m, 1H), 2.48 (br d, J = 0.9 Hz, 3H), 2.28 (br dd, J = 6.1, 13.4 Hz, 1H), 1H), 2.20-2.10 (m, 1H), 2.03 (br d, J = 13.6 Hz, 1H), 1.98-1.71 (m, 7H), 1.55-1.36 (m, 2H). ¹⁹ F NMR (400 MHz, CD ₃ OD) δ ppm -55.85 (s, 3F), -127.71 (br s, 1F), -135.41 (d, J = 151.1 Hz, 1F), -138.12 (d, J = 151.1 Hz, 1F). Example 25 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol

Step 1 ^: Add bis(phenylsulfonyl)fluoroamine (9.33 g, 29.59 mmol) and zirconium tetrachloride (0.10 g, 0.45 mmol) to a solution of 4-bromonaphthalene-2-ol (2.00 g, 8.96 mmol) in dichloromethane (30 mL) at 0 ° C. Stir the solution at 25 ^° C for 16 hours. Concentrate the solution and purify it by flash column chromatography (silica gel, 0-20% gradient of petroleum ether/ethyl acetate) to obtain a brown solid compound 4-bromo-1-fluoronaphthalene-2-ol (0.94 g, 3.50 mmol, 39% yield). LCMS (ESI): [MH] ⁺ = 240.8.

Step 2 : At 25 ^° C and under nitrogen protection, add bis(triphenylphosphine)palladium(II) chloride (44.0 mg, 0.06 mmol) to a solution of 4-bromo-1-fluoronaphthalen-2-ol (300 mg, 1.24 mmol), bis(pinacol borate) (475 mg, 1.87 mmol) and potassium acetate (367 mg, 3.73 mmol) in dioxane (6000 uL). Stir the solution at 110 ^° C for 3 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-25% gradient petroleum ether/ethyl acetate) to give a yellow solid compound 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (324 mg, 1.13 mmol, yield 90%). LCMS (ESI): [MH] ⁺ = 287.0.

Step 3 : Potassium carbonate (2.0 ^M aqueous solution, 409 uL, 0.82 mmol) and tetrakis(triphenylphosphine)palladium (32.0 mL) were added to a solution of 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (157 mg, 0.54 mmol) and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.27 mmol) in dioxane (3.00 mL) at 25 °C under nitrogen protection. The solution was stirred at 85 ^° C for 16 hours. The solution was concentrated and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.26 mmol, yield 97%). LCMS (ESI): [M+H] ⁺ = 677.2.

Step 4 : To ^a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.30 mmol) in acetonitrile (4000 uL) was added hydrogen chloride (4 M in dioxane, 739 uL, 2.96 mmol) at 25 o C. The solution was stirred at 25 ^o C for 1 hour. The pH was adjusted to 8 by adding triethylamine (206 uL, 1.48 mmol). The solution was then concentrated and purified by preparative HPLC to give a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol (formate salt, 77.19 mg, 0.13 mmol, yield 45%). LCMS (ESI): [M+H] ⁺ = 577.0. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.15 (s, 1H), 8.48 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65-7.51 (m, 2H), 7.42-7.30 (m, 2H), 5.55-5.33 (m, 1H), 4.77 (br d, J = 8.5 Hz, 2H), 4.48 (q, J = 11.3 Hz, 2H), 3.95 (br s, 2H), 3.89-3.78 (m, 2H), 3.70-3.49 (m, 3H), 3.23 (dt, J = 6.0, 9.8 Hz, 1H), 2.58-2.23 (m, 3H), 2.21-2.11 (m, 2H), 2.09-1.86 (m, 5H). Example 26 : 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile

Step 1: At 0 ^° C, add a solution of 2-bromo-3,4-difluorobenzoic acid (25.0 g, 105.49 mmol) in tetrahydrofuran (100 mL) dropwise with a solution of borane in tetrahydrofuran (422 mL, 422 mmol). Warm to room temperature and stir for 16 hours. Cool the solution with an ice bath, then slowly add a 10% aqueous sodium carbonate solution (180 mL). Concentrate the suspension in vacuo to obtain a white solid. Acidify with 3 mol/L aqueous hydrochloric acid solution (600 mL), dilute with dichloromethane (300 mL), and filter the mixture through diatomaceous earth. Separate the filtrate, dry the organic layer with anhydrous sodium sulfate, and then filter. The filtrate was concentrated in vacuo to give (2-bromo-3,4-difluorophenyl)methanol (22.0 g, 98.65 mmol, 94% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.57-7.45 (m, 1H), 7.43-7.31 (m, 1H), 5.58 (t, J = 5.6 Hz, 1H), 4.50 (br d, J = 5.4 Hz, 2H).

Step 2: At 0 ^o C, add methanesulfonic anhydride (25.78 g, 148 mmol) to a solution of (2-bromo-3,4-difluorophenyl)methanol (22.0 g, 98.65 mmol) and triethylamine in dichloromethane (220 mL). Stir the reaction at 0 ^o C for 1 hour. Add water (200 mL) to the mixture and extract with dichloromethane (100 mL * 3), and wash the organic phase with brine (200 mL * 1). The organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated in vacuo to obtain a brown oily compound 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol, yield 97%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.64-7.51 (m, 2H), 5.40-5.32 (m, 2H), 3.32-3.25 (m, 3H).

^Step 3: To a solution of 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol) in acetonitrile (300 mL) was added potassium carbonate (26.0 g, 192 mmol) and trimethylsilyl cyanide (19.0 g, 192 mmol) at 0 ° C. The reaction was stirred at 80 ^° C for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL), and the organic phase was washed with brine (200 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was rotary dried, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 2-(2-bromo-3,4-difluorophenyl)acetonitrile (9.80 g, 42 mmol, yield 44%). ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.64-7.52 (m, 1H), 7.50-7.42 (m, 1H), 4.14 (s, 2H).

Step 4: Add tetrakis(triphenylphosphine)palladium (4.73 g, 4.09 mmol) and zinc cyanide (5.77 g, 49.13 mmol) to a solution of 2-(2-bromo-3,4-difluorophenyl)acetonitrile (9.50 g, 40.94 mmol) in dimethylacetamide (100 mL). The mixture was heated at 120 ^° C for 5 hours under nitrogen protection. The reaction solution was rotary dried, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 6-(cyanomethyl)-2,3-difluorobenzonitrile (4.50 g, 25.26 mmol, yield 62%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.00-7.84 (m, 1H), 7.52 (br dd, J =4.1, 8.4 Hz, 1H), 4.33 (s, 2H).

Step 5: At 0 ^o C, the compound 6-(cyanomethyl)-2,3-difluorobenzonitrile (4.50 g, 25.26 mmol) was slowly dissolved in 33% hydrobromic acid/acetic acid solution (45.00 mL), and the mixture was stirred at 0 ^o C for 0.2 hours and then at 20 ^o C for 1.5 hours. The mixture was diluted with water (150 mL) and alkalized by saturated sodium carbonate solution. Extract with ethyl acetate (150 mL*3), dry the organic phase with anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue is purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 1-bromo-7,8-difluoroisoquinolin-3-amine (0.76 g, 2.90 mmol, yield 12%). LCMS (ESI): [M+H] ⁺ = 260.8. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.63 (dt, J = 7.4, 9.8 Hz, 1H), 7.49 (ddd, J = 1.6, 5.0, 9.3 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.49 (s, 2H).

Step 6: Under nitrogen atmosphere, hexabutyl ditin (1.00 g, 1.74 mmol), tricyclohexylphosphine (32.5 mg, 0.12 mmol), lithium chloride (123 mg, 2.9 mmol) and tris(dibenzylacetone) dipalladium (53 mg, 0.06 mmol) were added to a solution of 1-bromo-7,8-difluoroisoquinolin-3-amine (150 mg, 0.58 mmol) in dioxane (1.5 mL). The reaction solution was stirred at 120 ^° C for 16 hours. The mixture was dried under reduced pressure and rotary vortexed. The residue was purified by flash column chromatography (neutral alumina, 0-5% gradient ethyl acetate/petroleum ether) to give a yellow oily compound 7,8-difluoro-1-(tributylmethylstannyl)isoquinolin-3-amine (260 mg, 0.55 mmol, yield 95%). LCMS (ESI): [M+H] ⁺ = 471.0.

Step 7: Under nitrogen atmosphere, 7,8-difluoro-1-(tributylmethylstannyl)isoquinolin-3-amine (251 mg, 0.54 mmol), cuprous iodide (25.5 mg, 0.13 mmol), lithium chloride (47 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol) were added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.45 mmol) in dioxane (5 mL). The reaction was stirred under nitrogen atmosphere at 120 ^° C for 16 hours. The mixture was rotary dried and the crude product was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to give a yellow solid compound tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.18 mmol, yield 40%). LCMS (ESI): [M+H] ⁺ = 660.1.

Step 8: To a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 91 umol) in tetrahydrofuran (1 mL) was added 4A molecular sieve (60 mg), sodium tert-butoxide (11 mg, 0.11 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (17 mg, 0.11 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47.3 mg, 66 umol, yield 72%). LCMS (ESI): [M+H] ⁺ = 719.2.

Step 9: To a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47.3 mg, 66 umol) in acetonitrile (1 mL) was added hydrogen chloride (4 M in dioxane, 330 uL, 1.3 mmol). The reaction was stirred at 20 ^° C for 1 hour. The solution was concentrated and dissolved in acetonitrile (1 mL), neutralized with triethylamine and concentrated. The mixture was purified by preparative HPLC to give a yellow solid compound 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (9.45 mg, 15.3 umol, yield 23%). LCMS (ESI): [M+H] ⁺ = 619.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.35 (s, 1H), 7.55 (br d, J = 5.0 Hz, 2H), 7.01 (br s, 1H), 5.48 (br s, 1H), 4.64 (br d, J = 10.5 Hz, 2H), 4.49-4.38 (m, 2H), 3.91-3.79 (m, 4H), 3.48 (br d, J = 10.5 Hz, 3H), 3.20 (br s, 1H), 2.46-2.24 (m, 3H), 1.96 (br s, 7H). Example 27 : 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine Example 29 ：6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine

Step 1 : In a glove box, to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 2.85 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylmethanyl)pyridin-2-amine (3.27 g, 5.12 mmol), cuprous iodide (163 mg, 0.85 mmol) and lithium chloride (302 mg, 7.12 mmol) in dioxane (28 mL) was added tetrakis(triphenylphosphine)palladium (657 mg, 0.57 mmol). The mixture was stirred at 120 ^° C for 16 hours under nitrogen. Filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 2.24 mmol, yield 79%). LCMS (ESI): [M+H] ⁺ = 804.6.

Step 2 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.62 mmol) in acetonitrile (10 mL) was added N-iodosuccinimide (700 mg, 3.11 mmol) and p-toluenesulfonic acid (4.30 mg, 0.02 mmol). The mixture was stirred at 25 ^° C for 12 hours under nitrogen protection. The mixture was rotary dried, brine (10 mL) was added, and ethyl acetate (20 mL * 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain a crude product. The crude product was added to water (20 mL), stirred at room temperature for 1 hour, filtered, and washed with petroleum ether (10 mL). The filter cake was dried in vacuo to give a crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg) as a yellow solid. LCMS (ESI): [M+H] ⁺ = 930.3. ¹ HNMR (400 MHz, CDCl ₃ ) δ ppm 9.11 (s, 1H), 7.19 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.6 Hz, 4H), 6.52 (s, 1H), 4.92 (q, J = 8.3 Hz, 2H), 4.69 (s, 4H), 4.63-4.38 (m, 4H), 3.81 (s, 6H), 3.76 (br dd, J = 4.9, 12.4 Hz, 2H), 2.39 (s, 3H), 2.05-1.96 (m, 2H), 1.76 (br d, J = 7.7 Hz, 2H), 1.55 (s, 9H).

Step 3 : tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 0.31 mmol) and cuprous iodide (178 mg, 0.94 mmol) in N,N-dimethylacetamide (7.2 mL) were added with trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (468 mg, 1.87 mmol) at 0 ^° C. The mixture was stirred at 20 ^° C for 1 hour under nitrogen protection. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether). A mixture of the compounds tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mL) was obtained. mg) as a yellow solid. LCMS (ESI): [M+H] ⁺ = 872.5; 922.7.

Step 4 : To a mixture of tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (51.0 mg, 0.32 mmol) in tetrahydrofuran (2.8 mL) was added sodium tert-butoxide (23.0 mg, 0.24 mmol). The mixture was stirred at 20 ^° C for 2 hours under nitrogen protection. Water (5 mL) was added and ethyl acetate (10 mL * 3) Extraction 3, the combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary dried to obtain a crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclic A mixture of [3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg) was obtained as a yellow oily liquid. LCMS (ESI): [M+Na] ⁺ = 953.7; [M+H] ⁺ = 982.5.

Step 5 : tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (2.3 mL), stirred at 50 ^° C for 2 hours under nitrogen, and then rotated to dryness. Dichloromethane (0.5 mL) was added, and the pH was adjusted to 7 with triethylamine and rotated to dryness. The residue was purified by preparative HPLC to give two compounds. The compound with a shorter retention time was Example 27 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine) (43.98 mg, 0.07 mmol, 30% yield), which was a white solid. LCMS (ESI): [M+H] ⁺ = 591.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.03 (s, 1H), 6.63 (s, 1H), 5.48-5.16 (m, 1H), 4.70-4.54 (m, 2H), 4.38-4.18 (m, 2H), 3.75-3.59 (m, 4H), 3.31-3.18 (m, 3H), 3.02 (dt, J = 5.7, 9.4 Hz, 1H), 2.47 (br d, J = 1.2 Hz, 3H), 2.40-2.20 (m, 2H), 2.19-2.11 (m, 1H), 2.08-1.91 (m, 2H), 1.94-1.73 (m, 5H).

The compound with a longer retention time was Example 29 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine) (5.26 mg, 8.2 umol, yield 3%), which was a white solid. LCMS (ESI): [M+H] ⁺ = 641.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.99 (s, 1H), 6.64 (s, 1H), 5.44-5.21 (m, 1H), 4.60 (br s, 2H), 4.37-4.18 (m, 2H), 3.67 (br s, 4H), 3.30-3.14 (m, 3H), 3.03 (dt, J = 5.7, 9.3 Hz, 1H), 2.47 (br s, 3H), 2.41-2.21 (m, 2H), 2.20-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.96-1.71 (m, 5H). Example 28 : N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide

Step 1 : At 25 ^° C, compound 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (35.0 mg, 0.06 mmol) was added to dichloromethane (500 uL), triethylamine (89 uL, 0.59 mmol) and di-tert-butyl dicarbonate (15 uL, 0.07 mmol), and the mixture was stirred at 25 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.06 mmol, yield 98%). LCMS (ESI): [M+H] ⁺ = 691.2.

Step 2 : At 25 ^° C, dissolve the compound tert-butyl (1R,5S)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) in dimethylformamide (400 uL), cool to 0 ^° C, add pyridine (50 uL), and then slowly add acetyl chloride (7 uL, 0.10 mmol), and the mixture is heated to 25 ^° C and stirred for 1 hour. The reaction solution was separated by ethyl acetate (1 mL) and water (1 mL), and the aqueous layer was extracted with ethyl acetate (1 mL*2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to obtain a brown oily compound tert-butyl (1R, 5S)-3-(7-(6-acetamido-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, 0.05 mmol, yield 99%). LCMS (ESI): [M+H] ⁺ = 733.2.

Step 3 : At 0 ^° C, the compound tert-butyl (1R,5S)-3-(7-(6-acetamido-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) was dissolved in acetonitrile (1 mL), and hydrogen chloride (4 M in dioxane, 239 uL, 0.96 mmol) was added, and the reaction was stirred at 20 ^° C for 2 hours. The reaction solution was concentrated in vacuo, the residue was dissolved in acetonitrile (500 uL) and neutralized with triethylamine to pH>7, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to obtain white solid N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide (15.0 mg, 0.02 mmol, yield 50%). LCMS (ESI): [M+H] ⁺ = 633.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.05 (s, 1H), 8.33 (s, 1H), 5.44-5.19 (m, 1H), 4.60 (br d, J = 19.3 Hz, 3H), 4.37-4.21 (m, 2H), 3.77-3.57 (m, 4H), 3.27-3.19 (m, 2H), 3.09-2.97 (m, 1H), 2.71-2.57 (m, 3H), 2.42-2.10 (m, 6H), 2.06-1.97 (m, 2H), 1.95-1.72 (m, 5H). Example 30 : 4-(4-(-3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

Step 1 : To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (269 mg, 0.63 mmol) and (dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)-methanol (115 mg, 0.63 mmol) in dioxane (2.5 mL) was added diisopropylethylamine (334 uL, 1.88 mmol), and the mixture was stirred at 80 ^o C under nitrogen for 16 hours. The reaction mixture was spun dry. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol/dichloromethane) to give a yellow solid compound tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (83 mg, 0.14 mmol, yield 23%). LCMS (ESI): [M+H] ⁺ = 575.4.

Step 2 : In a glove box, potassium phosphate (1.5 M in water, 386 μL, 0.58 μL) was added to a solution of tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.19 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (83 mg, 0.23 mmol) in dioxane (2.2 mL). mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (14 mg, 0.02 mmol), and the mixture was stirred at 100 ^° C for 3 hours under nitrogen. The reaction mixture was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol/dichloromethane) to give yellow oily compound tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (129 mg, 0.17 mmol, yield 87%). LCMS (ESI): [M+H] ⁺ = 773.5.

Step 3 : To a solution of tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.14 mmol) in dichloromethane (1760 uL) was added trifluoroacetic acid (440 uL). The mixture was stirred at 25 ^o C for 1 hour. Most of the solvent was removed with a stream of nitrogen and then the mixture was rotated to dryness using an oil pump. Then triethylamine (0.5 mL) and tetrahydrofuran (0.5 mL) were added and the mixture was rotated to dryness. The residue was purified by preparative HPLC to give a white solid compound 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30.6 mg, 0.05 mmol, yield 34%). LCMS (ESI): [M+H] ⁺ = 629.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.07 (s, 1H), 7.69 (dd, J = 5.8, 9.1 Hz, 1H), 7.32 (d, J = 5.7, 9.2 Hz, 1H), 7.70 (d, J = 5.9, 10.8 Hz, 1H). 3.71 (m, 2H), 3.59 (d, J = 10.5 Hz, 1H), 3.55 (t, J = 9.4 Hz, 1H), 3.24 (d, J = 2.5 Hz, 1H), 3.75 (t, J = 10.8 Hz, 1H), 3.54 (t, J = 3.1, 10.6 Hz, 1H), 3.85 (m, 2H), 3.24 (d, J = 10.5 Hz, 1H), 3.55 (t, J = 10.8 Hz, 1H), 3.54 (t, J = 2.5, 10.6 Hz, 1H), 3.85 (t, J = 3.1, 10.8 Hz, 1H), 3.94 (t, J = 3.2, 10.8 Hz, 1H), 2.28-2.12 (m, 1H), 2.05-1.93 (m, 3H), 1.91-1.76 (m, 6H), 0.81 (dt, J = 2.4, 7.3 Hz, 3H). Example 31A and Example 31B : 4-(4 -((1R,5S)- (3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and 4-(4 -(( 1R,5S )- (3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

Example 30 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 1, Example 31A : LCMS (ESI): [M+H] ⁺ = 629.3; SFC analysis (column: Chiralpak AD-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B for 5 minutes, flow rate: 4 ml/min): the elution position of the palmar column is 0.660 min; ¹ H NMR (400 MHz, MeOD) δ ppm 9.07 (s, 1H), 7.69 (dd, J = 5.9, 9.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.27 (t, J = 9.4 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.73 3H), 4.68-4.56 (m, 4H), 4.27-4.12 (m, 2H), 3.81-3.63 (m, 4H), 3.54 (d, J = 10.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.97 (d, J = 10.4 Hz, 1H), 2.78 (td, J = 5.3, 10.8 Hz, 1H), 2.62-2.42 (m, 2H) , 2.24-2.14 (m, 1H), 2.07-1.93 (m, 3H), 1.93-1.75 (m, 6H), 0.81 (dt, J = 2.8, 7.4 Hz, 3H).

Isomer 2 , Example 31B : LCMS (ESI): [M+H] ⁺ = 629.3; SFC analysis (column: Chiralpak AD-3 (50mm * 4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B for 5 minutes, flow rate: 4 ml/min): the elution position of the palmar column is 2.147 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.07 (s, 1H), 7.69 (dd, J = 5.8, 9.1 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.27 (t, J = 9.4 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 3H), 4.73 (dd, J = 1.3, 6.1 Hz, 2H), 4.68-4.56 (m, 4H), 4.30-4.10 (m, 2H), 3.81-3.63 (m, 4H), 3.55 (d, J = 10.5 Hz, 1H), 3.13-2.94 (m, 2H), 2.87-2.74 (m, 1H), 2.63-2.43 (m, 2H), 2.25-2.15 (m, 1H), 2.07-1.94 (m, 3H), 1.93-1.77 (m, 6H), 0.82 (dt, J = 2.7, 7.4 Hz, 3H). Example 32 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol dicarboxylate

Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.16 mmol) and (hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methanol (106 mg, 0.58 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (375 mg, 2.90 mmol). The reaction was stirred at 25 ^° C for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 430 mg, 0.39 mmol, 67% yield). LCMS (ESI): [M+H] ⁺ = 773.4.

Step 2 : To ^a reaction bottle containing tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 410 mg, 0.37 mmol) was added a trifluoroacetic acid/dichloromethane mixed solution (1/4 by volume, 5 mL) at 0 °C. The reaction was stirred at 25 ^° C for 1 hour. The mixture was blown dry at room temperature with a stream of nitrogen, diluted with dichloromethane (1 mL) and triethylamine was added to adjust the pH to 7-8. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (dicarboxylate, 17.6 mg, 27 umol, 7% yield). LCMS (ESI): [M+H] ⁺ = 629.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.14 (s, 1H), 8.49 (s, 2H), 7.70 (dd, J = 6.0, 9.0 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.28 (t, J = 9.3 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 4.86-4.75 (m, 2H), 4.65-4.71 (m, 2H), 4.54 (t, J = 4.3 Hz, 1H), 4.19-4.08 (m, 3H), 4.23-4.84 (m, 3H), 3.90-3.81 (m, 1H), 3.50-3.40 (m, 1H), 3.27 (br dd, J = 5.4, 10.2 Hz, 1H), 2.57-2.51 (m, 1H), 2.51-2.43 (m, 1H), 2.33-2.02 (m, 12H), 0.84-0.77 (m, 3H)

The following examples were prepared by the synthetic route of Example 32 : Example 33A : trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((1aR,6aS,6bS)-hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 599.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.12 (s, 1H), 8.64-8.37 (m, 2H), 7.68 (dd, J = 9.1, 5.8 Hz, 1H), 7.41-7.20 (m, 2H), 7.05 (d, J = 2.6 Hz, 1H), 4.78-4.64 (m, 4H), 3.96-3.75 (m, 4H), 3.66 (br d, J = 11.4 Hz, 2H), 3.38 (br dd, J = 11.7, 4.3 Hz, 2H), 2.55-2.15 (m, 6H), 2.03-1.87 (m, 6H), 0.92-0.70 (m, 5H). Example 33B : cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[a]pyrrolizine-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 599.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.06 (s, 1H), 7.68 (dd, J = 9.1, 5.9 Hz, 1H), 7.38-7.18 (m, 2H), 7.06 (d, J = 2.6 Hz, 1H), 4.73-4.57 (m, 2H), 4.49-4.24 (m, 2H), 3.80-3.63 (m, 4H), 3.44 (br dd, J = 11.6, 4.10 Hz, 1H), 3.07 (br d, J = 5.5 Hz, 1H), 2.91 (d, J = 11.6 Hz, 1H), d, J = 3.2 Hz, 1H), 2.08 (br d, J = 3.2 Hz, 1H), 2.02-1.93 (m, 3H), 1.92-1.76 (m, 5H), 1.70 (br d, J = 7.6 Hz, 1H), 0.88-0.67 (m, 4H), 0.36-0.25 (m, 1H). Example 34 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol carboxylate

LCMS (ESI): [M+H] ⁺ = 613.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.12 (s, 1H), 8.54 (br s, 1H), 7.69 (dd, J = 6.0, 9.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J = 2.3 Hz, 1H), 4.67-4.56 (m, 4H), 3.83-3.67 (m, 7H), 3.16 (m, 1H), 2.56-2.05 (m, 8H), 1.88 (br s, 2H), 1.79 (br d, J = 8.8 Hz, 2H), 0.87-0.67 (m, 7H). Example 35 : trans-4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 649.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.08 (s, 1H), 7.69 (dd, J = 6.0, 9.0 Hz, 1H), 7.35-7.24 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 4.70-4.59 (m, 2H), 4.42-4.35 (m, 2H), 3.78-3.65 (m, 4H), 3.32-3.27 (m, 1H), 3.20-3.14 (m, 1H), 2.86 (d, J = 12.3 Hz, 1H), 2.75-2.68 (m, 1H), 2.51 (br dd, J = 7.0, 15.1 Hz, 1H), 2.33-2.12 (m, 3H), 2.04 (d, J = 13.6 Hz, 1H), 1.95-1.77 (m, 7H), 1.52-1.35 (m, 2H), 0.88-0.75 (m, 3H). Example 35A and Example 35B : 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

Example 35 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is ethanol; phase B is maintained at 45%; flow rate: 80 ml/min) to obtain chiral monomer 35A with a shorter elution time and chiral monomer 35B with a longer elution time.

Example 35A : Isomer 1 , white solid, LCMS (ESI): [M+H] ⁺ = 649.3; SFC analysis (column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 4 minutes, keep 40% phase B for 2.5 minutes, keep 5% phase B for 1.5 minutes, flow rate: 2.8 ml/min): RT = 2.311 min, ee = 98.68%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.96 (s, 1H), 7.57 (dd, J = 5.9, 8.9 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), rms, 5H), 7.14 (t, J = 9.4 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 4.56-4.48 (m, 2H), 4.31-4.20 (m, 2H), 3.66-3.51 (m, 4H), 3.19-3.16 (m, 1H), 3.09-3.01 (m, 1H), 2.74 (br d, J = 12.3 Hz, 1H), 2.63-2.55 (m, 1H), 2.38 (br dd, J = 7.1, 13.9 Hz, 1H), 2.21-2.01 (m, 3H), 1.96-1.91 (m, 1H), 1.82-1.64 (m, 7H), 1.37-1.28 (m, 2H), 0.69 (br t, J = 7.3 Hz, 3H).

Example 35B : Isomer 2 , white solid, LCMS (ESI): [M+H] ⁺ = 649.3; SFC analysis (column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 4 minutes, keep 40% phase B for 2.5 minutes, keep 5% phase B for 1.5 minutes, flow rate: 2.8 ml/min): RT = 3.397 min, ee = 96.08%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.00-8.92 (m, 1H), 7.61-7.53 (m, 1H), 7.24-7.10 (m, 2H), 7.00-6.93 3H), 1.77-1.64 (m, 4H), 1.22-1.83 (m, 7H), 1.40-1.62 (m, 5H ), 0.71-0.71 (m, 3H ). : cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 649.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.01-8.95 (m, 1H), 7.55 (dd, J = 5.8, 8.8 Hz, 1H), 7.23-7.17 (m, 2H), 7.04 (br s, 1H), 4.68-4.47 (m, 2H), 4.24-4.16 (m, 2H), 3.73-3.57 (m, 4H), 3.28 (d , J = 10.5 Hz, 1H), 3.17 (td, J = 5.2, 10.2 Hz, 1H), 2.86-2.72 (m, 2H), 2.5 Hz, 1H), 2.41-2.33 (m, 1H), 2.27-2.08 (m, 3H), 2.05-1.83 (m, 7H), 1.39-1.31 (m, 2H), 0.88-0.81 (m, 3H). Example 37 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-(( hexahydrocyclopropane [b] pyrrolazin -5a(3H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -7- yl )-5- ethynyl -6- fluoronaphthalen -2- ol

Step 1 : To a solution of (1R,5S)-tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.47 mmol) in dioxane (5 mL) was added (hexahydrocyclopropane[b]pyrrolizine-5a(3H)-yl)methanol (85% purity, 257 mg, 1.40 mmol), diisopropylethylamine (0.39 mL, 2.33 mmol). The reaction was stirred at 80 ^° C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.24 mmol, yield 51%). LCMS (ESI): [M+H] ⁺ = 545.3.

Step 2 : To a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.22 mmol) in dioxane (2 mL) and water (0.40 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (135 mg, 0.26 mmol), cesium carbonate (215 mg, 0.66 mmol) and [(bis(1-adamantyl)-N-butylphosphino)-2-(2-aminobiphenyl)palladium(II) chloride (14.72 mg, 0.02 mmol) were added and the mixture was stirred at 100 ^° C for 3 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44 mg, 0.05 mmol, yield 22%). LCMS (ESI): [M+H] ⁺ = 896.5.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.04 mmol) in dichloromethane (400 uL) was added trifluoroacetic acid (80 uL) at 0 ^° C. The reaction was stirred at 25 ^° C for 2 hours. The mixture was concentrated in vacuo to give the crude product compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydrocycloprop[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (30 mg) as a brown solid. LCMS (ESI): [M+H] ⁺ = 751.4.

Step 4 : To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydrocyclopropyl[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (40 mg, 0.05 mmol) in dimethylformamide (400 uL) was added cesium fluoride (162 mg, 1.07 mmol). The reaction was stirred at 20 ^° C for 2 hours. The reaction solution was concentrated in vacuo, and the residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydrocycloprop[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (3.06 mg, 4.5 umol, yield 9%). LCMS (ESI): [M+H] ⁺ = 595.3. ¹ HNMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J = 5.8, 9.0 Hz, 1H), 7.41-7.30 (m, 2H) , 7.23 (d, J = 2.3 Hz, 1H), 4.28-4.15 (m, 2H), 3.78-3.65 (m, 4H), 3.28-3.21 (m, 1H), 3.03-2.95 (m, 1H), 2.79-2.71 (m, 1H), 2.23-2.13 (m, 2H), 2.08 (br dd, J = 6.1, 13.4 Hz, 1H), 2.01-1.77 (m, 8H), 1.65 (br dd, J = 5.0, 9.0 Hz, 1H), 1.33 (br d, J = 18.3 Hz, 1H), 0.69 (q, J = 7.7 Hz, 1H), 0.50 (br s, 1H).

The following examples were prepared by the synthetic route of Example 37 : Example 38 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 609.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.86 (dd, J = 5.7, 9.1 Hz, 1H), 7.38-7.28 (m, 2H), 7.21 (d, J = 2.2 Hz, 1H), 4.52-4.32 (m, 2H), 3.79-3.61 (m, 5H), 3.36 (br d, J = 4.5 Hz, 2H), 3.23-3.16 (m, 1H), 3.03-2.80 (m, 3H), 2.17-1.78 (m, 10H), 0.70-0.54 (m, 4H). Example 39 ： 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 625.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.87 (dd, J = 5.6, 9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.22 (d, J = 2.0 Hz, 1H), 4.73 (br d, J = 6.0 Hz, 2H), 4.70-4.52 (m, 4H), 4.26-4.10 (m, 2H), 3.79-3.60 (m, 4H), 3.53 (d, J = 10.3 Hz, 1H), 3.37 (d, J = 9.0 Hz, 1H), 3.09-3.01 (m, 1H), 2.97 (br d, J = 10.5 Hz, 1H), 2.83-2.70 (m, 1H), 2.55 (dd, J = 2.3, 13.3 Hz, 1H), 2.04 (s, 3H), 1.92-1.76 (m, 6H). Example 40A : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1 ^: To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (547 mg, 0.65 mmol) and ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1A ( 120 mg, 0.59 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (85 The solution was stirred at 25 ^° C for 2 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 50%, 470 mg, 0.25 mmol, yield 42%). LCMS (ESI): [M+H] ⁺ = 944.9.

Step 2 : To ^a solution of tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 470 mg, 0.25 mmol) in dimethylformamide (5 mL) was added cesium fluoride (604 mg, 3.98 mmol) at 25 °C. The suspension was stirred at 25 ^° C for 2 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give a brown oily compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol, yield 93%). LCMS (ESI): [M+H] ⁺ = 789.4.

Step 3 : Dissolve tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane ^- 1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol) in trifluoroacetic acid/dichloromethane (1/4 by volume, 4 mL) and stir at 25 °C for 2 hours. The solution was adjusted to neutrality with triethylamine (1.5 mL) and diluted with water (8 mL), and extracted with ethyl acetate (4 mL * 3). The combined organic layers were dried and concentrated, and the crude product was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (27.3 mg, 39.8 umol, yield 11%). LCMS (ESI): [M+H] ⁺ = 645.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.01 (s, 1H), 7.85 (dd, J = 5.7, 9.2 Hz, 1H), 7.39-7.28 (m, 2H), 7.24-7.19 (m, 1H), 4.69-4.43 (m, 2H), 4.35-4.17 (m, 2H), 3.79-3.62 (m, 4H), 3.36-3.33 (m, 1H), 3.26-3.21 (m, 1H), 3.14-3.07 (m, 1H), 2.92-2.79 (m, 2H), 2.32 (dd, J = 5.1, 13.4 Hz, 1H), 2.15-1.76 (m, 9H), 1.52-1.39 (m, 2H).

The following examples were prepared by the synthetic route of Example 40A : Example 40B : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 645.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.01 (s, 1H), 7.86 (br dd, J = 5.8, 8.8 Hz, 1H), 7.39-7.29 (m, 2H), 7.21 (s, 1H), 4.68-4.57 (m, 2H), 4.31-4.19 (m, 2H), 3.81-3.61 (m, 4H), 3.36 (br d, J = 7.3 Hz, 1H), 3.24 (br d, J=10.8 Hz, 1H), 3.10 (br d, J = 5.3 Hz, 1H), 2.95-2.77 (m, 2H), 2.31 (br dd, J = 4.8, 13.3 Hz, 1H), 2.13-1.79 (m, 9H), 1.52-1.41 (m, 2H). Example 40C : 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] oct - 3- yl )-2-((((1S,7a'S)-2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H)-yl) methoxy ) -8 - fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol carboxylate

LCMS (ESI): [M+H] ⁺ = 645.3 1H NMR (400 MHz, CD ₃ OD) δ ppm 9.08 (s, 1H), 8.49 (br s, 1H), 7.89 (dd, J =5.7, 9.0 Hz, 1H), 7.42-7.29 (m, 2H), 7.23 (d, J =2.2 Hz, 1H), 4.79 (br s, 2H), 4.58-4.49 (m, 2H), 4.05 (br s, 2H), 3.89 (br s, 2H), 3.60 (br dd, J =6.5, 12.3 Hz, 1H), 3.50-3.42 (m, 1H), 3.38 (s, 1H), 3.11 (br d, J =12.2 Hz, 1H), 3.00-2.87 (m, 1H), 2.43 (br dd, J =6.1, 13.6 Hz, 1H), 2.27 (br dd, J =5.8, 11.7 Hz, 1H), 2.19-1.89 (m, 8H), 1.68-1.52 (m, 2H). Example 40D : 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan - 3- yl )-2-((((1R,7a'R)-2,2 -difluorodihydro -1'H),3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H)-yl ) methoxy ) -8- fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl -6- fluoronaphthalen -2- ol dicarboxylate

LCMS (ESI): [M+H] ⁺ = 645.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.07 (s, 1H), 8.44 (br s, 2H), 7.88 (dd, J = 5.8, 9.0 Hz, 1H), 7.39-7.29 (m, 2H), 7.21 (d, J = 2.5 Hz, 1H), 4.83-4.73 (m, 2H), 4.62-4.72 (m, 2H), 4.10 (br s, 2H), 3.90 (br t, J = 11.4 Hz, 2H), 3.72-3.61 (m, 1H), 3.51 (td, J = 5.6, 11.2 Hz, 1H), 3.37 (s, 1H), 3.15 (d, J = 12.3 Hz, 1H), 3.02-2.91 (m, 1H), 2.45 (dd, J = 6.0, 13.6 Hz, 1H), 2.28 (br dd, J = 6.3, 11.3 Hz, 1H), 2.19-1.92 (m, 8H), 1.68-1.55 (m, 2H). Example 41 : 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane-7a'(7'H)-ylmethoxy]-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1: Under N2 atmosphere, ethyl (tert-butyloxycarbonyl)glycine (10 g, 49.20 mmol) and 3,3-bis(bromomethyl)oxoalkane (14.4 g, 59.04 mmol) were dissolved in DMA (100 mL) at 0°C and slowly added dropwise to the reaction solution containing NaH (7.9 g, 196.81 mmol) and DMA (50 mL). After the addition was completed, the reaction solution was stirred at 20°C for 2 hours. The reaction solution was quenched with NH4Cl aqueous solution (100 mL) and then extracted with EtOAc (100 mL x 3). The organic phase was washed with anhydrous _{Na2SO 4} was dried, filtered and concentrated, and then purified by column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain compound 6-(tert-butyl)7-ethyl 2-oxo-6-azaspiro[3.4]octane-6,7-dicarboxylate (11.2 g) as a colorless oily liquid. TLC (hexanes:EtOAc =2:1) confirmed the product.

