TW202417455A - Novel triheterocyclic compounds and pharmaceutical composition - Google Patents

Abstract

Provided are triheterocyclic compounds, and more specifically triheterocyclic compounds useful as KRAS protein inhibitors, and a pharmaceutical composition including the same for treating cancers.

Description

New tricyclic compounds

The present disclosure relates to novel tricyclic compounds, and more particularly to novel tricyclic compounds that can be used as inhibitors of Hirsten rat sarcoma viral oncogene homolog protein and a pharmaceutical composition containing the tricyclic compounds for treating cancer.

The rat sarcoma (RAS) gene is responsible for signal transduction within the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) pathways and is known as an oncogene due to its frequent mutations. The RAS gene family is divided into Kirsten Rat Sarcoma Virus Oncogene Homolog (KRAS), Neuroblastoma RAS Virus Oncogene Homolog (NRAS) and Harvey Rat Sarcoma Virus Oncogene Homolog (HRAS), wherein the three genes encode four proteins, namely splice variants K-Ras4A, K-Ras4B, N-Ras and H-Ras. K-Ras is the most frequently mutated isoform in Ras-induced cancers (86%), followed by N-Ras (11%) and H-Ras (3%) (Non-patent document 1). For example, oncogenic mutations of KRAS are observed in 15.95% of cancers, including pancreatic cancer, lung cancer, colon cancer, colorectal cancer, and rectal cancer (Non-patent Document 2).

Gain-of-function missense mutations, mainly located at codons 12, 13, and 61, constitutively activate RAS proteins and have been detected in various types of human cancers. 98% of tumor Ras mutations are found in the active site amino acid residues G12, G13, and Q61, and these mutations impair intrinsic guanosine triphosphate (GTP) hydrolysis mediated by GTPase-activating protein (GAP) and abnormally activate downstream signaling (Non-patent document 3). K-Ras G12 mutations (89%) dominate human cancers, followed by G13 mutations (9%) and Q61 mutations (1%). Codon 12 mutations include codon 12 Gly→Asp (G12D) (36%), codon 12 Gly→Val (G12V) (23%), and codon 12 Gly→Cys (G12C) (14%), and G12D is the most common mutation among codon 12 mutations. In addition, mutations at codon 13 Gly→Asp (G13D) (7%) and codon 61 Gln→His (Q61H) (0.6%) were also observed (Non-patent Document 1).

The well-known role of KRAS in malignant tumors and reports of KRAS mutations in various tumor types suggest that KRAS may be a highly effective target for cancer treatment. The inventors have developed a novel KRAS inhibitor to accomplish the present invention. [Prior Technical Documents] (Non-patent Document 1) Scientific Reports 6 (1):21949 (Non-patent Document 2) J Cancer Metastasis Treat 2021 ;7:26 (Non- patent Document 3) Cancer Biol Ther. 2006 Aug;5(8):928-932

[Technical Problem] Provide novel tricyclic compounds with KRAS protein inhibitory activity. The present disclosure relates to: novel tricyclic compounds; stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the tricyclic compounds; and a pharmaceutical composition for treating cancer comprising the tricyclic compounds and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the tricyclic compounds. [Technical Solution]

According to one aspect of the embodiment, a compound is provided, wherein the compound is selected from the compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1.

According to one aspect of another embodiment, a pharmaceutical composition is provided, comprising a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1. [Beneficial Effects]

The present disclosure relates to novel tricyclic compounds that can be used as KRAS protein inhibitors and stereoisomers, non-mirror image isomers, mirror image isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the tricyclic compounds, as well as a pharmaceutical composition for treating cancer comprising the tricyclic compounds and stereoisomers, non-mirror image isomers, mirror image isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the tricyclic compounds.

Hereinafter, the present disclosure will be described in more detail.

Unless otherwise defined, all technical terms used in this disclosure are used with the same meanings as those commonly understood by those skilled in the art associated with this disclosure. In addition, although preferred methods or samples are described in this specification, methods or samples similar or equivalent thereto are also included in the scope of this disclosure.

In addition, unless expressly stated otherwise, the numerical values described herein should be construed as including the meaning of "about". All publications disclosed herein as references are incorporated by reference in their entirety.

According to one aspect of the embodiment, a compound is provided, wherein the compound is selected from the compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1. [Formula 1]

In Formula 1, X is N or CR ¹¹ ; R ¹ is phenyl which may be substituted by R ^1A , naphthyl which may be substituted by R ^1A , or benzothiophenyl which may be substituted by R ^1A ; each R ^1A is independently selected from hydrogen, hydroxyl, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ , and CN; R ² is hydrogen or halogen; R ³ is hydrogen, -OLW, or ; L is a bond or a C ₁ -C ₃ alkylene group which is substituted or unsubstituted by ^LA ; ^LA is hydrogen, halogen or C ₁ -C ₃ alkyl; W is a C ₁ -C ₃ alkyl group which is substituted or unsubstituted by R ⁶ , a 3- to 10-membered monocyclic heterocyclic ring which is substituted or unsubstituted by R ⁶ , or a 6- to 14-membered bicyclic heterocyclic ring which is substituted or unsubstituted by R ⁶ ; each R ⁶ is independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, amine, CN, =CH ₂ , pendoxy (=O), S(C ₁ -C ₃ alkyl), SO ₂ NH ₂ , SO ₂ NH(C ₁ -C ₃ alkyl), SO ₂ (C ₁ -C ₃ alkyl), SO ₂ (C ₁ -C ₃ halogenated alkyl), or halogenated C ₁ -C ₃ alkoxy; R ⁴ is hydrogen, C ₁ -C ₆ halogenated alkyl substituted or unsubstituted by R ^4A , C ₁ -C ₆ alkyl substituted or unsubstituted by R ^4A , C ₃ -C ₁₀ cycloalkyl substituted or unsubstituted by R ^4A , C ₅ -C ₈ aryl substituted or unsubstituted by R 4A, 3- to 10-membered heterocyclic substituted or unsubstituted ^by R ^4A , or 5- to 10-membered heteroaryl substituted or unsubstituted by R ^4A ; each R ^4A is independently selected from hydrogen, CN, NR ⁹ R ¹⁰ , =O, OR ⁷ , SR ⁸ , SO ₂ R ⁸ , C(O)N(R ⁷ ) ₂ , C(O)R ⁷ , C ₁ -C ₆ halogenated alkyl substituted or unsubstituted by R ^4B , C ₁ -C ₆ alkyl substituted or unsubstituted by R ^4B , C ₃ -C ₁₀ cycloalkyl substituted or unsubstituted by R ^4B , C ₅ -C ₈ aryl substituted or unsubstituted by R ^4B , 3 to 6 membered heterocyclic ring substituted or unsubstituted by R ^4B , and 5 to 9 membered heteroaryl substituted or unsubstituted by R ^4B ; wherein two of R ^4A together form C ₃ -C ₁₀ cycloalkyl substituted or unsubstituted by R ^4B , C ₅ -C ₈ aryl substituted or unsubstituted by R ^4B , 3 to 10 membered heterocyclic ring substituted or unsubstituted by R ^{4B, or 5 to 9 membered heteroaryl substituted or unsubstituted by R 4B} . R ^{4B is} independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl _, CN, NR ⁹ R ¹⁰ , =O, C 1 -C 3 alkoxy, halogenated C ₁ -C ₃ alkoxy, hydroxy, SCH ₃ , SO ₂ NH ₂ , SO ₂ CH ₃ , C(O)NH ₂ , C(O)CH ₃ , 3- to 6-membered heterocyclic, C ₅ -C ₈ aryl, and 5- or 6-membered heteroaryl; each R ⁵ is independently selected from hydrogen, _hydroxy , halogen, C ₁ -C ₃ halogenated alkyl and C ₁ -C ₃ alkyl, each R ^R7 is independently selected from hydrogen, amino, _C1 - _C3 halogenated alkyl, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, and 3- or 4-membered heterocyclic ring; each ^R8 is independently selected from hydrogen, amino and _C1 - _C3 alkyl; ^R9 and ^R10 are each independently selected from hydrogen, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, C(O) _NH2 , C(O) _CH3 , and 3- to 6-membered heterocyclic ring; each ^R11 is independently selected from hydrogen, hydroxyl, halogen, _C1 - _C3 halogenated alkyl and _C1 - _C3 alkyl, n is an integer selected from 0 to 2; and wherein the heterocyclic group or the heteroaryl group each contains 1 to 3 heteroatoms independently selected from N, O and S.

In an embodiment, L is methylene; W is a 3- to 10-membered monocyclic heterocycle which is unsubstituted or substituted by R ⁶ , or a 6- to 14-membered bicyclic heterocycle which is unsubstituted or substituted by R ⁶ ; and each R ⁶ is independently selected from halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CN, =CH ₂ , =O, SCH ₃ , SO ₂ NH ₂ , SO ₂ NH(CH ₃ ), SO ₂ CH ₃ and SO ₂ CF ₃ .