Step 2: The reaction solution containing 7-[(tert-butyl)oxycarbonyl]-2-oxo-7-azaspiro[3.4]octane-6-carboxylic acid ethyl ester (5 g, 17.52 mmol), TFA (10 mL) and DCM (50 mL) was stirred at 20°C for 4 hours. Triethylamine (4 mL) was added to the reaction solution and concentrated to obtain the compound 2-oxo-6-azaspiro[3.4]octane-7-carboxylic acid ethyl ester (6.9 g) as a yellow oily liquid. TLC (DCM:MeOH=10:1) confirmed the product.

Step 3: A reaction solution containing ethyl 2-oxo-6-azaspiro[3.4]octane-7-carboxylate (6.9 g, 37.25 mmol), 3-(bromomethyl)oxoalkane-3-carbaldehyde (8 g, 44.70 mmol), triethylamine (11.5 g, 111.76 mmol), and methanol (50 mL) was stirred at 20 °C for 1 h. The reaction solution was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed with anhydrous Na ₂ SO ₄ was dried, filtered and concentrated, and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to give compound 6-((3-(bromomethyl)oxoalkane-3-yl)methyl)-2-oxo-6-azaspiro[3.4]octane-7-carboxylic acid ethyl ester (2.9 g) as a colorless oily liquid. LCMS (ESI): [M+H] ⁺ = 348.1.

Step 4: KHMDS (11 mL, 111.26 mmol) was added dropwise to a solution containing ethyl 6-((3-(bromomethyl)oxoalkane-3-yl)methyl)-2-oxo-6-azaspiro[3.4]octane-7-carboxylate (2.8 g, 8.04 mmol), THF (18 mL) and DMF (90 mL) at -78°C under N2 atmosphere. The reaction solution was stirred at -78°C for 30 minutes. Triethylamine (20 mL) was added to the reaction solution and then poured into water (100 mL). The mixture was then extracted with EA (100 mL x 3). The organic phase was washed with anhydrous _Na2SO4 . ₄ , dried, filtered and concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate/petroleum ether) to give compound 1'H,3'H,5'H-dithiocyanatoethyl[cyclohexane-3,2'-pyrrolizine-6',3'-cyclohexane]-7a'(7'H)-carboxylic acid ethyl ester (640 mg) as a yellow oily product. LCMS (ESI): [M+H] ⁺ = 268.1.

Step 5: At 0°C, LiAlH4 (80 mg, 2.24 mmol) was added to a solution containing 1'H, 3'H, 5'H-dithiocyanatoethyl [cyclohexane-3,2'-pyrrolidine-6', 3'-cyclohexane]-7a'(7'H)-carboxylic acid ethyl ester (600 mg, 2.24 mmol) and THF (6 mL). The reaction solution was stirred at room temperature for 1 hour. An excess of aqueous sodium sulfate was added to the reaction solution. After stirring for 30 minutes, the solution was filtered. The filtrate was concentrated to obtain the compound (1'H, 3'H, 5'H-dipyrrole [cyclohexane-3,2'-pyrrolidine-6', 3'-cyclohexane]-7a'(7'H)-yl)methanol (210 mg), as a yellow oily product. LCMS (ESI): [M+H]+ = 226.2.

Step 6: A mixture containing tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.24 mmol), (1'H, 3'H, 5'H-dipyrrolo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane]-7a'(7'H)-yl)methanol (54 mg, 0.24 mmol), sodium tert-butoxide (70 mg, 0.71 mmol) and THF (2 The reaction solution (20 mL) was stirred at 60 °C for 3 h, poured into water (20 mL) and washed with EA (20 mL x 3) extraction, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and then purified by column chromatography (silica gel, 0-30% gradient methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-dispiro[oxacyclobutane-3,2'-pyrrolizine-6', 3'-oxacyclobutane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50 mg), as a yellow oily liquid. LCMS (ESI): [M/2+H]+ = 484.5.

Step 7: At 0°C, trifluoroacetic acid (0.5 mL) was added to a reaction solution containing tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-dispiro[cyclohexane-3,2'-pyrrolizine-6', 3'-cyclohexane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50 mg, 0.052 mmol) and dichloromethane (3 mL). The reaction solution was stirred at 0°C for 30 minutes. Triethylamine (1 The reaction solution was poured into water (20 mL), extracted with EA (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane-7a'(7'H)-yl]methoxy)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (30 mg) as a yellow oily product. LCMS (ESI): [M/2+H]+ = 412.2.

Step 8: A reaction solution containing 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidin-6', 3'-oxacyclobutane-7a'(7'H)-yl]methoxy)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (30 mg, 0.036 mmol), cesium fluoride (28 mg, 0.18 mmol) and DMF (1 mL) was stirred at 50°C for 2 hours. The reaction solution was poured into water (20 mL) and washed with EA (20 mL x 10% ethyl acetate). 3) extraction, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and then purified by column chromatography (C18, 0-50% gradient of water/acetonitrile) to obtain compound 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane-7a'(7'H)-ylmethoxy]-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (0.85 mg) as a white solid product. LCMS (ESI): [M/2+H]+ = 667.4. Example 42 ：4-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6', 1''-cyclopropane]-7a'(7'hydrogen)-yl)methoxy)-4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1 : At 20°C, add iodomethane (6.60 g, 45.59 mmol) to a solution of 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylic acid (10.00 g, 41.44 mmol) and potassium carbonate (11.70 g, 82.89 mmol) in N,N-dimethylformamide (100 mL). Stir the reaction solution at 20°C for 12 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oily liquid 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (7.2 g, yield 68.1%). LCMS (ESI): [M+H] ⁺ =156.1.

Step 2 : Add trifluoroacetic acid (15.0 mL, 195.84 mmol) to a solution of methyl 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylate (5.00 g, 19.58 mmol) in dichloromethane (20 mL) at 20°C. Stir the reaction mixture at 20°C for 2 hours. Concentrate the reaction mixture to obtain viscous yellow liquid methyl 6-azaspiro[2.4]heptane-5-carboxylate (3.0 g, yield 99%). LCMS (ESI): [M+H] ⁺ =156.2.

Step 3 : Potassium carbonate (3.40 g, 24.16 mmol) was added to a solution of methyl 6-azaspiro[2.4]heptane-5-carboxylate (1.50 g, 9.66 mmol), ((1-(bromomethyl)cyclopropyl)methoxy)(tert-butyl)diphenylsilane (3.90 g, 9.66 mmol) in acetonitrile (20 mL) at 20 °C. The reaction was stirred at 60 °C for 16 hours. The reaction solution was filtered, 10 g of silica gel was added, and the mixture was concentrated and chromatographed on a column (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain 5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (3.8 g, yield 82.5%) as a colorless oily liquid. LCMS (ESI): [M+H]+ =478.4.

Step 4 : Stir a mixed solution of methyl 5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-5-azaspiro[2.4]heptane-6-carboxylate (1.5 g, 3.14 mmol) and dioxane hydrochloride (15.0 mL, 60.01 mmol) for 1 hour at 20°C. Concentrate the reaction solution to obtain a residue, which is purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-10% gradient of methanol/dichloromethane) to obtain 1 g of crude product. The crude product was purified again by column chromatography (silica gel, 0-3% gradient of methanol/dichloromethane) to obtain methyl 6-{[(hydroxymethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (480 mg, yield 63.9%) as a white viscous solid. LCMS (ESI): [M+H]+ =240.2.

Step 5 : Under nitrogen protection at 20°C, triphenylphosphine (385 mg, 1.47 mmol) and carbon tetrabromide (491 mg, 1.47 mmol) were added to a solution of methyl 6-{[(hydroxymethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (270 mg, 1.13 mmol) in dichloromethane (5 ml). The reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated to obtain a residue, which was purified by column chromatography (silica gel, 0-20% ethyl acetate/petroleum ether, 0-5% gradient methanol/dichloromethane) to obtain colorless liquid 6-{[(bromomethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (140 mg, yield 41.2%). LCMS (ESI): [M+H]+ =302.2.

Step 6 : At 20°C, methyl 6-{[(bromomethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (300 mg, 0.99 mmol) was dissolved in N,N-dimethylformamide (15 mL) and tetrahydrofuran (5 mL), replaced with nitrogen three times, and cooled to -70°C. Potassium bis(trimethylsilyl)amide (1.4 mL, 1.39 mmol, 1 M) was added dropwise to the reaction solution, and the reaction solution was stirred at this temperature for 50 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the aqueous phase was extracted with dichloromethane/methanol (20 mL x 3, 20:1). The organic phase was dried over anhydrous sodium sulfate, and the organic phase was combined, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a gray oily substance 1'H, 3'H, 5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropane]-7a'(7'H)-carboxylic acid methyl ester (30 mg, yield 13.7%). LCMS (ESI): [M+H]+ =194.2.

Step 7 : At 0°C, lithium aluminum hydroxide (15 mg, 0.39 mmol) was added to a solution of 1'hydro, 3'hydro, 5'hydro-dispiro[cyclopropane-1,2'-pyrrolizine-6', 1''-cyclopropane]-7a'(7'hydro)-carboxylic acid methyl ester (30 mg, 0.15 mmol) in tetrahydrofuran (2 mL), and the reaction solution was stirred at 0°C for 1 hour. At 1 hour. Lithium aluminum hydroxide (15 mg, 3 eq) was added to the reaction solution and stirred at 20°C for 1 hour. Water (30 ul) and 15% sodium hydroxide solution (90 uL) were added to the reaction solution and stirred at 20°C for 10 minutes. The reaction mixture was filtered and concentrated to obtain a white solid (1'H, 3'H, 5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6', 1''-cyclopropane]-7a'(7'H)-yl)methanol (25 mg, yield 99%). LCMS (ESI): [M+H]+ =.

Step 8: Sodium tert-butoxide (17 mg, 0.18 mmol) was added to tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl-2-(2,2,2-trifluoroethyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (78 mg, 0.093 mmol) and (1'hydro,3'hydro,5'hydro-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'hydro)-yl)methanol (24.00 mg, 0.12 mmol) in tetrahydrofuran (3 mL). The reaction solution was stirred at 20°C for 4 hours. Sodium tert-butoxide (2 mg x 3) was added three times to the reaction solution and stirred at 60°C for 2 hours. Water (2 mL) was added to the reaction solution and extracted with ethyl acetate (2 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-5% gradient of methanol/dichloromethane) to obtain a colorless oily substance (1R,5S)-3-(2-((1'hydro,3'hydro,5'hydro-dispiro[cyclopropane-1,2'-pyrrole) tert-Butyl pyridazine-6',1''-cyclopropane-7a'(7'-hydrogen)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, yield 33%). LCMS (ESI): [M+H]+ =468.5.

Step 9 : CsF (61 mg, 0.40 mmol) was added to tert-butyl (1R,5S)-3-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, 0.039 mmol) in N,N-dimethylformamide (3 mL) at 20°C. The reaction solution was stirred at 20°C for 1.5 hours. The reaction solution was diluted with ethyl acetate (2 mL) and washed with water (1 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-5% gradient of methanol/dichloromethane) to obtain a colorless viscous liquid (1R,5S)-3-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2 '-Pyrrolizine-6',1''-cyclopropane]-7a'(7'-hydrogen)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (29 mg, yield 62.7%, 2 batches combined). LCMS (ESI): [M+H]+ =390.4.

Step 10 : To a solution of tert-butyl (1R,5S)-3-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7 mg, 0.009 mmol) in acetonitrile (1 mL) was added trifluoroacetic acid (480 ul, 6.29 mmol) at 20°C, and the reaction mixture was stirred under nitrogen at 20°C for 4 hours. The reaction solution was concentrated and diluted with acetonitrile (1 mL), the pH was adjusted to 7 with triethylamine, and purified by reverse phase column chromatography (C18, 5-95% acetonitrile/water gradient) to give 4-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'H)-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (1.80 mg, yield 32%). LCMS (ESI): [M+H]+=635.4. Example 43 : 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile

Step 1 : Under nitrogen, add di-tert-butyl dicarbonate (13 mL, 56.5 mmol) and diphenyl phosphate azide (147 mL, 682 mmol) to a solution of 2-chloro-3-fluoroisonicotinic acid (100 g, 569 mmol) and triethylamine (158 mL, 1133 mmol) in toluene (500 mL) and tert-butyl alcohol (500 mL), and stir the solution at 80 ^° C for 16 hours. The mixture is concentrated and 500 mL of saturated brine is added, and extracted with 500 mL of ethyl acetate. The organic layer was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain a light yellow oily compound (2-chloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (112 g, 454 mmol, yield 80%). LCMS (ESI): [M+H] ⁺ = 247.1.

Step 2 : A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (50 g, 202 mmol) and tetramethylethylenediamine (70.6 g, 608 mmol) in anhydrous methyl tert-butyl ether (500 mL) was cooled to -70 ^° C. And n-butyl lithium (2.5 M in n-hexane, 203 mL, 506 mmol) was slowly added to the mixture. Stirred under nitrogen at -70 ^° C for 1 hour, then the mixture was warmed to -30 ^° C, stirred under nitrogen for 1 hour, then cooled to -70 ^° C, and a bag containing dry carbon dioxide was connected to the stirred solution. After half an hour, the mixture was slowly warmed to 20 ^° C and stirred for 10 hours. Water (500 mL) was added to the mixture to quench the mixture and the mixture was allowed to stand for separation. The organic phase was discarded and the aqueous phase was cooled to 0 ^° C. The pH was adjusted to 6-7 with dilute hydrochloric acid (4 M). A white solid was precipitated. The mixture was filtered, the filter cake was collected and vacuum dried to obtain a white solid compound 4-((tert-butoxycarbonylamino)-6-chloro-5-fluoronicotinic acid (39.8 g, 136 mmol, yield 68%). LCMS (ESI): [M+H] ⁺ = 291.0.

Step 3 : Triphosgene (7.45 g, 25.1 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10 g, 34.4 mmol) in dioxane (100 mL), and the mixture was stirred at 100 ^° C for 4 hours. The reaction solution was concentrated in vacuo, and the residue was slurried with petroleum ether to obtain 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (7.40 g, 34.4 mmol, yield 99%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.84 (br s, 1H), 8.73 (s, 1H).

Step 4 : Ethyl 2-cyanoacetate (4.23 g, 37.4 mmol) and triethylamine (6.91 mL, 49.8 mmol) were added to a solution of 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (5.40 g, 24.9 mmol) in xylene (54 mL). The reaction was stirred at 145 ^° C for 5 hours. The mixture was concentrated in vacuo and the residue was slurried with petroleum ether/ethyl acetate (1:1 by volume) to give a brown solid compound 7-chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (4.30 g, 17.95 mmol, 72% yield). LCMS (ESI): [M+H] ⁺ = 239.9.

Step 5 : Carefully add 7-chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (5.80 g, 24.2 mmol) to phosphorus oxychloride (50 mL, 536 mmol). The reactants were stirred at 90 ^° C for 16 hours. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate (100 ml), and the aqueous phase was extracted with ethyl acetate (50 ml * 3). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient ethyl acetate/petroleum ether) to obtain a yellow solid compound 2,4,7-trichloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (3.10 g, 11.2 mmol, yield 46%). LCMS (ESI): [M+H] ⁺ =275.9, 277.9.

Step 6 : Add a solution of (1R,5S)-tert-butyl 3,8-diazobicyclo[3.2.1]octane ^- 8-carboxylate (1.38 g, 6.51 mmol) in dichloromethane (10 mL) to a solution of 2,4,7-trichloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (2.00 g, 7.23 mmol) in dichloromethane (30 mL) at -70 ° C. Then slowly add a solution of triethylamine (2.52 mL, 18.1 mmol) in dichloromethane (10 mL). The reaction was stirred at -70 ^° C for 0.5 hours. Water (20 ml) was added to the mixture, and then extracted with dichloromethane (20 mL*3), and the combined organic phases were washed with brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-12% gradient tetrahydrofuran/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.20 g, 4.86 mmol, yield 67%). LCMS (ESI): [M+H] ⁺ = 452.1.

Step 7 : To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.21 mmol) in tetrahydrofuran (20 mL) was added 4A molecular sieve (1.00 g), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (0.35 g, 2.21 mmol) and sodium tert-butoxide (0.32 g, 3.32 mmol). The reaction was stirred at 20 ^o C for 2 hours. Water (30 mL) was added to the mixture, and then extracted with ethyl acetate (30 mL*2) and dichloromethane (30 mL * 2). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0-8% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.10 g, 1.91 mmol, yield 86 %). LCMS (ESI): [M+H] ⁺ = 575.3.

Step 8 : In a nitrogen atmosphere, tert-butyl (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.87 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (535 mg, 1.04 mmol) and cesium carbonate (850 mg, 2.61 mmol) in dioxane (5 mL) and water (1 mL) were added. To the 1% 4-nitropropene (2-nitropropene) solution was added chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (58 mg, 0.09 mmol), and the mixture was stirred at 100 ^° C for 3 hours. Water (5 mL) was added to the mixture, and then extracted with ethyl acetate (5 mL * 2), and the combined organic phases were washed with brine (6 mL * 1), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to give a brown solid compound tert-butyl (1R, 5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 0.86 mmol, yield 99%). LCMS (ESI): [M+H] ⁺ = 925.5

Step 9 : To a solution of tert-butyl (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (750 mg, 0.81 mmol) in dimethylformamide (7.5 mL) was added cesium fluoride (2.40 g, 15.8 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of methanol/dichloromethane) to give tert-butyl (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol, 73% yield) as a brown solid. LCMS (ESI): [M+H] ⁺ = 768.9.

Step 10 : To trifluoroacetic acid (1.80 mL) in dichloromethane (7.20 mL) was added tert-butyl (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was concentrated in vacuo to a residue. The residue was diluted with dichloromethane (3 mL) and triethylamine was added to adjust the pH to 7-8. The mixture was then concentrated in vacuo, and the residue was purified by preparative HPLC to give a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile (13.5 mg, 21 umol, yield 3.5%). LCMS (ESI): [M+H] ⁺ = 625.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.23 (s, 1H), 7.88 (dd, J = 5.8, 9.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.24 (s, 1H), 5.47-5.26 (m, 1H), 4.47-4.32 (m, 2H), 4.05-3.92 (m, 2H), 3.90-3.78 (m, 2H), 3.70 (br s, 2H), 3.51-3.36 (m, 2H), 3.23-3.14 (m, 2H), 3.19-3.28 (m, 1H), 2.45-1.98 (m, 10H). Example 44 : 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol

Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.19 mmol) and (2-fluoro-6-hydroxyphenyl)boronic acid (59 mg, 0.38 mmol) in dioxane (3 mL) and water (600 uL) was added sodium carbonate (76 mg, 0.72 mmol), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (17 mg, 0.02 mmol) and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate (20 mg, 0.02 mmol), 60 ^° C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-80% gradient of tetrahydrofuran/petroleum ether) to obtain the compound tert-butyl (1R, 5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (67% purity, 40 mg, 0.04 mmol, yield 21%). LCMS (ESI): [M+H] ⁺ = 660.0.

Step 2 : Compound tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 mg, 0.03 mmol) was dissolved in dichloromethane/trifluoroacetic acid (volume ratio of 4:1, 600 uL), and the reaction solution was stirred at 20 ^o C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (0.5 mL) was added, and then the pH was adjusted to 8 with triethylamine. The concentrated residue was purified by preparative HPLC to obtain a white solid compound 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol (12.0 mg, 21.5 umol, yield 71%). LCMS (ESI): [M+H] ⁺ = 560.1; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.49-9.92 (m, 1H), 8.10-7.70 (m, 1H), 7.52-7.23 (m, 1H), 6.99-6.62 (m, 2H), 5.46-5.03 (m, 1H), 4.27 (br t, J = 9.2 Hz, 2H), 4.15-3.93 (m, 2H), 3.51 (br s, 3H), 3.48 (br d, J = 4.8 Hz, 1H), 3.08 (br d, J = 5.8 Hz, 2H), 3.01 (s, 1H), 2.88-2.75 (m, 1H), 2.16-2.10 (m, 1H), 2.06-1.93 (m, 2H), 1.91-1.71 (m, 3H), 1.62 (br s, 4H). Example 45 : 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and Example 46 : 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one

Examples 45 and 46 were prepared by the synthetic route of Example 44 , using an intermediate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane and an intermediate tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-4 The third step and the fourth step were combined into one step, and the reaction mixture was deprotected with TFA/DCM to obtain the main product 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. LCMS (ESI): [M+H] ⁺ = 634.4; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.89-7.79 (m, 2H), 7.37-7.27 (m, 2H), 7.05 (d, J = 2.1 Hz, 1H), 5.45-5.24 (m, 1H), 4.58-4.41 (m, 2H), 4.35-4.20 (m, 2H), 3.68 (br s, 3H), 3.61 (br dd, J = 6.2, 12.6 Hz, 1H), 3.27 (m, 4H), 3.10-2.99 (m, 1H), 2.44-2.23 (m, 2H), 2.16 (m, 1H), 2.07-1.96 (m, 2H), 1.90 (br s, 5H).

At the same time, the secondary product 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one was obtained. LCMS (ESI): [M+H] ⁺ = 652.3; ¹ HNMR (400 MHz, MeOD- d ₄ ) δ ppm 7.98-7.85 (m, 2H), 7.39-7.29 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 5.44-5.23 (m, 1H), 4.57-4.45 (m, 2H), 4.38-4.19 (m, 2H), 3.79-3.62 (m, 4H), 3.50-3.37 (m, 1H), 3.31-3.21 (m, 2H), 3.14-2.99 (m, 1H), 2.46-2.31 (m, 1H), 2.30-2.16 (m, dH), 2.13 (s, 3H), 2.08-1.98 (m, 2H), 1.96-1.77 (m, 5H). Example 47 : 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile

Step 1: Compound tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 292 mg, 0.57 mmol) was added to dioxane (5 mL) and water (1 mL), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (200 mg, 0.29 mmol) and potassium phosphate (182 mg, 0.86 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (41 mg, 0.06 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 100 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(6-cyano-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 (70% purity, 187 mg, 0.14 mmol, yield 53%). LCMS (ESI): [M+H] ⁺ = 866.5.

Step 2: Compound tert-butyl (1R,5S)-3-(6-cyano-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 (70% purity, 147 mg, 0.12 mmol) was added to tetrahydrofuran (2 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57 mg, 0.36 mmol) and sodium tert-butoxide (17 mg, 0.18 mmol) were added, and stirred at 50 ^° C for 2 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated by reduced pressure to obtain the compound tert-butyl (1R, 5S)-3-(6-cyano-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 (66% purity, 156 mg, 0.11 mmol, yield 93%). LCMS (ESI): [M+H] ⁺ = 924.9.

Step 3: Compound tert-butyl (1R,5S)-3-(6-cyano-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 (66% purity, 156 mg, 0.11 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (169 mg, 1.11 mmol) was added, and stirred at 20 ^° C for 1 hour. The reaction solution was diluted with water (500 uL), extracted with ethyl acetate (1 mL * 3), and the organic phase was concentrated under reduced pressure to obtain the compound tert-butyl (1R, 5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 135 mg, 0.10 mmol, yield 94%). LCMS (ESI): [M+H] ⁺ = 769.3.

Step 4: Compound tert-butyl (1R,5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 135 mg, 0.10 mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio of 4:1, 2.5 mL) and stirred at 20 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (9.11 mg, 15 umol, yield 14%). LCMS (ESI): [M+H] ⁺ = 624.9; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.40-10.21 (m, 1H), 8.29 (s, 1H), 8.02 (dd, J = 5.9, 9.2 Hz, 1H), 7.56-7.40 (m, 2H), 7.17 (s, 1H), 5.41-5.14 (m, 1H), 4.44-4.23 (m, 2H), 4.10 (dd, J = 6.5, 10.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.65 (br d, J = 12.3 Hz, 1H), 3.5 10.3 Hz, 3H), 3.16-3.04 (m, 2H), 3.01 (s, 1H), 2.89-2.77 (m, 1H), 2.12 (br s, 1H), 2.07-1.94 (m, 2H), 1.90-1.72 (m, 3H), 1.70-1.54 (m, 4H).

The following examples were prepared by the synthetic route of Example 47 : In the second step, the intermediate compound tert-butyl (1R, 5S)-3-(6-cyano-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 was reacted with the intermediate A16-2 to obtain the trans product under similar reaction conditions. After SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 45%; flow rate: 80 ml/min), the target compounds Example 48A to Example 48D were obtained. Example 48A to Example 48D ：4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(R)-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6- Nitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(S)-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6- Nitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6- Nitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile , , ,

Example 48A : Isomer 1, SFC analysis (column: Chiralpak IE 100*4.6mm 3um; mobile phase: phase A is 0.1% diethylamine/n-heptane, phase B is isopropanol; gradient: A/B = 60/40, flow rate: 1 ml/min): RT = 4.236 min, chiral purity: 100%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.11 (s, 1H), 7.78 (br dd, J = 5.8, 9.0 Hz, 1H), 7.32-7.17 (m, 2H), 7.05 (d, J = 2.1 Hz, 1H), 4.50 (br d, J = 11.8 Hz, 1H), 4.39 (br d, J = = 12.4 Hz, 1H), 4.31-4.17 (m, 2H), 3.69-3.49 (m, 4H), 3.26 (s, 1H), 3.17 (br s, 1H), 3.10-3.00 (m, 1H), 2.74 (br d, J = 12.3 Hz, 1H), 2.65-2.53 (m, 1H), 2.18 (br dd, J = 6.0, 13.4 Hz, 1H), 2.03 (br dd, J = 6.6, 11.9 Hz, 1H), 1.92 (br d, J = 13.5 Hz, 1H), 1.83-1.61 (m, 7H), 1.41-1.28 (m, 2H).

Example 48B : Isomer 2, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes, flow rate: 4 ml/min): RT = 1.942 min, chiral purity: 100%; LCMS (ESI): [M+H] ⁺ = 669.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.23 (s, 1H), 7.90 (dd, J = 5.8, 9.0 Hz, 1H), 7.44-7.30 (m, 2H), 7.17 (d, J = d, J = 12.0 Hz, 1H), 2.76-2.67 (m, 1H), 2.33-2.25 (m, 1H) , 2.20-2.11 (m, 1H), 2.04 (br d, J = 13.6 Hz, 1H), 1.97-1.75 (m, 7H), 1.52-1.37 (m, 2H).

Example 48C : Isomer 3, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes, flow rate: 4 ml/min): RT = 2.343 min, chiral purity = 97.12%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.23 (s, 1H), 7.89 (dd, J = 5.8, 9.1 Hz, 1H), 7.42-7.32 (m, 2H), 7.17 (d, J = 2.3 Hz, 1H), 4.62-4.48 (m, 2H), 4.36 (s, 2H), 3.80-3.61 (m, 4H), 3.37 (s, 1H), 3.31-3.26 (m, 1H), 3.20-3.12 (m, 1H), 2.85 (d, J = 12.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.28 (dd, J = 6.2, 13.6 Hz, 1H), 2.19-2.12 (m, 1H), 2.03 (d, J = 13.6 Hz, 1H), 1.96-1.74 (m, 7H), 1.50-1.37 (m, 2H).

Example 48D : Isomer 4, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes, flow rate: 4 ml/min): RT = 3.004 min, chiral purity: 98.43%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.11 (s, 1H), 7.77 (br dd, J = 5.9, 8.9 Hz, 1H), 7.32-7.18 (m, 2H), 7.05 (s, 1H), 4.48 (br d, J = 12.8 Hz, 1H), 4.38 (br d, J = 12.4 Hz, 1H), 4.23 (q, J = 10.5 Hz, 2H), 3.67-3.49 (m, 4H), 3.26 (s, 1H), 3.17 (br d, J = 7.0 Hz, 1H), 3.09-3.01 (m, 1H), 2.73 (br d, J = 12.3 Hz, 1H), 2.59 (br d, J = 6.4 Hz, 1H), 2.17 (br dd, J = 6.0, 13.5 Hz, 1H), 2.03 (br dd, J = 5.8, 10.5 Hz, 1H), 1.91 (br d, J = 13.5 Hz, 1H), 1.84-1.62 (m, 7H), 1.40-1.25 (m, 2H).

The following examples were prepared by the synthetic route of Example 47 : In the second step, the intermediate compound tert-butyl (1R, 5S)-3-(6-cyano-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 was reacted with the intermediate A16-1 to obtain the cis product under similar reaction conditions. After SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 50%; flow rate: 80 ml/min), the target compounds Example 49A to Example 49D were obtained. Example 49A to Example 49D: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile , 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile , , ,

Example 49A : Isomer 1, SFC analysis (column: Chiralpak IC-3 (100 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: 40% phase B, flow rate: 2.8 ml/min): RT = 2.414 min, chiral purity: 100%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.10 (s, 1H), 7.76 (dd, J = 5.7, 9.2 Hz, 1H), 7.27-7.16 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 4.52 (br d, J = 11.6 Hz, 1H), 4.37 (br d, J = 12.5 Hz, 1H), 4.17-4.07 (m, 2H), 3.65 (br d, J = 12.1 Hz, 1H), 3.58-3.43 (m, 3H), 3.26 (s, 1H), 3.11 (d, J = 10.8 Hz, 1H), 3.01-2.93 (m, 1H), 2.79-2.64 (m, 2H), 2.19 (d, J = 13.3 Hz, 1H), 2.05-1.62 (m, 9H), 1.37-1.30 (m, 2H).

Example 49B : Isomer 2, SFC analysis (column: Chiralpak IC-3 (100mm * 4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: 40% phase B, flow rate: 2.8 ml/min): RT = 3.344 min, chiral purity: 92.10%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.22 (s, 1H), 7.93-7.85 (m, 1H), 7.40-7.30 (m, 2H), 7.17 (d, J = 2.2 Hz, 1H), 4.56 (br d, J = 12.3 Hz, 2H), 4.31-4.18 (m, 2H), 3.78-3.62 (m, 4H), 3.41-3.37 (m, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.16-3.04 (m, 1H), 2.94-2.78 (m, 2H), 2.37-2.27 (m, 1H), 2.09 (ddd, J = 5.9, 11.2, 14.5 Hz, 2H), 2.01-1.91 (m, 3H), 1.87-1.77 (m, 4H), 1.49-1.44 (m, 2H).

Example 49C : Isomer 3, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 4 ml/min): RT = 1.150 min, chiral purity: 91.48%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.28-8.18 (m, 1H), 7.94-7.80 (m, 1H), 7.42-7.28 (m, 2H), 7.22-7.15 (m, 1H), 4.64 (br d, J = 12.5 Hz, 1H), 4.49 (br d, J = 12.3 Hz, 1H), 4.27-4.19 (m, 2H), 3.81-3.62 (m, 4H), 3.38 (s, 1H), 3.23 (d, J = 10.8 Hz, 1H), 3.14-3.05 (m, 1H), 2.93-2.76 (m, 2H), 2.31 (br d, J = 13.3 Hz, 1H), 2.18-2.04 (m, 2H), 2.01-1.90 (m, 3H), 1.88-1.73 (m, 4H), 1.49-1.41 (m, 2H).

Example 49D : Isomer 4, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 4 ml/min): RT = 2.203 min, chiral purity: 98.67%; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.10 (s, 1H), 7.76 (dd, J = 5.8, 9.1 Hz, 1H), 7.28-7.18 (m, 2H), 7.05 (d, J = 2.4 Hz, 1H), 4.44 (br d, J = 12.4 Hz, 2H), 4.20-4.04 3.65-3.44 (m, 4H), 3.31-3.23 (m, 1H), 3.12 (d, J = 10.8 Hz, 1H), 2.98 (td, J = 5.6, 10.8 Hz, 1H), 2.80-2.64 (m, 2H), 2.21 (d, J = 13.4 Hz, 1H), 1.99-1.61 (m, 9H), 1.41-1.26 (m, 2H). Example 50 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol

Step 1 : Compound tert-butyl (1R,5S)-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 N,N-dimethylformamide (15 mL). Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.03 g, 10.5 mmol) and cuprous iodide (2.02 g, 10.5 mmol) were added at 20 ^° C in a nitrogen atmosphere. The reaction was stirred at 60 ^° C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound tert-butyl (1R, 5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.80 g, 1.32 mmol, yield 88%). LCMS (ESI): [M+H] ⁺ = 605.0.

Step 2 : Under nitrogen atmosphere, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-2-ol (107 mg, 0.40 mmol), potassium phosphate (1.5 M aqueous solution, 663 uL, 0.99 mmol), (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate palladium (28 mg, 0.03 mmol). The mixture was stirred at 60 ^° C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (190 mg, 0.29 mmol, yield 86%). LCMS (ESI): [M+H] ⁺ = 667.2.

Step 3 : Dissolve tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.26 mmol) in dichloromethane (3 mL) and cool to 0 ^o C. Slowly add diisopropylethylamine (133 uL, 0.77 mmol) and bromomethyl methyl ether (27 uL, 0.33 mmol) to the reaction solution and stir at 25 ^o C for 16 hours. After the reaction, quench with water (5 mL), then extract with dichloromethane (3 mL * 2), and combine the organic phases and concentrate under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.24 mmol, yield 94%). LCMS (ESI): [M+H] ⁺ = 710.8.

Step 4 : Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (40 mg, 0.25 mmol) in tetrahydrofuran (1 mL) and cool to 0 ^o C. Slowly add sodium hydride (60% content, 13 mg, 0.32 mmol) to the reaction solution and stir at 20 ^o C for 1 hour. Then add tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.21 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 20 ^° C for 16 hours. Acetic acid (500 uL) was added to the reaction solution to adjust the pH to 5-6, and the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.16 mmol, yield 80%). LCMS (ESI): [M+H] ⁺ = 770.2.

Step 5 : Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added at 20 ^° C. The reaction was stirred at 20 ^° C for 2 hours. Concentrated under nitrogen. The residue was dissolved in tetrahydrofuran (2 mL), triethylamine (400 uL) was added to the solution to adjust the pH to 7-8, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol (1.03 mg, 1.64 umol, yield 0.77%). LCMS (ESI): [M+H] ⁺ = 626.1. ¹ H NMR (400 MHz, CH ₃ OD) δ ppm 8.24 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.53-7.37 (m, 1H), 7.27 (s, 1H), 7.19 (br d, J = 3.6 Hz, 2H), 7.05 (s, 1H), 5.43-5.29 (m, 1H), 4.58 (m, 2H), 4.41-4.30 (m, 2H), 3.77 (m, 4H), 3.22-3.00 (m, 4H), 2.40-2.17 (m, 3H), 2.06 (m, 2H), 1.91 (m, 5H). Example 51 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-(methylsulfonyl)quinazolin-7-yl)naphthalen-2-ol

Preparation of Example 51 Referring to the synthetic route of Example 50 , the first step is to tert-butyl (1R, 5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, cuprous iodide and sodium methanesulfinate. The corresponding intermediate is obtained by reaction, and then 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(methylsulfonyl)quinazolin-7-yl)naphthalen-2-ol is prepared through similar reaction. LCMS (ESI): [M+H] ⁺ = 636.1; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.70-8.62 (m, 1H), 8.36-7.73 (m, 1H), 7.45-7.33 (m, 1H), 7.30-6.91 (m, 4H), 5.40-5.19 (m, 1H), 4.64-4.56 (m, 2H), 4.35-4.20 (m, 2H), 3.74-3.62 (m, 4H), 3.27-3.16 (m, 3H), 3.06-2.96 (m, 1H), 2.68-2.39 (m, 3H), 2.38-1.78 (m, 10H). Example 52 : (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)dimethylphosphine oxide

Preparation of Example 52 Referring to the synthetic route of Example 50 , the first step is to react tert-butyl (1R, 5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate with dimethylphosphine oxide, diisopropylethylamine, tri(dibenzylacetone)dipalladium, 4,5- Bis(diphenylphosphino)-9,9-dimethyloxanthracene was reacted to obtain the corresponding intermediate, and then (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)dimethylphosphine oxide was prepared through a similar reaction. LCMS (ESI): [M+H] ⁺ = 634.2; ¹ H NMR (400MHz, CD ₃ OD) δ ppm 8.62 (d, J = 14.1 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.49-7.42 (m, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.28-7.21 (m, 2H), 7.15 (d, J = 2.5 Hz, 1H), 5.42-5.22 (m, 1H), 4.65-4.58 (m, 2H), 4.38-4.19 (m, 2H), 3.77-3.65 (m, 4H), 3.21-3.13 (m, 3H), 3.08-2.98 (m, 1H), 2.41-2.11 (m, 3H), 2.08-1.96 (m, 2H), 1.94-1.79 (m, 5H), 1.50 (d, J = 13.6 Hz, 3H), 0.95 (d, J = 13.6 Hz, 3H). Example 53 : 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)ethan-1-one

Step 1: Dissolve the compound tert-butyl (1R,5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 200 umol) and tributyl(1-ethoxyvinyl)tinane (280 mg, 775 umol) in dioxane (2.00 mL), add tetrakis(triphenylphosphine)palladium (22.0 mg, 20 umol) under nitrogen, and stir the reaction at 100 ^o 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 ethyl acetate/petroleum ether) to obtain the compound tert-butyl (1R, 5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.0 mg, 112 umol, yield 56%). LCMS (ESI): [M+H] ⁺ = 713.3.

Step 2: Add the compound tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65.0 mg, 91 umol) to tetrahydrofuran (0.60 mL), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (21.0 mg, 136 umol) and sodium tert-butoxide (26.0 mg, 274 umol), and stir at 20 ^o C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.0 mg, 90 umol, yield 99%). LCMS (ESI): [M+H] ⁺ = 772.3.