In one embodiment, W may be a substituted monocyclic or bicyclic non-aromatic ring. For example, W includes but is not limited to , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In the embodiment, wherein L is methylene; each W is independently substituted or unsubstituted by R ⁶ , , , , , , , , , , , , , , , , or ; and each R ⁶ is independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CN, =CH ₂ , =O, SCH ₃ , SO ₂ NH ₂ , SO ₂ NH(CH ₃ ), SO ₂ CH ₃ and SO ₂ CF ₃ .

In one embodiment, for example, W can be 1-methylpyrrolidinyl ( ）、1-(2,2-difluoroethyl)azetidine（ ）、2-fluorohexahydro- 1H -pyrrolizinyl（ ）、2,6-dimethoxyhexahydro- 1H -pyrrolizinyl（ ）、1-methyloctahydro- 1H -cyclopenta[ b ]pyridine ( ) or 2-oxabicyclo[2.1.1]hexane ( ), but is not limited to this.

In one embodiment, for example, W can be a substituted 4- to 10-membered heterocyclic ring. For example, W can be morpholine ( ), but is not limited to them.

In embodiments, wherein R ⁴ is C ₁ -C ₃ alkyl substituted or unsubstituted by R ^4A ; each R ^4A is independently selected from hydrogen, halogen, CN, NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ , =O, C ₃ -C ₆ cycloalkyl substituted or unsubstituted by R ^4C , phenyl substituted or unsubstituted by R ^4C , pyridinyl substituted or unsubstituted by R ^4C , pyrimidinyl substituted or unsubstituted by R ^4C , and pyrazinyl substituted or unsubstituted by R ^4C ; or wherein two of R ^4A together form a 5- to 10-membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; and each R ^4C is independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, NH ₂ , NH(C ₁ -C ₃ alkyl) and N(C ₁ -C ₃ alkyl) ₂ .

In one embodiment, R ⁴ may be a substituted or unsubstituted C ₁ -C ₆ alkyl group, a C ₃ -C ₁₀ cycloalkyl group, an azetidinyl group, a pyrrolizinyl group or a pyridinyl group, but is not limited thereto.

In one embodiment, R ⁴ may be a C ₃ -C ₁₀ cycloalkyl group which may or ^{may not be substituted by R 4A ,} and the C ₃ -C ₁₀ cycloalkyl group includes a spirocyclo C ₃ -C ₁₀ cycloalkyl group. For example, R ⁴ may be a substituted or unsubstituted spiro[3.3]alkane group (e.g., ), but is not limited to them.

In one embodiment, ^R4 can be halogen, amino, ( _C1 - _C6 alkyl)amino, di( _C1 - _C6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino( _C3 - _C10 cycloalkyl), di( _C1 - _C6 alkyl)amino( _C3 - _C10 cycloalkyl) or 1-morpholinyl( _C3 - _C10 cycloalkyl) (e.g., 1-morpholin-4-ylcyclobutyl ( )) but is not limited to it.

^R4 may be, for example, a _C1 - _C6 alkyl or _C3-C10 cycloalkyl substituted with halogen, amino, ( _C1 - _C6 alkyl)amino, di( _C1 - _C6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C3-C10 cycloalkyl), di( _C1 -C6 alkyl)amino( _C3 - _C10 cycloalkyl), or ₁ -morpholin _{- 4 -} ylcyclobutyl.

R ⁴ may be, for example, an unsubstituted azetidinyl group or an unsubstituted pyrrolizinyl group. R ⁴ may be, for example, an amino-substituted spiro[3.3]heptyl group, an amino-substituted pyridine group, or an amino-substituted C ₃ -C ₁₀ cycloalkyl group.

In an embodiment, wherein X is CR ¹¹ , each R ¹¹ is independently selected from hydrogen, halogen, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl; R ¹ is benzothienyl which may be substituted by R ^1A ; each R ^1A is independently selected from hydrogen, halogen, NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ and CN.

In an embodiment, wherein R ¹ is each substituted or unsubstituted with one or more substituents independently selected from hydrogen, hydroxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, amino and CN. , or ; R ² is F; R ³ is hydrogen, -OLW or ; L is methylene; W is each substituted 1 to 3 times by R ⁶ or not substituted by R ⁶ , , , , , , , , , , , , , , , , or ; each R ⁶ is independently selected from hydrogen, halogen, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CN, =CH ₂ and =O; R ⁴ is each substituted or unsubstituted with one or more substituents independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, NH ₂ , NH(C ₁ -C ₃ alkyl) and N(C ₁ -C ₃ alkyl) ₂ , , , , , , , , , , , , , , , or ; and n is selected from 1 and 2.

In the embodiments, the compound is selected from the group consisting of the following compounds and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

According to an aspect of another embodiment, a pharmaceutical composition is provided, comprising a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1.

In an embodiment, the pharmaceutical composition exhibits KRAS protein inhibitory activity.

Unless otherwise stated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

Unless otherwise stated, the term "alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon group.

Unless otherwise stated, the term "alkylene" used herein refers to a divalent straight or branched chain hydrocarbon group having ( _-CH2- ) _n , and includes but is not limited to methylene, ethylene, propylene, butylene, isobutylene and the like.

As used herein, unless otherwise stated, the term "alkenyl" refers to a monovalent hydrocarbon group comprising at least one carbon-carbon double bond, wherein each double bond has an E or Z configuration.

As used herein, unless otherwise stated, the term "alkynyl" refers to a monovalent hydrocarbon group including at least one carbon-carbon triple bond.

As used herein, unless otherwise stated, the term "alkoxy" refers to a straight-chain or branched hydrocarbon residue linked through an oxygen.

Unless otherwise stated, the term "aryl" used herein refers to an aromatic group that may be substituted or unsubstituted, and includes a substituted or unsubstituted monocyclic, bicyclic or more than bicyclic aromatic group, and may include unsaturated or partially saturated aromatic groups. For example, the aryl group includes but is not limited to a C _6-15 aryl group, and may include but is not limited to phenyl, biphenyl, naphthyl, tolyl, etc.

Unless otherwise stated, the term "heteroaryl" used herein refers to an aromatic group that may be substituted or unsubstituted and includes one or more heteroatoms selected from N, O and S, and includes a substituted or unsubstituted monocyclic, bicyclic or more than bicyclic aromatic group, and may include unsaturated or partially saturated heteroaryl groups. For example, heteroaryl groups include but are not limited to C _4-15 heteroaryl groups, and may include but are not limited to morpholinyl, piperidinyl, pyrrolidinyl or pyrrolidinyl, etc.

Unless otherwise stated, the term "fused heteroaryl" as used herein refers to an unsaturated or partially saturated, substituted or unsubstituted ring system in which the heteroaryl is linked to another aryl, heteroaryl or heterocycloalkyl in a fused manner. For example, the fused heteroaryl may include a C _8-20 heteroaryl, and may include but is not limited to a 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered or 15-membered benzo-fused heteroaryl. For example, the fused heteroaryl may include but is not limited to a 5+5 fused ring system, a 5+6 fused ring system, a 5+7 fused ring system, a 6+6 fused ring system or a 6+7 fused ring system. For example, the fused heteroaryl group may include, but is not limited to, pyrrolizine, benzothiazole, benzothiazolinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, benzothionyl, indolyl, isoindolyl, indazolyl, indazolinyl, benzimidazolyl, benzoxazolinyl, benzoisoxazolinyl, benzothiadiazolinyl, benzoxadiazolinyl, benzotriazolinyl, quinolinyl, isoquinolinyl, quinazolinyl, and the like.

As used herein, the term "partially saturated" refers to an aryl, heteroaryl or fused heteroaryl ring as defined above that includes at least one saturated site (i.e., at least one single bond). As used herein, the term "unsaturated" refers to an aryl, heteroaryl or fused heteroaryl ring as defined above that does not include a saturated site (i.e., a single bond).

The term "cycloalkyl" used herein refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon ring that may be substituted or unsubstituted, and unless otherwise stated, the cycloalkyl may include a bridged cycloalkyl, a fused cycloalkyl and a spirocycloalkyl. For example, the cycloalkyl includes but is not limited to a _C3-10 cycloalkyl or a _C3-6 cycloalkyl, and may include but is not limited to a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, etc. The term "cycloalkylene" used herein refers to a free radical (a divalent free radical) derived from a cycloalkene. Unless otherwise stated, the term "heterocycloalkyl" used herein refers to a cycloalkyl group which may be substituted or unsubstituted and includes one or more heteroatoms selected from N, O and S, and includes a substituted or unsubstituted monocyclic, bicyclic or more than bicyclic aromatic group.

Unless otherwise stated, the term "heterocyclic ring" used herein refers to a saturated or partially unsaturated aromatic ring, a monocyclic ring, a bicyclic ring or a polycyclic ring which may be substituted or unsubstituted and contains one or more heteroatoms selected from N, O and S, and the heterocyclic ring may include a bridged heterocyclic ring, a fused heterocyclic ring and a spirocyclic heterocyclic ring. For example, the heterocyclic ring includes but is not limited to a C _4-15 heterocycloalkyl group, and may include but is not limited to piperidinyl, piperazinyl, pyrrolidinyl, oxolinyl, thiooxolinyl, tetrahydrofuranyl, tetrahydro- 2H -pyranyl, imidazolidinyl, pyrrolidin-2-one, pyrrolazinyl or pyrrolyl, etc. The heterocyclic ring may be carbon-linked or heteroatom-linked. For example, the heterocyclic ring may be linked to the base molecule via a ring atom (which may be C or N). For example, the heterocyclic ring linked to the base molecule via a nitrogen atom of the heterocyclic ring may include but is not limited to N-morpholinyl, N-piperidinyl, N-pyrrolidinyl or N-pyrrolyl, etc.

Unless otherwise stated, the term "fused heterocyclic ring" or "fused cycloalkyl" as used herein refers to a substituted or unsubstituted ring system, and depending on the number of rings, the fused heterocyclic ring or fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or higher polycyclic fused cycloalkyl. Fused cycloalkyl is a polycyclic ring in which each ring shares a pair of adjacent carbon atoms with another ring and one or more rings may share one or more double bonds, but none of the rings have a completely conjugated π-electron system. For example, the fused cycloalkyl group includes but is not limited to a C _3-20 fused cycloalkyl group, and may include but is not limited to a 5+5 fused ring system, a 5+6 fused ring system, a 5+7 fused ring system, a 6+6 fused ring system, or a 6+7 fused ring system, depending on the number of atoms forming each of the two rings to be fused. Bicyclic fused cycloalkyl groups are also referred to as "bicyclic alkyl groups" or "bicyclic heterocyclic groups", and as long as the valence permits, "bicyclic alkyl groups" or "bicyclic heterocyclic groups" include any combination of saturated, unsaturated, and aromatic bicyclic groups. In an exemplary embodiment, an aromatic ring (e.g., pyridyl) may be fused with a saturated or unsaturated ring.

The term "fused heterocycloalkyl" used herein refers to a substituted or unsubstituted fused cycloalkyl group including one or more heteroatoms selected from N, O and S. For example, the fused heterocycloalkyl group includes but is not limited to a _C8-20 fused heterocycloalkyl group. For example, a bicyclic fused heterocycloalkyl group is also referred to as a "heterobicycloalkyl group", and the bicyclic fused heterocycloalkyl group includes but is not limited to a 5+5 fused ring system, a 5+6 fused ring system, a 5+7 fused ring system, a 6+6 fused ring system or a 6+7 fused ring system, depending on the number of atoms forming each of the two rings to be fused. For example, the bicyclic fused heterocycloalkyl group may be hexahydro-1H-pyrrolizine, but is not limited thereto.

As used herein, the term "stereoisomer" refers to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. Stereoisomers are compounds that have the same chemical or molecular formula but are optically or spatially different. As used herein, the term "mirror image isomer" refers to various stereoisomers and geometric isomers that may exist for compounds according to the present disclosure. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "mirror image isomers" which refers to two stereoisomers where the molecule is a non-superimposable mirror image of each other.

The compounds described herein may have asymmetric centers, geometric centers (e.g., double bonds), or both. Unless a specific stereochemistry or isomeric form is specified, all chiral forms, non-mirror isomeric forms, racemic forms, and all geometric isomeric forms of the structure are contemplated.

The compound of Formula 1 according to one aspect of the present disclosure may have an asymmetric carbon center (asymmetric carbon), and thus may exist as a mirror image isomer ( R or S isomer), a racemate, a non-mirror image isomer, or any mixture thereof, and all such isomers and mixtures are included within the scope of the present disclosure.

The compounds described herein may have asymmetric centers, geometric centers (e.g., double bonds), or both asymmetric centers and geometric centers. Unless a specific stereochemistry or isomeric form is specifically indicated, all chiral forms, non-mirror isomeric forms, racemic forms, and all geometric isomeric forms of the structure are expected. In some embodiments, the compounds described herein have one or more chiral centers. It should be understood that if the absolute stereochemistry is not explicitly indicated, each chiral center can independently be in the R-configuration or S-configuration or a mixture thereof. Therefore, the compounds described herein include enriched or decomposed optical isomers at any or all asymmetric atoms that are apparent by reading the drawings. Racemic mixtures of R-mirror image isomers and S-mirror image isomers, and stereoisomeric mixtures enriched in mirror image isomers comprising R-mirror image isomers and S-mirror image isomers, and individual optical isomers can be isolated or synthesized to be substantially free of their mirror image isomer partners or non-mirror image isomer partners, and these stereoisomers are within the scope of the present invention.

Compounds of the present disclosure containing asymmetric substituted atoms can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, for example by resolution of a racemic form, by synthesis from optically active starting materials or by the use of chiral auxiliary agents.

As used herein, the term "configurational isomers" refers to all stereoisomers that can be separated from each other. Configurational isomers are isomers that occur when a single bond formed between carbon and carbon among the bonds constituting a compound cannot rotate freely due to bulky substituents. Configurational isomers refer to stereoisomers generated by an asymmetry axis and include complete isolation of stable non-interconverting diastereomeric species or enantiomeric species. In addition, configurational isomers may be caused by limited rotation around a single bond, in which the rotational barrier is high enough to enable the isomeric species to be distinguished.

The compounds according to one embodiment may generate configurational isomers with a high probability.

The term "tautomer" as used herein refers to one of two or more structural isomers that are easily converted from one isomeric form to another isomeric form and exist in equilibrium. The compounds according to one embodiment may also include "tautomers". Tautomers result from the exchange of a single bond with an adjacent double bond and the concomitant proton transfer. Tautomeric forms include prototropic tautomers that are isomeric protonation states with the same empirical formula and total charge. By appropriate substitution, tautomeric forms can be in equilibrium or fixed in space to one form.

The term "solvent complex" as used herein may include a molecular complex comprising a compound of Formula 1 and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol or water). A complex in which the solvent molecule is water is also referred to as a "hydrate."

As used herein, the term "pharmaceutically acceptable salt" includes any salt as long as the salt has low toxicity to the human body and does not adversely affect the biological activity and physicochemical properties of the parent compound.

Compounds according to one embodiment may include "isotopic variants". The present disclosure also encompasses isotopically labeled compounds that are identical to those described herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature ("isotopologues"). Compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H ("D"), ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. For example, the compounds described herein may have one or more H atoms replaced with deuterium.

Generally speaking, a reference to or depiction of an element (e.g., hydrogen or H) is meant to include all isotopes of the element. For example, if the R group is defined to include hydrogen or H, then the R group also includes deuterium and tritium. Compounds containing radioactive isotopes (e.g., tritium, ¹⁴ C, ³² P, and ³⁵ S) are therefore within the scope of the present invention. Based on the disclosure herein, the procedure for inserting such labels into the compounds of the present invention will be apparent to those skilled in the art.

Unless otherwise stated, compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures but for the replacement of a hydrogen by a deuterium or tritium, or a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of this disclosure.

In some embodiments, certain isotopically labeled compounds (e.g., compounds labeled with ³ H and ¹⁴ C) may be useful in compound distribution assays and/or substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by procedures analogous to those disclosed herein (eg, in the Examples section) by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

As used herein, the term "treatment" includes the treatment, amelioration, improvement or management of a disease. As used herein, the term "treating" or "treatment" refers to inhibiting the disease (e.g., inhibiting the disease, disorder or disorder), preventing further development of the pathology and/or symptoms, ameliorating the disease, or reversing the pathology and/or symptoms (e.g., reducing the severity of the disease) in a subject experiencing or displaying the pathology or symptoms of a disease, disorder or disorder.

As used herein, the terms "preventing" and "prevention" refer to preventing a disease, such as preventing a disease, condition or disorder in a subject who may be susceptible to the disease, condition or disorder but who has not yet experienced or displayed the pathology or symptoms of the disease.

As used herein, the term "subject" or "patient" refers to any animal including mammals (eg, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and humans).

The terms "having", "may have", "include" or "may include" may refer to the presence of a feature (e.g., component (e.g., number, component, etc.)) and do not exclude the presence of additional features. KRAS protein inhibitors

KRAS is a GTPase that integrates signals from outside the cell into intracellular proliferation and survival signals. It is a member of the small GTPase family consisting of Ras, Rho, Rab, Arf, and Ran. KRAS receives signals from various receptor tyrosine kinases (especially epidermal growth factor receptor (EGFR) at the upper level) and transmits the signals mainly to Raf and PI3K at the lower level through the KRAS GTPase cycle, thereby regulating various processes including cell proliferation.