Step 3: Compound tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65.0 mg, 84 umol) was added to trifluoroacetic acid/dichloromethane (volume ratio of 4:1, 1.20 mL) and stirred at 20 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, triethylamine was added to adjust the pH to 8, and the mixture was purified by preparative HPLC to obtain a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)ethan-1-one (8.14 mg, 15 umol, yield 14%). LCMS (ESI): [M+H] ⁺ = 600.6. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.24 (s, 1H), 7.77 (br d, J = 8.3 Hz, 1H), 7.43 (br t, J = 7.4 Hz, 1H), 7.35 (br d, J = 8.4 Hz, 1H), 7.30-7.19 (m, 2H), 7.02 (d, J = 2.0 Hz, 1H), 5.46-5.23 (m, 1H), 4.67-4.58 (m, 2H), 4.39-4.23 (m, 2H), 3.71 (br s, 4H), 3.43-3.35 (m, 1H), 3.31-3.22 (m, 2H), 3.12-3.00 (m, 1H), 2.46-2.13 (m, 3H), 2.08-1.80 (m, 10H).

The following Examples 54 to 65 were prepared by the synthetic route of Example 53: Example 54 : 4- (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 598.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.72 (br d, J = 8.0 Hz, 1H), 7.43-7.30 (m, 2H), 7.27-7.11 (m, 3H), 7.04 (br d, J = 2.3 Hz, 1H), 5.41-5.19 (m, 1H), 4.71-4.38 (m, 3H), 4.31-4.16 (m, 2H), 3.61 (br s, 3H), 3.20 (br d, J = 15.6 Hz, 3H), 3.00 (br d, J = 4.8 Hz, 1H), 2.48-1.80 (m, 10H), 1.58-1.46 (m, 1H), 0.79-0.51 (m, 4H). Example 55 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ =583.9. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.05 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.40 (ddd, J = 8.2, 6.2, 1.8 Hz, 1H), 7.28-7.14 (m, 3H), 7.00-6.93 (m, 1H), 6.23 (dd, J = 17.6, 11.0 Hz, 1H), 5.69 (d, J = 17.6 Hz, 1H), 5.42-5.21 (m, 1H), 5.07 (d, J = 11.3 Hz, 1H), 4.61-4.46 (m, 2H), 4.34-4.16 (m, 2H), 3.71-3.59 (m, 4H), 3.27-3.17 (m, 3H), 3.06-2.97 (m, 1H), 2.39-2.11 (m, 3H), 2.04-1.94 (m, 2H), 1.86 (m, 5H). Example 56 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 582.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.04 (s, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.40 (br t, J = 7.3 Hz, 1H), 7.30-7.15 (m, 3H), 7.07 (br s, 1H), 5.43-5.20 (m, 1H), 4.55 (br s, 2H), 4.32-4.19 (m, 2H), 3.63 (br s, 4H), 3.27-3.15 (m, 4H), 3.02 (br d, J = 5.0 Hz, 1H), 2.41-2.09 (m, 4H), 2.00 (br s, 2H), 1.84 (br s, 4H). Example 57 : 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

Preparation of Example 57 Referring to the synthetic route of Example 50 , the first step is to react tert-butyl (1R, 5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate with benzophenone imine, cesium carbonate, tris(dibenzylacetone)dipalladium, (±) -2,2-bis(diphenylphosphino)-1,1-binaphthyl to obtain the corresponding intermediate, and then a similar reaction was performed to prepare 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol. LCMS (ESI): [M+H] ⁺ = 573.6; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.56 (br s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.38-7.28 (m, 2H), 7.26-7.13 (m, 2H), 7.10 (s, 1H), 5.56-5.30 (m, 1H), 4.60-4.36 (m, 4H), 3.99 (br s, 2H), 3.74-3.71 (m, 5H), 3.24 (br s, 1H), 2.60-2.37 (m, 2H), 2.28 (br d, J = 8.3 Hz, 1H), 2.23-2.11 (m, 4H), 2.06 (br d, J = 8.5 Hz, 3H). Example 58 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

Step 1: Compound tert-butyl (1R, 5S)-3-(6-amino-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.15 mmol) was dissolved in acetic acid (5 mL), and paraformaldehyde (45.0 mg, 1.52 mmol) and sodium cyanoborohydride (29.0 mg, 0.46 mmol) were added to the reaction solution ^at 20 ^{o C. The reaction was stirred at 20 o} C for 16 hours. The reaction mixture was poured into 0.1 M sodium hydroxide solution (20 mL) at 0 ^o C and extracted with dichloromethane (10 mL * 2). The combined organic phases were 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 ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(6-(dimethylamino)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.12 mmol, yield 77%). LCMS (ESI): [M+H] ⁺ = 686.2.

Step 2: Dissolve the compound tert-butyl (1R,5S)-3-(6-(dimethylamino)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.12 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (40 mg, 0.25 mmol) in tetrahydrofuran (1.00 mL). At 0 ^o C, sodium tert-butoxide (27.9 mg, 0.29 mmol) was slowly added to the reaction solution. The reaction was stirred at 20 ^o C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(6-(dimethylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 80%, 75.0 mg, 0.08 mmol, yield 69%). LCMS (ESI): [M+H] ⁺ = 745.3.

Step 3: Dissolve the compound tert-butyl (1R,5S)-3-(6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 80%, 70.0 mg, 0.07 mmol) in acetonitrile (1.00 mL), and add hydrogen chloride (4 M dioxane solution, 376 uL, 1.50 mmol) at 20 ^o C. The reaction was stirred at 20 ^o C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in a dimethyl sulfoxide solution (2 mL) of triethylamine (400 uL) and purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (9.19 mg, 0.01 mmol, yield 17%). LCMS (ESI): [M+H] ⁺ = 601.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.74 (d, J = 8.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.29-7.17 (m, 3H), 7.12 (d, J = 1.5 Hz, 1H), 5.51-5.28 (m, 1H), 4.54 (br s, 2H), 4.47-4.32 (m, 2H), 3.98-3.64 (m, 4H), 3.53-3.37 (m, 3H), 3.20-3.11 (m, 1H), 2.51 (s, 6H), 2.42-1.91 (m, 10 H). Example 59 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-(pyrrolidin-1-yl)quinazolin-7-yl)naphthalen-2-ol

Example 59 was prepared by a similar method with reference to the synthetic route of Example 58 ; LCMS (ESI): [M+H] ⁺ = 627.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.74 (br d, J = 8.0 Hz, 1H), 7.45-7.36 (m, 2H), 7.28-7.16 (m, 2H), 7.08 (s, 1H), 6.96 (s, 1H), 5.48-5.23 (m, 1H), 4.51 (br t, J = 11.3 Hz, 2H), 4.41-4.25 (m, 2H), 3.83 (br s, 2H), 3.67-3.57 (m, 2H), 3.41 (br d, J = 5.0 Hz, 3H), 3.17-3.05 (m, 1H), 2.87 (br d, J = 6.5 Hz, 2H), 2.73 (br d, J = 5.8 Hz, 2H), 2.45-2.21 (m, 3H), 2.10-1.94 (m, 7H), 1.66 (br s, 4H). Example 60 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)quinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 638.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.80 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.18-7.09 (m, 2H), 7.08-6.97 (m, 2H), 6.87 (d, J = 2.3 Hz, 1H), 6.79 (s, 1H), 5.36-5.09 (m, 1H), 4.65-4.41 (m, 2H), 4.23-4.07 (m, 2H), 3.73-3.44 (m, 7H), 3.19-3.03 (m, 3H), 3.00-2.85 (m, 1H), 2.44-2.12 (m, 2H), 2.04 (br d, J = 8.3 Hz, 1H), 1.94-1.70 (m, 7H). Example 61 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(1-methyl-1H-imidazol-2-yl)quinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 638.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.94 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.58-7.49 (m, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.25-7.17 (m, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.87 (s, 2H), 6.78 (s, 1H), 5.42-5.22 (m, 1H), 4.66-4.54 (m, 2H), 4.35-4.22 (m, 2H), 3.69-3.56 (m, 4H), 3.27-3.14 (m, 3H), 3.08-2.98 (m, 1H), 2.94 (s, 3H), 2.42-2.10 (m, 3H), 2.06-1.74 (m, 7H). Example 62 : 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(oxacyclobutane-3-yl)quinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 614.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.55 (br s, 1H), 7.84-7.78 (m, 1H), 7.76-7.71 (m, 1H), 7.41 (br t, J =7.5 Hz, 1H), 7.34 (br d, J =8.5 Hz, 1H), 7.22 (d, J =2.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.01 (d, J =2.1 Hz, 1H), 5.49-5.34 (m, 1H), 5.25-5.04 (m, 2H), 4.65 (br d, J =11.9 Hz, 2H), 4.43 (br dd, J =4.3, 15.5 Hz, 2H), 4.01-3.85 (m, 2H), 3.78-3.70 (m, 4H), 3.47 (br d, J =17.9 Hz, 4H), 3.23-3.12 (m, 1H), 2.54-2.24 (m, 3H), 2.19-2.09 (m, 3H), 1.99 (br s, 4H). Example 63 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 640.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.77-7.66 (m, 2H), 7.45-7.31 (m, 2H), 7.26-7.15 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 5.71 (br s, 1H), 5.45-5.23 (m, 1H), 4.63-4.51 (m, 2H), 4.35-4.20 (m, 2H), 4.08-3.94 (m, 2H), 3.71-3.60 (m, 4H), 3.43-3.34 (m, 2H), 3.29-3.15 (m, 3H), 3.03 (td, J = 9.4, 5.8 Hz, 1H), 2.42-2.13 (m, 3H), 2.08-1.80 (m, 8H), 1.66 (br d, J = 17.1 Hz, 1H). Example 64 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-7-yl)naphthalen-2-ol

^Step 1: To a solution of tert-butyl (1R,5S)-3-(6-(3,6-dihydro-2H-pyran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.14 mmol) in ethyl acetate (2.00 mL) was added wet palladium on carbon (10% content, 7.19 mg, 0.01 mmol) at 20°C. The solution was stirred at 20 ^° C for 16 hours under 15 psi of hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol, yield 99%). LCMS (ESI): [M+H] ⁺ = 742.3.

^Step 2: To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol) in acetonitrile (1.50 mL) was added hydrogen chloride (4 M in dioxane, 673 uL, 2.69 mmol) at 20 ^{°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 white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-7-yl)naphthalen-2-ol (dicarboxylate, 9.84 mg, 15.2 umol, yield 11%). LCMS (ESI): [M+H] ⁺ = 642.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.48 (br s, 2H), 7.84-7.70 (m, 2H), 7.43 (ddd, J = 8.2, 5.1, 2.9 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.22-7.12 (m, 2H), 7.07-6.95 (m, 1H), 5.59-5.36 (m, 1H), 4.66 (br d, J = 12.9 Hz, 2H), 4.59-4.49 (m, 2H), 4.08 (br s, 2H), 3.87 (br d, J = 9.9 Hz, 3H), 3.84-3.75 (m, 3H), 3.71-3.63 (m, 2H), 3.20-3.09 (m, 1H), 2.99 (br t, J = 10.9 Hz, 1H), 2.64-1.98 (m, 12H), 1.86-1.69 (m, 3H), 1.48 (br d, J = 12.3 Hz, 1H). Example 65 ：1-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one

LCMS (ESI): [M+H] ⁺ = 681.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.53 (br s, 1H), 7.79-7.71 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.35 (br t, J = 8.6 Hz, 1H), 7.28-7.19 (m, 2H), 7.06-7.02 (m, 1H), 5.78-5.67 (br s, 1H), 5.58-5.37 (m, 1H), 4.76-4.65 (m, 2H), 4.59-4.46 (m, 2H), 4.01 (br s, 2H), 3.98-3.79 (m, 4H), 3.77-3.52 (m, 3H), 3.32-3.00 (m, 3H), 2.62-2.38 (m, 2H), 2.31 (m, 1H), 2.26-2.16 (m, 2H), 2.04 (m, 5H), 1.98-1.89 (m, 4H), 1.85-1.68 (m, 1H).

The following Example 66 was prepared by the synthetic route method of Example 64 : Example 66 : 1-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)piperidin-1-yl)ethan-1-one

LCMS (ESI): [M+H] ⁺ = 683.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.78 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.49-7.35 (m, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.21 (s, 2H), 7.05 (s, 1H), 5.43-5.24 (m, 1H), 4.66-4.43 (m, 4H), 4.35-4.19 (m, 2H), 3.90-3.80 (m, 1H), 3.75-3.62 (m, 4H), 3.24-3.16 (m, 3H), 3.03 (dt, J = 11.1 Hz, 7.83 5.6, 9.3 Hz, 1H), 2.84-2.48 (m, 2H), 2.43-2.11 (m, 4H), 2.06 (d, J = 8.9 Hz, 3H), 2.04-1.97 (m, 2H), 1.96-1.82 (m, 6H), 1.68-1.61 (m, 2H). Example 67 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol

Step 1 : Stir a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.50 g, 14.96 mmol) and urea (8.98 g, 149.56 mmol) at 200 ^° C for 2 hours. Cool to 100 ^° C, add water (30 mL), stir for 1 hour, filter, add water (25 mL) to the solid product, stir at 50 ^° C for 1 hour, filter, add water (25 mL) to the solid product, stir at 25 ^° C for 12 hours, filter, and vacuum dry the solid to obtain the crude product compound 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g) as a gray solid. LCMS (ESI): [M+H] ⁺ = 258.8.

Step 2 : Potassium nitrate (3.43 g, 33.97 mmol) was added to a concentrated sulfuric acid solution (35 mL) of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g, 14.96 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, yield 77%). LCMS (ESI): [M+H] ⁺ = 303.9. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.98 (br s, 1H), 11.85 (s, 1H), 8.34 (s, 1H).

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 rotated to dryness, ethyl acetate (30 mL) was added, and then ice and ice water (30 mL) were added, and ethyl acetate (20 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated to dryness to obtain the crude product compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g) as a gray solid. LCMS (ESI): [M+H] ⁺ = 341.8.

Step 4 : Add triethylamine (1.84 mL, 13.20 mmol) 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). Stir the mixture at 25 ^° C for 2 hours. Add water (10 mL), extract with dichloromethane (15 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain 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.

Step 5 : To a solution of (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) in trifluoroethanol (4.4 mL) was added diisopropylethylamine (944 uL, 5.71 mmol). The mixture was stirred at 70 ^° C for 12 hours and then rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain a yellow solid compound 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, yield 75%). LCMS (ESI): [M+H] ⁺ = 581.7.

Step 6 : In a glove box, potassium phosphate (1.5 M aqueous solution, 517 uL, 0.78 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (18.8 mg, 0.03 mmol) were added 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 (150 mg, 0.26 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (90.8 mg, 0.34 mmol) in dioxane (3 mL). mmol). The mixture was stirred at 100 ^° C for 12 hours under nitrogen protection. Filtered, the filtrate was diluted with water (3 mL), extracted with ethyl acetate (5 mL * 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 1.21 mmol, yield 66%). LCMS (ESI): [M+H] ⁺ = 644.1.

Step 7 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.16 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (49.5 mg, 0.31 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (22.4 mg, 0.23 mmol). The mixture was stirred at 20 ^° C for 4 hours under nitrogen protection. Add water (5 mL) to dilute, extract with ethyl acetate (10 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and spin dry the filtrate to obtain the crude product compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 703.4.

Step 8 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3 ^- hydroxynaphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (145 mg, 0.14 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 722 uL, 2.89 mmol) at 20 °C. The solution was stirred at 20 ^° C for 1 hour. The solution was blown dry with nitrogen. The residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol (formate salt, 5.95 mg, 0.98 umol, 7% yield). LCMS (ESI): [M+H] ⁺ = 603.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.66 (s, 1H), 8.53 (br s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.36-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.02 (d, J = 2.3 Hz, 1H), 5.55-5.32 (m, 1H), 4.72 (br d, J = 12.0 Hz, 2H), 4.53-4.38 (m, 2H), 4.01-3.79 (m, 4H), 3.54 (br d, J = 12.0 Hz, 1H). J = 12.5 Hz, 3H), 3.26-3.16 (m, 1H), 2.58-2.21 (m, 3H), 2.20-2.09 (m, 2H), 2.08-1.90 (m, 5H). Example 68 : 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1 : In a glove box, potassium phosphate (1.5 M in water, 1.40 mL, 2.10 mL) was added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.70 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (466 mg, 0.91 mmol) in 1,4-dioxane (10.0 mL). mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl)palladium (II) (51 mg, 0.07 mmol). The mixture was stirred at 100 ^° C for 2 hours under nitrogen protection. Water (10 mL) was added, extracted with dichloromethane (10 mL) three times, dried over anhydrous sodium sulfate, filtered and rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(6-((diphenylmethyl)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 (650 mg, 1.21 mmol, yield 91%) was obtained. LCMS (ESI): [M+H] ⁺ = 1020.7.

Step 2 : To a solution of tert-butyl (1R,5S)-3-(6-((diphenylmethyl)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 (150 mg, 0.15 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (60 mg, 0.29 mmol) in tetrahydrofuran (3.00 mL) was added sodium tert-butoxide (42.0 The mixture was stirred at 60 ^° C for 12 hours under nitrogen protection. The reaction solution was diluted with water (3 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The crude product compound tert-butyl (1R, 5S)-3-(2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg) was obtained as a yellow oily compound. LCMS (ESI): [M+2H] ²⁺ /2 = 562.7.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.20 mmol) in N,N-dimethylformamide (4.6 mL) was added cesium fluoride (249 mg, 1.64 mmol). The mixture was stirred at 20 ^° C for 1 hour under nitrogen protection. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.17 mmol, yield 86%). LCMS (ESI): [M+H] ⁺ = 967.5.

Step 4 : To ^a solution of tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.05 mmol) in acetonitrile (540 uL) at 0 °C was added hydrogen chloride (4 M in dioxane, 270 uL, 1.08 mmol). The mixture was stirred at 25 ^° C for 1 hour under nitrogen protection. The mixture was dried with nitrogen, acetonitrile (0.50 mL) was added and stirred, the mixture was centrifuged, the liquid was separated, and the solid was purified by preparative HPLC to obtain a yellow solid compound 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (4.99 mg, 0.75 umol, yield 16%). LCMS (ESI): [M+H] ⁺ = 659.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.85 (dd, J = 5.8, 9.0 Hz, 1H), 7.40-7.24 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.04 (s, 1H), 4.66 (br s, 1H), 4.47-4.35 (m, 2H), 4.34-4.25 (m, 2H), 3.67 (br s, 2H), 3.51 (br t, J = 13.9 Hz, 2H), 3.20 (br d, J = 3.0 Hz, 2H), 2.87 (br d, J = 12.0 Hz, 1H), 2.79-2.62 (m, 1H), 2.31 (br dd, J = 5.4, 13.0 Hz, 1H), 2.17 (br dd, J = 5.5, 11.1 Hz, 1H), 2.09-1.75 (m, 8H), 1.57-1.36 (m, 2H). Example 69 : 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Step 1 : In a glove box, potassium phosphate (1.5 M in water, 286 μL, 0.43 μL) was added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (112 mg, 0.16 mmol) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (50.0 mg, 0.14 mmol) in dioxane (2.10 mL). mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.014 mmol). The mixture was stirred at 100 ^° C for 2 hours under nitrogen protection. After cooling to room temperature, water (2.00 mL) was added for dilution, and it was extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 1.21 mmol, yield 86%) was obtained. LCMS (ESI): [M+H] ⁺ = 858.4.

Step 2 : Dissolve tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.12 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (36.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL) and add sodium tert-butoxide (34.0 mg, 0.35 mmol). The mixture was stirred at 60 ^° C for 5 hours under nitrogen. Water (3 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 rotary dried to give a crude product compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 961.5.

Step 3 : To ^a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylamino)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.05 mmol) in acetonitrile (200 uL) at 0 o C was added hydrogen chloride (4 M in dioxane, 234 uL, 0.94 mmol). The mixture was stirred at 25 ^o C for 1 hour under nitrogen protection. The mixture was dried with nitrogen, acetonitrile (0.5 mL) was added and stirred, the mixture was centrifuged, the liquid was separated, and the solid was purified by preparative HPLC to obtain a yellow solid compound 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (6.13 mg, 0.94 umol, yield 20%). LCMS (ESI): [M+H] ⁺ = 653.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.61 (br dd, J = 4.5, 8.8 Hz, 1H), 7.46-7.34 (m, 1H), 7.31 (s, 1H), 7.12 (br s, 2H), 4.44 (br d, J = 12.3 Hz, 2H), 4.39-4.27 (m, 2H), 3.74 (br s, 2H), 3.54 (br d, J = 12.0 Hz, 2H), 3.40-3.35 (m, 1H), 3.23 (br d, J = 5.3 Hz, 1H), 2.96 (br d, J = 12.3 Hz, 1H), 2.83-2.66 (m, 1H), 2.33 (br dd, J = 6.0, 13.4 Hz, 1H), 2.24-2.13 (m, 1H), 2.10-1.79 (m, 8H), 1.57-1.35 (m, 2H). Example 70 ：N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)methanesulfonamide

Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylamino)-8-fluoroquinazolin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.09 mmol) and sodium acetate (76.8 mg, 0.94 mmol) in methanol (1.44 mL) and tetrahydrofuran (0.45 mL) was added hydroxylamine hydrochloride (42.3 mg, 0.61 mmol). The mixture was stirred at 20 ^° C for 16 hours under nitrogen protection. Water (5 mL) was added for dilution, and dichloromethane (10 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-amino-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 797.5.

Step 2 : To a solution of tert-butyl (1R,5S)-3-(6-amino-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.05 mmol) and triethylamine (112 uL, 0.80 mmol) in dichloromethane (1.6 mL) was added methanesulfonic anhydride (35.0 mg, 0.20 mmol) at 0 ^° C. The mixture was stirred at 20 ^° C for 1 hour under nitrogen protection. The mixture was dried by rotary evaporation, and ammonia (7M in methanol, 2.00 mL, 14.0 mmol) was added, and the mixture was stirred at 25 ^° C for 4 hours and dried by rotary evaporation. The crude product compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-(methylsulfonyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44.0 mg) was obtained as a brown solid. LCMS (ESI): [M+2H] ²⁺ /2 = 874.8.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-(methylsulfonyl)quinazolin-4-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 in dioxane, 229 uL, 0.91 mmol) at 0 ^° C. The mixture was stirred at 20 ^° C for 1 hour. The mixture was blown dry with nitrogen. The residue was purified by preparative HPLC to give a yellow solid compound N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)methanesulfonamide (4.30 mg, 0.58 umol, yield 13%). LCMS (ESI): [M+H] ⁺ = 731.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.96 (d, J = 1.3 Hz, 1H), 7.60 (br dd, J = 4.1, 8.5 Hz, 1H), 7.45-7.34 (m, 1H), 7.31 (s, 1H), 7.11 (d, J = 2.1 Hz, 1H), 4.58-4.42 (m, 2H), 4.40-4.28 (m, 2H), 3.69 (br s, 2H), 3.59 (br dd, J = 12.8, 18.1 Hz, 2H), 3.34 (br s, 1H), 3.22-3.09 (m, 1H), 2.85 (d, J = 12.1 Hz, 1H), 2.79-2.64 (m, 4H), 2.30 (br dd, J = 5.6, 12.8 Hz, 1H), 2.16 (br dd, J = 5.3, 10.9 Hz, 1H), 2.05-1.77 (m, 8H), 1.54-1.35 (m, 2H).

Examples 71 to 73 were prepared by referring to the synthetic route of Example 70 under similar reaction conditions. Example 71 : N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-6-yl)methanesulfonamide

LCMS (ESI): [M+H] ⁺ = 737.2. ¹ H NMR (400 MHz, MeOD) δ ppm 7.96 (s, 1H), 7.87 (dd, J = 5.8, 9.2 Hz, 1H), 7.40-7.26 (m, 2H), 7.12 (d, J = 2.5 Hz, 1H), 4.63 (br s, 1H), 4.51-4.42 (m, 2H), 4.39-4.28 (m, 2H), 3.70 (br s, 2H), 3.63-3.51 (m, 2H), 3.35-3.33 (m, 1H), 3.23-3.12 (m, 1H), 2.85 (br d, J = 12.0 Hz, 1H), 2.80 (s, 3H), 2.76-2.64 (m, 1H), 2.38-2.23 (m, 1H), 2.21-2.11 (m, 1H), 2.06-1.76 (m, 8H), 1.52-1.38 (m, 2H). Example 72 : N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)acetamide

LCMS (ESI): [M+H] ⁺ = 695.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.50 (s, 1H), 8.27 (s, 1H), 7.63 (br dd, J = 4.4, 8.7 Hz, 1H), 7.47-7.37 (m, 1H), 7.34 (s, 1H), 7.07 (d, J = 1.7 Hz, 1H), 4.70 (br d, J = 12.7 Hz, 1H), 4.65-4.72 (m, 3H), 4.13 (br s, 2H), 3.93-3.73 (m, 2H), 3.68 (br dd, J = 6.2, 12.2 Hz, 1H), 3.52 (br dd, J = 5.7, 11.1 Hz, 1H), 3.17 (br d, J = 12.2 Hz, 1H), 2.98 (br d, J = 8.8 Hz, 1H), 2.48 (br dd, J = 5.0, 13.9 Hz, 1H), 2.37-2.25 (m, 1H), 2.24-2.09 (m, 6H), 2.08-1.94 (m, 2H), 1.90 (s, 3H), 1.69-1.54 (m, 2H). Example 73 ：N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-6-yl)acetamide

LCMS (ESI): [M+H] ⁺ = 701.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.48 (s, 1H), 8.37 (s, 1H), 7.88 (dd, J = 5.7, 9.1 Hz, 1H), 7.42-7.26 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 4.67-4.59 (m, 2H), 4.57-4.45 (m, 3H), 4.05 (br s, 2H), 3.79-3.71 (m, 2H), 3.59-3.51 (m, 1H), 3.40 (br dd, J = 5.5, 10.3 Hz, 1H), 3.08 (br d, J = 12.4 Hz, 1H), 2.97-2.83 (m, 1H), 2.47-2.34 (m, 1H), 2.29-2.17 (m, 2H), 2.16-1.99 (m, 6H), 1.92 (s, 4H), 1.64-1.46 (m, 2H). Example 74 : 1-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one

Step 1 : To a solution of 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 (250 mg, 0.43 mmol) in dioxane (5 mL) was added 7,8-difluoro-1-(tributylmethylstannyl)isoquinolin-3-amine (244 mg, 0.52 mmol), cuprous iodide (25 mg, 0.13 mmol), lithium chloride (46 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium (100 mg, 0.09 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 120 ^° C for 16 hours under nitrogen atmosphere. The mixture was rotary dried and the crude product was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to give a yellow solid compound tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.2 mmol, yield 46%). LCMS (ESI): [M+H] ⁺ = 677.1.

Step 2 : To a solution of tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.12 mmol) in tetrahydrofuran (800 uL) was added 4A molecular sieves (80 mg), sodium tert-butoxide (17 mg, 0.18 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (28 mg, 0.18 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.50 mg, 33 umol, yield 28%). LCMS (ESI): [M+H] ⁺ = 736.1.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.50 mg, 33 umol) in acetonitrile (500 uL) was added hydrogen chloride (4M in dioxane, 166 uL, 0.67 mmol). The reaction was stirred at 20 ^° C for 1 hour. The solution was concentrated and dissolved in acetonitrile (1 mL), quenched with triethylamine to pH = 7 and concentrated. The residue was purified by preparative HPLC to give a yellow solid compound 1-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (formate salt, 13.08 mg, 20.6 umol, yield 62%). LCMS (ESI): [M+H] ⁺ = 636.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.53 (br s, 1H), 8.44 (s, 1H), 7.53-7.44 (m, 2H), 6.90 (d, J = 2.3 Hz, 1H), 5.56-5.41 (m, 1H), 4.80-4.72 (m, 2H), 4.59-4.50 (m, 2H), 4.07 (br s, 2H), 3.93 (dt, J = 5.5, 14.1 Hz, 2H), 3.77-3.57 (m, 3H), 3.32-3.26 (m, 1H), 2.63-2.33 (m, 6H), 2.25-2.03 (m, 7H). Example 75 ：1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one

Step 1 : 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), tributyl (1-ethoxyvinyl) tin ane (510 mg, 1.41 mmol) was added, and tetrakis(triphenylphosphine)palladium (170 mg, 0.15 mmol) was added under nitrogen atmosphere, and stirred at 100 ^° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound 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, yield 74%). LCMS (ESI): [M+H] ⁺ = 605.0.

Step 2 : At 25 ^° C, add the compound 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 (2 M aqueous solution, 1.65 mL, 3.30 mmol) to tetrahydrofuran (8.00 mL), and react at 20 ^° C for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 7, and extract with ethyl acetate (4 mL*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 a white solid compound 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, yield 58%). LCMS (ESI): [M+H] ⁺ = 579.2.

Step 3 : At 25 ^° C, 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 (90.0 mg, 0.16 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (81.9 mg, 0.23 mmol) and sodium carbonate (49.6 mg, 0.47 mmol) were added to dioxane (1.80 mL) and water (360 uL). Tetrakis(triphenylphosphine)palladium (10.2 mg, 0.02 mmol) was added under nitrogen atmosphere. The reaction system was heated to 80 ^°C . C for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify the residue by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 140 mg, 0.12 mmol, yield 75%). LCMS (ESI): [M+H] ⁺ = 721.4.

Step 4 : At 25 ^° C, tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 83.0 mg, 0.07 mmol) was added to tetrahydrofuran (200 uL), ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (12.1 mg, 0.08 mmol) and sodium tert-butoxide (20.0 mg, 0.21 mmol) were added, and the reaction system was reacted at 20 ^° C for 2 hours. Water (1 mL) was added, and the mixture was extracted with ethyl acetate (1 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 100 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 780.4.

Step 5 : At 25 ^° C, tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 90.0 mg, 0.06 mmol) was added to acetonitrile (1.00 mL), and hydrochloric acid (4 M dioxane solution, 216 uL, 0.86 mmol) was added, and the reaction system was reacted at 20 ^° C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (1 mL) and the pH was adjusted to 7-8 with triethylamine. The mixture was purified by preparative HPLC to give a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (formate salt, 4.03 mg, 6.35 umol, yield 11%). LCMS (ESI): [M+H] ⁺ = 635.9. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.54 (br s, 1H), 8.32 (s, 1H), 7.61 (br dd, J = 4.4, 8.4 Hz, 1H), 7.44-7.32 (m, 1H), 7.28 (br s, 1H), 6.93 (s, 1H), 5.55-5.30 (m, 1H), 4.76-4.62 (m, 2H), 4.48 (q, J = 11.5 Hz, 2H), 4.07-3.77 (m, 4H), 3.61-3.37 (m, 3H), 3.27-3.19 (m, 1H), 2.55-2.26 (m, 6H), 2.18 (br d, J = 6.1 Hz, 2H), 2.02 (m, 5H). Example 75A and Example 75B : 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((S)-7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one and 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((R)-7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one

Example 75 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia/ethanol; gradient: phase B was maintained at 40%; flow rate: 80 ml/min) to obtain the target product.

Isomer 1, Example 75A : LCMS (ESI): [M+H] ⁺ = 636.4; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; phase B is increased from 5% to 40% in 2 minutes, 40% phase B is maintained for 1.2 minutes, and 5% phase B is maintained for 0.8 minutes; flow rate: 4 ml/min): the palmar column peak position is 1.787 min; ¹ H NMR (400 MHz, MeOD) δ ppm 8.33 (s, 1H), 7.60 (br dd, J = 4.2, 8.3 Hz, 1H), 7.41-7.34 (m, 1H), 7.30-7.26 (m, 1H), 6.92 (d, J = 1.7 Hz, 1H), 5.47-5.24 (m, 1H), 4.57 (br d, J = 6.0 Hz, 2H), 4.40-4.29 (m, 2H), 3.83-3.59 (m, 4H), 3.45-3.35 (m, 3H), 3.10 (br d, J = 5.0 Hz, 1H), 2.43-2.13 (m, 6H), 2.06 (br dd, J = 6.8, 10.9 Hz, 2H), 1.98-1.85 (m, 5H).

Isomer 2 , Example 75B : LCMS (ESI): [M+H] ⁺ = 636.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; phase B is increased from 5% to 40% in 2 minutes, 40% phase B is maintained for 1.2 minutes, and 5% phase B is maintained for 0.8 minutes; flow rate: 4 ml/min): the elution position of the palmar column is 2.089 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.39-8.25 (m, 1H), 7.61 (br dd, J = 4.5, 9.4 Hz, 1H), 7.45-7.34 (m, 1H), 7.28 (s, 7H), 5.76-5.11 (m, 1H), 4.54 (s, 2H), 4.70-4.83 (m, 2H), 3.54-3.30 (m, 3H), 3.20-3.08 (m, 1H), 2.53-2.17 (m, 6H), 2.15-2.06 (m, 2H), 1.94 (br s, 5H ) . ：1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one

Step 1 : At 25 ^° C, compound 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 (100 mg, 0.17 mmol) was dissolved in dioxane (2.00 mL) and water (400 uL), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (115 mg, 0.23 mmol) and potassium phosphate (110 mg, 0.52 mmol), and under nitrogen atmosphere, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (12.6 mg, 0.02 mmol) was added, and the mixture was stirred at 100 ^° C for 2 hours. The reaction solution was cooled to room temperature, 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 yellow oily compound tert-butyl (1R, 5S)-3-(6-acetyl-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 (90.0 mg, 0.10 mmol, yield 59%). LCMS (ESI): [M+H] ⁺ = 883.5.

Step 2 : At 25 ^° C, tert-butyl (1R,5S)-3-(6-acetyl-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 (90.0 mg, 0.10 mmol) was added to tetrahydrofuran (1.80 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (17.9 mg, 0.11 mmol) and sodium tert-butoxide (29.4 mg, 0.31 mmol) were added, and the reaction system was reacted at 20 ^° C for 2 hours. Water (1 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (1 mL * 3). The organic phase was concentrated under reduced pressure to obtain a crude product compound, tert-butyl (1R, 5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 942.5.

Step 3 : At 25 ^° C, tert-butyl (1R, 5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (85.0 mg, 0.09 mmol) was added to dimethylformamide (1.80 mL), and cesium fluoride (41.1 mg, 0.27 mmol) was added. The reaction system was reacted at 20 ^° C for 1 hour. Water (5 mL) and ethyl acetate (5 mL*3) extraction, the organic phase was concentrated under reduced pressure to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 100 mg), which is a yellow solid. LCMS (ESI): [M+H] ⁺ = 786.5.

Step 4 : At 25 ^° C, tert-butyl (1R,5S)-3-(6-acetyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 95 mg, 0.06 mmol) was added to acetonitrile (2.00 mL), and hydrogen chloride (4 M in dioxane, 393 uL, 1.57 mmol) was added, and the reaction system was reacted at 20 ^° C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (1 mL) and the pH was adjusted to 7-8 with triethylamine. The mixture was purified by preparative HPLC to obtain a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (formate salt, 3.65 mg, 5.68 umol, yield 9%). LCMS (ESI): [M+H] ⁺ = 642.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.54 (br s, 1H), 8.25 (s, 1H), 7.87 (br dd, J = 6.0, 8.9 Hz, 1H), 7.50-7.22 (m, 2H), 7.00-6.92 (m, 1H), 5.53-5.29 (m, 1H), 4.72-4.60 (m, 2H), 4.49-4.34 (m, 2H), 3.86 (br s, 3H), 3.73 (br dd, J = 7.0, 12.6 Hz, 1H), 3.60-3.39 (m, 4H), 3.18 (br s, 1H), 2.52-2.40 (m, 1H), 2.36 (br d, J = 8.9 Hz, 1H), 2.25 (br s, 1H), 2.20 (s, 3H), 2.17-2.09 (m, 2H), 1.98 (br s, 5H). Example 76A and Example 76B 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one, and 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one

Example 76 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 35%; flow rate: 120 ml/min) to obtain the target compound.

Isomer 1 , Example 76A : LCMS (ESI): [M+H] ⁺ = 642.3; SFC analysis (column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes; flow rate: 4 ml/min): palmaris column elution position is 1.696 min; ¹ H NMR (400 MHz, MeOD) δ ppm 8.26 (s, 1H), 7.89 (dd, J = 5.9, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 6.95 (d, J = 2.3 Hz, 1H), 5.61-5.43 (m, 1H), 4.83 (br d, J = 13.8 Hz, 1H), 4.71 (br d, J = 14.1 Hz, 1H), 4.68-4.55 (m, 2H), 4.21-4.12 (m, 2H), 4.01 (br d, J = 13.6 Hz, 1H), 3.94-3.68 (m, 4H), 3.41-3.35 (m, 2H), 2.69-2.47 (m, 2H), 2.41-2.34 (m, 1H), 2.34-2.23 (m, 2H), 2.20 (s, 3H), 2.15-1.99 (m, 5H).

Isomer 2 , Example 76B : LCMS (ESI): [M+H] ⁺ = 642.4; SFC analysis (column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes; flow rate: 4 ml/min): palmaris column elution position is 2.137 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.25 (s, 1H), 7.85 (dd, J = 5.8, 9.0 Hz, 1H), 7.34-7.30 (m, 2H), 6.95 (d, J = 2.3 Hz, 3H), 3.02 (dt, J = 5.9, 9.3 Hz, 1H) , 2.39-2.11 (m, 6H), 2.06-1.79 (m, 7H). Example 77 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Step 1 : Dissolve the compound tert-butyl (1R,5S)-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) in tetrahydrofuran (10 mL), add potassium trifluoro(vinyl)borate (220 mg, 1.66 mmol) and sodium carbonate (1 M aqueous solution, 4.54 mL, 4.54 mmol) at 20 ^° C. Under a nitrogen atmosphere, add [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane (120 mg, 0.15 mmol) to the reaction solution. Stir the reaction at 60 ^° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 85%, 500 mg, 0.75 mmol, yield 50%). LCMS (ESI): [M+H] ⁺ = 561.0.