KRAS plays an important role in cancer, but inhibiting its activity has been challenging due to the structure of the protein. Attempts to block signaling have shown some promise, but have also been met with problems of toxicity and treatment resistance. However, the discovery of the switch II pocket and compounds that bind to mutant cysteine led to the development of adagrasib and sotorasib, which have been approved by the U.S. Food and Drug Administration (FDA) for non-small cell lung cancer.

The compounds disclosed herein are novel KRAS inhibitor compounds that inhibit mutations in any one of KRAS codons 12, 13, and 61, such as but not limited to at least one of KRAS G12D, KRAS G12V, KRAS G12C, KRAS G13D, and KRAS Q61H mutations. Pharmaceutical composition

According to one aspect of another embodiment, a pharmaceutical composition for treating cancer is provided, the pharmaceutical composition comprising a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1.

In one embodiment, the composition may contain a therapeutically effective amount of a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1.

In one embodiment, in addition to the compound selected from the group consisting of the compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1, the composition may also contain other therapeutic drugs.

In one embodiment, the composition may further comprise a pharmaceutically acceptable carrier or excipient.

In one embodiment, the composition may contain a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of Formula 1 or other therapeutic drugs in the range of 0.005% to 100%, and may contain a pharmaceutically acceptable carrier or excipient in the remaining range.

In one embodiment, a compound selected from the compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates of the compound of Formula 1 or a pharmaceutical composition comprising the compound can be used for cancer treatment.

In one embodiment, a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, and solvates of the compound of Formula 1, or a pharmaceutical composition comprising the compound, can exhibit KRAS protein inhibitory activity.

According to one aspect of another embodiment, there is provided a use of a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates of the compound of Formula 1, or a pharmaceutical composition comprising the compound for treating cancer. Administration route and form

The compounds and pharmaceutical compositions disclosed herein can be provided by any suitable administration route and dosage form acceptable in pharmaceutical technology.

The compounds disclosed herein can be synthesized using organic synthesis techniques known to those skilled in the art. Some of the compounds and/or intermediates disclosed herein are commercially available, known in the literature, or can be prepared by those skilled in the art by selecting an appropriate synthesis method from known organic synthesis techniques. Some of the compounds disclosed herein can be synthesized using the schemes, examples, or intermediates described herein. Those skilled in the art will recognize that the reaction time, the number of equivalents of reagents, and/or the temperature can be modified according to the synthesis methods described herein, and different separation and purification techniques (work-up techniques) and/or purification techniques (purification techniques) can be utilized.

The structures of synthesized compounds can be verified by methods known to those skilled in the art, such as nuclear magnetic resonance (NMR) spectroscopy and/or mass spectroscopy.

Unless otherwise stated, reagents and solvents were obtained from commercial suppliers and used without purification or drying. ^1H NMR was recorded using a Bruker 400 MHz and 500 MHz, and TMS was used as an internal standard. Liquid chromatography-mass spectrometry (LCMS) analysis was performed on a Waters Ultra Performance Liquid Chromatography (UPLC) with a SQD-2 mass detector (Single quadruple), and HPLC analysis was performed on an Acquity UPLC H CLASS (Waters).

Even if not specifically stated, the numerical values described in this specification are deemed to include the meaning of "about". The term "about" means within 5% of a predetermined value or range, preferably within 1% to 2%.

In the present specification, a numerical range expressed using the term "to" includes a range including the numerical values written before and after the term "to" as the lower limit and the upper limit, respectively.

All references, publications, issued patents, and patent applications cited in the text of this specification are incorporated herein by reference for all purposes.

Hereinafter, the present disclosure will be described in more detail with reference to the following examples and experimental examples. However, the examples and experimental examples are intended to help understand the present disclosure, and the scope of the present disclosure is not limited thereto in any sense. 1. Synthesis scheme of Example 1 Experimental procedure of Example 1 : 4-(10-((1-( dimethylamino ) cyclobutyl ) methyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphth -2- ol Step 1 : 5,7- dichloro -2-( ethylthio )-8 -fluoropyrido [4,3- d ] pyrimidin -4(3 H )-one (Example 1- Intermediate 2 )

To a stirred solution of 5,7-dichloro-8-fluoro-2-hydroxypyrido[4,3- d ]pyrimidin-4( 3H )-one ( Example 1- Intermediate 1 ) (5.00 g, 18.9 mmol) in MeOH (50 mL, 10 vol) was added 0.1 M NaOH (25.0 mL, 5 vol) at room temperature and stirred for 30 min, followed by addition of ethyl iodide (2.20 mL, 28.4 mmol) at room temperature and stirring the reaction mixture for 2 h at room temperature. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was diluted with water and acidified with conc. HCl up to pH ~4 to obtain a solid, which was filtered, washed with water and dried under high vacuum to obtain a crude compound 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3- d ]pyrimidin-4( 3H )-one ( Example 1- Intermediate 2 ) (4.80 g, crude) as a light brown solid. The crude compound was used as is in the next step without further purification. MS (LC-MS): 294.12 m/z [M+H]. Step 2 : 7- Chloro -5-(2-(((1-( dimethylamino ) cyclobutyl ) methyl ) amino ) ethoxy )-2-( ethylthio )-8- fluoropyrido [4,3- d ] pyrimidin -4( 3H )-one (Example 1- Intermediate 5 )

To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol ( Example 1- Intermediate 4 ) (1.17 g, 6.80 mmol) in tetrahydrofuran (THF) (10 ml, 10 vol) at 0°C was added NaH (0.67 g, 15.3 mmol) and stirred at 0°C for 1 hour. To this was added 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3- d ]pyrimidin-4( 3H )-one ( Example 1- Intermediate 2 ) (1.00 g, 3.40 mmol) at 0°C and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with 10% methanol in dichloromethane (DCM) solution (2×30 mL), the combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give crude compound 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3- d ]pyrimidin-4(3 H )-one ( Example 1- Intermediate 5 ) (1.20 g, crude) as a yellow liquid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 430.33 m/z [M+H]. * Synthesis of 2-(((1-( dimethylamino ) cyclobutyl ) methyl ) amino ) ethan -1- ol (Example 1- Intermediate 4 )

Step 1a : To a stirred solution of 1-(aminomethyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 3 ) (1.00 g, 7.80 mmol) in THF (10 mL, 10 vol) at 0°C were added 2-bromoethan-1-ol (0.97 g, 7.80 mmol) and triethanolamine (TEA) (3.26 mL, 23.4 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 18 h. The progress of the reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was diluted with diethyl ether (20 ml), and the reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a crude compound 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol ( Example 1- Intermediate 4 ) (1.40 g, crude) as a yellow liquid. The crude compound was used as it was in the next step without further purification. MS (LC-MS): 173.48 m/z [M+H]. Step 3 : 1-((5- chloro -2-( ethylthio )-4- fluoro -8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 1- Intermediate 6 )

To a stirred solution of 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3- d ]pyrimidin-4( 3H )-one ( Example 1- Intermediate 5 ) (1.00 g, 2.32 mmol) in DCM (15 mL, 15 vol) at 0 °C was added Bis(2-oxo-3-oxazolidinyl)phosphonic acid chloride (Bis(2-oxo-3-oxazolidinyl)phosphonic acid chloride). chloride, BOP-Cl) (2.07 g, 8.14 mmol) and N,N-diisopropylethylamine (DIPEA) (6.07 ml, 34.9 mmol) were added and the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 ml) and extracted with 10% methanol in DCM (2×50 ml), the combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by reverse phase column chromatography using a C18 column eluted with 60% acetonitrile (ACN) in water to give 1-((5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 6 ) (0.45 g, yield (Y): 47%) as a white solid. MS (LC-MS): 412.36 m/z [M+H]. Step 4 : 1-((5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-2-( ethylthio )-4- fluoro -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 1- Intermediate 8 )

To a stirred solution of 1-((5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 6 ) (0.45 g, 1.09 mmol) in a mixture of 1,4-dioxane and water (3:1, 20 ml) was added _K3PO4 (0.81 g, 3.82 mmol) and _2- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( Example 1- Intermediate 7) at room temperature. ) (0.39 g, 1.09 mmol) and degassed under argon for 15 min. To this was added 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (Ruphos) PdG ₃ (0.092 g, 0.11 mmol) at room temperature and the reaction mixture was heated to 90° C. and stirred for 1 hour. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with 10% methanol in DCM (2×50 mL), the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 8 ) (0.61 g, crude) as a reddish solid. MS (LCMS): 610.48 m/z [M+H]. Step 5 : 1-((5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-2-( ethylsulfonyl )-4- fluoro -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 1- Intermediate 9 )