Step 2 : Under nitrogen atmosphere, 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane cyclopentane (200 mg, 0.57 mmol), potassium phosphate solution (1.5 M, 856 uL, 1.71 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (37.0 mg, 0.06 mmol). The mixture was stirred at 20 ^° C for 16 hours. Water (5 mL) was added, and ethyl acetate (5 mL * 2) was extracted. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, 0-65% gradient ethyl acetate/petroleum ether) to give a pale yellow solid compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.32 mmol, yield 57%). LCMS (ESI): [M+H] ⁺ = 704.8.

Step 3 : Dissolve tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.31 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (95.0 mg, 0.47 mmol) in tetrahydrofuran (3 mL). Slowly add sodium tert-butoxide (90.0 mg, 0.94 mmol) to the reaction mixture at 0 ^° C. The reaction mixture is stirred at 60 ^°C for 2 h. C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.30 mmol, yield 99%). LCMS (ESI): [M+H] ⁺ = 808.2.

Step 4 : Dissolve the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.30 mmol) in acetonitrile (3 mL), and add hydrogen chloride (4 M in dioxane, 1.49 mL, 5.96 mmol) at 0 ^° C. The reaction was stirred at 20 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in a solution of triethylamine (400 uL) and dimethyl sulfoxide (2 mL), and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (20.87 mg, 0.02 mmol, yield 10%). LCMS (ESI): [M+H] ⁺ = 664.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.99 (s, 1H), 7.59 (br dd, J = 8.5, 4.2 Hz, 1H), 7.42-7.33 (m, 1H), 7.29 (s, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.32 (dd, J = 17.4, 11.0 Hz, 1H), 5.69 (d, J = 17.4 Hz, 1H), 5.13 (d, J = 11.1 Hz, 1H), 4.64-4.50 (m, 2H), 4.40-4.32 (m, 2H), 3.77-3.64 3.40-3.34 (m, 1H), 3.24-3.16 (m, 1H), 2.87 (br d, J = 12.1 Hz, 1H), 2.78-2.68 (m, 1H), 2.31 (br dd, J = 13.5, 4.2 Hz, 1H), 2.23-2.12 (m, 1H), 2.04 (br d, J = 13.4 Hz, 1H), 1.96-1.86 (m, 6H), 1.81 (br dd, J = 11.9, 7.4 Hz, 1H), 1.53-1.37 (m, 2H). Example 78 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

The preparation of Example 78 refers to Example 76 and is synthesized using a similar synthetic route. LCMS (ESI): [M+H] ⁺ = 626.7. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 7.92 (s, 1H), 7.85 (dd, J = 5.9, 9.1 Hz, 1H), 7.36-7.27 (m, 2H), 7.00 (d, J = 2.5 Hz, 1H), 6.32-6.22 (m, 1H), 5.66 (d, J = 17.4 Hz, 1H), 5.45-5.25 (m, 1H), 5.15-5.07 (m, 1H), 4.62-4.46 (m, 2H), 4.36-4.19 (m, 2H), 3.76-3.60 (m, 4H), 3.41-3.34 (m, 1H), 3.29-3.15 (m, 3H), 3.10-3.00 (m, 1H), 2.45-2.15 (m, 3H), 2.07-1.86 (m, 7H). Example 79 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 79 was prepared by referring to Example 75 , and a similar synthetic route was used to obtain LCMS (ESI): [M+H] ⁺ = 618.7. ¹ H NMR (400 MHz, CD ₃ OD- d ₄ ) δ ppm 7.98 (s, 1H), 7.57 (dd, J = 9.0, 4.0 Hz, 1H), 7.41-7.31 (m, 1H), 7.26 (s, 1H), 7.07 (d, J = 2.3 Hz, 1H), 5.41-5.21 (m, 1H), 4.53 (br t, J = 17.8 Hz, 2H), 4.34-4.26 (m, 1H), 4.26-4.19 (m, 1H), 3.73-3.59 (m, 4H), 3.30-3.15 (m, 4H), 3.08-2.98 (m, 1H), 2.41-1.79 (m, 10H). Example 80 : 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one

Step 1: Dissolve tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (145 g, 856 mmol) in acetone (580 mL) and water (145 mL). Add potassium diatomite dihydrate (320 mg, 0.87 mmol) and N-methylmorpholine oxide (151 g, 1294 mmol) at 0 ^° C under nitrogen protection, and stir the reaction at 20 ^° C for 16 hours. The reaction solution was quenched with saturated sodium thiosulfate (2500 mL) at 0 ^o C, the pH was adjusted to 5 with 1 M salt, extracted with ethyl acetate (2 L * 3), the organic phases were combined, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily compound tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (120 g, 590 mmol, yield 69%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.24 (m, 2H), 3.58 (m 2H), 3.35 (m, 2H), 1.47 (s, 9H).

Step 2: Compound 3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (115 g, 565 mmol) was dissolved in tetrahydrofuran (575 mL) and water (230 mL), sodium periodate (157 g, 735 mmol) was added at 0 ^o C, and the reaction was stirred at 20 ^o C for 16 hours. The reaction solution was quenched with a solution of sodium sulfite (125 g) in water (1 L) at 0 ^o C, extracted with ethyl acetate (2 L * 3), and the organic phases were combined, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl bis(2-oxoethyl)carbamate (108 g, 537 umol, yield 95%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.59 (s, 1H), 9.58 (s, 1H), 4.11 (s, 2H), 3.90 (s, 2H), 1.38 (s, 9H).

Step 3: Add a solution of tert-butyl bis(2-oxoethyl)carbamate (50.0 g, 248 mmol) in tetrahydrofuran (108 mL) to vinyl magnesium bromide (1 M tetrahydrofuran solution, 1250 mL, 1250 mmol) at -70 ^° C and stir the reaction at 20 ^° C for 16 hours. The two batches of the reaction were combined, quenched with saturated ammonium chloride (1500 mL) at 0 ^° C, extracted with ethyl acetate (2 L * 3), and the organic phases were combined, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to give tert-butyl bis(2-hydroxybut-3-en-1-yl)carbamate (32.0 g, 124 mmol, yield 25%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.87-5.66 (m, 2H), 5.37-5.19 (m, 2H), 5.10 (m, 2H), 4.52-4.09 (m, 2H), 3.83-2.77 (m, 4H), 1.43-1.36 (m, 9H).

Step 4: Dissolve tert-butyl bis(2-hydroxybut-3-en-1-yl)carbamate (31.0 g, 120 mmol) in dichloromethane (320 mL), add trichloroacetonitrile (52.1 g, 361 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.00 mL, 60.2 mmol) at 0 ^° C, and stir the reaction at 0 ^° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 6% gradient ethyl acetate/petroleum ether) to obtain a yellow oily compound ((tert-butoxycarbonyl)azinediyl)bis(but-3-ene-1,2-diyl)bis(2,2,2-trichloroacetimidate) (44.0 g, 80.6 mmol, yield 67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.30 (s, 2H), 5.84-5.69 (m, 2H), 5.64-5.50 (m, 2H), 5.42-5.28 (m, 2H), 5.26-5.14 (m, 2H), 3.80-3.69 (m, 1H), 3.65-3.50 (m, 2H), 3.43-3.31 (m, 1H), 1.42-1.39 (m, 9H).

Step 5: Dissolve the compound 2-phenylpropan-2-amine (13.1 g, 96.7 mmol) in dichloroethane (100 mL ⁾ . Add 1,5-cyclooctadiene iridium chloride dimer (2.71 g, 4.03 mmol) and ((tert-butoxycarbonyl)azinediyl)bis(but-3-ene-1,2-diyl)bis(2,2,2-trichloroacetamide) (44 g, 80.6 mmol) in dichloroethane (350 mL) at 0 ° C under nitrogen protection. Stir the reaction at 0 ^° C for 2 hours, then heat to 20 ^° C and stir for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-3% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-1-carboxylic acid tert-butyl ester (22.0 g, 61.7 mmol, yield 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.56 (dd, J = 1.0, 8.3 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.26-7.16 (m, 1H), 6.05-5.92 (m, 2H), 5.18-5.06 (m, 2H), 5.01 (d, J = 10.4 Hz, 2H), 3.64-3.48 (m, 4H), 3.35 (br t, J = 13.8 Hz, 2H), 1.49-1.45 (m, 15H).

Step 6: Dissolve the compound (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-1-carboxylic acid tert-butyl ester (22.0 g, 61.7 mmol) in toluene (510 mL), add (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidene)dichloro(phenylisothiazolide)(tricyclohexylphosphine)ruthenium (2.62 g, 3.09 mmol) under nitrogen, and stir the reaction at 120 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-4% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (12.0 g, 36.4 mmol, yield 59%). LCMS (ESI): [M+H] ⁺ = 329.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.51 (br d, J = 7.9 Hz, 2H), 7.29-7.21 (m, 2H), 7.15 (br d, J = 7.4 Hz, 1H), 5.96-5.83 (m, 2H), 3.62-3.49 (m, 2H), 3.48-3.36 (m, 2H), 3.02 (ddd, J = 2.4, 11.6, 17.9 Hz, 2H), 1.34 (s, 9H), 1.18 (d, J = 6.1 Hz, 6H).

Step 7: Dissolve the compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (600 mg, 1.83 mmol) and 2,6-lutidine (590 mg, 5.48 mmol) in dichloromethane (10 mL), add trimethylsilyl trifluoromethanesulfonate (810 mg, 3.65 mmol) at 0 ^° C, and stir the reaction at 0 ^° C for 1 hour. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0 ^° C, and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain a yellow oily compound (1R, 5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene (560 mg, 1.72 mmol, yield 94%). LCMS (ESI): [M+H] ⁺ = 229.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.59-7.50 (m, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.29-7.22 (m, 1H), 6.16 (s, 2H), 3.68 (s, 2H), 3.14 (dd, J = 2.0, 11.9 Hz, 2H), 2.81 (dd, J = 1.7, 11.9 Hz, 2H), 1.26 (s, 6H).

Step 8: Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00 g, 11.88 mmol) and trifluoroethanol (1.43 g, 14.26 mmol) in toluene (60 mL), add sodium tert-butoxide (1.14 g, 11.88 mmol) at 0 ^° C, and stir the mixture at 0 ^° C for 2 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (30 mL * 3), the filtrate was washed with saturated brine (50 mL * 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 70%, 3.76 g, 8.31 mmol, yield 70%). LCMS (ESI): [M+H] ⁺ = 315.8.

Step 9: Compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (0.710 g, 4.43 mmol), diisopropylethylamine (0.790 mL, 4.43 mmol) and 4A molecular sieve (1 g) were mixed in methyltetrahydrofuran (10 mL), and 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 70%, 1.00 g, 2.21 mmol) was added at 0 ^° C. The reaction system was heated to 25 ^° C for 1 hour. The three batches of reactions were mixed, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 3.00 g, 5.10 mmol, yield 77%). LCMS (ESI): [M+H] ⁺ = 439.0.

Step 10: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (75% purity, 2.75 g, 4.69 mmol) in dioxane (60 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21 g, 6.27 mmol) and cesium carbonate (1.5 M aqueous solution, 12.5 mL, 18.80 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (419 mg, 0.63 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 80 ^° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane). The crude product was purified by flash column chromatography (C18, 0-60% gradient of acetonitrile/water (containing 1% formic acid)) to give a yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.90 mmol, yield 40%). LCMS (ESI): [M+H] ⁺ = 789.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.27 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 5.6, 8.9 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.57-5.38 (m, 1H), 5.36-5.29 (m, 2H), 5.27-5.17 (m, 1H), 5.11-4.92 (m, 1H), 4.87-4.51 (m, 2H), 3.85 (br s, 2H), 3.54 (s, 3H), 3.49-3.33 (m, 1H), 3.18 (br s, 1H), 2.66-2.10 (m, 6H), 0.91-0.82 (m, 18H), 0.54 (m, 3H).

Step 11: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 0.32 mmol) was dissolved in tetrahydrofuran (2.50 mL), and a solution of sodium hydroxide (44.0 mg, 1.09 mmol) in water (2.50 mL) was added. The reaction solution was stirred at 25 ^° C for 16 hours. Acetic acid (60 uL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain a yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (224 mg, 0.21 mmol, yield 67%). LCMS (ESI): [M+H] ⁺ = 707.2.

Step 12: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (230 mg, 0.33 mmol), (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene (223 mg, 0.98 mmol) and diisopropylethylamine (566 uL, 3.25 mmol) were dissolved in dimethylacetamide (2.3 mL), ^0. Benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (287 mg, 0.65 mmol) was added at 50 °C and the reaction was stirred at 50 ^° C for 2 hours. The mixture was quenched with saturated sodium bicarbonate (10 mL) at 0 ^° C, extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated brine (10 mL * 3). The mixture was washed with 4% paraformaldehyde (2% ethyl acetate) and 0.1% paraformaldehyde (2% paraformaldehyde). The mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, compound 8-fluoro-7-(7-fluoro-3-((methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (300 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 916.9;

Step 13: Compound 8-fluoro-7-(7-fluoro-3-((methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (300 mg, 0.33 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (500 mg, 3.27 mmol) was added, and stirred at 20 ^° C for 1 hour. The reaction solution was diluted with water (1500 uL) and ethyl acetate (3 mL * 3) extraction, the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (240 mg, 0.32 mmol, yield 96%). LCMS (ESI): [M+H] ⁺ = 760.9.

Step 14: Compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (190 mg, 0.25 mmol) was added to trifluoroacetic acid (1.9 mL) and stirred at 50 ^° C for 1 hour. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, triethylamine was added to adjust the pH to 8, and the solution was purified by preparative HPLC to obtain a red solid compound 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one (dicarboxylate, 16.06 mg, 23 umol, yield 9%). LCMS (ESI): [M+H] ⁺ = 617.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.09 (s, 1H), 8.46 (br s, 2H), 8.00-7.91 (m, 1H), 7.40-7.33 (m, 2H), 7.30 (s, 1H), 6.35 (s, 2H), 5.63-5.46 (m, 1H), 4.76-4.65 (m, 2H), 4.65-4.55 (m, 2H), 4.36 (br s, 2H), 4.05-3.92 (m, 2H), 3.88-3.68 (m, 3H), 3.40 (br dd, J = 4.5, 10.0 Hz, 1H), 2.72-2.48 (m, 2H), 2.43-2.14 (m, 7H). Example 81 : 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-ol

Step 1: Add triethylsilane (50.77 g, 432.22 mmol) to a solution of 4-fluoro-5-bromo-1-indanone (10.00 g, 43.22 mmol) in trifluoroacetic acid (10 mL), heat the reaction solution to 80°C and stir for 16 hours. After the reaction solution is cooled to room temperature, the pH is adjusted to 7 with a saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (100 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-4% gradient of ethyl acetate/petroleum ether) to obtain 5-bromo-4-fluoro-2,3-dihydro-1H-indene as a colorless oily liquid (8.00 g, 86%); ¹ H NMR (400 MHz, CD ₃ Cl) δ ppm 7.29 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 2.99-2.88 (m, 4H), 2.16-2.09 (m, 2H).

Step 2: Under nitrogen protection, 5-bromo-4-fluoro-2,3-dihydro-1H-indene (8.00 g, 37.20 mmol) and furan (12.79 g, 186.00 mmol) were added to toluene (50 mL). The reaction solution was cooled to -30°C. n-Butyl lithium (1.6 M, 25.57 mL) was slowly added dropwise to the reaction solution. After the addition, the reaction solution was heated to 25°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL x 3) were added to the reaction solution for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2,3,6,9-tetrahydro-1H-6,9-epoxycyclopenta[a]naphthalene as a brown-red solid (5.30 g, 77%).

Step 3: Add concentrated hydrochloric acid (10 mL, 12 M) to a solution of 2,3,6,9-tetrahydro-1H-6,9-epoxycyclopenta[a]naphthalene (5.30 g, 28.77 mmol) in ethanol (20 mL). Heat the reaction mixture to 85°C and stir for 2 hours. After the reaction mixture is cooled to room temperature, the pH is slowly adjusted to 6 with solid sodium hydroxide, extracted with ethyl acetate (50 mLx3), the organic phases are combined, and the residue is concentrated. The residue is subjected to rapid column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2,3-dihydro-1H-cyclopenta[a]naphthalene-9-ol as a brown solid (2.70 g, 51%).

Step 4: Add N,N-diisopropylethylamine (5.90 g, 44.78 mmol) to a solution of 2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-ol (3.30 g, 17.91 mmol) in dichloromethane (20 mL), and cool the reaction solution to 0°C. Slowly add bromo(methoxy)methane (5.59 g, 44.78 mmol) to the reaction solution, and after the addition, continue stirring the reaction solution at 0°C for 1 hour. Pour the reaction solution into water (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene as a white solid (2.70 g, 17.91 mmol).

Step 5: Under nitrogen protection, 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (2.70 g, 11.83 mmol), methoxy(cyclooctadiene) iridium dimer (380 mg, 0.591 mmol), pinacol borane (3.09 g, 23.65 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (393 mg, 1.42 mmol) were added to n-hexane (6 mL), heated to 85°C and reacted for 16 hours. After the reaction was cooled to room temperature, it was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined and concentrated to obtain the residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2-(9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a brown solid (1.80 g, 43%).

Step 6: To a solution of 2-(9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.80 g, 5.08 mmol) in tetrahydrofuran (5 mL) was added acetic acid (3.05 g, 50.81 mmol) and hydrogen peroxide (925 mg, 50.81 mmol, 30%). The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was poured into water (30 mL), and the pH was adjusted to 6 with solid sodium hydroxide. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-7-ol as a brown solid (1.20 g, 97%). LCMS (ESI): [M+H] ⁺ = 245.1

Step 7: Add N,N-diisopropylethylamine (1.94 g, 14.74 mmol) to a solution of 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-ol (1.20 g, 4.91 mmol) in dichloromethane (20 mL). The reaction solution was cooled to -40°C, and acetyl chloride (433 mg, 5.40 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at -40°C for 30 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient ethyl acetate/petroleum ether) to obtain 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate as a white solid (1.30 g, 92%). LCMS (ESI): [M+H] ⁺ = 287.1

Step 8: 9-(Methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate (1.39 g, 4.85 mmol) was added to dichloromethane (5 mL), and the reaction solution was cooled to -65°C. Ethyl acetate hydrochloride solution (4 M, 20 mL) was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at -65°C for 30 minutes, then slowly heated to 0°C and stirred for 30 minutes. The reaction solution was directly concentrated to obtain 9-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate as a brown solid (1.15 g, 97%). LCMS (ESI): [M+H] ⁺ = 243.1

Step 9: 9-Hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate (1.15 g, 4.75 mmol) was added to dichloromethane (10 mL), and the reaction solution was cooled to -65°C. N,N-Diisopropylethylamine (1.88 g, 14.24 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at -65°C for 15 minutes. Trifluoromethanesulfonic anhydride (1.60 g, 5.70 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -65°C for 30 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to give 9-((((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate as a white solid (1.05 g, 59%).

Step 10: 9-((((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate (1.05 g, 2.81 mmol) was added to a solution of tetrahydrofuran (10 mL) and water (3 mL), and the reaction solution was cooled to 0°C. Lithium hydroxide (0.10 g, 4.21 mmol) was added to the reaction solution, and the reaction solution was stirred at 0°C for 30 minutes. The reaction solution was adjusted to pH 6 with acetic acid, extracted with ethyl acetate (20 mL x 3), and the organic phase was saturated with aqueous sodium chloride solution (30 mL x 4). 3) Wash, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product 7-hydroxy-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl trifluoromethanesulfonate as a white solid (0.90 g, 96%). LCMS (ESI): [M+H] ⁺ = 333.1

Step 11: 7-Hydroxy-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl trifluoromethanesulfonate (900 mg, 2.71 mmol) was added to dichloromethane (5 mL), and the reaction solution was cooled to 0°C. N,N-Diisopropylethylamine (1.07 g, 8.12 mmol) was slowly added to the reaction solution. The reaction solution was stirred at 0°C for 5 minutes. Bromo(methoxy)methane (508 mg, 4.06 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at 0°C for 1 hour. Water (30 mL) was poured into the reaction solution, and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to give 7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-9-yl trifluoromethanesulfonate (750 mg, 74%).

Step 12: Under nitrogen protection, 7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-9-yl trifluoromethanesulfonate (750 mg, 1.99 mmol), pinacol diboron (1.01 g, 3.98 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (151 mg, 0.20 mmol), and potassium acetate (395 mg, 3.98 mmol) were added to N,N-dimethylformamide (3 mL), and the reaction solution was heated to 100°C and stirred for 4 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was poured into water (30 mL), extracted with ethyl acetate (30 mL), washed with saturated sodium chloride aqueous solution (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was subjected to rapid column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as a white solid (600 mg, 85%).

Step 13 : Under nitrogen protection, 2-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (128 mg, 0.36 mmol), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.36 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (26 mg, 0.04 mmol), potassium phosphate (157 mg, 0.72 mmol) were added to 1,4-dioxane (2 mL), and the reaction solution was heated to 95°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered, and the filtrate was purified by preparative thin layer chromatography (dichloromethane/methanol = 12/1) to obtain (1R,5S)-3- (8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate compound as white solid (180 mg, 66%). LCMS (ESI): [M+H] ⁺ = 743.3

Step 14 : (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.24 mmol) was added to ethyl acetate hydrochloride (4 M, 4 mL), and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash column chromatography (C18, 5-35% acetonitrile/water, 0.5% HCl) to give 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl))-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-ol hydrochloride as a light yellow solid (49 mg, 34%). LCMS (ESI): [M+H] ⁺ = 599.3; ¹ H NMR (400 MHz, DMSO) δ ppm 11.61-11.50 (m, 1H), 10.15-10.00 (m, 1H), 9.8 (s, 1H), 9.25(s, 1H), 7.65-7.55(m, 1H), 7.40-7.25(m, 2H), 7.10-7.00(m, 1H), 5.60-5.50(m, 1H), 4.79-4.65(m, 5H), 4.23-4.15(m, 3H), 4.00-3.75(m, 4H), 3.30-3.25(m, 1H), 2.90-2.75(m, 2H), 2.68-2.63 (m, 1H), 2.50-2.41 (m, 2H), 2.25-1.75 (m, 11H). Example 82 : 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1: To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.19 mmol) in dichloromethane (3.00 mL) was added m-chloroperbenzoic acid (85% purity, 844 mg, 4.16 mmol) and the mixture was stirred at 20 ^° C for 16 hours. The solution was concentrated, the residue was dissolved in ethyl acetate (5 mL), washed with saturated potassium carbonate solution (5 mL * 3), the organic phase was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-71% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid 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)pyrido[4,3-d]pyrimidine 6-oxide (420 mg, 0.49 mmol, yield 41%). LCMS (ESI): [M+H] ⁺ = 858.3.

Step 2: A mixture 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)pyrido[4,3-d]pyrimidine 6-oxide (200 mg, 0.23 mmol), diphenyl phosphate azide (1.92 g, 6.99 mmol) and pyridine (225 uL, 2.80 mmol) was stirred at 110 ^° C for 16 hours. The mixture was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether) to give yellow oily compound tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)tetraazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 200 mg, 0.23 mmol, 68% yield). LCMS (ESI): [M+H] ⁺ = 883.3.

Step 3: To a solution of compound tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)tetraazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 180 mg, 0.14 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (64.9 mg, 0.41 mmol) in tetrahydrofuran (3.60 mL) was added sodium tert-butoxide (60.0 mg, 0.61 mmol). The mixture was stirred at 20 ^° C for 16 hours. Water (4 mL) was added for dilution, and the mixture was extracted with ethyl acetate (4 mL * 3). The organic phase was concentrated to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg) as a yellow solid. LCMS (ESI): [M+H] ⁺ = 942.4.

Step 4: CsF (202 mg, 1.33 mmol) was added to a solution of tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg, 0.13 mmol) in dimethylformamide (2.00 mL). The reaction mixture was stirred at 20 ^° C for 1 hour, then diluted with water (3 mL) and washed with ethyl acetate (4 mL). * 3). The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the crude compound tert-butyl (1R,5S)-3-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg) as a yellow solid. LCMS (ESI): [M+H] ⁺ = 786.5.

Step 5: To a solution of tert-butyl (1R,5S)-3-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.03 mmol) in acetonitrile (900 uL) was added hydrogen chloride (4 M in dioxane, 143 uL, 0.57 mmol). The solution was stirred at 20 ^o C for 1.5 hours, concentrated, and the residue was dissolved in acetonitrile (2 mL) and triethylamine was added to adjust the pH to 8. The solution was purified by preparative HPLC to obtain compound 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (2.10 mg, 3.27 umol, yield 11%). LCMS (ESI): [M+H] ⁺ = 642.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.98 (dd, J = 5.6, 9.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.41 (t, J = 8.9 Hz, 1H), 5.42 (br d, J = 4.0 Hz, 1H), 4.69-4.53 (m, 2H), 4.44-4.27 (m, 3H), 3.82 (br dd, J = 1.6, 13.7 Hz, 2H), 3.69 (br dd, J = 5.6, 13.2 Hz, 1H), 3.57 (br dd, J = 3.3, 13.8 Hz, 1H), 3.30-3.20 (m, 3H), 3.10-3.03 (m, 1H), 2.42-2.14 (m, 5H), 2.08-1.88 (m, 5H). Example 83 : (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)(cyclopropyl)methanone formate

Example 83 was prepared by the synthetic route method of Example 53 : LCMS (ESI): [M+H] ⁺ = 626.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.53 (br s, 1H), 8.11 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.50-7.38 (m, 2H), 7.31-7.19 (m, 2H), 7.07 (d, J = 2.4 Hz, 1H), 5.51-5.36 (m, 1H), 4.70-4.40 (m, 4H), 3.95-3.86 (m, 2H), 3.83-3.75 (m, 2H), 3.56-3.48 (m, 3H), 3.24-3.18 (m, 1H), 2.56-2.36 (m, 2H), 2.32-2.24 (m, 1H), 2.21-2.11 (m, 2H), 2.05-1.96 (m, 5H), 1.75-1.66 (m, 1H), 0.98-0.87 (m, 1H), 0.79-0.70 (m, 1H), 0.64-0.55 (m, 1H), 0.42-0.39 (m, 1H). Example 84 ：(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-6-yl)(cyclohexyl)methanone

Step 1 : At -78 ^o C, add a solution of cuprous cyanide (13.5 mg, 0.15 mmol) in tetrahydrofuran (300 uL) to a solution of 1.3M isopropylmagnesium chloride and lithium chloride (232 uL, 0.30 mmol) in tetrahydrofuran (300 uL). The solution was stirred at -78 ^o C ^for 30 minutes. Then, tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.15 mmol) in tetrahydrofuran (300 uL) was added at -78 o C. uL) solution, remove the cooling bath, stir for 30 minutes, then add tetrahydrofuran (300 uL), stir for 40 minutes, then add cyclohexane methyl chloride (26.6 mg, 0.18 mmol) tetrahydrofuran solution (300 uL), stir for 15 minutes. The reaction solution was poured into saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to obtain a colorless liquid compound tert-butyl (1R,5S)-3-(7-bromo-6-(cyclohexanecarbonyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34.0 mg, 0.05 mmol, yield 34%). LCMS (ESI): [M+H] ⁺ = 647.2.

Step 2 : In a glove box, 1.5 M potassium phosphate aqueous solution (309 uL, 0.46 mmol) was added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-(cyclohexanecarbonyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.15 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (103.2 mg, 0.20 mmol) in 1,4-dioxane (2 mL). mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (11.3 mg, 0.02 mmol). The mixture was stirred at 100 ^° C for 2 hours under nitrogen. Water (3 mL) was added, and ethyl acetate (5 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary 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-(cyclohexanecarbonyl)-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 (100.0 mg, 0.04 mmol, purity 40%, yield 28%). LCMS (ESI): [M+H] ⁺ = 951.6.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-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 (100 mg, 0.10 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (33.5 mg, 0.21 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (15.2 mg, 0.16 mmol). The mixture was stirred at 50 ^° C for 3 hours under nitrogen. Water (5 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 rotary dried. The crude product compound tert-butyl (1R, 5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg) was obtained as a brown oily liquid. LCMS (ESI): [M+2H] ²⁺ /2=506.0.

Step 4 : To a solution of tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.12 mmol) in N,N-dimethylformamide (2.4 mL) was added cesium fluoride (180.4 mg, 1.19 mmol). The mixture was stirred at 25 ^° C for 1 hour. Add water (7 mL) to dilute, extract with ethyl acetate (10 mL * 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give brown oily compound tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42 mg, 0.05 mmol, yield 41%). LCMS (ESI): [M+H] ⁺ = 854.5.

Step 5 ^: To a solution of tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42 mg, 0.05 mmol) in acetonitrile (840 uL) was added hydrogen chloride (4 M in dioxane, 246 uL, 0.98 mmol) at 20 °C. The solution was stirred at 20 ^° C for 1 hour. The solution was purged with nitrogen to remove HCl gas and concentrated. The mixture was purified by preparative HPLC to give a white solid compound (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-6-yl)(cyclohexyl)methanone (7.88 mg, 0.01 mmol, yield 23%). LCMS (ESI): [M+H] ⁺ = 710.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.99 (s, 1H), 7.89 (dd, J = 5.8, 9.0 Hz, 1H), 7.37 (t, J = 8.9 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 5.43 - 5.28 (m, 1H), 4.69 - 4.49 (m, 3H), 4.40 - 4.26 (m, 2H), 3.77 - 3.63 (m, 4H), 3.36 (br d, J = 5.3 Hz, 2H), 3.13 - 3.06 (m, 1H), 2.62 - 2.53 (m, 1H), 2.47 - 2.26 (m, 2H), 2.25 - 1.98 (m, 4H), 1.92 (br s, 4H), 1.72 - 1.59 (m, 2H), 1.49 (br s, 2H), 1.28 - 0.99 (m, 5H), 0.95 - 0.86 (m, 1H), 0.58 (br d, J = 13.3 Hz, 1H). Example 85 ：1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one oxime

Step 1 : At 25 ^° C, compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (20.0 mg, 0.03 mmol), sodium carbonate (6.67 mg, 0.06 mmol) and hydroxylamine hydrochloride (21.8 mg, 0.31 mmol) were dissolved in ethanol (200 uL) and stirred at 20 ^° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one oxime (0.85 mg, 1.3 umol, yield 1%). LCMS (ESI): [M+H] ⁺ = 651.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.75-7.48 (m, 2H), 7.48-7.27 (m, 2H), 7.02-6.88 (m, 1H), 5.62-5.38 (m, 1H), 4.71-4.68 (m, 2H), 4.03 (br s, 2H), 3.84-3.60 (m, 7H), 3.05 (s, 1H), 2.62-2.48 (m, 2H), 2.29 (s, 3H), 2.08-1.99 (m, 5H), 1.59 (s, 3H). Example 86 ：1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one O-methyl oxime

Example 86 The compound was synthesized using the same operation method as Example 85. 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one O-methyloxime (1.43 mg, white solid). LCMS (ESI): [M+H] ⁺ = 665.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.83 (s, 1H), 7.67-7.54 (m, 1H), 7.49-7.21 (m, 2H), 6.97 (d, J = 2.1 Hz, 1H), 5.47-5.25 (m, 1H), 4.71-4.62 (m, 2H), 4.45-4.28 (m, 2H), 3.86-3.61 (m, 7H), 3.53-3.35 (m, 3H), 3.12 (br d, J = 6.0 Hz, 1H), 2.45-2.17 (m, 3H), 2.14-2.03 (m, 2H), 1.94 (br s, 5H), 1.64 (s, 3H). Example 87 : 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol

Step 1 ^: 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 (1.60 g, 2.76 mmol) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 g, 3.86 mmol) in dioxane (32 mL) was added sodium carbonate (1.3 M in water, 6.36 mL, 0.78 mmol) at 25 °C. Under nitrogen atmosphere, palladium tetrakis(triphenylphosphine) (18.8 mg, 0.03 mmol) was added. The reaction system was stirred at 100 ^° C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 5-12% gradient tetrahydrofuran/petroleum ether) to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-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 (1.40 g, 1.93 mmol, yield 70%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.63 (s, 1H), 7.62-7.58 (m, 1H), 7.51 (s, 1H), 7.36-7.34 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H), 5.33-5.28 (m, 2H), 4.92-4.88 (m, 2H), 4.60-4.52 (m, 2H), 4.47-4.44 (m, 2H), 3.79-3.72 (m, 2H), 3.54 (s, 3H), 2.05-2.01 (m, 2H), 1.84-1.80 (m, 2H), 1.55 (s, 9H).

Step 2 : Sodium tert-butoxide (279 mg, 2.90 ^mmol ) was added to a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-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 (700 mg, 0.97 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (176 mg, 1.10 mmol) in tetrahydrofuran (14 mL) at 25 ° C. The reaction system was stirred at 25 ^° C for 2 hours. Add water (50 mL) to dilute, extract with ethyl acetate (20 mL * 3), wash the combined organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, spin dry the filtrate, and purify the residue by flash column chromatography (silica gel, 1-5% gradient methanol/dichloromethane). The product was purified by preparative HPLC to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 383 umol, yield 39%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.62 (s, 1H), 7.60-7.57 (m, 1H), 7.50 (s, 1H), 7.38-7.31 (m, 1H), 7.11 (s, 1H), 5.56-5.42 (m, 1H), 5.33-5.28 (m, 2H), 4.77 (t, J = 7.8 Hz, 1H), 4.77-4.54 (m, 5H), 3.82-3.71 (m, 2H), 3.65-3.55 (m, 2H), 3.54 (m, 4H), 3.27-3.24 (m, 1H), 2.56-2.46 (m, 3H), 2.26-2.25 (m, 3H), 2.22-2.02 (m, 2H), 1.80-1.74 (m, 2H), 1.55 (s, 9H).

Step 3 : To ^a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.26 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 958 uL, 3.83 mmol) at 20 ° C. The solution was stirred at 20 ^° C for 2 hours. The solution was concentrated under reduced pressure, dissolved in acetonitrile (3 mL), triethylamine was added to adjust the pH to 7-8, the solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (51 mg, 79.9 umol, yield 31%). LCMS (ESI): [M+H] ⁺ = 639.2 Example 87A and Example 87B : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (R)- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 87 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 1, Example 87A : LCMS (ESI): [M+H] ⁺ = 639.1; SFC analysis (chromatographic column: Chiralpak IG-3, 50 mm * 4.6 mm, 3 um; 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 elution position of the palmar column is 0.829 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.71 (s, 1H), 7.63 (dd, J = 4.3, 8.8 Hz, 1H), 7.48-7.34 (m, 1H), 7.31 (s, 1H), 7.01 (d, J = 2.0 Hz, 1H), 5.53-5.30 (m, 1H), 4.78 (br d, J = 13.6 Hz, 1H), 4.69 (br d, J = 12.3 Hz, 1H), 4.56-4.43 (m, 2H), 4.11-3.84 (m, 4H), 3.60 (s, 1H), 3.58 (d, J = 3.5 Hz, 1H), 3.56 (s, 1H), 3.27-3.18 (m, 1H), 2.46-1.95 (m, 10H).

Isomer 2 , Example 87B : LCMS (ESI): [M+H] ⁺ = 639.1; SFC analysis (chromatographic column: Chiralpak IG-3, 50 mm * 4.6 mm, 3 um; 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 elution position of the palmar column is 2.576 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.70 (s, 1H), 7.61 (dd, J = 3.6, 9.2 Hz, 1H), 7.46-7.32 (m, 1H), 7.33-7.21 (m, 1H), 7.00 (d, J = 2.3 Hz, 1H), 5.41-5.17 (m, 1H), 4.69-4.49 (m, 2H), 4.35-4.20 (m, 2H), 3.84-3.63 (m, 4H), 3.30-3.14 (m, 3H), 3.02 (dt, J = 5.8, 9.3 Hz, 1H), 2.30-1.75 (m, 10H). Example 88 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1 : To a mixed 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 (3.10 g, 5.34 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.56 g, 6.94 mmol) in toluene (124 mL) and water (31 mL) under nitrogen atmosphere, cesium carbonate (5.22 g, 16.03 mmol) was added. mmol), 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 ^o C for 16 hours. The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL * 3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate and 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.

Step 2 : To a solution of 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 (500 mg, 0.56 mmol) in tetrahydrofuran (10 mL) was added 4A molecular sieve (500 mg), sodium tert-butoxide (108 mg, 1.12 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (180 mg, 1.12 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to give a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 0.49 mmol, yield 87%). LCMS (ESI): [M+H] ⁺ = 945.6.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (440 mg, 0.47 mmol) in dimethylformamide (5 mL) was added cesium fluoride (566 mg, 3.7 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 0.42 mmol, yield 89%). LCMS (ESI): [M+H] ⁺ = 789.2.