To a stirred solution of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 8 ) (0.60 g, 0.98 mmol) in a mixture of solvent ACN and water (4:1, 20 ml) was added potassium hydrogen persulfate (Oxone) (3.02 g, 9.83 mmol) at 0°C and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (30 mL), extracted with 10% methanol in DCM solution (2 x 30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a residue. The residue was washed with 20% THF in hexane to give a solid, which was filtered and dried under high vacuum to give crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 9 ) (0.30 g, crude) as a brown solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 642.44 m/z [M+H]. Step 6 : 1-((5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H )-yl ) methoxy ) -8,9- dihydro - 10H- 7- oxa - 1,3,6,10 - tetraazacyclohepta [ de ] naphthalen- 10 - yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 1- Intermediate 10 )

To a stirred solution of (( 2R )-2-fluorotetrahydro- 1H -pyrrolizin- 7a ( 5H )-yl)methanol ( Example 1- Intermediate 9 ) (0.099 g, 0.62 mmol) in toluene (10 mL, 30 vol) at 0°C was added ^NaOtBu (0.06 g, 0.62 mmol) and stirred for 15 min followed by the addition of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine (0.33 g, 0.51 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with ethyl acetate (EA) (2×15 mL), the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrolizin-7 a (5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 10 ) (0.32 g, crude). The crude compound was used as such in the next step without further purification. MC (LC-MS): 707.58 m/z [M+H]. Step 7 : 4-(10-((1-( dimethylamino ) cyclobutyl ) methyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10- tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol ( Example 1 )

To a stirred solution of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin -7a ( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 1- Intermediate 10 ) (0.32 g, 0.45 mmol) at 0°C was added 4 mol/L HCl in 1,4-dioxane (5.0 mL), and the reaction mixture was stirred at 0°C for 1 hour. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude compound. The crude was purified by preparative HPLC to obtain Example 1 (0.037 g, yield (Y): 12%) as a white solid. ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 0.80 (t, J = 7.38 Hz, 3H), 1.65-1.85 (m, 7H), 1.96 (brs, 1H), 2.03-2.13 (m, 4H), 2.23 (s, 6H), 2.26-2.30 (m, 1H), 2.36-2.42 (m, 1H), 2.79-2.85 (m, 1H), 3.01 (brs, 1H), 3.08 (d, J = 6.50 Hz, 2H), 3.97-4.25 (m, 6H), 4.57 (t, J = 4.88 Hz, 2H), 5.21-5.34 (m, 1H), 7.01 (d, J = 2.50 Hz, 1H), 7.30 (d, J = 2.50 Hz, 1H), 7.34 (t, J = 9.38 Hz, 1H), 7.74 (dd, J = 9.01, 6.00 Hz, 1H), 9.91 (s, 1H). MS (LC-MS): 663.47 m/z [M+H]. 2. Synthesis scheme of Example 2 Experimental procedure of Example 2 : 4-(10-((1-( dimethylamino ) cyclobutyl ) methyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5H) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl - 6- fluoronaphthalen -2- ol Step 1 : 5,7- dichloro -8- fluoro - 2-( methylthio ) pyrido [4,3- d ] pyrimidin -4(3 H )-one (Example 2- Intermediate 2 )

To a stirred solution of 5,7-dichloro-8-fluoro-2-hydroxypyrido[4,3- d ]pyrimidin-4(3H)-one ( Example 2- Intermediate 1 ) (7.60 g, 28.69 mmol) in MeOH (477 mL, 63 vol) at room temperature were added 0.1 mol NaOH (477 mL, 240.99 mmol) and MeI (3.30 mL, 40.17 mmol), and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water (250 mL) and acidified with conc. HCl up to pH ~6 to obtain a solid, which was filtered, washed with water and dried under high vacuum to obtain crude compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4( 3H )-one ( Example 2- Intermediate 2 ) (4.0 g, crude) as an off-white solid. The crude compound was used as is in the next step without further purification. MS (LC-MS): 279.97 m/z [M+H]. Step 2 : 7- Chloro -5-(2-(((1-( dimethylamino ) cyclobutyl ) methyl ) amino ) ethoxy )-8- fluoro -2-( methylthio ) pyrido [4,3- d ] pyrimidin -4( 3H )-one (Example 2- Intermediate 3 )

To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol ( Example 1- Intermediate 4 ) (0.37 g, 2.16 mmol) in THF (10 ml, 20 vol) was added NaH (0.35 g, 8.09 mmol) at 0°C and stirred at 0°C for 1 hour. To this was added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3 -d ]pyrimidin-4( 3H )-one ( Example 2- Intermediate 2 ) (0.50 g, 1.80 mmol) at 0°C and the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with ethyl acetate (2 × 30 mL), the combined organic layers were washed with brine (30 mL), dried over anhydrous _Na2SO4 , filtered and evaporated under reduced pressure to give crude compound 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3 _- d ]pyrimidin-4( 3H )-one ( Example 2- Intermediate 3 ) (0.40 g, crude) as a yellow liquid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 416.29 m/z [M+H]. Step 3 : 1-((5- chloro -4- fluoro -2-( methylthio )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) methyl )-N,N -dimethylcyclobutane -1- amine (Example 2- Intermediate 4 )

To a stirred solution of 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3 -d ]pyrimidin-4( 3H )-one ( Example 2- Intermediate 3 ) (0.40 g, 0.96 mmol) in DCM (10 mL, 25 vol) at 0°C was added BOP-Cl (0.86 g, 3.36 mmol) and DIPEA (2.51 mL, 14.42 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 ml) and extracted with ethyl acetate (2 x 20 ml), the combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to get the crude compound. The crude compound was purified by reverse phase column chromatography using a C18 column eluted with 60% ACN in water to give 1-((5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 4 ) (0.30 g, yield: 78%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.65-1.69 (m, 2H), 1.80 (brs, 2H), 2.08 (brs, 2H), 2.27 (brs, 3H), 2.54 (s, 6H), 3.17 (d, J = 5.00 Hz, 2H), 4.00-4.11 (m, 2H), 4.20 (brs, 2H). MS (LC-MS): 398.32 m/z [M+H]. Step 4 : 1-((4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 -yl )-2-( methylthio )-8,9- dihydro - 10H- 7- oxa - 1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 2- Intermediate 6 )

To a stirred solution of 1-((5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane- ₁ -amine ( Example 2- Intermediate 4 ) (0.28 g, 0.71 mmol) in a mixture of 1,4-dioxane and water (4:1, 5.0 mL) was added _K3PO4 at room temperature. (0.53 g, 2.47 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane ( Example 2- Intermediate 5 ) (0.36 g, 0.71 mmol) were added and degassed under argon for 15 minutes. Ruphos PdG ₃ (0.06 g, 0.07 mmol) was added thereto at room temperature, and the reaction mixture was heated to 100° C. and stirred for 1 hour. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL), extracted with ethyl acetate (2 x 20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to get a crude compound. The crude compound was purified by reverse phase column chromatography using a C18 column eluting with 80% ACN and _H2O to give 1-((4-chloro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H - 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 6 ) (0.30 g, yield: 56%) as a yellow solid. ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 0.86 (dd, J = 7.38, 3.63 Hz, 18H), 1.13-1.18 (m, 3H), 1.67-1.87 (m, 4H), 2.06-2.15 (m, 2H), 2.24 (s, 6H), 2.53 (s, 3H), 3.42-3.44 (m, 3H), 3.91-4.02 (m, 3H), 4.40-4.48 (m, 2H), 4.59-4.63 (m, 1H), 5.34 (d, J = 10.81 Hz, 2H), 7.31 (d, J = 2.75 Hz, 1H), 7.54-7.59 (m, 1H), 7.72 (d, J = 2.50 Hz, 1H), 8.07-8.12 (m, 1H). MS (LCMS): 748.62 m/z [M+H]. Step 5 : 1-((4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 - yl )-2-( methylsulfonyl )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen - 10 -yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 2- Intermediate 7 )

To a stirred solution of 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H -7 -oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 6 ) (0.29 g, 0.39 mmol) in a mixture of solvent ACN and water (4:1, 10 ml) at 0°C was added potassium hydrogen persulfate (1.19 g, 3.88 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL), extracted with 10% methanol in DCM solution (2 × 20 mL), dried over anhydrous _Na2SO4 , and concentrated under reduced pressure to give crude compound 1-((4-fluoro- _5- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H - 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 7 ) (0.35 g, crude) as a yellow solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 780.63 m/z [M+H]. Step 6 : 1-((4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 -yl )-2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolazin - 7a ( 5H )-yl ) methoxy ) -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) methyl ) -N , N - dimethylcyclobutane -1- amine (Example 2- Intermediate 8 )

To a stirred solution of (( 2R )-2-fluorotetrahydro- 1H -pyrrolizin- 7a ( 5H )-yl)methanol (0.32 g, 0.41 mmol) in THF (5 mL, 16 vol) was added NaH (0.02 g, 0.49 mmol) at 0°C and stirred for 30 min, followed by the addition of 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 7 ) at 0°C. ) (0.32 g, 0.41 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with 10% MeOH in DCM (2 × 20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by reverse phase column chromatography using a C18 column eluting with 70% ACN and _H2O to give 1-((4-chloro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin- 7a ( 5H )-yl)methoxy)-8,9-dihydro-10H - 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 8 ) (0.30 g, crude) as a yellow solid. MS (LC-MS): 859.89 m/z [M+H]. Step 7 : 1-((5-(8- ethynyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-(((2 R ,7 aS )-2- fluorotetrahydro -1 H -pyrrolizin -7 a (5 H ) -yl ) methoxy )-8,9- dihydro -10 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen - 10- yl ) methyl ) -N , N -dimethylcyclobutane -1- amine (Example 2- Intermediate 9 )

To a stirred solution of 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrolizin-7 a (5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl)- N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 8 ) (0.29 g, 0.34 mmol) in THF (3.0 mL, 10 vol) at 0° C. was added 1 mol of tetrabutylammonium fluoride. fluoride, TBAF) in THF (0.35 mL, 0.34 mmol), and the reaction mixture was stirred at 0°C for 1 hour. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL), extracted with 10% MeOH in DCM (2 × 20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by reverse phase column chromatography using a C18 column eluted with 70% ACN and H ₂ O to give 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrolazin-7 a (5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 9 ) (0.23 g, yield: 96%) as a yellow solid. MS (LC-MS): 703.64 m/z [M+H]. Step 8 : 4-(10-((1-( dimethylamino ) cyclobutyl ) methyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy )-9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol ( Example 2 )

To 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin- 7a ( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)methyl) -N , N -dimethylcyclobutane-1-amine ( Example 2- Intermediate 9 ) (0.22 g, 0.31 mmol) was added a 4 mol HCl solution in 1,4-dioxane (2.0 mL) at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with NaHCO ₃ solution (20 mL) and extracted with ethyl acetate (20 mL), the separated organic layer was washed with brine solution (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a crude compound. The crude was purified by preparative HPLC to obtain Example 2 (0.053 g, yield: 26%) as a light brown solid. ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 1.67-1.91 (m, 8H), 2.05-2.10 (m, 4H), 2.26 (brs, 6H), 2.85 (d, J = 6.01 Hz, 1H), 3.03-3.11 (m, 4H), 3.93-4.17 (m, 6H), 4.45 (dd, J = 14.13, 4.88 Hz, 1H), 4.56 (brs, 2H), 5.22-5.35 (m, 1H), 7.15 (d, J = 2.25 Hz, 1H), 7.37 (d, J = 2.50 Hz, 1H), 7.46 (t, J = 9.01 Hz, 1H), 7.96 (dd, J = 9.13, 5.88 Hz, 1H), 10.14 (brs, 1H). MS (LC-MS): 659.39 m/z [M+H]. 3. Synthesis scheme of Example 3 Experimental procedure of Example 3 : 4-(( 8S )-10-(1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5- yl )-5- ethyl -6- fluoronaphthalen -2- ol Step 1 : (3- acetylpyridin -2- yl ) carbamic acid tert- butyl ester (Example 3- Intermediate 2 )

To a mixture of 1-(2-aminopyridin-3-yl)ethan-1-one ( Example 3- Intermediate 1 ) (25.0 g, 183 mmol) in t-BuOH (200 ml) was added Boc ₂ O (59.8 g, 274 mmol), and the mixture was stirred at 90° C. for 16 hours. LCMS indicated that the starting material was consumed and the desired mass was formed. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (polyethylene (PE)/ethyl acetate (EA) = 2/1) to give tert-butyl (3-acetylpyridin-2-yl) carbamate (30 g, yield 69.4%) as a white solid. MS: m/z = 237.2 (M+H ⁺ , ESI+) Step 2 : (S,Z)-(3-(1-((2- hydroxypropyl ) imino ) ethyl ) pyridin -2- yl ) carbamic acid tert -butyl ester (Example 3- Intermediate 3 )

To a solution of tert- butyl (3-acetylpyridin-2-yl)carbamate (30 g, 127 mmol) in EtOH (150 mL) was added ( S )-1-aminopropan-2-ol (28.5 g, 381 mmol), and the mixture was stirred at 90°C for 3 hours. LCMS showed that 39% of the starting material was retained and 51% of the desired mass was formed. The reaction mixture was diluted with water and extracted with EA (100 mL x ₂ ). The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE/EA = 1/1) to give (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (25 g, yield 67.2%) as a white solid. MS: m/z = 294.2 (M+H ⁺ , ESI+) Step 3 : (3-(1-((( S )-2- hydroxypropyl ) amino ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 3- Intermediate 4 )

To a solution of (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (25 g, 85.3 mmol) in MeOH (100 mL) was added NaBH ₄ (4.19 g, 110 mmol) at 0° C., and the mixture was stirred at 25° C. for 1 hour. TLC (EA/MeOH = 10/1) indicated that SM1 (Rf = 0.4) was consumed and a new spot (Rf = 0.2) was formed. The reaction mixture was diluted with water and extracted with EA (100 mL×2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (DCM/MeOH = 10/1) to give tert-butyl (3-(1-((( S )-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate as a white solid (12 g, yield 47.6%). MS: m/z = 296.2 (M+H ⁺ , ESI+). Step 4 : tert-butyl (3-(1-((( S )-2-((7- chloro -8- fluoro -2-( methylthio )-4 -oxo -3,4- dihydropyrido [4,3- d ] pyrimidin -5- yl ) oxy ) propyl ) amino ) ethyl ) pyridin -2- yl ) carbamate (Example 3- Intermediate 5 )

To a mixture of tert - butyl (3-(1-((( S )-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (9.00 g, 30.5 mmol) in THF (100 ml) was added NaH (4.88 g, 122 mmol, 60% mineral oil suspension), and the mixture was stirred at 0° C. for 0.5 h. After 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4(3H)-one (8.5 g, 30.5 mmol) was added to the mixture, and the mixture was stirred at 25° C. for another 1 h. TLC (EA/MeOH=15/1) indicated that SM2 was consumed (Rf=0.2) and a new spot was formed (Rf=0.4). The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (PE/EA = 0/1) to obtain tert-butyl (3-(1-((( S )-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3- d ]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (12 g, yield 73.1%) as a yellow solid. MS: m/z =539.1 (M+H ⁺ , ESI+) Step 5 : (3-(1-(( S )-5 - chloro -4- fluoro -8- methyl -2-( methylthio )-8,9 - dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 3- Intermediate 6 )

To a solution of tert-butyl (3-(1-((( S )-2-((7-chloro- 8 -fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3- d ]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (7 g, 13.0 mmol) in DCM (70 mL) was added BoPCl (9.95 g, 39.0 mmol) and N,N-diisopropylethylamine (DIEA) (15.1 g, 117 mmol). The mixture was then stirred at 25 °C for 12 h. TLC (PE/EA = 0/1) indicated consumption of SM2 (Rf = 0.2) and formation of a new spot (Rf = 0.5). The reaction mixture was diluted with water (100 mL) and extracted with DCM (60 mL x 2). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (PE/EA = 1/1) to give (3-(1-(( S )-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (4.00 g, yield 59.2%) as a yellow solid. Structural confirmation was confirmed by two-dimensional NMR. MS: m/z = 521.2 (M+H ⁺ , ESI+) Step 6 : 3-(1-(( S )-5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro - 8- methyl -2-( methylthio )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin - 2- amine (Example 3- Intermediate 7 )

Under N ₂ atmosphere at 100° C., tert-butyl (3-(1-(( S )-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen- 10 -yl)ethyl)pyridin-2-yl)carbamate (1 g, 1.92 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane (0.69 g, 1.92 mmol), RuPhos-Pd-G ₃ (0.40 g, 0.47 mmol) and K ₃ PO ₄ (1.22 g, 5.75 mmol) were reacted in dioxane/H ₂ O (30 mL/10 mL) was stirred for 4 hours. TLC (PE/EA = 0/1) showed that about 10% of SM1 (Rf = 0.5) was retained and a new main spot (Rf = 0.6) was formed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (40 mL × 2). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (PE/EA = 0/1) to give 3-(1-(( S )-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (460 mg, yield 38.8%) as a yellow solid. MS: m/z = 619.2 (M+H ⁺ , ESI+) Step 7 : 3-(1-(( S )-5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4 - fluoro - 8- methyl -2-( methylsulfonyl )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 3- Intermediate 8 )