Step 4 : To a solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 0.42 mmol) in acetonitrile (6.5 mL) was added hydrogen chloride (4 M in dioxane, 2 mL, 8 mmol). The reaction was stirred at 20 ^° C for 1 hour. After vacuum rotary drying, it was dissolved in acetonitrile (5 mL) and neutralized with triethylamine, then concentrated under reduced pressure. The residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (118 mg, 0.18 mmol, yield 43%). LCMS (ESI): [M+H] ⁺ = 645.1. Example 88A and Example 88B : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and (R)- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 88 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 1, Example 88A : LCMS (ESI): [M+H] ⁺ = 645.2; SFC analysis (column: ChiralPak AD-3, 150 * 4.6 mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B; flow rate: 2.5 ml/min;): the elution position of the palmar column is 1.865 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69-8.65 (m, 1H), 7.86 (dd, J = 5.6, 9.2 Hz, 1H), 7.35-7.29 (m, 2H), 7.00 (d, J = 2.3 Hz, 1H), 5.40-5.24 (m, 1H), 4.67 (br d, J = 12.5 Hz, 1H), 4.52 (br d, J = 12.5 Hz, 1H), 4.36-4.21 (m, 2H), 3.82 (br d, J = 12.0 Hz, 1H), 3.72-3.62 (m, 3H), 3.36 (s, 1H), 3.32-3.19 (m, 3H), 3.04 (dt, J = 5.6, 9.5 Hz, 1H), 2.40-2.12 (m, 3H), 2.05-1.79 (m, 7H).

Isomer 2, Example 88B : LCMS (ESI): [M+H] ⁺ = 645.1; SFC analysis (column: ChiralPak AD-3, 150 * 4.6 mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B; flow rate: 2.5 ml/min;): the palmar column peak position is 3.293 min; ¹ H NMR (400 MHz, CD ₃ OD) δppm 8.68-8.65 (m, 1H), 7.86 (dd, J = 5.8, 9.3 Hz, 1H), 7.35-7.30 (m, 2H), 7.00 (d, J = 2.5 Hz, 1H), 5.40-5.24 (m, 1H), 4.66 (br d, J = 12.3 Hz, 1H), 4.54 (br d, J = 12.3 Hz, 1H), 4.29 (q, J = 10.5 Hz, 2H), 3.80 (br d, J = 12.0 Hz, 1H), 3.71-3.65 (m, 3H), 3.38-3.36 (m, 1H), 3.32-3.19 (m, 3H), 3.04 (dt, J = 5.8, 9.5 Hz, 1H), 2.40-2.14 (m, 3H), 2.04-1.80 (m, 7H). Example 89 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 89 The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' - pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (formate salt, 220 mg, yellow solid) was synthesized by the same method as Example 87. LCMS (ESI): [M+H] ⁺ = 683.1. ¹ H-NMR (400 MHz, CD ₃ OD) δ ppm 8.71 (s, 1H), 8.46 (s, 1H), 7.63 (dd, J = 4.0, 9.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (s, 1H), 7.01 (d, J = 2.1 Hz, 1H), 4.78-4.69 (m, 2H), 4.59-4.51 (m, 2H), 4.07 (br s, 2H), 4.00-3.83 (m, 2H), 3.61 (br dd, J = 6.3, 12.1 Hz, 1H), 3.51-3.42 (m, 1H), 3.13 (br d, J = 12.4 Hz, 1H), 3.00-2.88 (m, 1H), 2.44 (br dd, J = 4.1, 13.6 Hz, 1H), 2.27 (br dd, J = 5.9, 11.7 Hz, 1H), 2.19-1.90 (m, 8H), 1.67-1.53 (m, 2H). Example 89AB , Example 89C and Example 89D : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol , and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 89 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 55%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 1 & 2 mixture, Example 89AB : LCMS (ESI): [M+H] ⁺ = 683.1; SFC analysis (column: Chiralpak AD-3 150 * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.5 ml/min): palmitic column peak positions are 1.771 min and 2.830 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (s, 1H), 7.60 (dd, J = 3.7, 9.2 Hz, 1H), 7.38 (q, J = 9.1 Hz, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 3.86 (m, 4H), 3.24-3.32 (m, 1H), 3.19 (d, J = 12.3 Hz, 1H), 3.73-3.76 (m, 1H), 3.25 (br dd, J = 5.3, 13.4 Hz, 1H), 3.14 (br dd, J = 5.8, 10.5 Hz, 1H), 3.55 (d, J = 12.3 Hz, 1H), 3.24 (m, 4H), 3.16 (m, 1H) , 3.54 (d, J = 12.3 Hz, 1H), 3.25 (m, 1H), 3.30 (m, 1H), 3.19 (m, 1H), 3. 7H), 1.50-1.35 (m, 2H).

Isomer 3 , Example 89C : LCMS (ESI): [M+H] ⁺ = 683.1; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the palmar column peak position is 6.175 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (s, 1H), 7.60 (dd, J = 3.7, 9.3 Hz, 1H), 7.45-7.31 (m, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.66-4.55 (m, 2H), 4.40-4.31 (m, 2H), 3.81-3.61 (m, 4H), 3.27 (br d, J = 6.9 Hz, 1H), 3.18-3.12 (m, 1H), 2.83 (d, J = 12.1 Hz, 1H), 2.75-2.64 (m, 1H), 2.32-2.09 (m, 2H), 2.02 (br d, J = 13.5 Hz, 1H), 1.96-1.72 (m, 7H), 1.49-1.36 (m, 2H).

Isomer 4 , Example 89D : LCMS (ESI): [M+H] ⁺ = 683.1; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the elution position of the palmar column is 9.134 min; ¹ H NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.38 (q, J = 8.9 Hz, 1H), 7.28 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.67 (br d, J = 11.6 Hz, 1H), 4.57 (br d, J = 12.3 Hz, 1H), 4.43-4.33 (m, 2H), 3.85-3.67 (m, 4H), 3.38-3.32 (m, 1H), 3.23-3.15 (m, 1H), 2.87 (d, J = 12.1 Hz, 1H), 2.79-2.66 (m, 1H), 2.29 (dd, J = 6.2, 13.7 Hz, 1H), 2.22-2.09 (m, 1H), 2.03 (br d, J = 13.5 Hz, 1H), 1.98-1.75 (m, 7H), 1.52-1.36 (m, 2H). Example 90 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 90 The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' - pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 328 mg, yellow solid 0.47 mmol) was synthesized by the same method as Example 88. LCMS (ESI): [M+H] ⁺ = 689.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (s, 1H), 8.47 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.38-7.29 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 4.77-4.64 (m, 2H), 4.59-4.49 (m, 2H), 4.07 (br s, 2H), 3.97 (br d, J = 13.3 Hz, 1H), 3.88-3.78 (m, 1H), 3.65-3.54 (m, 1H), 3.50-3.40 (m, 1H), 3.39-3.35 (m, 1H), 3.11 (d, J = 12.3 Hz, 1H), 2.97-2.88 (m, 1H), 2.49-2.36 (m, 1H), 2.32-2.20 (m, 1H), 2.18-1.89 (m, 8H), 1.66-1.52 (m, 2H). Example 90A , Example 90B and Example 90C : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol , and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 90 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 55%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 1 & 2 mixture, Example 90A : LCMS (ESI): [M+H] ⁺ = 689.2; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): palmitic column peak positions are 1.381 min and 1.413 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.8, 9.1 Hz, 1H), 7.35-7.25 (m, 2H), 6.98 (d, J = 2.3 Hz, 1H), 4.65 (br d, J = 12.9 Hz, 1H), 4.51 (br d, J = 12.4 Hz, 1H), 4.39-4.30 (m, 2H), 3.79 (br d, J = 12.4 Hz, 1H), 3.67 (br s, 3H), 3.36-3.33 (m, 1H), 3.29-3.24 (m, 1H), 3.20-3.09 (m, 1H), 2.83 (d, J = 12.3 Hz, 1H), 2.74-2.64 (m, 1H), 2.26 (td, J = 5.6, 13.4 Hz, 1H), 2.18-2.09 (m, 1H), 2.18 (br d, J = 13.6 Hz, 1H), 1.94-1.75 (m, 7H), 1.49-1.35 (m, 2H).

Isomer 3 , Example 90B : LCMS (ESI): [M+H] ⁺ = 689.2; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the palmar column peak position is 2.974 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.8, 9.1 Hz, 1H), 7.37-7.27 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.64 (br d, J = 11.5 Hz, 1H), 4.52 (br d, J = 12.6 Hz, 1H), 4.35 (s, 2H), 3.79 (br d, J = 12.0 Hz, 1H), 3.71-3.63 (m, 3H), 3.36-3.34 (m, 1H), 3.30-3.24 (m, 1H), 3.18-3.11 (m, 1H), 2.83 (d, J = 12.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.30-2.10 (m, 2H), 2.01 (br d, J = 13.5 Hz, 1H), 1.96-1.75 (m, 7H), 1.50-1.35 (m, 2H).

Isomer 4 , Example 90C : LCMS (ESI): [M+H] ⁺ = 689.2; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the palmar column peak position is 6.670 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.9, 9.1 Hz, 1H), 7.35-7.27 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.65 (br d, J = 12.0 Hz, 1H), 3.54 (m, 2H), 3.76 (m, 3H), 3.23 (d, J = 6.8 Hz, 1H), 3.12 (m, 1H), 3.54 (d, J = 12.1 Hz, 1H), 3.74 (m, 2H), 3.85 (m, 3H), 3.24 (d, J = 12.2 Hz, 1H), 3.19 (m, 1H), 3.85 (m, 1H), 3.23 (d, J = 12.1 Hz, 1H), 3.28 (m, 1H), 3.82 (m, 1H), 3.60 (m, 3H), 3.89 (m, 1H), 3.91 (m, 1H), 3.80 (m, 1H), (m, 7H), 1.50-1.35 (m, 2H). Example 91 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 91 The target compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H - spiro[cyclopropane- 1,2' -pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol was synthesized using the same method as Example 87. LCMS (ESI): [M+H] ⁺ = 683.1. ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 10.32 (br s, 1H), 8.64 (s, 1H), 7.74 (dd, J = 4.6, 8.9 Hz, 1H), 7.61-7.53 (m, 1H), 7.35 (s, 1H), 7.07 (s, 1H), 4.51-4.33 (m, 2H), 4.10-3.96 (m, 2H), 3.75-3.49 (m, 4H), 3.03 (d, J = 10.3 Hz, 1H), 2.99-2.93 (m, 1H), 2.77 (br dd, J = 5.9, 10.4 Hz, 1H), 2.67 (td, J = 6.5, 9.6 Hz, 2H), 2.13-2.08 (m, 1H), 1.99-1.72 (m, 5H), 1.68-1.58 (m, 4H), 1.57-1.49 (m, 2H). Example 92 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 92 The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' - pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (52.95 mg, yellow solid) was synthesized by the same method as Example 88. LCMS (ESI): [M+H] ⁺ = 689.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (s, 1H), 8.47 (br s, 1H), 7.88 (dd, J = 5.7, 9.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 4.77-4.64 (m, 2H), 4.52-4.43 (m, 2H), 4.10-3.92 (m, 3H), 3.85 (br dd, J = 6.5, 13.6 Hz, 1H), 3.58-3.46 (m, 1H), 3.43-3.35 (m, 2H), 3.23-3.07 (m, 2H), 2.45 (br d, J = 13.4 Hz, 1H), 2.26-2.14 (m, 3H), 2.13-1.95 (m, 6H), 1.64-1.56 (m, 2H). Example 93 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2,8-bis((1-(oxolinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 94 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxo-1-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Step 1 : At 0 ^° C, sodium tert-butoxide (106 mg, 1.11 mmol) was slowly added to a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-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 (200 mg, 0.28 mmol) and (1-(morpholinomethyl)cyclopropyl)methanol (236 mg, 1.38 mmol) in tetrahydrofuran (3 mL) at 0 ° C. The reaction was stirred at 25 ^° C for 2 hours. The reaction solution was diluted with water (4 mL), extracted with ethyl acetate (3 mL * 2), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to give a yellow oily compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75% purity, 210.0 mg, 0.17 mmol, yield 62%). LCMS (ESI): [M+2H] ²⁺ /2 = 398.0 and compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-bis((1-(phenolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.09 mmol, yield 35%). LCMS (ESI): [M+2H] ²⁺ /2 = 473.6.

^Step 2 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.19 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 943 uL, 3.77 mmol) at 25 °C. The solution was stirred at 20 ^° C for 1 hour. The solution was quenched with triethylamine (100 uL) and concentrated. The mixture was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 94 (formate salt, 17.10 mg, 26.0 umol, yield 14%). LCMS (ESI): [M+H] ⁺ = 650.9. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (s, 1H), 8.43 (br s, 1H), 7.61 (dd, J = 9.4, 4.0Hz, 1H), 7.45-7.35 (m, 1H), 7.29 (s, 1H), 6.99 (d, J = 1.9Hz, 1H), 4.80-4.56 (m, 2H), 4.49-4.41 (m, 2H), 4.11 (br s, 2H), 3.96-3.83 (m, 2H), 3.68 (br t, J = 4.2Hz, 4H), 2.67-2.54 (m, 6H), 2.08 (br s, 4H), 0.75 (s, 2H), 0.56 (s, 2H).

Using the compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-bis((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a raw material, the same method was used to obtain the compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2,8-bis((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 93 (dicarboxylate, 27.57 mg, 34.0 umol, yield 36%). LCMS (ESI): [M+H] ⁺ = 801.9. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.68 (s, 1H), 8.44 (br s, 2H), 7.65 (br dd, J = 8.4, 4.4Hz, 1H), 7.51-7.35 (m, 1H), 7.28 (s, 1H), 6.95 (d, J = 2.1Hz, 1H), 4.77-4.44 (m, 6H), 4.30 (d, J = 10.9Hz, 1H), 4.14-3.77 (m, 9H), 3.69 (br t, J = 4.4Hz, 4H), 3.53 (br d, J = 12.8Hz, 2H), 3.10 (br d, J = 9.5Hz, 1H), 2.83 (br d, J = 12.8 Hz, 1H), 2.66-2.47 (m, 5H), 2.29 (br d, J = 12.6 Hz, 1H), 2.15-1.82 (m, 4H), 0.82-0.66 (m, 2H), 0.64-0.43 (m, 4H), 0.31-0.24 (m, 2H). Example 94A and Example 94B : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 94 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 1, Example 94A : LCMS (ESI): [M+H] ⁺ = 651.3; SFC analysis (column: Chiralpak AD-3, 50 *4.6 mm, 3 um; 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 elution position of the palmar column is 0.435 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (d, J = 1.25 Hz, 1H), 7.60 (dd, J = 9.16, 2.4 Hz, 1H), 7.38 (q, J = 8.9 Hz, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.5 Hz, 1H), 4.74-4.51 (m, 4H), 4.46-4.38 (m, 2H), 3.77 (br d, J = 12.8 Hz, 1H), 3.70 (br d, J = 10.5 Hz, 3H), 3.63 (t, J = 4.5 Hz, 4H), 2.56-2.44 (m, 4H), 1.93-1.78 (m, 4H), 0.74-0.67 (m, 2H), 0.53-0.46 (m, 2H).

Isomer 2 , Example 94B : LCMS (ESI): [M+H] ⁺ = 651.3; SFC analysis (column: Chiralpak AD-3, 50 *4.6mm, 3um; 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 elution position of the palmar column is 1.264 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (d, J = 1.3 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.39 (q, J = 9.0 Hz, 1H), 7.28 (s, 1H), 7.00 (d, J = 2.3 Hz, 1H), 4.77-4.53 (m, 4H), 4.49-4.38 (m, 2H), 3.87-3.70 (m, 4H), 3.64 (t, J = 4.6 Hz, 4H), 2.61-2.47 (m, 4H), 2.01-1.83 (m, 4H), 0.77-0.67 (m, 2H), 0.55-0.47 (m, 2H). Example 95 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxo- linomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 95 The same method as Example 88 was used to synthesize the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxo-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 9 mg, yellow solid). LCMS (ESI): [M+H] ⁺ = 657.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.65 (s, 1H), 8.41 (br s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.41-7.26 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 4.77 (br d, J = 13.9 Hz, 1H), 4.69 (br d, J = 13.5 Hz, 1H), 4.52-4.40 (m, 2H), 4.21 (br s, 2H), 4.00 (br d, J = 13.5 Hz, 1H), 3.89 (br d, J = 13.4 Hz, 1H), 3.75 (br t, J = 4.4 Hz, 4H), 3.39 (s, 1H), 2.87-2.67 (m, 6H), 2.21-2.01 (m, 4H), 0.86-0.77 (m, 2H), 0.69-0.58 (m, 2H). Example 96 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Step 1 : Zinc powder (23.44 g, 358.45 mmol) was added in batches to a dioxane solution (240 mL) of 2-methyl-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (15.0 g, 71.69 mmol) at 25 °C under nitrogen protection, followed by slow dropwise addition of trichloroacetyl chloride (65.18 g, 358.45 mmol). After the addition, the reaction solution was stirred at 25 °C for 4 hours. The reaction solution was filtered through diatomaceous earth and rinsed with ethyl acetate (100 mL * 3). The filtrate was then washed with a saturated sodium bicarbonate solution (300 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to obtain a crude product compound 2,2-dichloro-3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (22.0 g), which was a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 320.2

Step 2 : Zinc powder (23.44 g, 358.46 mmol) was added in batches to a solution of 2,2-dichloro-3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (22.0 g, 68.71 mmol) in acetic acid (220 mL) at 25 °C under nitrogen protection. The reaction solution was then stirred at 50 ^° C for 16 hours. The reaction solution was diluted with ethyl acetate (500 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution (500 mL * 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily product, 3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (4.50 g, 17.91 mmol, yield 26%). LCMS (ESI): [M+H] ⁺ = 252.2

Step 3 : Slowly add diethylaminosulfur trifluoride (4.20 g, 26.26 mmol) to a solution of 3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (3.30 g, 13.13 mmol) in dichloromethane (33 mL) at -70 °C under nitrogen protection. Then the reaction solution was naturally raised to 20 ^° C and stirred at 20 ^° C under nitrogen protection for 16 hours. The reaction solution was washed with saturated sodium bicarbonate solution (30 mL * 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound 3,3-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (1.20 g, 4.39 mmol, yield 33%). LCMS (ESI): [M+H] ⁺ = 274.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.27-4.19 (m, 2H), 3.87-3.80 (m, 1H), 3.36-3.24 (m, 1H), 2.83-2.72 (m, 1H), 2.71-2.62 (m, 2H), 2.61-2.51 (m, 4H), 2.42 (ddd, J = 1.3, 9.2, 16.6 Hz, 1H), 2.13-2.02 (m, 1H), 1.98-1.91 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).

Step 4 : Dissolve the compound 3,3-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (400 mg, 1.46 mmol) in tetrahydrofuran (4 mL), and add lithium aluminum tetrahydrogen (333 mg, 8.78 mmol) at 0 ^o C. The reaction was stirred at 60 ^o C for 2 hours. After cooling, water (333 uL), sodium hydroxide (15% aqueous solution, 333 uL), water (666 uL), anhydrous magnesium sulfate (1 g) were carefully added to the reaction solution, and stirred for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oily crude product compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (0.39 g). LCMS (ESI): [M+H] ⁺ = 218.1

Step 5 : Dissolve the compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (390 mg, 1.79 mmol) and diisopropylethylamine (1.5 mL, 8.98 mmol) in dichloromethane (4 mL), add benzoyl chloride (420 uL, 3.59 mmol) at 0 ^o C, and stir the reaction solution at 25 ^o C for 16 hours. The reaction solution was diluted with water (15 mL), extracted with dichloromethane (5 mL * 3), the organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, filtered, the filtrate 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 yellow oily compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)benzoic acid methyl ester (360 mg, 1.11 mmol, yield 62%). LCMS (ESI): [M+H] ⁺ = 322.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.16-7.97 (m, 2H), 7.68-7.32 (m, 3H), 4.42-4.21 (m, 2H), 3.59 (d, J = 10.5 Hz, 1H), 3.35 (td, J = 6.7, 11.2 Hz, 1H), 2.95-2.75 (m, 3H), 2.72-2.57 (m, 3H), 2.31 (d, J = 13.6 Hz, 1H), 2.16-2.06 (m, 1H), 2.05-1.94 (m, 3H), 1.90-1.77 (m, 1H).

Step 6 : Compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)benzoic acid methyl ester (250 mg, 0.78 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of sodium hydroxide (93 mg, 2.33 mmol) in water (3 mL) was added. The reaction solution was stirred at 25 ^° C for 16 hours. The reaction solution was extracted with ethyl acetate (5 mL * 3), the organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (106 mg, 0.48 mmol, yield 62%). LCMS (ESI): [M+H] ⁺ = 218.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.36-3.22 (m, 2H), 3.18 (br d, J = 10.0 Hz, 1H), 2.97 (br s, 1H), 2.80 (br d, J = 10.0 Hz, 2H), 2.67-2.51 (m, 4H), 2.13 (br d, J = 13.3 Hz, 1H), 1.98-1.73 (m, 4H), 1.71-1.61 (m, 1H).

Step 7 : Dissolve the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-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, 138 umol) in tetrahydrofuran (2 mL), add (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (60 mg, 276 umol) and sodium tert-butoxide (26 mg, 276 umol), and stir at 20 ^o C for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((3,3-difluorodihydro-1'H, 3'H)-spiro[cyclobutane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg). LCMS (ESI): [M+H] ⁺ = 841.2.

Step 8: Dissolve the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((3,3-difluorodihydro-1'H,3'H)-spiro[cyclobutane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 142 umol) in acetonitrile (0.2 mL), add hydrogen chloride (4M in dioxane, 0.6 mL, 2.37 mmol), and stir at 20 ^o C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (500 uL). Triethylamine was added to adjust the pH to 8, and the mixture was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (25 mg, 36 umol, yield 15%). LCMS (ESI): [M+H] ⁺ = 697.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.71 (s, 1H), 7.61 (br d, J = 9.2 Hz, 1H), 7.39 (q, J = 8.7 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J = 2.2 Hz, 1H), 4.68-4.49 (m, 2H), 4.33-4.19 (m, 2H), 3.82-3.64 (m, 4H), 3.25 (d, J = 10.5 Hz, 1H), 3.16-3.05 (m, 1H), 2.92-2.80 (m, 2H), 2.76-2.56 (m, 4H), 2.38 (d, J = 13.3 Hz, 1H), 2.09-1.78 (m, 9H). Example 96B and Example 96C : 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol , and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol

Example 96 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 55%; flow rate: 80 ml/min) to obtain the target compound.

Mixture of isomers 1 & 2 , Example 96A : LCMS (ESI): [M+H] ⁺ = 697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 0.370 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (s, 1H), 7.52-7.45 (m, 1H), 7.27 (q, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.91-6.86 (m, 1H), 4.55-4.50 (m, 1H), 4.47-4.39 (m, 1H), 4.24-4.05 (m, 2H), 3.69-3.51 (m, 4H), 3.16-3.08 (m, 1H), 3.03-2.92 (m, 1H), 2.81-2.68 (m, 2H), 2.64-2.44 (m, 4H), 2.25 (br d, J = 13.4 Hz, 1H), 1.95-1.83 (m, 3H), 1.82-1.64 (m, 6H).

Isomer 3, Example 96B : LCMS (ESI): [M+H] ⁺ = 697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 0.739 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.68 (s, 1H), 7.59 (br d, J = 9.0 Hz, 1H), 7.37 (q, J = 8.9 Hz, 1H), 7.27 (br s, 1H), 6.99 (s, 1H), 4.63 (br d, J = 12.1 Hz, 1H), 4.54 (br d, J = 12.3 Hz, 1H), 4.33-4.18 (m, 2H), 3.82-3.62 (m, 4H), 3.25-3.18 (m, 1H), 3.12-3.03 (m, 1H), 2.86 (br d, J = 10.0 Hz, 2H), 2.74-2.55 (m, 4H), 2.35 (br d, J = 13.1 Hz, 1H), 2.05-1.95 (m, 3H), 1.90-1.73 (m, 6H).

Isomer 4, Example 96C : LCMS (ESI): [M+H] ⁺ = 697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 1.893 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (s, 1H), 7.59 (dd, J = 4.1, 9.1 Hz, 1H), 7.41-7.34 (m, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.58 (br d, J = 12.0 Hz, 2H), 4.31-4.17 (m, 2H), 3.79-3.60 (m, 4H), 3.24-3.17 (m, 1H), 3.10-3.01 (m, 1H), 2.87-2.76 (m, 2H), 2.75-2.55 (m, 4H), 2.39-2.29 (m, 1H), 2.06-1.96 (m, 3H), 1.90-1.74 (m, 6H). Example 97 ：4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Step 1 : Dissolve 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 (180 mg, 203 umol) in tetrahydrofuran (2 mL), add (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (88 mg, 406 umol) and sodium tert-butoxide (39 mg, 406 umol), and stir at 20 ^o C for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(2-((3,3-difluorodihydro-1'H, 3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg). LCMS (ESI): [M+H] ⁺ = 1003.3.

Step 2 : A solution of tert-butyl (1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.24 mmol) and cesium fluoride (364 mg, 2.4 mmol) in dimethylformamide (2 mL) was stirred at 25 ^° C for 2 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(2-((3,3-difluorodihydro-1'H, 3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg). LCMS (ESI): [M+H] ⁺ = 847.2.

Step 3 : Dissolve the compound tert-butyl (1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 237 umol) in acetonitrile (0.2 mL), add hydrogen chloride (4M solution in dioxane, 0.6 mL, 2.37 mmol), and stir at 20 ^o C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (500 uL). Triethylamine was added to adjust the pH to 8, and the mixture was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (25 mg, 36 umol, yield 15%). LCMS (ESI): [M+H] ⁺ = 703.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (s, 1H), 7.86 (dd, J = 5.9, 9.1 Hz, 1H), 7.37-7.26 (m, 2H), 7.00 (s, 1H), 4.69-4.49 (m, 2H), 4.32-4.17 (m, 2H), 3.86-3.75 (m, 1H), 3.67 (br s, 3H), 3.36 (d, J = 6.0 Hz, 1H), 3.21 (d, J = 10.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.89-2.77 (m, 2H), 2.74-2.55 (m, 4H), 2.36 (br d, J = 14.1 Hz, 1H), 2.09-1.80 (m, 9H). Example 97B and Example 97C : 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol , or 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

Example 97 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.

Isomer 4, Example 97C : LCMS (ESI): [M+H] ⁺ = 703.1; SFC analysis (chromatographic column: Chiralpak AD-3, 150 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is maintained at 40%; flow rate: 2.5 ml/min): the elution position of the palmar column is 4.050 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (d, J =1.1 Hz, 1H), 7.86 (dd, J =5.8, 9.1 Hz, 1H), 7.39-7.28 (m, 2H), 7.00 (d, J =2.3 Hz, 1H), 4.66-4.50 (m, 2H), 4.29-4.16 (m, 2H), 3.84-3.75 (m, 1H), 3.71-3.61 (m, 3H), 3.37 (s, 1H), 3.21 (br d, J =10.1 Hz, 1H), 3.11-3.00 (m, 1H), 2.88-2.79 (m, 2H), 2.75-2.56 (m, 4H), 2.35 (d, J =13.2 Hz, 1H), 2.04-1.79 (m, 9H). Example 98 : 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan - 3- yl )-2-(( dihydro -1'H,3'H- spiro [ oxacyclobutane -3,2'- pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8- fluoro -6- nitroquinazolin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol

Example 98 was prepared by a similar synthetic route to Example 97 : LCMS (ESI): [M+H] ⁺ = 669.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (s, 1H), 7.87 (dd, J = 5.6, 9.2 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.00 (s, 1H), 4.73 (br d, J = 6.3 Hz, 2H), 4.64 (br d, J = 6.3 Hz, 2H), 4.56 - 4.48 (m, 1H), 4.23 - 4.12 (m, 2H), 3.80 (br d, J = 13.3 Hz, 1H), 3.68 (br s, 3H), 3.54 (br d, J = 10.3 Hz, 1H), 3.38 - 3.36 (m, 1H), 3.08 - 3.01 (m, 1H), 2.97 (d, J = 10.3 Hz, 1H), 2.78 (td, J = 5.1, 10.8 Hz, 1H), 2.56 (d, J = 13.3 Hz, 1H), 2.11 - 1.91 (m, 4H), 1.91 - 1.77 (m, 6H). Example 99 ：4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline

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 (800 mg, 1.38 mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (810 mg, 1.79 mmol) were added to a mixed solution of toluene (32 mL) and water (8 mL), and then cesium carbonate (1.35 g, 4.14 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (200 mg, 0.28 mmol). The mixture was stirred at 100 ^° C for 16 hours. The residue was diluted with water (60 mL) and extracted with ethyl acetate (30 mL * 3), the combined organic phases were washed with brine (60 mL), dried over anhydrous magnesium sulfate and 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-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 (950 mg, 1.15 mmol, yield 83%). LCMS (ESI): [M+H] ⁺ = 826.3.

Step 2 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-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 (400 mg, 0.48 mmol) in tetrahydrofuran (8 mL) was added 4A molecular sieve (400 mg), sodium tert-butoxide (93 mg, 0.97 mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (137 mg, 0.97 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-6% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 0.31 mmol, yield 65%). LCMS (ESI): [M+H] ⁺ = 867.2.

Step 3 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.3 mmol) in dimethylformamide (3 mL) was added cesium fluoride (364 mg, 2.4 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.23 mmol, yield 77%). LCMS (ESI): [M+H] ⁺ = 711.3.

Step 4 : To a solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (155 mg, 0.22 mmol) in acetonitrile (3 mL) was added hydrogen chloride (4 M in dioxane, 1 mL, 4 mmol). The reaction was stirred at 20 ^° C for 1 hour. After vacuum rotary drying, it was dissolved in acetonitrile (2 mL), neutralized with triethylamine and concentrated. The residue was purified by preparative HPLC to give a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline (60 mg, 0.1 mmol, yield 45%). LCMS (ESI): [M+H] ⁺ = 611.1. ¹ H-NMR (400 MHz, CD ₃ OD) δ ppm 8.70 (d, J = 1.3 Hz, 1H), 8.17-8.04 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.49-7.37 (m, 2H), 4.68 (br d, J = 11.3 Hz, 1H), 4.54 (br d, J = 12.0 Hz, 1H), 4.36-4.27 (m, 2H), 3.82 (br d, J = 11.5 Hz, 1H), 3.72-3.63 (m, 3H), 3.45 (s, 1H), 3.21-3.09 (m, d, J = 6.3, 12.4 Hz, 2H), 2.02-1.75 (m, 10H).

Example 100 and Example 101 are prepared by the same synthetic route as Example 99 , and reacting with different alcohols in the second step to obtain: Example 100 : 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazoline

LCMS (ESI): [M+H] ⁺ = 629.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (d, J = 1.3 Hz, 1H), 8.15-8.05 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.49-7.38 (m, 2H), 5.39-5.23 (m, 1H), 4.70-4.64 (m, 1H), 4.57-4.49 (m, 1H), 4.34-4.20 (m, 2H), 3.81 (br dd, J = 5.2, 12.5 Hz, 1H), 3.72-3.62 (m, 3H), 3.46 (d, J = 5.4 Hz, 1H), 3.23-3.17 (m, 3H), 3.02 (dt, J = 5.4, 9.4 Hz, 1H), 2.41-2.12 (m, 3H), 2.04-1.78 (m, 7H). Example 101 : trans-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]

LCMS (ESI): [M+H] ⁺ = 673.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.71-8.68 (m, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.48-7.39 (m, 2H), 4.67 (br d, J = 13.1 Hz, 1H), 4.53 (br d, J = 12.8 Hz, 1H), 4.41-4.32 (m, 2H), 3.81 (br d, J = 12.5 Hz, 1H), 3.69 (br s, 3H), 3.44 (d, J = 2.1 Hz, 1H), 3.32-3.26 (m, 1H), 3.20-3.13 (m, d, J = 13.3 Hz, 1H ) , 1.95-1.77 (m, 7H), 1.52-1.37 (m, 2H) Example 101A: (1S,7a'S)-7a'-((((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], Example 101B : (1R,7a'R)-7a'-((((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], Example 101C: (1R,7a'R)-7a'-((((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine] and Example 101D: (1S,7a'S)-7a'-((((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]

Example 101 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um)); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain a mixture of isomers 1 and 2 , and a mixture of isomers 3 and 4 .

The mixture of isomers 1 and 2 was separated by SFC (column: REGIS (S, S) WHELK-O1 (250 mm*25 mm, 10 um)); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain optically pure Example 101A and Example 101B .

The mixture of isomers 3 and 4 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um)); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain optically pure Example 101C and Example 101D .

Example 101A : LCMS (ESI): [M+H] ⁺ = 673.4; SFC analysis (column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min): the elution position of the palmar column is 2.676 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (d, J = 1.4 Hz, 1H), 8.17-8.03 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.37 (m, 2H), 4.68 (br d, J = 11.6 Hz, 1H), 3.71 (m, 3H), 3.59 (d, J = 12.5 Hz, 1H), 3.55 (m, 2H), 3.25 (m, 3H), 3.30 (m, 1H), 3.54 (d, J = 12.5 Hz, 1H), 3.72 (m, 3H), 3.53 (br d, J = 12.5 Hz, 1H), 4.53 (br d, J = 12.5 Hz, 1H), 4.42-4.30 (m, 2H), 3.82 (br d, J = 12.3 Hz, 1H), 3.73-3.61 (m, 3H), 3.52-3.36 (m, 1H), 3.31-3.27 (m, 1H), 3.16 (ddd, J = 3.9, 5.8, 9.9 Hz, 1H), 2.84 (d, J = 12.1 Hz, 1H), 2.76-2.65 (m, 1H), 2.29 (dd, J = 6.3, 13.5 Hz, 1H), 1H), 1.98-1.75 (m, 7H), 1.52-1.37 (m, 2H).

Example 101B : LCMS (ESI): [M+H] ⁺ = 673.6; SFC analysis (column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min): the elution position of the palmar column is 3.176 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.57 (s, 1H), 8.04-7.93 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.37-7.26 (m, 2H), 4.55 (br d, J = 11.8 Hz, 1H), 4.42 (br d, J = 13.8 Hz, 1H), 4.80 (br d, J = 20.1 Hz, 1H), 4.69 (br d, J = 31.7 Hz, 1H), 4.80 (br d, J = 23.9 Hz, 1H), 4.64 ( br = 12.3 Hz, 1H), 4.24 (s, 2H), 3.69 (br d, J = 12.4 Hz, 1H), 3.56 (br d, J = 10.9 Hz, 3H), 3.33 (s, 1H), 3.19-3.15 (m, 1H), 3.08-3.01 (m, 1H), 2.72 (d, J = 12.1 Hz, 1H), 2.63-2.54 (m, 1H), 2.16 (dd, J = 6.2, 13.4 Hz, 1H), 2.07-2.01 (m, 1H), 1.94-1.88 (m, 1H), 1.84-1.65 (m, 7H), 1.38-1.25 (m, 2H).

Example 101C : LCMS (ESI): [M+H] ⁺ = 673.4; SFC analysis (column: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is maintained at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 0.634 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.69 (d, J = 1.4 Hz, 1H), 8.16-8.03 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 4.67 (br d, J = 11.9 Hz, 1H), 4.54 (br d, J = d, J = 12.3 Hz, 1H), 4.37 (s, 2H), 3.81 (br d, J = 11.3 Hz, 1H), 3.68 (br d, J = 10.8 Hz, 3H), 3.44 (s, 1H), 3.28 (br d, J = 7.0 Hz, 1H), 3.20-3.13 (m, 1H), 2.85 (d, J = 12.4 Hz, 1H), 2.76-2.65 (m, 1H), 2.28 (dd, J = 6.2, 13.6 Hz, 1H), 2.19-2.11 (m, 1H), 2.03 (d, J = 13.5 Hz, 1H), 1.97-1.81 (m, 7H), 1.51-1.37 (m, 2H).

Example 101D : LCMS (ESI): [M+H] ⁺ = 673.4; SFC analysis (column: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is maintained at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 1.129 min; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.57 (s, 1H), 8.03-7.92 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.36-7.27 (m, 2H), 4.56 (br d, J = 11.4 Hz, 1H), 4.41 (br d, J = 12.6 Hz, 1H), 4.30-4.17 (m, 2H), 3.69 (br d, J = 12.6 Hz, 1H), 3.60-3.51 (m, 3H), 3.31 (s, 1H), 3.19-3.14 (m, 1H), 3.08-3.01 (m, 1H), 2.73 (d, J = 12.1 Hz, 1H), 2.64-2.54 (m, 1H), 2.16 (dd, J = 6.3, 13.5 Hz, 1H), 2.07-1.98 (m, 1H), 1.91 (d, J = 13.5 Hz, 1H), 1.85-1.64 (m, 7H), 1.38-1.26 (m, 2H). Example 102 : 4-(4-(1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-( tetrahydro -2H- pyran -4- yl ) oxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol

LCMS (ESI): [M+H] ⁺ = 544.1. ¹ H NMR (400 MHz, CD ₃ OD) δ = 9.02 (br s, 1H), 8.53 (br s, 1H), 7.86 (dd, J = 5.7, 8.9 Hz, 1H), 7.43-7.26 (m, 2H), 7.21 (s, 1H), 5.45-5.34 (m, 1H), 4.75-4.61 (m, 2H), 4.09-3.93 (m, 4H), 3.85 (br d, J = 8.9 Hz, 2H), 3.65 (br t, J = 8.8 Hz, 2H), 3.38 (s, 1H), 2.14 (br d, J = 10.6 Hz, 2H), 2.08-1.91 (m, 4H), 1.85 (br dd, J = 3.4, 8.6 Hz, 2H). Example 103 : 1-(((4-((1R,5S)-3,8- diazabicyclo [3.2.1] oct -3- yl )-7-(8- ethynyl -7 - fluoro -3- hydroxynaphthalen -1- yl )-8- fluoropyridin [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) cyclopropane -1- carbonitrile

LCMS (ESI): [M+H] ⁺ = 539.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.06 (s, 1H), 8.52 (s, 1H), 7.89 (dd, J = 5.7, 9.2 Hz, 1H), 7.39-7.31 (m, 2H), 7.23 (d, J = 2.5 Hz, 1H), 4.78-4.69 (m, 2H), 4.57-4.52 (m, 2H), 3.96 (br s, 2H), 3.84 (br d, J = 13.0 Hz, 2H), 3.41-3.37 (m, 1H), 2.05-1.96 (m, 4H), 1.45-1.38 (m, 2H), 1.33-1.28 (m, 2H). Example 104 : 4-(4-(1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-(2,2,2 -trifluoroethoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl -6- fluoronaphthalen -2- ol

LCMS (ESI): [M+H] ⁺ = 542.0. ¹ H NMR (400 MHz, CH ₃ OD) δ ppm 9.07 (s, 1H), 7.87 (dd, J = 9.05, 5.8 Hz, 1H), 7.39-7.27 (m, 2 H), 7.22 (d, J = 2.6 Hz, 1H), 5.01 (q, J = 8.9 Hz, 2H), 4.71-4.57 (m, 2 H), 3.83-3.65 (m, 4H), 3.38 (s, 1H), 1.96-1.75 (m, 4H). Example 105 : 4-(4-(1R,5S)-3,8- diazabicyclo [3.2.1] octan -3- yl )-8- fluoro -2-( tetrahydro -2H- pyran -4- yl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol

LCMS (ESI): [M+H] ⁺ = 558.1. ¹ H NMR (400 MHz, CH ₃ OD) δ ppm 9.01 (s, 1H), 7.86 (dd, J = 9.0, 5.8 Hz, 1H), 7.41-7.27 (m, 2H), 7.21 (d, J = 2.1 Hz, 1H), 4.75-4.59 (m, 2H), 4.34 (br d, J = 5.4 Hz, 2H), 3.99 (br dd, J = 10.8, 3.7 Hz, 2H), 3.93-3.71 (m, 4H), 3.47 (br t, J = 11.2 Hz, 2H), 3.38 (s, 1H), 2.23-2.05 (m, 1H), 2.03-1.84 (m, 4H), 1.79 (br d, J = 12.5 Hz, 2H), 1.55-1.40 (m, 2H). Example 106 : 4-(2-((2- oxabicyclo [2.2.2] oct -4- yl ) methoxy )-4-((1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol

LCMS (ESI): [M+H] ⁺ = 584.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.91-7.84 (m, 1H), 7.37 (d, J = 2.4 Hz, 2H), 7.24-7.21 (m, 1H), 4.66-4.58 (m, 2H), 4.18 (d, J = 3.7 Hz, 2H), 3.90 (s, 2H), 3.83-3.80 (m, 1H), 3.75 (br s, 4H), 3.36-3.35 (m, 1H), 2.11-2.04 (m, 2H), 1.95-1.90 (m, 2H), 1.88-1.81 (m, 4H), 1.77-1.69 (m, 4H). Example 107 : 4-(2-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 556.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.04 (s, 1H), 7.88 (dd, J = 5.7, 9.0 Hz, 1H), 7.40-7.31 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H), 4.74 (br d, J = 3.1 Hz, 2H), 4.72-4.62 (m, 2H), 3.93 (br s, 2H), 3.88-3.77 (m, 4H), 3.38 (s, 1H), 3.00 (br s, 1H), 2.06-1.91 (m, 6H), 1.59 (br d, J = 4.8 Hz, 2H). Example 108 : 4-(((4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan -3- yl ) -7- (8- ethynyl- 7- fluoro -3- hydroxynaphthalen -1- yl )-8 -fluoropyridin [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) tetrahydro -2H- pyran -4- carbonitrile

LCMS (ESI): [M+H] ⁺ = 583.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.06 (s, 1H), 7.92-7.84 (m, 1H), 7.34 (s, 2H), 7.25-7.21 (m, 1H), 4.60 (s, 4H), 3.98 (br d, J = 1.8 Hz, 2H), 3.79-3.67 (m, 6H), 3.35-3.35 (m, 1H), 2.13-2.04 (m, 2H), 1.86 (br d, J = 15.6 Hz, 6H). Example 109 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3 -yl )-8- fluoro -2-((4-( trifluoromethyl ) tetrahydro -2H- pyran -4- yl ) methoxy ) pyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol

LCMS (ESI): [M+H] ⁺ = 626.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.05 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.24 (d, J = 2.5 Hz, 1H), 4.86 (br d, J = 3.3 Hz, 2H), 4.71-4.60 (m, 2H), 3.90 (br d, J = 12.0 Hz, 2H), 3.81-3.67 (m, 6H), 3.42-3.36 (m, 1H), 2.04-1.81 (m, 8H). Example 110 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3- yl )-8 - fluoro -2-( trans -3- hydroxycyclobutyl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl - 6- fluoronaphthalen -2- ol

LCMS (ESI): [M+H] ⁺ = 544.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.87 (dd, J = 5.7, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H), 4.69-4.59 (m, 2H), 4.49 (s, 2H), 4.48-4.39 (m, 1H), 3.72 (br d, J = 10.6 Hz, 4H), 3.37-3.36 (m, 1H), 2.78-2.67 (m, 1H), 2.30 (br d, J = 4.2 Hz, 2H), 2.17 (br s, 2H), 1.87 (br d, J = 17.2 Hz, 4H). Example 111 : 4-(2-((3- oxabicyclo [3.1.0] hex -6- yl ) methoxy )-4-((1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6 -fluoronaphthalen -2 - ol

LCMS (ESI): [M+H] ⁺ = 556.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 4.72-4.59 (m, 3H), 4.40 (d, J = 7.4 Hz, 1H), 4.07-4.00 (m, 1H), 3.97-3.86 (m, 2H), 3.84-3.69 (m, 5H), 3.43-3.37 (m, 1H), 1.99-1.76 (m, 6H), 1.55-1.26 (m, 1H). Example 112 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3- yl )-8 - fluoro -2-( cis -3- hydroxycyclobutyl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl - 6- fluoronaphthalen -2- ol

LCMS (ESI): [M+H] ⁺ = 544.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.39-7.29 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 4.70-4.59 (m, 2H), 4.49-4.41 (m, 2H), 4.15 (quin, J = 7.4 Hz, 1H), 3.84-3.68 (m, 4H), 3.39-3.35 (m, 1H), 2.53-2.42 (m, 2H), 2.37-2.24 (m, 1H), 1.98-1.78 (m, 6H). Example 113 ：4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

LCMS (ESI): [M+H] ⁺ = 583.5. Example 114 : 4- ( 2- ( bicyclo [2.2.2] octan -1 -ylmethoxy ) -4 -(( 1R,5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl ) -8 - fluoropyrido [4,3-d] pyrimidin -7- yl ) -5- ethynyl- 6- fluoronaphthalen -2 -ol

LCMS (ESI): [M+H] ⁺ = 582.5. Example 115 : 4-(4-(1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-((4- methoxybicyclo [2.2.2] oct -1 -yl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol

LCMS (ESI): [M+H] ⁺ = 612.6. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.01 (s, 1H), 7.88 (dd, J = 5.7, 9.2 Hz, 1H), 7.40-7.29 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 4.67-4.55 (m, 2H), 4.16-4.09 (m, 2H), 3.77-3.66 (m, 4H), 3.40-3.36 (m, 1H), 3.21 (s, 3H), 1.92-1.79 (m, 4H), 1.78-1.70 (m, 12H). Example 116 : 1-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : Under nitrogen atmosphere, 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (550 mg, 1.14 mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-cyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (670 mg, 1.48 mmol) were added to a mixed solution of toluene (20 mL) and water (5 mL), followed by cesium carbonate (1.1 g, 3.4 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (166 mg, 0.23 mmol). The mixture was stirred at 100 ^° C for 16 hours. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-15% gradient tetrahydrofuran/petroleum ether) to obtain a brown solid compound 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (565 mg, 0.78 mmol, yield 68%). LCMS (ESI): [M+H] ⁺ = 729.3.

Step 2 : To a solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg, 0.55 mmol) in tetrahydrofuran (8 mL) was added 4A molecular sieve (400 mg), sodium tert-butoxide (105 mg, 1.1 mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (155 mg, 1.1 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown solid compound 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (254 mg, 0.33 mmol, yield 60%). LCMS (ESI): [M+H] ⁺ = 770.2.

Step 3 : To a solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (244 mg, 0.32 mmol) in dimethylformamide (3 mL) was added cesium fluoride (385 mg, 2.53 mmol). The reaction was stirred at 20 ^° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown solid compound 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (140 mg, 0.23 mmol, yield 72%). LCMS (ESI): [M+H] ⁺ = 614.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.88 (s, 1H), 8.15-8.06 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.48-7.40 (m, 2H), 4.56 (br d, J = 13.6 Hz, 1H), 4.39-4.23 (m, 3H), 3.70-3.51 (m, 2H), 3.45-3.39 (m, 1H), 3.27-3.17 (m, 2H), 2.90-2.79 (m, 2H), 2.20-2.09 (m, 2H), 2.06-1.76 (m, 10H), 1.30 (s, 3H). Example 116A: (R)-1-((R)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol Example 116B: (R)-1-((S)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol,

Example 116 was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 40%; flow rate: 110 ml/min) to obtain the target compound.

Example 116A : SFC analysis (chromatographic column: ChiralCel OD-3, 150 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; phase B is maintained at 40%; flow rate: 2.5 ml/min): the elution position of the palmicular column is 3.754 min; LCMS (ESI): [M+H] ⁺ = 614.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.80 (d, J = 1.1 Hz, 1H), 8.08-7.87 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.40-7.27 (m, 2H), 4.53-4.39 (m, 3H), 4.21 (br d, J = 13.5 Hz, 1H), 3.51-3.42 (m, 2H), 3.41-3.34 (m, 2H), 3.33-3.24 (m, 1H), 3.03-2.94 (m, 2H), 2.19-2.06 (m, 3H), 2.05-1.84 (m, 6H), 1.79-1.65 (m, 3H), 1.19 (s, 3H).

Example 116B : SFC analysis (chromatographic column: ChiralCel OD-3, 150 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; phase B is maintained at 40%; flow rate: 2.5 ml/min): the elution position of the palmar column is 3.131 min; LCMS (ESI): [M+H] ⁺ = 614.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.84 (s, 1H), 8.10-7.91 (m, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.40-7.24 (m, 2H), 4.61-4.46 (m, 3H), 4.21 (br d, J = 13.4 Hz, 1H), 3.65-3.51 (m, 3H), 3.39-3.26 (m, 2H), 3.20-3.13 (m, 2H), 2.28-2.18 (m, 2H), 2.15-1.95 (m, 7H), 1.83-1.66 (m, 3H), 1.22 (s, 3H). Example 117 ： 1-(7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) quinazolin - 4- yl )-3- methylpiperidin -3- ol

Step 1 : To a solution of 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (20 mg, 0.032 mmol) in tetrahydrofuran (400 uL) was added 2-nitrobenzenesulfonylhydrazine (70.8 mg, 0.32 mmol) and triethylamine (45.4 uL, 0.32 mmol). The reaction was stirred at 20 ^° C for 16 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*2). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (7.00 mg, 11.3 umol, 35%). LCMS (ESI): [M+H] ⁺ = 618.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.10-8.84 (m, 1H), 8.07-7.88 (m, 2H), 7.54-7.36 (m, 2H), 7.23 (br s, 1H), 4.53 (br s, 1H), 4.45-4.20 (m, 3H), 3.83-3.54 (m, 1H), 3.48 (br s, 1H), 3.18 (br s, 1H), 3.00-2.61 (m, 3H), 2.48 (br s, 1H), 2.30-1.68 (m, 13H), 1.33 (br d, J = 15.2 Hz, 3H), 0.88 (br s, 3H).

Examples 118 and 119 , as well as Examples 127 to 131 , refer to the synthetic route of Example 116 , and react with different alcohols in the second step to prepare: Example 118 : 1-(7-(8- ethynyl -7- fluoronaphthyl -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 632.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.87 (br s, 1H), 8.17-8.01 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.47-7.37 (m, 2H), 5.45-5.23 (m, 1H), 4.82-4.68 (m, 1H), 4.66-4.15 (m, 6H), 3.68-3.45 (m, 1H), 3.50-3.37 (m, 2H), 3.16-3.03 (m, 1H), 2.47-2.13 (m, 4H), 2.11-2.00 (m, 2H), 1.99-1.72 (m, 4H), 1.30 (d, J = 7.6 Hz, 3H). Example 119 : 1-(2-(( trans -2,2- difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 676.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.87 (s, 1H), 8.14-8.05 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.48-7.39 (m, 2H), 4.54 (br d, J = 12.8 Hz, 1H), 4.42-4.34 (m, 2H), 4.28 (br d, J = 13.2 Hz, 1H), 3.64-3.53 (m, 2H), 3.41 (br t, J = 11.0 Hz, 1H), 3.32-3.26 (m, 1H), 3.20-3.16 (m, 1H), d, J = 12.1 Hz, 1H), 2.75-2.66 (m, 1H), 2.31-2.12 (m, 3H), 2.04 (br d, J = 13.9 Hz, 1H), 1.95-1.74 (m, 6H), 1.52-1.36 (m, 2H), 1.30 (s, 3H). Example 120 : (3R)-1-(7-(8- ethynyl-7-fluoronaphthalen- 1 - yl ) -8- fluoro -2-((2 -methyltetrahydro -1H- pyrrolizin -7a(5H)-yl ) methoxy ) -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 626.1; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.87 (br d, J = 3.4 Hz, 1H), 8.14-8.03 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.38 (m, 2H), 5.06 (br s, 2H), 4.58-4.18 (m, 4H), 3.89 (br d, J = 13.7 Hz, 1H), 3.66-3.35 (m, 4H), 2.85 (br d, J = 13.3 Hz, 2H), 2.56 (br d, J = 16.0 Hz, 1H), 2.26-1.69 (m, 9H), 1.29 (d, J = 7.6 Hz, 3H). Example 120A : (R)-1-((R)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((S)-2- methyltetrahydro -1H- pyrrole -7a(5H) -methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol, Example 120B: (R)-1-((S)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((S)-2- methyltetrahydro - 1H- pyrrole -7a(5H) -methoxy )-6- nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol , Example 120C: (R)-1-((R)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((R)-2- methyltetrahydro -1H- pyrrol -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol and Example 120D: (R)-1-((S)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((R)-2- methyltetrahydro -1H- pyrrol -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Example 120 : The target compound was obtained by SFC separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 45%; flow rate: 80 ml/min).

Example 120A : LCMS (ESI): [M+H] ⁺ = 626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 1.343 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.87 (s, 1H), 8.15-8.01 (m, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.50-7.36 (m, 2H), 5.03 (br s, 2H), 4.55-4.16 (m, 4H), 3.83 (br d, J = 14.2 Hz, 1H), 3.69-3.56 (m, 1H), 3.47-3.37 (m, 2H), 3.27-3.18 (m, 1H), 2.87-2.72 (m, 2H), 2.52 (br d, J = 15.3 Hz, 1H), 2.28-2.12 (m, 2H), 2.09-1.71 (m, 7H), 1.30 (s, 3H).

Example 120B : LCMS (ESI): [M+H] ⁺ = 626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 1.527 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.89 (s, 1H), 8.15-8.04 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 5.22-5.11 (m, 2H), 4.58-4.44 (m, 3H), 4.27 (br d, J = 13.5 Hz, 1H), 4.10 (br d, J = 13.8 Hz, 1H), 3.73-3.59 (m, 2H), 3.57-3.44 (m, 2H), 3.09-2.91 (m, 2H), 2.72-2.60 (m, 1H), 2.36-1.74 (m, 9H), 1.35-1.25 (m, 3H).

Example 120C : LCMS (ESI): [M+H] ⁺ = 626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 1.739 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.87 (s, 1H), 8.14-8.01 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 5.06 (br s, 2H), 4.55 (br d, J = 14.3 Hz, 1H), 4.45-4.24 (m, 3H), 3.89 (br d, J = 14.1 Hz, 1H), 3.63-3.34 (m, 4H), 2.86 (br d, J = 15.1 Hz, 2H), 2.56 (br d, J = 15.9 Hz, 1H), 2.29-1.72 (m, 9H), 1.29 (s, 3H).

Example 120D : LCMS (ESI): [M+H] ⁺ = 626.2; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 2.203 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.87 (s, 1H), 8.15-8.00 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.48-7.35 (m, 2H), 5.05 (br s, 2H), 4.54 (br d, J = 13.2 Hz, 1H), 4.45-4.23 (m, 3H), 3.94-3.83 (m, 1H), 3.63-3.36 (m, 4H), 3.16-3.12 (m, 1H), 2.91-2.78 (m, 2H), 2.55 (br d, J = 15.8 Hz, 1H), 2.29-2.12 (m, 2H), 2.12-1.71 (m, 6H), 1.29 (s, 3H). Example 121 : (3R)-1-(7-(8- ethynyl- 7- fluoronaphthyl -1 - yl )-8- fluoro -2-(-2-( fluoromethyl ) tetrahydro -1H- pyrroline -7a(5H) -methoxy )-6- nitroquinazolin- 4- yl )-3 -methylpiperidin -3- ol Example 122 : (3R)-1-(2-(2-( difluoromethyl ) tetrahydro -1H - pyrrol -7a(5H) -methoxy )-7-(8- ethynyl- 7- fluoronaphthyl -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : To a solution of potassium tert-butoxide (0.95 g, 8.52 mmol) in N,N-dimethylformamide (11 mL) at -50 ^° C, add a solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (1.0 g, 4.73 mmol) and 2-(difluoromethylsulfonyl)pyridine (0.82 g, 4.26 mmol) in N,N-dimethylformamide (5 mL). The mixture was slowly heated to 25 ^° C under nitrogen protection and stirred at 25 ^° C for 0.5 hours. Under ice bath, add saturated ammonium chloride solution (5 mL) and 2M hydrochloric acid (9 mL), add water (30 mL), extract with ethyl acetate (30 mL * 3), dry the combined organic phase with anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue is purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow oily compound 2-(difluoromethyl)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (250 mg, 1.02 mmol, yield 22%). LCMS (ESI): [M+H] ⁺ = 246.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.36 (br d, J = 14.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.75 (br d, J = 14.7 Hz, 1H), 3.13 (td, J = 1.3, 15.4 Hz, 1H), 2.90-2.73 (m, 1H), 2.63 (ddd, J = 2.0, 9.2, 13.2 Hz, 1H), 2.55-2.34 (m, 2H), 2.15 (td, J = 10.1, 13.2 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H).

Step 2 : At 0 ^o C, add 2-(difluoromethyl)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (100.0 mg, 0.41 mmol) in tetrahydrofuran (1 mL) to a solution of lithium aluminum tetrahydrate (15.5 mg, 0.41 mmol) in tetrahydrofuran (1 mL). Stir the mixture at 65 ^o C for 5 hours, add lithium aluminum tetrahydrate (7.7 mg, 0.20 mmol), and stir at 65 ^o C for 3 hours. Cool to 0 ^o C, add water (23 uL), 15% sodium hydroxide (23 uL), and water (69 uL). Dry with anhydrous sodium sulfate, filter, and spin dry the filtrate. A crude product mixture of (2-(difluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol and (2-(fluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (74.0 mg) was obtained as a yellow oily compound. LCMS (ESI): [M+H] ⁺ = 190.1 and 172.1.

Step 3 : To a solution of (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (229.7 mg, 0.40 mmol) and a mixture of (2-(difluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol and (2-(fluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (69.0 mg, 0.36 mmol) in tetrahydrofuran (2.3 mL) was added sodium tert-butoxide (70.1 mg, 0.73 mmol). The mixture was stirred at 25 ^° C for 3 hours under nitrogen protection. Water (6 mL) was added for dilution at 0 ^° C, and ethyl acetate (10 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified twice by preparative HPLC to obtain two compounds: Example 121 (3R)-1-(7-(8- ethynyl- 7- fluoronaphthyl -1- yl )-8- fluoro -2-(-2-( fluoromethyl ) tetrahydro -1H- pyrroline -7a(5H) -methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol ( 23.97 mg, 0.04 mmol, yield 10%, yellow solid). LCMS (ESI): [M+H] ⁺ = 644.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.90 (br s, 1H), 8.18-8.00 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.51-7.36 (m, 2H), 6.97-6.58 (m, 1H), 4.60-4.39 (m, 3H), 4.35-4.22 (m, 1H), 4.13-3.92 (m, 1H), 3.75-3.44 (m, 3H), 3.43-3.35 (m, 2H), 3.01-2.79 (m, 2H), 2.77-2.52 (m, 1H), 2.32-2.16 (m, 2H), 2.14-1.93 (m, 3H), 1.93-1.73 (m, 3H), 1.31 (d, J = 7.8 Hz, 3H).

Example 122 (3R)-1-(2-(2-( difluoromethyl ) tetrahydro -1H- pyrrole -7a(5H) -methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol ( 13.75 mg, 0.02 mmol, yield 6%, yellow solid). LCMS (ESI): [M+H] ⁺ = 662.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.88 (d, J = 7.3 Hz, 1H), 8.24-7.99 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51-7.31 (m, 2H), 4.59-4.45 (m, 1H), 4.44-4.35 (m, 1H), 4.35-4.18 (m, 2H), 3.83 (br d, J = 13.8 Hz, 1H), 3.70-3.39 (m, 4H), 3.23-3.13 (m, 1H), 2.89-2.70 (m, 2H), 2.88 (d, J = 7.3 Hz, 1H), 2.54 (br d, J = 15.8 Hz, 1H), 2.30-2.09 (m, 2H), 2.08-1.72 (m, 6H), 1.31 (d, J = 8.0 Hz, 3H). Example 123 : (3R)-1-(2-((2- cyclopropanetetrahydro -1H- pyrrolizine -7a(5H) yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : At 25 ^° C and nitrogen protection, sodium hydroxide (60% content, 378.73 mg, 9.47 mmol) was added in batches to a tetrahydrofuran solution (15 mL) of cyclopropyltriphenylphosphonium bromide (3.63 g, 9.47 mmol). After the reaction solution was stirred at 25 ^° C for 2 hours, 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (1.00 g, 4.73 mmol) and tri(3,6-dioxoheptyl)amine (153.13 mg, 473.45 umol) were slowly added to the reaction solution in sequence. After stirring the reaction solution at 25 ° C for 10 minutes, the temperature was raised to 62 ^° C and stirred at 62 ^° C for 18 hours. The reaction mixture was slowly added to saturated ammonium chloride (20 mL) for quenching, and then extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound 2-cyclopropyl-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (0.10 g, 425.03 umol, yield 8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.43-4.31 (m, 1H), 4.25-4.15 (m, 2H), 3.85-3.75 (m, 1H), 3.23-3.13 (m, 1H), 2.85-2.75 (m, 1H), 2.68-2.59 (m, 1H), 2.56-2.42 (m, 2H), 2.23-2.08 (m, 1H), 1.30-1.21 (m, 3H), 1.15-1.03 (m, 4H).

Step 2 : Under nitrogen atmosphere at 0 ^° C, lithium aluminum tetrahydride (83.9 mg, 2.21 mmol) was added to a solution of 2-cyclopropyl-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (130 mg, 0.55 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at 65 ^° C for 2 hours. After the solution was cooled to room temperature, it was quenched with water (84 uL), 15% sodium hydroxide solution (84 uL), and water (252 uL) in sequence. The suspension was dried over anhydrous sodium sulfate, stirred at 25 ^° C for 0.5 hours, and then filtered. The filtrate was concentrated to obtain a yellow oily compound (2-cyclopropanetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (95.0 mg, 0.530 mmol, yield 96%). LCMS (ESI): [M+H] ⁺ = 180.1

Step 3 : To a solution of (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.27 mmol) in tetrahydrofuran (2 mL) at 25 °C, sodium tert-butoxide (52.7 mg, 0.55 mmol) and (2-cyclopropenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (9.18 mg, 0.05 mmol) were added. The solution was stirred at 25 °C for 2 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 3), and the combined organic phases were dried, filtered, and the filtrate was rotary dried. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a brown solid compound (3R)-1-(2-(2-cyclopropyltetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.248 mmol, yield 90%). LCMS (ESI): [M+H] ⁺ = 808.3.

Step 4 : (3R)-1-(2-(2-cyclopropyltetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.19 mmol) was added to a solution of cesium fluoride (141 mg, 0.93 mmol) in dimethylformamide (2 mL) at 25 °C. The solution was stirred at 25 °C for 2 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) and preparative HPLC to give a yellow solid compound (3R)-1-(2-((2-cyclopropanetetrahydro-1H-pyrrolizine-7a(5H)yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (14.14 mg, 21.7 umol, yield 12%). LCMS (ESI): [M+H] ⁺ = 652.4. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.89 (br s, 1H), 8.15-8.04 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.47-7.38 (m, 2H), 4.60-4.44 (m, 3H), 4.33-4.21 (m, 1H), 4.09 (br d, J = 13.9 Hz, 1H), 3.73-3.54 (m, 2H), 3.52 (s, 2H), 2.98 (br d, J = 12.8 Hz, 2H), 2.76-2.65 (m, 1H), 2.32-1.72 (m, 9H), 1.30 (d, J = 6.8 Hz, 3H), 1.21-1.04 (m, 4H). Example 124 : (3R)-1-(2-((2,6- dimethyltetrahydro -1H- pyrrolizine -7a(5H) -yl ) methoxy )-7-(8- ethynyl-7- fluoronaphthalen - 1 - yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : Dissolve methyltriphenylphosphine bromide (20. g, 56.0 mmol) in tetrahydrofuran (75 mL), cool to 0 ^o C, add potassium tert-butoxide (1M tetrahydrofuran solution, 66.0 mL, 66.0 mmol) under nitrogen protection, and stir at 0 ^o C for 0.5 hours. Add a solution of 1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (11.3 g, 46.4 mmol) in tetrahydrofuran (150 mL) to the reaction solution, and stir the reaction solution at 20 ^o C for 16 hours. The reaction mixture was quenched by adding saturated ammonium chloride (100 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain a colorless oily compound 1-tert-butyl 2-methyl 4-methylpyrrolidine-1,2-dicarboxylate (5.80 g, 24.0 mmol, yield 50%). LCMS (ESI): [M+H-56] ⁺ = 186.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.02-4.87 (m, 2H), 4.49-4.27 (m, 1H), 4.00 (br d, J = 15.0 Hz, 2H), 3.71-3.61 (m, 3H), 2.97-2.82 (m, 1H), 2.62-2.50 (m, 1H), 1.43-1.32 (m, 9H).

Step 2 : Dissolve the compound 1-tert-butyl 2-methyl 4-methylpyrrolidine-1,2-dicarboxylate (5.80 g, 24.0 mmol) in tetrahydrofuran (75 mL), cool to -78 ^° C, add lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 48.0 mL, 48.0 mmol) under nitrogen, and stir at -78 ^° C for 1 hour. Add 3-chloro-2-(chloromethyl)prop-1-ene (7.51 g, 60.1 mmol) to the reaction solution, and stir the reaction solution at 20 ^° C for 16 hours. The reaction mixture was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain a colorless oily compound 1-tert-butyl 2-methyl 2-[2-(chloromethyl)prop-2-en-1-yl]-4-methylpyrrolidine-1,2-dicarboxylate (6.20 g, 20.6 mmol, yield 78%). LCMS (ESI): [M-56+H] ⁺ = 274.1.

Step 3 : Dissolve the compound 1-tert-butyl 2-methyl 2-[2-(chloromethyl)prop-2-en-1-yl]-4-methylpyrrolidine-1,2-dicarboxylate (6.20 g, 20.6 mmol) in dichloromethane (68 mL), add trifluoroacetic acid (23 mL, 309 mmol), and stir the reaction at 20 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), and triethylamine was added to make it alkaline. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound 2,6-dimethyltetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid methyl ester (3.50 g, 17.9 mmol, yield 87%). LCMS (ESI): [M+H] ⁺ = 194.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.98-4.88 (m, 4H), 3.83 (br d, J = 15.0 Hz, 2H), 3.70-3.67 (m, 3H), 3.23 (br dd, J = 1.8, 15.0 Hz, 2H), 2.95 (dd, J = 1.1, 16.6 Hz, 2H), 2.54 (dd, J = 1.8, 16.6 Hz, 2H).

Step 4 : Dissolve lithium aluminum tetrahydride (147 mg, 3.88 mmol) in tetrahydrofuran (4 mL), add 2,6-dimethyltetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid methyl ester (500 mg, 2.58 mmol) at 0 ^o C, and stir the reaction solution at 20 ^o C for 2 hours. Add water (147 uL), sodium hydroxide (15% aqueous solution, 147 uL), and water (147 uL*3) to the reaction solution for quenching, filter the mixture, and concentrate the filtrate under reduced pressure to obtain (2,6-dimethyltetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (250 mg, 1.50 mmol, yield 58%). LCMS (ESI): [M+H] ⁺ = 166.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.92-4.80 (m, 4H), 3.59 (dd, J = 0.8, 15.1 Hz, 2H), 3.24-3.13 (m, 4H), 2.50-2.41 (m, 2H), 2.38-2.29 (m, 2H).

Step 5 : Compound (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.14 mmol) and (2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (45 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL), sodium tert-butoxide (40 mg, 0.41 mmol) was added, and the mixture was stirred at 20 ^° C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product compound (3R)-1-(2-((2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg). LCMS (ESI): [M+H] ⁺ = 794.3.

Step 6 : Compound (3R)-1-(2-((2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.12 mmol) was added to N,N-dimethylformamide (2.0 mL), and cesium fluoride (352 mg, 2.32 mmol) was added, and the mixture was stirred at 20 ^° C for 1 hour. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (3R)-1-(2-((2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (8.10 mg, 12 umol, yield 10%). LCMS (ESI): [M+H] ⁺ = 638.5; ¹ H NMR (400MHz, CD ₃ OD) δ ppm 8.78 (d, J = 1.3 Hz, 1H), 8.06-7.93 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.39-7.28 (m, 2H), 4.97 (br d, J = 6.5 Hz, 4H), 4.44 (br d, J = 13.1 Hz, 1H), 4.37-4.27 (m, 2H), 4.19 (br d, J = 13.4 Hz, 1H), 3.77 (br d, J = 14.9 Hz, 2H), 3.53-3.43 (m, 2H), 3.39-3.28 (m, 3H), 2.81-2.70 (m, 2H), 2.54 (br d, J = 1 6.5 Hz, 2H), 2.17-2.02 (m, 1H), 1.81-1.62 (m, 3H), 1.21 (s, 3H). Example 125 : (3R)-1-(-(8- ethynyl- 7- fluoronaphthalen- 1- yl )-8 - fluoro- (2-(((1aR,6aR)-4- methylhexahydrocyclopropane [b] pyrrolizine -5a(3H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : Under nitrogen protection, cool the tetrahydrofuran (30 mL) solution of the compound 2-tert-butyl 3-ethyl (1R, 3R, 5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.50 g, 5.87 mmol) to -78 ^o C, add 91M lithium bis(trimethylsilyl)amide in tetrahydrofuran (10.0 mL, 10.0 mmol), and stir at -78 ^o C for 1 hour. Add 3-chloro-2-(chloromethyl)prop-1-ene (1.84 g, 14.7 mmol) to the reaction solution, and stir the reaction solution at 20 ^o C for 16 hours. The reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate (50 mL * 3), and 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, 0-10% gradient ethyl acetate/petroleum ether) to obtain a colorless oily compound 2-tert-butyl 3-ethyl (1R, 3R, 5R)-3-(2-(chloromethyl)allyl) 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20 g, 3.48 mmol, yield 59%). LCMS (ESI): [M-56+H] ⁺ = 288.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.36-5.27 (m, 1H), 5.09-5.03 (m, 1H), 4.20-4.09 (m, 1H), 4.07-3.95 (m, 3H), 3.32-3.05 (m, 2H), 2.59-2.34 (m, 2H), 2.12-2.03 (m, 1H), 1.40-1.35 (m, 9H), 1.26-1.18 (m, 3H), 0.97 (dq, J =2.6, 5.3 Hz, 1H), 0.83-0.60 (m, 2H).

Step 2 : Dissolve 2-tert-butyl 3-ethyl (1R,3R,5R)-3-(2-(chloromethyl)allyl) 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20 g, 3.48 mmol) in dichloromethane (17 mL), add trifluoroacetic acid (4 mL, 52 mmol), and stir the reaction at 20 ^° C for 16 hours. The reaction solution was concentrated under reduced pressure, and then diluted with dichloromethane (50 mL). The pH was adjusted to ＞ 7 by adding triethylamine, and the solution was concentrated under reduced pressure again to obtain the crude product compound (1R,5R)-3-(2-(chloromethyl)allyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (1.20 g) as a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 244.1.

Step 3 : Dissolve the compound (1R,5R)-3-(2-(chloromethyl)allyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (1.20 g, 4.92 mmol) in ethanol (12 mL), add potassium iodide (81.0 mg, 0.49 mmol) and potassium carbonate (2.00 g, 14.7 mmol) at 25 ^{° C} . C 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, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound (1aR, 6aR)-4-methylhexahydrocyclopropane [b] pyrrolizine-5a (3H) -carboxylic acid ethyl ester (0.60 g, two-step yield: 80%). LCMS (ESI): [M + H] ⁺ = 208.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.89-4.77 (m, 2H), 4.22-4.07 (m, 2H), 3.96 (br d, J = 4.3 Hz, 1H), 3.27 (dd, J = δ 5.1 (m, 2H), 1.81 (dd, J = 4.6, 13.1 Hz, 1H), 1.46-1.36 (m, 1H) , 1.20 (t, J = 7.1 Hz, 3H), 0.50-0.42 (m, 1H), 0.20 (ddd , J = 2.9, 4.0, 6.9 Hz, 1H).

Step 4 : Dissolve lithium aluminum tetrahydride (220 mg, 5.79 mmol) in tetrahydrofuran (6 mL), add (1aR,6aR)-4-methylhexahydrocyclopropane[b]pyrrolizine- ^5a (3H)-carboxylic acid ethyl ester (600 mg, 2.89 mmol) at 0 ° C, and stir the reaction solution at 20 ^° C for 2 hours. Water (220 uL), sodium hydroxide (15% aqueous solution, 220 uL), and water (220 uL*3) were added to the reaction solution for quenching, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product compound ((1aR, 6aR)-4-methylhexahydrocyclopropane [b] pyrrolizine-5a (3H) -yl) methanol (300 mg, 1.81 mmol, yield 62%). LCMS (ESI): [M+H] ⁺ = 166.2.

Step 5 : To a solution of compound (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.17 mmol) and ((1aR,6aR)-4-methylhexahydropropano[b]pyrrolizin-5a(3H)-yl)methanol (60 mg, 0.36 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (60 mg, 0.62 mmol) and stirred at 20 ^° C for 16 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound (3R)-1-(-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-(2-(((1aR,6aR)-4-methylhexahydrocyclopropane[b]pyrrolizine-5a(3H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (8.66 mg, 13 umol, yield 7%). LCMS (ESI): [M+H] ⁺ = 638.5; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.74 (d, J =1.4 Hz, 1H), 8.05-7.92 (m, 2H), 7.49 (t, J =7.7 Hz, 1H), 7.37-7.28 (m, 2H), 4.87 (br s, 2H), 4.41 (br d, J =13.1 Hz, 1H), 4.18-4.05 (m, 3H), 3.71 (br d, J =14.4 Hz, 1H), 3.54-3.43 (m, 3H), 3.34-3.25 (m, 1H), 2.71-2.65 (m, 1H), 2.59 (dt, J =2.7, 6.5 Hz, 1H), 2.52 (br d, J =15.4 Hz, 1H), 2.14-2.06 (m, 2H), 1.98-1.91 (m, 2H), 1.70 (br dd, J =3.7, 13.9 Hz, 2H), 1.60-1.54 (m, 1H), 1.18 (s, 3H), 0.71-0.63 (m, 1H), 0.45-0.37 (m, 1H). Example 126 : (3R)-1-(2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 640.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.89 (s, 1H), 8.14-8.05 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.49-7.38 (m, 2H), 4.58-4.46 (m, 3H), 4.35-4.22 (m, 1H), 3.71-3.45 (m, 2H), 3.44-3.34 (m, 2H), 3.23 (br s, 1H), 3.10 (br s, 1H), 3.00 (br d, J = 6.2 Hz, 1H), 2.31-1.72 (m, 10H), 1.35-1.25 (m, 3H), 0.78-0.69 (m, 2H), 0.68-0.55 (m, 2H). Example 126A : (R)-1-((R)-2-(((S) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H)-yl ) methoxy ) -7-(8- ethynyl- 7 - fluoronaphthalen -1- yl ) -8 - fluoro -6- nitroquinazolin -4- yl ) -3- methylpiperidin -3- ol Example 126B: (R)-1-((S)-2-(((S) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H)-yl ) methoxy ) -7-(8 -ethynyl -7- fluoronaphthalen -1- yl ) -8 - fluoro -6- nitroquinazolin -4- yl ) -3 -methylpiperidin -3- ol Example 126C: (R)-1-((R)-2-(((R) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl -7 - fluoronaphthalen -1- yl ) -8 - fluoro -6- nitroquinazolin -4- yl ) -3- methylpiperidin -3- ol Example 126D: (R)-1-((S)-2-(((R) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl - 7 - fluoronaphthalen - 1- yl ) -8- fluoro -6- nitroquinazolin -4- yl ) -3- methylpiperidin -3- ol

Example 126 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain three components: a mixture of isomers 1 and 2, optically pure isomers 3, and optically pure isomers 4. The mixture of isomers 1 and 2 was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/methanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain optically pure Example 126A and optically pure Example 126B .