To a solution of 3-(1-(( S )-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (460 mg, 0.74 mmol) in ammonium ceric nitrate (CAN)/ _H2O (10 mL/10 mL) was added potassium persulfate (2.28 g, 3.72 mmol) and the mixture was stirred at 25°C for 1 hour. LCMS indicated that the starting material was consumed and the desired mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over _{Na2SO4 ,} filtered and concentrated in vacuo to give 3-(1-(( S )-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, crude) as a yellow oil. MS: m/z = 651.1 (M+H ⁺ , ESI+) Step 8 : 3-(1-(( S )-5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H )-yl )methoxy ) -8 - methyl -8,9- dihydro -10 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 3- Intermediate 9 )

To a solution of 3-(1-(( S )-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, 0.77 mmol) and ((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol (140 mg, 1.07 mmol) in THF (10 mL) was added t-BuONa (150 mg, 1.54 mmol) and the mixture was stirred at -70° C. for 1 h. LCMS indicated that the starting material was consumed and the desired mass was detected. The reaction mixture was diluted with water (40 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a residue. The residue was purified by medium pressure liquid chromatography (MPLC) (fatty acid (FA) conditions) to give 3-(1-(( S )-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolazin-7a(5 H )-yl)methoxy)-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (250 mg, yield 44.5%) as a white solid. MS: m/z = 730.3 (M+H ⁺ , ESI+) Step 9 : 4-((8 S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-8- methyl - 9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol (Example 3 )

To a solution of 3-(1-(( S )-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.27 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (2 mL) and the mixture was stirred at 0°C for 1 h, LCMS indicated that the starting material was consumed and the desired mass was formed. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (NH ₃ ·H ₂ O conditions) to give Example 3 (100 mg, 53%) as a white solid. MS: m/z = 686.2 (M+H ⁺ , ESI+) Step 10 : Example 3a and Example 3b

Compound Example 3 (100 mg) was purified by supercritical fluid chromatography (SFC) (column: REGIS (S,S) WHELK-O1, MeOH (+0.1% 7.0 mol/L ammonium in MeOH)/CO ₂ = 50/50) to give Example 3a (30.43 mg , 30.43%) and Example 3b (20.87 mg, 20.87%). Example 3a : 4-(( S )-10-(( R )-1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H- 7-oxa - 1,3,6,10 -tetraazacyclohepta [ de ] naphth - 5- yl )-5- ethyl -6- fluoronaphth -2- ol LC-MS: (ES, m/z ): [M+H] ⁺ =686.2

¹ H NMR (400 mHz, MeOD) δ 7.91 (d, J = 4.7 Hz, 1H), 7.70 (d, J = 7.1 Hz, 1H), 7.55 (dd, J = 8.9, 5.9 Hz, 1H), 7.25 – 7.07 (m, 2H), 6.99 - 6.87 (m, 1H), 6.78 – 6.65 (m, 1H), 6.57 - 6.48 (m, 1H), 5.24 (d, J = 54.6 Hz, 1H), 4.53 - 4.45 (m, 1H), 4.29 – 4.15 (m, 2H), 3.54 – 3.40 (m, 2H), 3.20 - 3.11 (m, 2H), 3.04 - 2.92 (m, 1H), 2.53 – 2.06 (m, 5H), 2.01 - 1.73 (m, 3H), 1.62 - 1.48 (m, 3H), 1.20 - 1.06 (m, 3H), 0.78 (t, J = 7.3 Hz, 3H). Example 3b : 4-(( S )-10-(( S )-1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H- 7-oxa- 1,3,6,10 - tetraazacyclohepta [ de ] naphth - 5- yl )-5- ethyl -6- fluoronaphthalen -2- ol LC-MS: (ES, m/z ): [M+H] ⁺ =686.3

¹ H NMR (400 mHz, MeOD) δ 7.96 (s, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.31 - 7.17 (m, 2H), 7.03 (d, J = 23.2 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.72 - 6.62 (m, 1H), 5.31 (d, J = 54.4 Hz, 1H), 4.69 – 4.53 (m, 2H), 4.34 (dd, J = 23.5, 10.5 Hz, 2H), 3.75 - 3.64 (m, 1H), 3.27 - 3.17 (m, 2H), 3.06 - 2.97 (m, 1H), 2.57 – 2.12 (m, 5H), 2.05 - 1.85 (m, 3H), 1.76 - 1.64 (m, 3H), 1.36 - 1.22 (m, 3H), 0.96 - 0.79 (m, 3H). 4. Synthesis scheme of Example 4 Experimental procedure of Example 4 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-2((2,6- dimethyltetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-4- fluoro -8 - methyl - 9,10- dihydro - 8H- 7- oxa- 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen- 5- yl )-5- ethynyl - 6 - fluoronaphthalen -2- ol Step 1 : ( E )-ethyl 2-((4- bromobenzylidene ) amino ) acetate (Example 4- Intermediate 2 )

To a solution of 4-bromobenzaldehyde ( Example 4- Intermediate 1 ) (5 g, 27.024 mmol) in DCM (75 mL) was added ethyl glycine hydrochloride (3.77 g, 27.024 mmol), _{Mg2SO4 (} 3.74 g, 31.078 mmol) and TEA (5.47 g, 54.048 mmol). The mixture was stirred at 25°C under argon for 14 hours. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DCM (25 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with H ₂ O (50 mL) and extracted with methyl tert-butyl ether (MTBE) (50 mL). The organic phase was washed with brine (50 mL) and dried over Na ₂ SO _4. Filtration and concentration under reduced pressure gave the desired product ethyl ( E )-2-((4-bromobenzylidene)amino)acetate (6 g, yield 82%) as a colorless liquid. MS: m/z =288.0 (M+H ⁺ , ESI+) Step 2 : ( E )-ethyl 2-(( 4- bromobenzylidene ) amino )-4-( chloromethyl )-2-(2-( chloromethyl ) allyl ) pent -4- enoate (Example 4- Intermediate 3 )

To a solution of ethyl ( E )-2-((4-bromobenzylidene)amino)acetate (5.0 g, 18.510 mmol) in THF (125 mL) was added NaH (1.63 g, 8.144 mmol) at 25°C under _N2 . The mixture was stirred at 25°C for 5 min. To the above mixture was added dropwise 3-chloro-2-(chloromethyl)prop-1-ene (6.95 g, 55.530 mmol) at 25°C under _N2 . The resulting mixture was stirred at 65°C under _N2 for another 5 h. The reaction was monitored by LCMS. The reaction mixture was diluted with _H2O (250 mL) and extracted with EA (150 mL). _The organic phase was washed with brine (250 mL) and dried over _Na2SO4 . Filtration and concentration under reduced pressure were performed to obtain the desired product ( E )-ethyl 2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (6.5 g, yield 78%) as a brown liquid. MS: m/z = 447.8 (M+H ⁺ , ESI+) Step 3 : Ethyl 2,6- dimethyltetrahydro - 1H - pyrrolazine -7a( 5H ) -carboxylate (Example 4- Intermediate 4 )

To a solution of ( E )-ethyl 2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (1.5 g, 3.354 mmol) in THF (15 mL) was added 1 mol HCl (10 mL, 10.063 mmol). The mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with _H2O (60 mL). The aqueous layer was extracted with EA (40 mL) to give the crude desired product ethyl 2-amino-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate in the aqueous layer. MS: m/z = 280.0 (M+H ⁺ , ESI+) Step 4 : 2,6- Dimethy1enetetrahydro - 1H - pyrrolizine -7a( 5H )-carboxylic acid ethyl ester (Example 4- Intermediate 5 )

1 mol NaOH (12 ml, 11.572 mmol) was added dropwise to the above aqueous layer to adjust pH = 9-10. The resulting mixture was stirred at 25°C for 0.5 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was extracted with EA (2 x 40 ml). The combined organic layers were washed with brine (90 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography based on silica gel eluted with (DCM / MeOH = 10:1) to obtain the desired product 2,6-dimethyltetrahydro- 1H -pyrrolazine-7a( 5H )-carboxylic acid ethyl ester (140 mg, 2 steps, yield 20%) as a brown liquid. MS: m/z = 208.0 (M+H ⁺ , ESI+) Step 5 : (2,6- dimethyltetrahydro - 1H - pyrrolazine -7a( 5H )-yl ) methanol (Example 4- Intermediate 6 )

To a solution of ethyl 2,6-dimethyltetrahydro- 1H -pyrrolizine-7a( 5H )-carboxylate (680 mg, 3.278 mmol) in THF (7 mL) was added _LiAlH4 (6.6 mL, 6.562 mmol) at 0°C under _N2 . The mixture was stirred at 25°C for 14 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0°C by adding _H2O (0.3 mL), 15% NaOH solution (0.3 mL) and _H2O (0.6 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with _H2O (80 mL). The aqueous layer was extracted with DCM (60 mL). The organic layer was concentrated under reduced pressure to give (2,6-dimethyltetrahydro- 1H -pyrrolizine-7a( 5H ) -yl ) methanol (420 mg, yield 77%) as a colorless liquid. MS: m/z = 166.0 (M+H ⁺ , ESI+) Step 6 : 3-(1-(( S )-4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl ) -8- methyl -2-( methylthio )-8,9 - dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 4 - Intermediate 7 )