Example 126A : LCMS (ESI): [M+H] ⁺ = 640.1; SFC analysis (column: Cellulose 2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/methanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 3.304 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.89 (d, J = 1.4 Hz, 1H), 8.15-8.02 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.50-7.35 (m, 2H), 4.62-4.48 (m, 3H), 4.27 (br d, J = 13.1 Hz, 3.69-3.60 (m, 1H), 3.52-3.33 (m, 4H), 3.15 (br d, J = 11.9 Hz, 1H), 3.05 (br d, J = 10.6 Hz, 1H), 2.34-1.98 (m, 7H), 1.93-1.72 (m, 3H), 1.37-1.24 (m, 3H), 0.82-0.59 (m, 4H).

Example 126B : LCMS (ESI): [M+H] ⁺ = 640.1; SFC analysis (column: Cellulose 2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/methanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the elution position of the palmar column is 4.369 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.89 (s, 1H), 8.14-8.00 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.49-7.35 (m, 2H), 4.64-4.50 (m, 3H), 4.26 (br d, J = 13.0 Hz, 1H), 3.64 (d, J = 13.4 Hz, 1H), 3.51-3.36 (m, 4H), 3.13-3.01 (m, 2H), 2.33-1.74 (m, 10H), 1.36-1.21 (m, 3H), 0.81-0.57 (m, 4H).

Example 126C : LCMS (ESI): [M+H] ⁺ = 640.2; SFC analysis (column: Chiralpak IC-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the elution position of the palmar column is 4.500 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.88 (s, 1H), 8.15-8.03 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.36 (m, 2H), 4.64-4.45 (m, 3H), 4.30 (br d, J = 13.4 Hz, 1H), 3.64-3.51 (m, 2H), 3.46-3.33 (m, 2H), 3.15 (br d, J = 9.1 Hz, 1H), 3.09-2.92 (m, 2H), 2.30-1.74 (m, 10H), 1.29 (s, 3H), 0.77-0.54 (m, 4H).

Example 126D : LCMS (ESI): [M+H] ⁺ = 640.2; SFC analysis (column: Chiralpak IC-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 5.555 min; ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.87 (s, 1H), 8.15-7.99 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.37 (m, 2H), 4.59-4.43 (m, 3H), 4.30 (br d, J = 13.2 Hz, 1H), 3.65-3.52 (m, 2H), 3.39 (br t, J = 13.3 Hz, 2H), 3.15 (br d, J = 10.9 Hz, 1H), 3.08-2.88 (m, 2H), 2.28-1.72 (m, 10H), 1.40 (s, 3H), 0.75-0.56 (m, 4H). Example 127A : Two stereoisomers of (R)-1-(7-((S) -8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-((1-( fluoroquinolinemethyl ) cyclopropyl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 127B : (R)-1-(7-((R)- 8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-((1-( fluoroquinolinemethyl ) cyclopropyl ) methoxy )-6 -nitroquinazolin -4- yl )-3- methylpiperidin -3 - ol

Example 127A (16.56 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.586 min; LCMS (ESI): [M+H] ⁺ = 644.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.89 (d, J = 1.2 Hz, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.49-7.39 (m, 2H), 4.49-4.41 (m, 3H), 4.20 (br d, J = 13.2 Hz, 1H), 3.68-3.61 (m, 5H), 3.52-3.40 (m, 2H), 2.55-2.47 (m, 4H), 2.44 (d, J = 2.8 Hz, 2H), 2.27-2.18 (m, 1H), 1.88 (br s, 1H), 1.85-1.78 (m, 2H), 1.32 (s, 3H), 0.75-0.68 (m, 2H), 0.53-0.46 (m, 2H).

Example 127B (20.17 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.607 min; LCMS (ESI): [M+H] ⁺ = 644.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.86 (d, J = 1.2 Hz, 1H), 8.14-8.05 (m, 2H), 7.60 3H), 3.54-3.81 (m, 2H) , 3.70-3.77 (m, 3H), 1.89-1.91 (m, 4H) , 1.30-1.53 (m, 3H) , 3.57-3.58 (m, 2H), 3.54-3.53 ( m, 3H), 3.70-3.71 (m, 2H), 3.57-3.58 (m, 3H), 3.57-3.58 (m, 2H), 3.57-3.58 (m, 3H), 3.57-3.58 (m, 2H), 0.54-0.48 (m, 2H). Example 128 : (3R)-1-(7-(8- ethynyl- 7 - fluoronaphthalen -1- yl )-8- fluoro -2-((1-((4- methylpiperazine -1- yl ) methyl ) cyclopropyl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 657.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.88 (d, J = 9.9 Hz, 1H), 8.19-8.02 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.50-7.34 (m, 2H), 4.76-4.20 (m, 5H), 3.72-3.34 (m, 4H), 2.78 (br s, 6H), 2.53 (br t, J = 6.1 Hz, 2H), 2.48 (br d, J = 2.4 Hz, 3H), 2.22 (br d, J = 10.8 Hz, 1H), 1.92-1.70 (m, 3H), 1.32 (d, J = 8.1 Hz, 3H), 0.75 (s, 2H), 0.53 (s, 2H). Example 129 : (3R)-1-(7-(8- ethynyl- 7- fluoronaphthyl- 1- yl )-8- fluoro -6- nitro -2-(((S)-1-(2,2,2- trifluoroethyl ) pyrrolidin -2- yl ) methoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 656.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.89 (d, J = 1.4 Hz, 1H), 8.16-8.04 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51-7.37 (m, 2H), 4.57-4.44 (m, 2H), 4.33-4.19 (m, 2H), 3.78-3.59 (m, 2H), 3.51-3.39 (m, 2H), 3.31-3.13 (m, 3H), 2.63-2.56 (m, 1H), 2.29-2.17 (m, 1H), 2.13-1.98 (m, 1H), 1.93-1.74 (m, 6H), 1.32 (s, 3H). Example 130 : (3R)-1-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-1 -methylpyrrolidin -2 - yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 588.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.92-8.85 (m, 1H), 8.15-8.01 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.50-7.39 (m, 2H), 4.68-4.48 (m, 3H), 4.35-4.23 (m, 1H), 3.67-3.37 (m, 3H), 3.30-3.21 (m, 1H), 2.80-2.64 (m, 4H), 2.29-2.14 (m, 2H), 2.02-1.75 (m, 6H), 1.36-1.26 (m, 3H). Example 131A : (R)-1-(7-((S) -8 -ethynyl- 7 -fluoronaphthyl- 1 -yl )-8 - fluoro -2-((3-( oxolinomethyl ) oxacyclobutan -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 131B : (R)-1-(7-((S) -8- ethynyl- 7 -fluoronaphthyl- 1- yl )-8- fluoro -2-((3-( oxolinomethyl ) oxacyclobutan -3- yl ) methoxy )-6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Example 131A (7.62 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.539 min; LCMS (ESI): [M+H] ⁺ = 660.2; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.91 (d, J = 1.3 Hz, 1H), 8.11 (dt, J = 6.6, 9.7 Hz, 7.7 Hz, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51-7.37 (m, 2H), 4.86-4.82 (m, 1H), 4.82-4.77 (m, 1H), 4.64 (dd, J = 4.2, 6.2 Hz, 2H), 4.60-4.56 (m, 2H), 4.51 (br d, J = 13.4 Hz, 1H), 4.24 (br d, J = 13.4 Hz, 1H), 3.70-3.57 (m, 5H), 3.54-3.41 (m, 2H), 2.85 (s, 2H), 2.51-2.34 (m, 4H), 2.31-2.17 (m, 1H), 1.95-1.76 (m, 3H), 1.33 (s, 3H).

Example 131B (7.91 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.565 min; LCMS (ESI): [M+H] ⁺ = 660.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.88 (d, J = 1.3 Hz, 1H), 8.19-7.99 (m, 2H), 7.60 (t, 7.7 Hz, 1H), 7.49-7.36 (m, 2H), 4.82 (s, 1H), 4.66-4.54 (m, 5H), 4.28 (br d, J = 13.4 Hz, 1H), 3.67-3.59 (m, 5H), 3.56 (s, 1H), 3.42 (br t, J = 11.0 Hz, 1H), 2.84 (s, 2H), 2.50-2.32 (m, 4H), 2.30-2.16 (m, 1H), 1.95-1.68 (m, 3H), 1.37-1.22 (m, 3H). Example 132A: (R)-1-(2-((1-((4,4 -difluoropiperidin -1 -yl ) methyl ) cyclopropyl ) methoxy )-7-((S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8 - fluoro -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol and Example 132B: (R)-1-(2-((1-((4,4 -difluoropiperidin -1 -yl ) methyl ) cyclopropyl ) methoxy )-7-((R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Example 132A : LCMS (ESI): [M+H] ⁺ = 678.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.94-8.83 (m, 1H), 8.17-8.05 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.36 (m, 2H), 4.54-4.15 (m, 4H), 3.63 (d, J = 13.4 Hz, 1H), 3.51-3.39 (m, 2H), 2.96-2.58 (m, 6H), 2.22 (d, J = 13.6 Hz, 1H), 2.05 (dt, J = 6.2, 13.2 Hz, 4H), 1.93-1.64 (m, 3H), 1.32 (s, 3H), 0.83-0.73 (m, 2H), 0.58 (s, 2H).

Example 132B : SFC analysis (chromatographic column: ChiralCel OD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; 2 min from 5% phase B to 40% phase B, keep 40% phase B for 1.2 min, and then keep 5% phase B for 0.8 min; flow rate: 4 ml/min): the peak position of the palmar column is 1.763 min. LCMS (ESI): [M+H] ⁺ = 678.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.85 (s, 1H), 8.15-8.06 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.41 (m, 2H), 4.53-4.22 (m, 4H), 3.64-3.52 (m, 2H), 3.44-3.37 (m, 1H), 2.76-2.48 (m, 6H), 2.23 (d, J = 13.0 Hz, 1H), 2.04-1.93 (m, 4H), 1.90-1.74 (m, 3H), 1.34-1.27 (m, 3H), 0.75 (s, 2H), 0.57-0.49 (m, 2H). Example 133 : (3R)-1-(7-(8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-((1-( piperidin -1- yl ) methyl ) cyclopropyl ) methoxy ) quinazolin -4- yl )-3 -methylpiperidin -3- ol carboxylate

LCMS (ESI): [M+H] ⁺ = 642.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.93-8.85 (m, 1H), 8.56 (s, 1H), 8.18-8.07 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.50-7.41 (m, 2H), 4.60-4.46 (m, 3H), 4.43-4.22 (m, 2H), 3.65-3.52 (m, 2H), 3.45-3.36 (m, 2H), 3.21-2.83 (m, 4H), 1.97-1.72 (m, 8H), 1.62 (br s, 2H), 1.33-1.29 (m, 3H), 0.91 (br s, 2H), 0.82-0.71 (m, 2H). Example 134 : (3R)-1-(2-((1-( dimethylamino ) methyl ) cyclopropyl ) methoxy )-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 602.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.93-8.87 (m, 1H), 8.15-8.07 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.49-7.40 (m, 2H), 4.57-4.37 (m, 3H), 4.32-4.20 (m, 1H), 3.67-3.58 (m, 1H), 3.50-3.37 (m, 2H), 2.72 (br s, 2H), 2.51 (br s, 6H), 2.22 (br d, J = 7.3 Hz, 1H), 1.92-1.77 (m, 3H), 1.34-1.29 (m, 3H), 0.82 (s, 2H), 0.64 (br s, 2H). Example 135 : 1-(7-(8- ethynyl - 7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-((1-( oxo-1-ylmethyl ) cyclopropyl ) methoxy )-6 -nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol

Step 1 ^: Add diisopropylethylamine (2.33 mL, 13.35 mmol) to a solution of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (1.40 g, 3.34 mmol) in trifluoroethanol (15 mL) at 25 °C. Stir the solution at 70 ^° C for 3 hours. Concentrate the solution and purify it by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a brown oily compound 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.29 g, 2.67 mmol, 80% yield). LCMS (ESI): [M+H] ⁺ = 485.1.

Step 2 ^: To a solution of 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.50 g, 1.03 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.80 g, 1.55 mmol) in toluene (20 mL) and water (5 mL) at 25 °C under nitrogen atmosphere was added cesium carbonate (1.01 g, 3.10 mmol) and (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate in dichloromethane (0.15 g, 4% ethanol). g, 0.21 mmol). The solution was stirred at 100 ^° C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether) to obtain a brown solid compound 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 (0.58 g, 0.62 mmol, yield 60%). LCMS (ESI): [M+H] ⁺ = 789.1.

Step 3 : To ^a solution of 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 (500 mg, 0.63 mmol) and (1-(morpholinomethyl)cyclopropyl)methanol (217 mg, 1.27 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (122 mg, 1.27 mmol) at 25 ° C. The solution was stirred at 25 ^° C for 2 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The organic layer was then dried and concentrated, and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(fluoromethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (540 mg, 0.50 mmol, yield 88%). LCMS (ESI): [M+H] ⁺ = 860.4.

Step 4 : To ^a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (500 mg, 0.58 mmol) in dimethylformamide (5 mL) at 25 °C was added cesium fluoride (883 mg, 5.81 mmol). The solution was stirred at 25 ^° C for 2 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (280 mg, 0.34 mmol, yield 58%). LCMS (ESI): [M+H] ⁺ = 704.2.

Step 5 : To ^a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (20 mg, 28.4 umol) in acetonitrile (200 uL) was added hydrogen chloride (4M in dioxane, 71 uL, 0.28 mmol) at 25 o C. The solution was stirred at 25 ^o C for 1 hour. The solution was concentrated and the residue was dispersed in acetonitrile (1 mL). The pH was adjusted to 8 by adding triethylamine. The solution was concentrated and purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(oxo-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (6.63 mg, 9.9 umol, yield 35%). [M+H] ⁺ = 660.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.84 (d, J = 10.3 Hz, 1H), 7.84 (dd, J = 5.8, 8.9 Hz, 1H), 7.36-7.25 (m, 2H), 7.00 (dd, J = 2.4, 10.6 Hz, 1H), 4.51-4.37 (m, 3H), 4.20 (br dd, J = 13.5, 19.9 Hz, 1H), 3.68-3.56 (m, 5H), 3.51-3.34 (m, 2H), 2.62-2.37 (m, 6H), 2.28-2.14 (m, 1H), 1.92-1.72 (m, 3H), 1.29 (d, J = 8.1 Hz, 3H), 0.75-0.67 (m, 2H), 0.53-0.44 (m, 2H). Example 136 : 1-(7-(8- ethyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8 - fluoro -2-((1-( fluoroquinolinemethyl ) cyclopropyl ) methoxy )-6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

^Step 1 : To a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 0.04 mmol) in tetrahydrofuran (100 uL) at 25 °C under nitrogen atmosphere, 2-nitrobenzenesulfonylhydrazine (47 mg, 0.21 mmol) and triethylamine (30 uL, 0.21 mmol) were added. The solution was stirred at 25 ^° C for 16 hours. The solution was diluted with water (500 uL) and extracted with ethyl acetate (500 uL * 3). The organic phase was dried, filtered, and the filtrate was rotary dried to obtain a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(oxo-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 38.1 umol, yield 89%). LCMS (ESI): [M+H] ⁺ = 708.4.

^Step 2 : To a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(phenolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 0.04 mmol) in acetonitrile (300 uL) at 25 °C was added hydrogen chloride (4 M in dioxane, 106 uL, 0.42 mmol). The solution was stirred at 25 ^° C for 1 hour. The solution was concentrated and then diluted with dichloromethane (1 mL) and its pH was adjusted to 8 by the addition of triethylamine. The solution was concentrated and purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(fluoroquinolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (4.95 mg, 7.1 umol, yield 17%). LCMS (ESI): [M+H] ⁺ = 664.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.93 (d, J = 16.8 Hz, 1H), 7.67 (dd, J = 5.9, 9.0 Hz, 1H), 7.30-7.21 (m, 2H), 6.85-6.78 (m, 1H), 4.50-4.40 (m, 3H), 4.28-4.16 (m, 1H), 3.66 (br t, J = 4.5 Hz, 4H), 3.63-3.53 (m, 1H), 3.51-3.40 (m, 1H), 2.60 (br s, 5H), 2.52 (br s, 2H), 2.40 (br s, 1H), 2.19 (br d, J = 8.4 Hz, 1H), 1.92-1.75 (m, 3H), 1.32 (d, J = 15.9 Hz, 3H), 0.83 (q, J = 7.4 Hz, 3H), 0.73 (s, 2H), 0.53 (s, 2H).

To a solution of (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (81 mg, 0.11 mmol) and cesium carbonate (541 mg, 1.66 mmol) was added (425 mg, 0.83 mmol) in toluene (12 mL) and water (3 mL). The solution was stirred at 100 ^° C for 16 hours. The reaction solution was spin dried and purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the crude product compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (290 mg) as a brown solid. [M+H] ⁺ = 848.4

Step 6 : At 25 ^° C, add cesium fluoride (771 mg, 5.07 mmol) to a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (430 mg, 0.51 mmol) in dimethylformamide (4300 uL). Stir the solution at 25 ^° C for 2 hours. The reaction solution was diluted with water (8 mL) and extracted with ethyl acetate (4 mL * 3). The combined organic layers were washed with brine (8 mL) and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown solid compound 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (300 mg, 0.36 mmol, yield 72%). [M+H] ⁺ = 692.3

Step 7 : To ^a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 43.37 umol) in acetonitrile (300 uL) was added hydrogen chloride (4M in dioxane, 109 uL, 0.436 mmol) at 25 °C and stirred for 2 hours. The solution was spun dry and diluted with dichloromethane (1 mL) and the pH was adjusted to 8 with triethylamine. The crude product was purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (formate salt, 5.66 mg, 8.57 umol, yield 20%). [M+H] ⁺ = 648.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.89 (s, 1H), 8.51 (s, 1H), 7.87 (dd, J = 6.2, 9.0 Hz, 1H), 7.38-7.29 (m, 2H), 7.02 (dd, J = 2.3, 8.9 Hz, 1H), 5.54-5.33 (m, 1H), 4.84-4.75 (m, 1H), 4.56-4.44 (m, 2H), 4.29 (br dd, J = 13.3, 19.7 Hz, 1H), 3.70-3.40 (m, 6H), 3.23 (br s, 1H), 2.57-1.74 (m, 10H), 1.32 (d, J = 7.0 Hz, 3H). Example 137 : 1-(7-(8- ethynyl- 7 - fluoro - 3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : At 0 ^o C, potassium nitrate (14.05 g, 138.98 mmol) was added in batches to a solution of 7-bromo-8-fluoro-1,3-dihydroquinazoline-2,4-dione (18.00 g, 69.49 mmol) in sulfuric acid (150 mL). The mixture was stirred at 0 ^o C for 1 hour, carefully poured into ice water (400 mL), filtered, and the filter cake was washed with water (100 mL * 3) and vacuum dried to obtain a brown solid compound 7-bromo-8-fluoro-6-nitro-1,3-dihydroquinazoline-2,4-dione (21.50 g, 63.64 mmol, yield 92%). LCMS (ESI): [M+H] ⁺ = 303.8

Step 2 : At 0 ^° C, diisopropylethylamine (3.45 mL, 19.74 mmol) was added to a toluene (30 mL) solution of 7-bromo-8-fluoro-6-nitro-1,3-dihydroquinazoline-2,4-dione (2.00 g, 6.58 mmol) and phosphorus oxychloride (4.89 mL, 52.63 mmol). The solution was stirred at 110 ^° C for 0.33 hours, and the plate showed that the reaction was complete. The solution was diluted with ethyl acetate (15 mL), and then ice (30 g) was added. The mixture was extracted with ethyl acetate (30 mL * 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.28 mmol, yield 80%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.56 (d, J = 2.0 Hz, 1H)

Step 3 : Add diisopropylethylamine (2.30 ^mL , 12.91 mmol) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.87 mmol) and 3-methylpiperidin-3-ol (0.89 g, 5.87 mmol) in dichloromethane (20 mL) at -40 ° C. Stir the mixture at -40 ^° C for 1 hour. Add water (20 ml) to the mixture and extract with dichloromethane (20 mL * 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid compound 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.28 g, 4.52 mmol, yield 77%). LCMS (ESI): [M+H] ⁺ = 420.9

Step 4 : To ^a suspension of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (750 mg, 1.49 mmol) and cesium carbonate (971 mg, 2.98 mmol) in dioxane (8 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (237 mg, 1.49 mmol) at 25 °C. The solution was stirred at 100 ^° C under nitrogen atmosphere for 16 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (490 mg, 0.90 mmol, yield 61%). LCMS (ESI): [M+H] ⁺ = 544.1

Step 5 : At 25 ^° C under nitrogen atmosphere, 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (300 mg, 0.55 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-1-yl) Example 138 were added to the mixture. ：1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol

Step 1 : Add diisopropylethylamine (2.30 mL, 12.91 ^mmol ) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.87 mmol) and 3-methylpiperidin-3-ol (0.89 g, 5.87 mmol) in dichloromethane (20 mL) at -40 ° C. Stir the mixture at -40 ^° C for 1 hour. Add water (20 ml) to the mixture and extract with dichloromethane (20 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product compound 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazoline-4-yl)-3-methylpiperidin-3-ol (2.28 g) as a brown solid. LCMS (ESI): [M+H] ⁺ = 420.9

Step 2 : Add diisopropylethylamine (3.33 mL, 19.06 ^mmol ) to a solution of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.00 g, 4.77 mmol) in trifluoroethanol (20 mL) at 25 °C. Stir the solution at 70 ^° C for 3 hours. Rotate the solution to dryness and purify by flash column chromatography (silica gel, petroleum ether/ethyl acetate = 0-40%) to obtain a yellow solid compound 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.82 g, 3.77 mmol, yield 79%). LCMS (ESI): [M+H] ⁺ = 483.1

Step 3 ^: To a solution of 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.80 g, 3.32 mmol) and 1-ethyl-2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl(1,3,2-dioxaborol-2-yl)) in toluene (400 uL) and water (100 uL) at 25 °C under nitrogen atmosphere, (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate dichloromethane (0.48 g, 0.66 mmol) and cesium carbonate (3.24 g, 9.96 mmol) were added. The solution was stirred at 100 ^° C for 16 hours. The reaction solution was rotary dried and purified by flash column chromatography (silica gel, petroleum ether/tetrahydrofuran = 0-30%) to obtain a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.10 g, 1.58 mmol, yield 48%). LCMS (ESI): [M+H] ⁺ = 637.3

Step 4 : To ^a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (500 mg, 0.79 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (125 mg, 0.79 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide at 25° C. The mixture was stirred at 25 ^° C for 16 hours. The mixture was rotary dried and purified by flash column chromatography to give a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (350 mg, 0.50 mmol, yield 64%). LCMS (ESI): [M+H] ⁺ = 696.3

Step 5 : To ^a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (350 mg, 0.50 mmol) in acetonitrile (4 mL) was added hydrogen chloride (4M in dioxane, 1.26 mL, 5.03 mmol) at 25 °C and stirred for 4 hours. The solution was spun dry and diluted with dichloromethane (4 mL) and the pH was adjusted to 8 with triethylamine. The crude product was purified by preparative HPLC to give a white solid compound 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.23 mmol, yield 46%). LCMS (ESI): [M+H] ⁺ = 652.3. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.00-8.91 (m, 1H), 8.52 (s, 1H), 7.68 (dd, J = 5.8, 9.1 Hz, 1H), 7.31-7.22 (m, 2H), 6.81 (dd, J = 2.6, 5.0 Hz, 1H), 5.44 (br s, 1H), 4.53-4.21 (m, 4H), 3.67-3.48 (m, 2H), 3.42 (br s, 3H), 3.14 (br s, 1H), 2.71-1.83 (m, 12H), 1.30 (s, 3H), 0.87-0.80 (m, 3H). Example 139 : 1-(7-(8- ethynyl- 7- fluoro -3- hydroxynaphthyl )-8- fluoro -6- nitro -2-(2,2,2 -trifluoroethoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol

LCMS (ESI): [M+H] ⁺ = 589.5. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.90 (dd, J = 1.4, 14.1 Hz, 1H), 7.87 (dd, J = 5.8, 9.1 Hz, 1H), 7.36-7.29 (m, 2H), 7.03 (dd, J = 2.4, 9.9 Hz, 1H), 5.06-4.97 (m, 2H), 4.63-4.51 (m, 1H), 4.30 (br dd, J = 13.4, 18.9 Hz, 1H), 3.68-3.58 (m, 1H), 3.51-3.36 (m, 2H), 2.24 (br d, J = 14.0 Hz, 1H), 1.93-1.74 (m, 3H), 1.32 (d, J = 8.6 Hz, 3H). Example 140A : (R)-1-(7-(S)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(4- methyltetrahydro -2H- pyran -4- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 140B : (R)-1-(7-(R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(4- methyltetrahydro -2H- pyran -4- yl ) methoxy )-6- nitroquinazolin - 4- yl )-3- methylpiperidin -3- ol

Example 140A : LCMS (ESI): [M+H] ⁺ = 603.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.89 (s, 1H), 8.23-8.02 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.54-7.30 (m, 2H), 4.47 (br d, J = 13.2 Hz, 1H), 4.40-4.15 (m, 3H), 3.85-3.58 (m, 5H), 3.54-3.41 (m, 2H), 2.31-2.16 (m, 1H), 1.94-1.68 (m, 5H), 1.48 (br d, J = 13.9 Hz, 2H), 1.32 (s, 3H), 1.21 (s, 3H).

Example 140B : LCMS (ESI): [M+H] ⁺ = 603.0. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.86 (s, 1H), 8.20-7.96 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.37 (m, 2H), 4.51 (br d, J = 13.6 Hz, 1H), 4.34-4.21 (m, 3H), 3.83-3.65 (m, 4H), 3.63-3.53 (m, 2H), 3.45-3.35 (m, 1H), 2.30-2.16 (m, 1H), 1.91-1.71 (m, 5H), 1.47 (br d, J = 13.9 Hz, 2H), 1.30 (s, 3H), 1.21 (s, 3H). Example 141A : (R)-1-(7-(S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -2-(4- hydroxymethyl ) bicyclo [2.2.2] octan -1- yl ) oxy )-6 -nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol Example 142B : (R)-1-(7-(R)-8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(4-( hydroxymethyl ) bicyclo [2.2.2] octan -1- yl ) oxy -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Example 141A : LCMS (ESI): [M+H] ⁺ = 629.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.88 (s, 1H), 8.22-8.00 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.49-7.31 (m, 2H), 4.45 (br d, J = 13.0 Hz, 1H), 4.24-4.05 (m, 3H), 3.63 (d, J = 13.2 Hz, 1H), 3.52-3.39 (m, 2H), 2.29-2.14 (m, 1H), 1.92-1.63 (m, 15H), 1.39-1.23 (m, 3H).

Example 142B : LCMS (ESI): [M+H] ⁺ = 629.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.84 (d, J = 0.9 Hz, 1H), 8.16-7.99 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.52-7.33 (m, 2H), 4.48 (br d, J = 13.2 Hz, 1H), 4.23 (br d, J = 13.4 Hz, 1H), 4.18-4.05 (m, 2H), 3.64-3.50 (m, 2H), 3.43-3.34 (m, 1H), 2.30-2.15 (m, 1H), 1.91-1.63 (m, 15H), 1.36-1.24 (m, 3H). Example 143A : (R)-1-(2-( Bicyclo [1.1.1] pentan -1 -ylmethoxy )-7-((S)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 143B : (R)-1-(2-( Bicyclo [1.1.1] pentan -1 -ylmethoxy )-7-((R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Example 143A : LCMS (ESI): [M+H] ⁺ = 571.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02-8.83 (m, 1H), 8.18-8.02 (m, 2H), 7.67-7.53 (m, 1H), 7.52-7.29 (m, 2H), 4.56-4.14 (m, 4H), 3.75-3.38 (m, 3H), 2.58-2.48 (m, 1H), 2.30-2.16 (m, 1H), 1.88 (s, 7H), 1.85-1.76 (m, 2H), 1.36-1.25 (m, 3H).

Example 143B : LCMS (ESI): [M+H] ⁺ = 571.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.02-8.81 (m, 1H), 8.24-7.99 (m, 2H), 7.66-7.52 (m, 1H), 7.48-7.30 (m, 2H), 4.58-4.14 (m, 4H), 3.66-3.36 (m, 3H), 2.57-2.50 (m, 1H), 2.27-2.13 (m, 1H), 1.87 (s, 7H), 1.83-1.73 (m, 2H), 1.28 (s, 3H). Example 144A : 4-(((7-((S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8 - fluoro -4-((R)-3 - hydroxy -3- methylpiperidin -1- yl )-6- nitroquinazolin -2- yl ) oxy ) methyl ) tetrahydro -2H- pyran -4- cyanoacetate Example 144B : 4-(((7-((R)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8 - fluoro -4-((R)-3- hydroxy -3- methylpiperidin -1- yl )-6- nitroquinazolin -2- yl ) oxy ) methyl ) tetrahydro -2H- pyran -4- cyanoacetate

Example 144A : LCMS (ESI): [M+H] ⁺ = 614.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.06-8.75 (m, 1H), 8.22-7.98 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51-7.25 (m, 2H), 4.68-4.50 (m, 3H), 4.25 (br d, J = 13.2 Hz, 1H), 4.09-3.96 (m, 2H), 3.81-3.58 (m, 3H), 3.54-3.39 (m, 2H), 2.31-1.75 (m, 8H), 1.32 (s, 3H).

Example 144B : LCMS (ESI): [M+H] ⁺ = 614.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.88 (d, J = 1.1 Hz, 1H), 8.17-7.99 (m, 2H), 7.64-7.55 (m, 1H), 7.48-7.32 (m, 2H), 4.64-4.49 (m, 3H), 4.34-4.20 (m, 1H), 4.08-3.95 (m, 2H), 3.79-3.66 (m, 2H), 3.63-3.51 (m, 2H), 3.46-3.37 (m, 1H), 2.33-1.71 (m, 8H), 1.36-1.23 (m, 3H). Example 145A : (R)-1-(7-(S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -2-(3- methyloxacyclobutane -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 145B : (R)-1-(7-(R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(3- methyloxacyclobutane -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3 - ol

Example 145A : LCMS (ESI): [M+H] ⁺ = 575.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.90 (d, J = 1.1 Hz, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.48-7.40 (m, 2H), 4.70 (dd, J = 3.1, 5.9 Hz, 2H), 4.65-4.50 (m, 3H), 4.47 (d, J = 5.9 Hz, 2H), 4.24 (br d, J = 13.2 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.51-3.41 (m, 2H), 2.29-2.16 (m, 1H), 1.94-1.77 (m, 3H), 1.47 (s, 3H), 1.32 (s, 3H).

Example 145B : LCMS (ESI): [M+H] ⁺ = 575.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.87 (s, 1H), 8.25-7.98 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.39 (m, 2H), 4.69 (d, J = 5.9 Hz, 2H), 4.59 (s, 2H), 4.53 (br d, J = 13.0 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 4.27 (br d, J = 13.4 Hz, 1H), 3.65-3.52 (m, 2H), 3.44-3.36 (m, 1H), 2.30-2.16 (m, 1H), 1.93-1.74 (m, 3H), 1.47 (s, 3H), 1.30 (s, 3H). Example 146A : (R)-1-(2-(4,4 -difluorocyclohexyl ) oxy )-7-((S)-8- ethynyl- 7 -fluoronaphthyl -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 146B : (R)-1-(2-(4,4 -difluorocyclohexyl ) oxy )-7-((R)-8- ethynyl- 7- fluoronaphthyl -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol

Example 146A : LCMS (ESI): [M+H] ⁺ = 609.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.05-8.76 (m, 1H), 8.21-7.98 (m, 2H), 7.68-7.53 (m, 1H), 7.49-7.35 (m, 2H), 5.47-5.29 (m, 1H), 4.56-4.43 (m, 1H), 4.31-4.15 (m, 1H), 3.69-3.59 (m, 1H), 3.52-3.39 (m, 2H), 2.32-1.75 (m, 12H), 1.31 (s, 3H).

Example 146B : LCMS (ESI): [M+H] ⁺ = 609.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.92-8.79 (m, 1H), 8.17-8.04 (m, 2H), 7.65-7.53 (m, 1H), 7.49-7.39 (m, 2H), 5.42-5.31 (m, 1H), 4.58-4.44 (m, 1H), 4.26 (br d, J = 13.2 Hz, 1H), 3.64-3.56 (m, 2H), 3.44-3.35 (m, 1H), 2.30-1.93 (m, 9H), 1.91-1.72 (m, 3H), 1.29 (s, 3H). Example 147A : (R)-1-(7-(S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -2-(3 -fluorooxocyclobutane -3 - yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 147B : (R)-1-(7-(R)-8- ethynyl- 7 -fluoronaphthalen -1 -yl )-8- fluoro - 2-(3 -fluorooxocyclobutane -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3 - ol

Example 147A : LCMS (ESI): [M+H] ⁺ = 579.0. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.98-8.75 (m, 1H), 8.26-7.95 (m, 2H), 7.67-7.54 (m, 1H), 7.52-7.35 (m, 2H), 4.89-4.76 (m, 6H), 4.58-4.46 (m, 1H), 4.31-4.22 (m, 1H), 3.69-3.57 (m, 1H), 3.51-3.39 (m, 2H), 2.37-2.11 (m, 1H), 2.00-1.69 (m, 3H), 1.41-1.22 (m, 3H).

Example 147B : LCMS (ESI): [M+H] ⁺ = 579.0. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.93-8.84 (m, 1H), 8.18-8.01 (m, 2H), 7.65-7.53 (m, 1H), 7.50-7.36 (m, 2H), 4.90-4.74 (m, 6H), 4.61-4.51 (m, 1H), 4.36-4.22 (m, 1H), 3.66-3.51 (m, 2H), 3.44-3.35 (m, 1H), 2.29-2.11 (m, 1H), 1.93-1.70 (m, 3H), 1.34-1.23 (m, 3H). Example 148A : (R)-1-(7-(S)-8- ethynyl- 7- fluoronaphthalen -1 -yl )-8- fluoro -2-(2- methoxy -2- methylpropoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 148B : (R)-1-(7-(R)-8- ethynyl- 7 -fluoronaphthalen -1 -yl )-8- fluoro -2-(2- methoxy -2- methylpropoxy )-6 -nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol

Example 148A : LCMS (ESI): [M+H] ⁺ = 577.0. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.08-8.80 (m, 1H), 8.33-7.95 (m, 2H), 7.72-7.58 (m, 1H), 7.53-7.36 (m, 2H), 4.54-4.33 (m, 3H), 4.22 (br d, J = 13.4 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.52-3.41 (m, 2H), 3.34-3.32 (m, 3H), 2.36-2.12 (m, 1H), 1.99-1.69 (m, 3H), 1.47-1.21 (m, 9H).

Example 148B : LCMS (ESI): [M+H] ⁺ = 577.1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.86 (d, J = 1.3 Hz, 1H), 8.17-7.97 (m, 2H), 7.63-7.36 (m, 3H), 4.56-4.15 (m, 4H), 3.65-3.50 (m, 2H), 3.44-3.35 (m, 1H), 3.31 (s, 3H), 2.37-2.10 (m, 1H), 1.91-1.69 (m, 3H), 1.42-1.16 (m, 9H).

Example 149 , Example 152 and Example 153 were prepared by referring to the synthetic route of Example 137 : Example 149 : 4-(7-(8- ethynyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizine -7a(5H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-6- methyl -1,4- oxazolidinone -6- ol

LCMS (ESI): [M+H] ⁺ = 664.5; 1H NMR (400 MHz, CD ₃ OD) δ ppm 9.27-9.17 (m, 1H), 7.75 (dd, J = 5.8, 9.1 Hz, 1H), 7.25-7.15 (m, 2H), 6.90 (d, J = 2.3 Hz, 1H), 5.31-5.09 (m, 1H), 4.46-4.35 (m, 2H), 4.26-4.08 (m, 3H), 3.99-3.72 (m, 3H), 3.66-3.55 (m, 2H), 3.35-3.23 (m, 1H), 3.20-3.09 (m, 3H), 2.92 (dt, J = 5.7, 9.4 Hz, 1H), 2.30-1.99 (m, 3H), 1.95-1.75 (m, 3H), 1.22 (s, 3H). Example 150 : 4-(7-(8- ethyl -7- fluoro -3 - hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H - pyrrolizin -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-6- methyl -1,4- oxazolidinone -6- ol Example 151 : 4-(8- fluoro -7-(7- fluoro -3- hydroxy -8- vinylnaphthalen -1- yl )-2-(((2R,7aS)- 2- Fluorotetrahydro -1H- pyrrolizin -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-6- methyl -1,4- oxazolocycloheptan - 6- ol

Embodiment 150 and embodiment 151 are prepared by referring to the synthetic route of embodiment 136 :

Example 150 : 4-(7-(8- ethyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-6 - methyl -1,4- oxazinecycloheptan- 6- ol (5.43 mg, 7 umol, yield 5%) was obtained as a yellow solid. LCMS (ESI): [M+H] ⁺ = 668.5; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.54-9.36 (m, 1H), 7.69 (dd, J = 5.9, 9.0 Hz, 1H), 7.32-7.21 (m, 2H), 6.87-6.79 (m, 1H), 5.41-5.21 (m, 1H), 4.58-4.47 (m, 2H), 4.38-4.17 (m, 3H), 4.09-3.82 (m, 3H), 3.72 (s, 2H), 3.28-3.16 (m, 2H), 3.08-2.99 (m, 1H), 2.72-2.57 (m, 1H), 2.45-2.31 (m, 2H), 2.31-2.08 (m, 3H), 2.05-1.86 (m, 3H), 1.37-1.30 (m, 3H), 0.89-0.77 (m, 3H).

Example 151 : 4-(8- fluoro -7-(7- fluoro -3- hydroxy -8- vinylnaphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-6 - methyl -1,4- oxazinecycloheptan -6- ol (2.29 mg, 3 umol, yield 2%) was obtained as a yellow solid. LCMS (ESI): [M+H] ⁺ = 666.5; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.43-9.11 (m, 1H), 7.82-7.59 (m, 1H), 7.25-7.10 (m, 2H), 6.90-6.76 (m, 1H), 6.10-5.89 (m, 1H), 5.41-4.86 (m, 3H), 4.41 (br dd, J = 4.9, 14.5 Hz, 2H), 4.28-4.05 (m, 3H), 3.97-3.69 (m, 3H), 3.60 (s, 2H), 3.19-3.02 (m, 3H), 2.98-2.85 (m, 1H), 2.29-1.99 (m, 3H), 1.94-1.73 (m, 3H), 1.25-1.17 (m, 3H). Example 152 6-(7-(8- ethynyl- 7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H))- yl ) methoxy )-6- nitroquinazolin -4- yl )-6- azaspiro [3.5] nonan -2- ol

LCMS (ESI): [M+H] ⁺ = 674.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.67 (s, 1H), 7.87 (br dd, J = 5.8, 8.9 Hz, 1H), 7.37-7.18 (m, 2H), 7.01 (s, 1H), 5.42-5.22 (m, 1H), 4.66-4.58 (m, 1H), 4.41-4.25 (m, 3H), 4.07-3.86 (m, 4H), 3.37 (br d, J = 3.9 Hz, 1H), 3.26 (br s, 1H), 3.24-3.18 (m, 1H), 3.04 (br s, 1H), 2.44-2.35 (m, 2H), 2.31-2.11 (m, 3H), 2.08-1.94 (m, 3H), 1.92-1.72 (m, 6H). Example 153 : 3- Chloro -5-(7-(8- ethynyl- 7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -6- nitro- 2-(( tetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) -quinazolin - 4- yl )-N,N -dimethyl -5,6,7,8- tetrahydro -4H- pyrazolo [1,5-a][1,4] diazocycloheptane -2- carboxamide

LCMS (ESI): [M+H] ⁺ = 757.3; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.65 (s, 1H), 7.87 (dd, J = 5.8, 9.1 Hz, 1H), 7.36-7.26 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 5.19 (s, 2H), 4.52-4.48 (m, 2H), 4.44-4.32 (m, 4H), 3.42 (s, 1H), 3.26-3.26 (m, 2H), 3.14 (d, J = 14.0 Hz, 6H), 2.91-2.82 (m, 2H), 2.54 (br d, J = 4.4 Hz, 2H), 2.17-2.08 (m, 2H), 1.98 (qt, J = 6.6, 13.6 Hz, 4H), 1.89-1.79 (m, 2H). Example 154 : 4-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizine -7a(5H) -yl ) methoxy ) quinazolin -4- yl )-1,4- oxazolidine cycloheptane

Step 1 : Add diisopropylethylamine (1.5 mL, 8.43 ^mmol ) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (500 mg, 1.47 mmol) and 1,4-oxazolidinone hydrochloride (141.3 mg, 1.03 mmol) in dichloromethane (10 mL) at -40 o C. Stir the mixture at -40 ^o C for 1 hour under nitrogen protection. Add water (20 mL), extract with dichloromethane (20 mL * 3), and dry the combined organic phases with anhydrous sodium sulfate, filter, and spin dry. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 4-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-1,4-oxazolidinone (330 mg, 0.81 mmol, yield 55%). LCMS (ESI): [M+H] ⁺ = 407.1.

Step 2 : Add diisopropylethylamine (568 uL, 3.25 mmol) to a solution of 4-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-1,4-oxazacycloheptane (330 mg, 0.81 mmol) in trifluoroethanol (3.3 mL). Stir the mixture at 70 ^° C for 3 hours under nitrogen protection and rotate to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 4-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazacycloheptane (340 mg, 0.73 mmol, yield 89%). LCMS (ESI): [M+H] ⁺ = 468.9.

Step 3 : In a glove box, cesium carbonate (250 mg, 0.77 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (37.3 mL) were added to a solution of 4-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazinecycloheptane (120 mg, 0.26 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (151 mg, 0.33 mmol) in toluene (4.8 mL) and water (1.2 mL). The mixture was stirred at 100 ^° C under nitrogen for 16 hours. Water (5 mL) was added for dilution, and ethyl acetate (10 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran/petroleum ether) to obtain a brown solid compound 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazacycloheptane (150 mg, 0.21 mmol, yield 82%). LCMS (ESI): [M+H] ⁺ = 715.3.

Step 4 : To a solution of 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazolidine cycloheptane (140 mg, 0.20 mmol) and (tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (55.0 mg, 0.39 mmol) in tetrahydrofuran (2.8 mL) was added sodium tert-butoxide (37.6 mg, 0.39 mmol). The mixture was stirred at 25 ^° C under nitrogen for 6 hours. The reaction mixture was cooled to 0 ^° C and diluted with water (3 mL). The mixture was extracted with ethyl acetate (3 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain the crude product 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazolidine cycloheptane (240 mg) as a brown oily liquid. LCMS (ESI): [M+H] ⁺ = 756.4.

Step 5 : To a solution of 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazinecycloheptane (230.0 mg, 0.20 mmol) in dimethylformamide (4.6 mL) was added cesium fluoride (192 mg, 3.04 mmol). The solution was stirred at 25 ^° C for 1 hour. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by preparative HPLC to give a yellow solid compound 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazolidine cycloheptane (55.0 mg, 0.09 mmol, yield 30%). LCMS (ESI): [M+H] ⁺ = 600.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.74 (s, 1H), 8.24 (dd, J = 6.2, 9.2 Hz, 1H), 8.17 (d, J = 7.3 Hz, 1H), 7.70-7.56 (m, 2H), 7.50 (d, J = 6.8 Hz, 1H), 4.24-4.15 (m, 3H), 4.14-4.09 (m, 2H), 4.07 (s, 2H), 3.97 (br t, J = 4.6 Hz, 2H), 3.86-3.72 (m, 2H), 2.98-2.90 (m, 2H), 2.60-2.53 (m, 2H), 2.14 (br d, J = 4.0 Hz, 2H), 1.95-1.85 (m, 2H), 1.85-1.69 (m, 4H), 1.58 (td, J = 7.4, 12.0 Hz, 2H). Example 155 : 5-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) quinazolin - 4- yl )-N,N -dimethyl -5,6,7,8- tetrahydro -4H- pyrazolo [1,5-a][1,4] diazocycloheptane -2- carboxamide

Example 155 prepared by the synthetic route: LCMS (ESI): [M+H] ⁺ = 707.5; ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.80 (s, 1H), 8.16-8.01 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.47-7.37 (m, 2H), 6.88 (s, 1H), 5.32-5.16 (m, 2H), 4.60 (br d, J = 4.4 Hz, 2H), 4.48-4.33 (m, 2H), 4.32-4.24 (m, 2H), 3.48 (s, 1H), 3.35 (s, 3H), 3.15-3.07 (m, 5H), 2.80-2.68 (m, 2H), 2.45 (br d, J = 5.1 Hz, 2H), 2.10-2.02 (m, 2H), 1.98-1.85 (m, 4H), 1.81-1.71 (m, 2H). Example 156 : (3R)-1-(7-(7,8 -difluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol

Step 1 : Add 1-bromo-2,3,4-trifluorobenzene (10.0 g, 47.40 mmol) and furan (20.4 mL, 284.39 mmol) to toluene (130 mL), cool to -15 ^° C, slowly add n-butyl lithium (2 M, 28.4 mL, 56.8 mmol) under nitrogen protection, stir the mixture at -15 ^° C for 30 minutes, then heat to 25 ^° C and stir for 16 hours. Quench the reaction mixture with water (100 mL) and filter. Extract the filtrate with ethyl acetate (50 mL*3). Dry the combined organic layers with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by flash column chromatography (C18, 0-65% gradient water/acetonitrile) to obtain a brown oily compound 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (2.00 g, 11.10 mmol, yield 23%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.12-7.03 (m, 2H), 6.98-6.90 (m, 1H), 6.84-6.73 (m, 1H), 5.99 (s, 1H), 5.73 (s, 1H).

Step 2 : Slowly add concentrated hydrochloric acid (10.2 mL, 122 mmol) to a solution of 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (1.80 g, 9.99 mmol) in ethanol (10.8 mL), and stir the mixture at 80 ^° C for 16 hours. Remove the solvent in vacuo, add saturated sodium bicarbonate to the residue (until pH > 7), add ethyl acetate (5 mL*3) for extraction, and dry the combined organic layers with anhydrous magnesium sulfate, filter and concentrate under reduced pressure to obtain a black solid compound 7,8-difluoronaphthalene-1-ol (1.70 g, 9.39 mmol, yield 94%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.64-7.56 (m, 1H), 7.42-7.35 (m, 2H), 7.02 (br d, J = 6.2 Hz, 1H), 6.76-6.54 (m, 1H)

Step 3 : 7,8-difluoronaphthalene-1-ol (500 mg, 2.78 mmol) and diisopropylethylamine (1.38 mL, 8.33 mmol) were added to dichloromethane (5 mL), and then trifluoromethanesulfonic anhydride (0.70 mL, 4.16 mmol) was slowly added dropwise at -40 ^° C. The mixture was stirred at -40 ^° C for 30 minutes. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain a yellow oily compound 7,8-difluoronaphthalene-1-yl trifluoromethanesulfonate (610 mg, 1.95 mmol, yield 70%). LCMS (ESI): [M+H] ⁺ = 313.0.

Step 4 : Under nitrogen protection, 7,8-difluoronaphthalen-1-yl trifluoromethanesulfonate (500 mg, 1.60 mmol), bis(xanthocyanol) borate (813 mg, 3.20 mmol) and potassium acetate (658 mg, 8.01 mmol) were added to N,N-dimethylformamide (5 mL), and then [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium (117 mg, 0.16 mmol) was added, and the mixture was stirred at 80 ^° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain a white solid compound 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (400 mg, 1.38 mmol, yield 86%). LCMS (ESI): [M+H] ⁺ = 291.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.87 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.61 (ddd, J = 1.6, 4.8, 9.0 Hz, 1H), 7.49 (dd, J = 6.9, 8.2 Hz, 1H), 7.40 - 7.30 (m, 1H), 1.47 (s, 12H).

Step 5 : 2-(7,8-Difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (135 mg, 0.46 mmol) and (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.31 mmol) were added to dioxane (3 mL). Under nitrogen protection, 1.3 M aqueous sodium carbonate solution (0.72 mL, 0.92 mmol) and tetrakis(triphenylphosphine)palladium (35.9 mg, 0.03 mmol) were added. The mixture was stirred at 100 ^° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to obtain a brown solid compound (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.26 mmol, yield 85%). LCMS (ESI): [M+H] ⁺ = 567.1.

Step 6 : Add (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (140 mg, 0.25 mmol) and (tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (69.8 mg, 0.49 mmol) to a tetrahydrofuran (2.80 mL) solution, then add sodium tert-butoxide (47.5 mg, 0.49 mmol) and stir at 25 ^° C for 6 hours. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (1 mL * 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain a yellow solid purified compound (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (formate, 21.3 mg, 0.25 mmol, yield 14%). LCMS (ESI): [M+H] ⁺ = 608.2. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.05-8.92 (m, 1H), 8.56 (s, 1H), 8.09 (br d, J = 8.4 Hz, 1H), 7.94-7.85 (m, 1H), 7.67-7.59 (m, 1H), 7.59-7.49 (m, 1H), 7.46-7.40 (m, 1H), 4.59-4.49 (m, 3H), 4.30 (br dd, J = 5.4, 13.3 Hz, 1H), 3.63 (dd, J = 13.4, 16.3 Hz, 1H), 3.51-3.40 (m, 3H), 3.14-3.02 (m, 2H), 2.24 (br dd, J = 6.5, 12.2 Hz, 3H), 2.15-2.04 (m, 4H), 2.03-1.95 (m, 2H), 1.93-1.77 (m, 3H), 1.33 (d, J = 8.6 Hz, 3H). Example 1 : AlphaLISA compound screening experiment

Experimental methods:

1. Prepare the assay buffer: Ingredients and final concentration of buffer 1: 25 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Triton X-100 Ingredients and final concentration of buffer 2: 25 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT

2. Experimental design and compound preparation: 1＞ Prepare compounds using ECHO555 automated plate reader, test concentration: the highest concentration of the compound is 10 uM or 1 uM, 3-fold dilution, 10 concentrations, 2 replicates for each concentration, 0.5% DMSO. 2＞ High signal control group (High control): 30 replicates, 0.5% DMSO, KRAS protein participates in the reaction, as 0% inhibition 3＞ Low signal control group (Low control): 30 replicates, 0.5% DMSO, no KRAS protein participates in the reaction, as 100% inhibition

3. Experimental steps:

a. KRAS-GDP protein experimental steps 1> Add 5 μl of KRAS solution prepared with 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 (40 nM initially, 5 nM after optimization) 5 nM, and incubate at room temperature for 1 hour. 2> Add 5 μl of SOS1 and GTP mixed solution prepared with buffer 2 to each well of the test plate. The final concentrations of the reaction are (250 nM and 625 μM initially) 50 nM and 125 μM, respectively, and incubate at room temperature for 1 hour. 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptor beads mixed solution prepared in buffer 2 to each well of the test plate, the final reaction concentration is 50 nM and 20 μg/ml, respectively, and incubate at room temperature for 1 hour. 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared in buffer 2 to each well of the test plate, the final reaction concentration is 20 μg/ml, and incubate at room temperature for 1 hour. 5> Read the signal value of the test plate using the EnVision enzyme label reader, the excitation wavelength is 680 nm, and the emission wavelength is 615 nm.

b. KRAS-GTP protein experimental steps 1> Mix the prepared protein solution with the SOS1-GTP mixed solution (the concentration is the same as that of GDP protein) at a volume ratio of 1:1, and pre-incubate at room temperature for 1 hour. 2> Add 10 μl of the mixed solution in 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. 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, and the final reaction concentrations are 50 nM and 20 μg/ml, respectively, and incubate at room temperature for 1 hour. 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final concentration of the reaction is 20 μg/ml. Incubate at room temperature for 1 hour. 5> Read the signal value of the test plate using the EnVision enzyme label reader. The excitation wavelength is 680 nm and the emission wavelength is 615 nm.

c. KRAS-GCP protein experimental steps 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, and incubate at room temperature for 1 hour. 2> Add 5 μl of buffer 2 to each well of the test plate, and incubate at room temperature for 1 hour. 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptor beads mixed solution prepared in buffer 2 to each well of the test plate, the final concentration of the reaction is 50 nM and 20 μg/ml, respectively, and incubate at room temperature for 1 hour. 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final reaction concentration is 20 μg/ml. Incubate at room temperature for 1 hour. 5> Read the signal value of the test plate using the EnVision enzyme label reader. The excitation wavelength is 680 nm and the emission wavelength is 615 nm.

4. Experimental data analysis: 1> Calculate the high control average and low control average based on the original data. 2> Calculate the inhibition rate of the compound sample well (Sample signal), the calculation formula is as follows: (High control average-Sample signal/High control average-Low control average)*100% 3> Use the four-parameter fitting model (log (inhibitor) vs. response -- Variable slope (four parameters)) in Graphpad Prism software to fit the concentration response curve of the compound and its inhibition rate on the experimental signal at different concentrations, and calculate the IC50 value of the compound. Experimental materials: Experimental reagents company Item No. 1M HEPES pH 7.5 TEKNOVA H1035 2M _MgCl2 Sigma 7786-30-3 Triton X-100 Aladdin 9002-93-1 DTT 1M Invitrogen P2325 GTP Thermo R0461 AlphaScreen GSH Donor beads PerkinElmer 6765301 AlphaLISA Nickel Acceptor beads PerkinElmer AL108M DMSO Sigma D2650 384-well opaque white plate PerkinElmer 6007290 His-tag-KRAS G12D WuXi AppTec In house SOS1 WuXi AppTec In house GST-tag-cRAF WuXi AppTec In house Sealing film Axygen PCR-AS-200 Experimental equipment: Instruments company Lab Water Purification Systems MILLIPORE Envision Multible Reader PerkinElmer ECHO555 Labcyte Centrifuge 5810R Eppendorf

Experimental results: The inhibitory effects of the compounds of the present invention on GDP, GTP, and GCP proteins of KRAS G12D are shown in Table 1. Table 1 Embodiment GDP-format IC50 (nM)/Binding assay GTP-format IC50 (nM)/Binding assay GCP-format IC50 (nM)/Binding assay 1 44.62 382 2 165.7 1599 4 126 ＞10000 5 59.95 589.2 6 15.08 130.2 7 15.4 62.17 8 17 64.67 9 156.7 251.1 10 5.79 4.27 ＞1000 11 29.27 ＞1000 ＞1000 12 13.85 ＞1000 ＞1000 13 6.82 26.09 ＞1000 14 15.96 11.75 ＞1000 15 178.6 ＞1000 ＞1000 17 ＞1000 ＞1000 ＞1000 18 59.36 3.32 ＞1000 19 6.53 72.72 739.1 20 1084 7687 ＞10000 twenty one 2.718 ＞10000 ＞10000 twenty two 2.24 4.1 ＞1000 twenty three 23.69 25.95 ＞1000 twenty four 2.6 2.12 ＞1000 25 2.2 3.48 ＞1000 26 7.58 9.17 ＞1000 27 1.8 2.74 ＞1000 28 ＞1000 ＞1000 ＞1000 29 12.02 17.86 ＞1000 30 12.47 99.02 31A 2.51 101.50 1333 31B 1.69 71.70 498.6 32 21.91 97.57 33A 1.85 34.26 167.2 33B 1.51 71.59 435.5 35 1.76 19.92 165.9 35A 0.90 1.72 296 35B 1.974 135 529.8 36 1.71 25.14 269 37 2.36 39.6 134.1 38 2.36 9.91 51 39 2.13 14.58 137 40A 1.12 2.82 18.79 40B 1.18 2.28 55.05 40C 0.89 1.76 7.64 40D 0.94 2.22 186 43 125.2 378.4 ＞1000 44 4.39 ＞1000 ＞1000 45 6.11 10.72 32.69 46 2.51 3.12 ＞1000 47 1.28 6.79 14.47 48A 633 ＞1000 ＞1000 48C 1.53 1.96 12.47 48D 1.13 2 36.06 49A 97.71 473.2 ＞1000 49B 569.7 ＞1000 ＞1000 49C 1.28 61.57 9.11 49D 1.15 34.14 36.71 50 7.75 11.75 ＞1000 51 8.6 ＞1000 ＞1000 52 8.62 11.25 ＞1000 53 3.18 6.04 250.2 54 4.72 8.36 ＞1000 55 2.82 3.64 706 56 2.21 3.48 ＞1000 57 3.28 2.73 ＞1000 58 6.61 8.61 1296 59 9.01 10.68 ＞1000 60 9.21 24.52 ＞1000 61 134.4 170.1 ＞1000 62 5.06 7.3 ＞1000 63 12.97 12.82 ＞1000 64 12.32 26.69 ＞1000 65 38.27 62.36 ＞1000 66 16.68 70.41 ＞1000 67 2.256 3.46 102.4 68 4.86 11.42 39.24 69 3.48 6.34 274.7 70 6.78 7.92 ＞1000 71 3.98 18.63 168.9 72 10.5 20.7 ＞1000 73 3.94 32.74 518.7 74 2.47 2.97 82 75 3.11 8.62 28.32 75A 43.6 68.05 829.3 75B 2.87 5.08 26.88 76 2.62 6.22 5.5 76A 70.96 100.5 ＞1000 76B 1.267 1.63 4.396 77 3.36 13.06 250.6 78 3.27 7.54 32.8 79 2.85 9.28 376.4 80 1.41 3.34 ＞1000 81 2.08 12.57 398.1 84 2.79 4.15 22.74 87A 149.3 177.6 ＞1000 87B 1.31 1.7 16.15 88A 206.2 308.2 ＞1000 88B 1.33 1.65 6.7 89C 1.12 1.8 18.57 89D 1.42 2.26 181 90B 1.15 1.59 4.95 90C 0.7 0.96 23.15 91B 0.8907 1.345 20.36 91C 1.07 1.499 142.5 94A 122.6 121.8 ＞1000 94B 1.32 2.14 69.7 95B 0.89 1.467 13.67 96B 186.6 196.1 19.38 96C 1.62 2.28 80.82 97C 1.69 1.81 22.23 98 2.701 3.778 36.71 99A 0.74 0.84 109.9 100 1.3 1.4 163.9 101 1.33 1.59 242.9 103 1.22 1.04 ＞1000 105 2.78 2.86 ＞1000 120C 2.02 2.62 204.7 126C 2.03 2.34 244 137 2.51 3.42 47.07 139 17 37 ＞1000 NT: not tested for effect Example 2 : ERK phosphorylation cell experiment

AGS_ERK protein phosphorylation detection

Day 1: AGS cells were seeded into 384-well cell culture plates and cultured overnight in a 37°C, 5% CO2 cell culture incubator.

The next day: Add the compound to the plate using Echo550 and continue to culture at 37°C in a 5% carbon dioxide cell culture incubator for 3 hours. Finally, the cell culture plate was fixed with paraformaldehyde, permeabilized with methanol, and sealed with sealing solution, and then the primary antibody mixture (rabbit anti pERK, mouse anti GAPDH) was added and incubated at 4°C overnight.

Day 3: Discard the primary antibody and add the secondary antibody mixture (goat anti rabbit 800CW, goat anti mouse 680RD) and incubate at room temperature in the dark. Finally, wash with PBST three times and centrifuge the cell culture plate upside down for 1 minute. Read the fluorescence signal value with Odyssey CLx.

ERK phosphorylation was calculated according to the following formula: Relative expression: (fluorescence signal ratio of compound – average value of positive control)/ (average value of negative control – average value of positive control) Negative control: DMSO Positive control: 10 μM Reference

XLFit 5.0 calculates the IC50 value according to the parameter formula: Y = Bottom + ( Top – Bottom ) / ( 1 + 10 ^ ( ( Log IC50 – X ) × HillSlope ) ) X: log value of compound concentration Y: average relative expression of p-ERK between duplicate wells

The inhibitory effects of the compounds of the present invention on pERK of AGS and AsPC-1 cells are shown in Table 2. Table 2 Embodiment AGS_IC50 (nM)/pERK assay AsPC-1_IC50 (nM)/pERK assay 1 7668 5967 2 4646 ＞10000 3 3074/2359 8208/6623 4 1074 3269 5 624 2173 6 67 1130 7 932.1 3546 8 48 426 9 ＞10000 ＞10000 13 7272 ＞10000 14 3396 7979 16 2459 4944 17 3687 NT 18 2457 ＞10000 19 1.8 3.97 20 ＞10000 ＞10000 twenty one 105 401 twenty two 90 447 twenty three 697 4059 twenty four 62 194 25 78 487 26 397 NT 27 133 348 28 5898 ＞10000 29 1011 2293 30 22.23/61.1/2.6/3.3 176.4/210.9/30/59 31A 7.5 154 31B 1.96 44 32 6.6 29 33A 1.6 8.4 33B 2.3 9.4 34 5.1 25 35 0.75 2.7 35A 0.52 2.5 35B 4.99 twenty four 36 1.5 6.7 37 7.4 43 38 16 61 39 51 297 40A 0.84 2.6 40B 1.8 8.6 40C 0.34 2.4 41 3013 ＞10000 42 15 NT 43 2189 2211 44 179 797 45 5.8 twenty four 47 6.7 14 48B 368 1127 48C 0.75 4.9 48D 7.3 37 49C 6.8 40 49D 20 153 51 6099 ＞10000 52 ＞10000 ＞10000 53 twenty four 178 54 168 638 55 109 427 56 73 161 57 637 2849 58 432 459 60 7690 ＞10000 61 1361 3342 66 ＞10000 NT 67 7.03 52 68 17 161 69 44 460 70 709 1925 71 1095 4194 72 2954 7333 73 750 2396 74 213 NT 75 2.8 17 75A 32 212 75B 1.3 9.9 76 2.8 15 76A 310 1508 76B 1.04 6.3 77 34 60 78 3.7 13 79 35 86 80 303 1249 81 8.2 9.4 82 twenty four 159 83 481 NT 84 25 NT 85 73 NT 86 125 NT 87 0.85 3.6 87A 55.6 NT 87B 0.4 1.1 88 0.3 2.1 88A 32.4 NT 88B 0.14 0.44 89 2.02 4.6 89A 1092 NT 89B 240 NT 89C 0.62 0.81 89D 4.54 NT 90 0.68 2.4 90A 170 NT 90B 0.18 0.45 90C 0.91 NT 91 3.01 12 91A 477.44 NT 91B 1.41 4.76 91C 5.62 NT 92 0.96 4.1 93 ＞10000 NT 94 4.2 14 94A 141 NT 94B 1.38 2.1 95 0.22 1.4 95A 27 NT 95B 0.25 0.59 96 12 33 96A 12.9 NT 96B 341 NT 96C 5.59 11 97 3.4 14 97A 229 NT 97B 8.2 NT 97C 0.87 2.8 98 15 NT 99 9.65 34.41 99A 5.9 twenty two 99B 258 532 100 13 34 101 30 65 101A 1819 1900 101B 883 1660 101C 8.6 19/15 101D 146 159 102 87 NT 103 89 NT 104 37 NT 105 20 NT 106 7.3 54 107 158 399 108 93 663 109 43 161 110 283 1511 111 54 378 112 706 4338 116 38/28/27 60/49/47 116A 18/17/14 63/42/33 116B 4145 9349 117 211 394 118 29 70 119A 401 802 119B 42 105 120 12 31 120A 1140 NT 120B 18 NT 120C 6.4 NT 120D twenty two NT 121 18 NT 122 58 NT 123 38 124 54 61 125 NT NT 126 twenty four 75 126A 2743 NT 126B 3360 NT 126C 11 NT 126D 82 NT 127A ＞10000 ＞10000 127B twenty four twenty one 128 78 188 129A ＞10000 ＞10000 129B ＞10000 ＞10000 130 137 106 131A ＞10000 ＞10000 131B 649 669 132A 2313 7874 132B 157 350 133 42 85 134 33 62 135 0.34 1.3 136 12 39 137 0.53 1.9 138 3.9 14 139 131 NT 140A 2001 NT 140B 2334 NT 141A ＞10000 NT 142B 3517 NT 143A ＞10000 NT 143B ＞10000 NT 144A ＞10000 NT 144B 736 NT 145A ＞10000 NT 145B 1246 NT 146A ＞10000 NT 146B ＞10000 NT 147A ＞10000 NT 147B 1069 NT 148A ＞10000 NT 148B 6513 NT 149 1.3 8.5 150 5.2 twenty four 151 3.4 15 152A 1.3 2.8 152B 1.3 2.7 153 12 132 154 178 133 155 16 79 156 182 296 NT: not tested for effect Example 3 : 3D cell proliferation assay

AGS , AsPC-1 Cellular 3D Proliferation experiment

The diluted test compound was added to a 384-well low-adhesion cell culture plate using a nanoliter pipetting system (LABCYTE, P-0200). After the cells were placed, the culture plate was placed in a 37°C, 5% CO ₂ constant temperature incubator. After the compound and cells were co-cultured for 5 days, CellTiter-Glo® 3D reagent was added and the luminescence value was read using an Envision multifunctional enzyme labeled reader (the light signal is proportional to the amount of ATP in the system, and the ATP content directly characterizes the number of live cells in the identification system). Finally, the IC50 (half-maximal inhibitory concentration) of the compound was obtained using the nonlinear fitting formula using the XLFIT software.

Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)× HillSlope)) X: log value of compound concentration Y: inhibition rate (%) Inhibition rate (%)=100× (negative control average value-compound reading)/ (negative control average value-positive control average value) Negative control: DMSO Positive control: Medium only

The inhibitory effects of the compounds of the present invention on 3D proliferation of AGS and AsPC-1 cells are shown in Table 3. Table 3 Embodiment AGS_IC50 (nM)/ 3D assay AsPC-1_IC50 (nM)/ 3D assay 2 8276.9 ＞10000 3 1959.3 ＞10000 4 875.12 3162.05 5 1997 8498 6 362.79 836 8 356.06 583.44 9 ＞10000 ＞10000 10 2581 6102 16 73.57 20 ＞10000 ＞10000 twenty one 442 1280 twenty four 221.44 442.15 30 5.13/14.07 52.52/78.09 31A 70.75 157.5 31B 23.03 52.35 32 34.81 103.89 33A 5.79 34.72 33B 6.33 20.1 34 7.63 68.59 35 2.28 4.89 35A 1.21 6.83 35B 14.37 83.07 36 5.07 16.3 37 24.4 231.9 38 26.8 154.7 39 173 862 40A 3.24 30.23 40B 7.9 92.55 40C 0.77 7.26 40D 5.44 36.08 42 14.04 45 52.98 324.9 46 247.81 1487.51 47 30.14 185.34 48C 7.75 22.63 49C 60.46 133.89 50 825.08 1718.3 52 ＞10000 53 38.43 59 381.21 3174.22 62 ＞10000 ＞10000 63 3569 ＞10000 67 21.58 74 256.82 75 10.4 49.2 76 6.94 37.72 76B 3.64 78 17.8 126.1 81 16.5 72.3 83 45.88 87B 1.04 10.54 88B 1.23 3.32 89C 0.94 2.02 90B 0.37 0.89 94B 3.07 11.33 96C 27.51 65.28 97C 9.23 16.17 116A 87 154 120 113 85 126 147 167 135 2.89 3.26 137 13.4 7.52 155 79 312 Table 4 Comparison of the activities of the compounds of the present invention and the compounds previously published Nitro series example number Structure GDP-format IC50 (nM)/Binding assay GTP-format IC50 (nM)/Binding assay GCP-format IC50 (nM)/Binding assay AGS_IC50 (nM)/pERK assay AsPC-1_IC50 (nM)/pERK assay AGS_IC50 (nM)/3D assay AsPC-1_IC50 (nM)/3D assay 45 6.11 10.72 32.69 5.8 twenty four 52.98 324.9 47 1.28 6.79 14.47 6.7 14 30.14 185.34 88 0.3 2.1 88B 1.33 1.65 6.7 0.14 0.44 1.23 3.32 48A 633 ＞1000 ＞1000 48B 368 1127 48C 1.53 1.96 12.47 0.75 4.9 7.75 22.63 48D 1.13 2 36.06 7.3 37 90 0.68 2.4 90A 170 90B 1.15 1.59 4.95 0.18 0.45 0.37 0.89 90C 0.7 0.96 23.15 0.91

Experimental conclusion: The compounds of the present invention have better activity than known compounds. Experimental Example 4. Pharmacokinetic study of the test compounds in CD-I mice after oral administration and intravenous injection

Objective: To test the pharmacokinetics of the compound in CD-I mice after oral and intravenous administration

Experimental procedures: The test compound was mixed with a 5% DMSO/40% PEG400/55% Water aqueous solution, vortexed and sonicated to prepare a 0.6 mg/mL clear solution (intravenous) or 3 mg/mL clear solution (oral), filtered through a microporous filter membrane and set aside. Male CD mice aged 6 to 8 weeks were selected and given a candidate compound solution by intravenous injection at a dose of approximately 3 mg/kg. The candidate compound solution was administered orally at a dose of approximately 60 mg/kg and 100 mpk. Whole blood was collected at a certain time and plasma was prepared. The drug concentration was analyzed by LC-MSMS method, and the pharmacokinetic parameters were calculated using WinNonlin (Phoenix ^TM , version 8.3) software. Table 5 : Intravenous (IV) PK data Intravenous injection Unit Example 48C/3mpk Example 101C/3mpk Example 116/ 3mpk Cl_obs mL/min/kg 134 71.1 54.8 T _1/2 h 9.3 12.3 3.33 AUC _last h*ng/mL 348 559 836 V _ss _obs L/kg 48.1 58.5 8.42 Table 6 : Oral (PO) PK data oral Unit Example 48C Embodiment 101C Embodiment 116 Embodiment 116 10mpk 100mpk 60mpk 100mpk T _1/2 h NA 8.36 2.51 3.06 _Tmax h 5.5 3 0.25 0.25 C _max ng/mL 15 520 2095 2210 AUC _last h*ng/mL 47.8 3878 8211 9547 F % 4.2 18.8 45.1 34.1

Experimental conclusion: The compound of the present invention has good oral bioavailability.

Claims (8)

A heterocyclic compound as shown in formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

wherein Ring K is an aromatic ring; ^X1 is CR ^X1 ; ^X2 is N; ^RX1 is _NO2 ; ^X3 is CH; ^R1 is a _C6 - _C14 aryl group or a C6- _C14 aryl group substituted by one or more ^R1-1s ; ^R1-1s are each independently a halogen, OH, CN, _NO2 , a _C1 - _C6 alkyl group, a _C2 - _C6 alkenyl group or a _C2 - _C6 alkynyl group; R ^a and R ^b are each independently a hydrogen or a _C1 - _C6 alkyl group; ^R2 is H, a halogen, _{a C1} - _C6 alkyl group, ORa, ^a cyano group, a nitro ^group or ^-NRaRb ; _L2 is -O-( _C1 - _C6 alkylene group); ^R3 is

,

or

; Ring A is a C ₃ -C ₈ aliphatic carbon ring substituted by one or more halogens; R ⁴ is

or

; R ^4-1 is H or C ₁ -C ₆ alkyl. The heterocyclic compound as shown in formula I-0 as described in claim 1, its pharmaceutically acceptable salt or stereoisomer thereof, characterized in that ring K is an aromatic ring; ^X1 is CR ^X1 , ^RX1 is _NO2 ; ^X2 is N; ^X3 is CH; ^R1 is a _C6 - _C14 aryl group or a C6- _C14 aryl group substituted by one or more ^R1-1 ; ^R1-1 is each independently a halogen, OH, CN, a _{C1 -C6 alkyl} group or a _C2 - _C6 alkynyl group, ^R2 is a halogen, a _C1 - _C6 alkyl group or a _C1 - _C6 alkoxy group; _L2 represents -O-( _C1 - _C6 alkylene group); ^R3 is

,

,

; Ring A is a C ₃ -C ₈ aliphatic carbon ring substituted by one or more halogens; R ⁴ is

; wherein R ^4-1 is H or C ₁ -C ₆ alkyl. The heterocyclic compound of formula I-0 as described in claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer thereof is characterized in that it satisfies one or more of the following conditions: (1) R ¹ is a C ₆ ~C ₁₄ aryl group substituted by one or more R ^1-1 ; R ^1-1 is each independently a halogen, OH, a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkynyl group; (2) R ² is a halogen. The heterocyclic compound of formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1 is characterized in that it satisfies one or more of the following conditions: (1) in R ¹ , the C ₆ to C ₁₄ aryl groups are independently

,

(2) In R ^1-1 , the halogen is independently F or Cl; (3) In R ^1-1 , the C ₁ -C ₆ alkyl is independently methyl or ethyl; (4) In R ² , the halogen is F; (5) In R ² , the C ₁ -C ₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; (6) In L ₂ , the C ₁ -C ₆ alkylene is methylene; (7) In the definition of R ³ , the C ₃ -C ₈ aliphatic carbon ring is independently cyclopropane; (8) In the definition of R ³ , the halogen is F; (9) In R ^4-1 , the C ₁ -C ₆ alkylene is methyl. The heterocyclic compound of formula I-0, its pharmaceutically acceptable salt or its stereoisomer as described in claim 4 is characterized in that, in the definition of R ³ , the C ₃ -C ₈ aliphatic carbon ring is independently

or

The heterocyclic compound of formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1 is characterized in that it satisfies one or more of the following conditions: (1) R ¹ is

,

,

,

,

,

(2) R ² is F; (3) When R ³ is

,

,

,

,

,

,

,

,

or

When ^R4 is

,

or

. The heterocyclic compound of formula I-0, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1, is characterized in that the heterocyclic compound of formula I-0 is any of the following compounds,

A pharmaceutical composition comprising: (1) a heterocyclic compound as described in any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and (2) a pharmaceutically acceptable adjuvant.