To a solution of tert-butyl (3-(1-(( S )-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl) carbamate (2.8 g, 5.373 mmol) in dioxane (42 ml) and _H2O (14 ml) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3-dioxacyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.765 g, 5.373 mmol), Ruphos-Pd- _G3 (1.343 g, 1.607 mmol) and K ₃ PO ₄ (3.416 g, 16.094 mmol). The mixture was stirred at 100 °C under argon for 4 hours. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H ₂ O (140 ml). The resulting mixture was extracted with EA (100 ml). The combined organic layers were washed with brine (120 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with EA/PE (78%) to give the desired product 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (2.4 g, yield 57%) as a yellow solid. MS: m/z = 771.1 (M+H ⁺ , ESI+) Step 7 : 3-(1-(( S )-4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl) ethynyl ) naphthalen - 1- yl ) -8- methyl -2-( methylsulfonyl )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 4- Intermediate 8 )

To a solution of 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, 1.297 mmol) in THF (10 mL) and _H2O (10 mL) was added potassium persulfate (4 g, 6.483 mmol) under argon at 0°C. The resulting mixture was stirred at 25°C under argon for 2 hours. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with NaHSO ₃ solution at 0°C. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (100 mL). The mixture was extracted with EA (3×40 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, yield 96%) as a yellow solid. MS: m/z = 803.2 (M+H ⁺ , ESI+) Step 8 : 3-(1-(( S )-2-((2,6 -dimethylentetrahydro - 1H- pyrrolizin -7a( 5H ) -yl ) methoxy )-4 - fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen-1- yl )-8- methyl - 8,9- dihydro - 10H - 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 4- Intermediate 9 )

To a solution of (2,6-dimethylentetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (61 mg, 0.372 mmol) in THF (3 mL) was added NaH (20 mg, 0.500 mmol) under argon at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the above mixture was added 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.248 mmol) at 0°C under argon. The mixture was stirred at 0°C for another 1 hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NH4Cl solution (60 mL) at 0°C. The mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (60 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with (MeOH / DCM = 1:20) to give the desired product 3-(1-(( S )-2-((2,6-dimethylentetrahydro- 1H- pyrrolizin-7a( 5H )-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, yield 65%) as a yellow solid. MS: m/z = 888.3 (M+H ⁺ , ESI+) Step 9 : 3-(1-(( S )-2-((2,6 -dimethylentetrahydro - 1H- pyrrolizin -7a( 5H ) -yl ) methoxy )-5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -8- methyl -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 4- Intermediate 10 )

To a solution of 3-(1-(( S )-2-((2,6-dimethylentetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (160 mg, 0.180 mmol) in N,N-dimethylformamide (DMF) (3 ml) was added CsF (274 mg, 1.800 mmol). The mixture was stirred at 25°C for 1 hour under an atmosphere of argon. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was purified by reversed-phase flash chromatography under the following conditions to give the desired product 3-(1-(( S )-2-((2,6-dimethylentetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, yield 53%) as a yellow solid: C18 silica gel; mobile phase, ACN in H ₂ O solution (0.1% FA), gradient from 10% to 50% in 15 minutes; detector, ultraviolet (UV) 254 nm. MS: m/z = 732.3 (M+H ⁺ , ESI+) Step 10 : 4-((8 S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((2,6- dimethyltetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-4- fluoro -8- methyl - 9,10- dihydro -8 H -7- oxa - 1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethynyl- 6- fluoronaphth -2- ol (Example 4 )

To a solution of 3-(1-(( S )-2-((2,6-dimethylentetrahydro- 1H- pyrrolazin-7a( 5H )-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, 0.082 mmol) in ACN (1 mL) was added HCl/dioxane (1.5 mL, 1.476 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 4 ) (13.40 mg, yield 23%) as a yellow solid: Waters 2767/Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 10 mmol NH ₄ HCO ₃ /H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 50%~50%; retention time: 6.4-11 minutes in 16 minutes. MS: m/z =688.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, MeOD) δ 8.03 - 7.90 (m, 1H), 7.86 – 7.74 (m, 2H), 7.36 – 7.25 (m, 2H), 7.23 – 7.11 (m, 1H), 6.85 – 6.75 (m, 1H), 6.68 - 6.54 (m, 1H), 5.12 – 4.91 (m, 4H), 4.68 – 4.19 (m, 3H), 3.83 – 3.34 (m, 6H), 2.88 - 2.76 (m, 2H), 2.66 - 2.54 (m, 2H), 1.74 – 1.59 (m, 3H), 1.37 - 1.14 (m, 3H). 5. Synthesis scheme of Example 5 Experimental procedure of Example 5 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -8- methyl -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5 - yl )-5- ethynyl- 6- fluoronaphthalen - 2 - ol Step 1 : 3-(1-(( S )-4- fluoro - 5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-8 - methyl -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 5- Intermediate 2 )

To a solution of (1-(morpholinylmethyl)cyclopropyl)alcohol (64 mg, 0.372 mmol) in THF (3 mL) was added NaH (20 mL, 0.500 mmol) under hydrogen at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the above mixture was added 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 4- Intermediate 8 ) (200 mg, 0.248 mmol) at 0°C under argon. The resulting mixture was stirred at 0°C for another hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NH4Cl solution (60 mL) at 0°C. The resulting mixture was extracted with EA (3×40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM = 1:20) to give the desired product 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, yield 71%) as a yellow solid. MS: m/z = 894.4 (M+1, ESI+). Step 2 : 3-(1-(( S )-5-(8- ethynyl -7- fluoro -3-( methoxymethoxy ) naphthalen - 1- yl )-4- fluoro -8- methyl -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 5- Intermediate 3 )

To a solution of 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, 0.198 mmol) in DMF (3 mL) was added CsF (306 mg, 1.98 mmol). The mixture was stirred at 25 °C under argon for 1 hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was purified by reverse phase flash chromatography under the following conditions to give the desired product 3-(1-(( S )-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (100 mg, yield 60%) as a yellow solid: C18 silica gel; mobile phase, ACN in _H2O (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. MS: m/z =738.2 (M+1, ESI+). Step 3 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -8- methyl -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 5 )

To a solution of 3-(1-(( S )-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 0.108 mmol) in ACN (1 mL) was added HCl/dioxane (2 mL, 1.944 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 5 ) as a yellow solid (14.13 mg, yield 18%): Waters 2767/Qda, column: Exbridge C18 19*250 mm, 10 μm; mobile phase A: 10 mmol NH ₄ HCO ₃ /H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 46%~46%; retention time: 9.8-12.3 min in 18 min. MS: m/z =694.0 (M+1, ESI+). MS: m/z =694.0 (M+1, ESI+). ¹ H NMR (400 mHz, MeOD) δ 8.04 - 7.94 (m, 1H), 7.87 - 7.74 (m, 2H), 7.36 - 7.25 (m, 2H), 7.24 - 7.11 (m, 1H), 6.86 - 6.74 (m, 1H), 6.71 - 6.56 (m, 1H), 4.71 - 4.18 (m, 3H), 3.70 - 3.65 (m, 4H), 3.62 - 3.40 (m, 2H), 2.62 - 2.36 (m, 6H), 1.77 - 1.60 (m, 3H), 1.36 - 1.15 (m, 3H), 0.80 - 0.68 (m, 2H), 0.56 - 0.46 (m, 2H). 6. Synthesis scheme of Example 6 Experimental procedure of Example 6 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl-9,10-dihydro-8H - 7-oxa- 1,3,6,10 - tetraazacyclohepta [ de ] naphthalen - 5 -yl ) -5- ethynyl- 6- fluoronaphthalen -2 -ol Step 1 : 3-(1-(( S )-4- fluoro - 5- (7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl )ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro - 8H -7-oxa-1,3,6,10-tetraazacyclohepta[de ] naphthalen -5- yl )-5- ethynyl -6- fluoronaphthalen - 2 - ol -pyrrolizine -7a( 5H )-yl ) methoxy ) -8- methyl -8,9- dihydro - 10H- 7- oxa - 1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 6- Intermediate 2 )

3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 4- Intermediate 8 ) (300 mg, 0.374 mmol) and (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol ( Example 6 - Intermediate 1 ) were added to the mixture under anhydrous conditions at -78°C. To a solution of 4-(4-(4-(4-(4-nitro-1-yl)-2-nitropropene) (89 mg, 0.560 mmol) in THF (3 ml) was added t-BuONa (72 mg, 0.748 mmol). The mixture was stirred at -78°C for 1 hour. The reaction was quenched with NH ₄ Cl solution (60 ml) at -78°C. The mixture was extracted with EA (3×40 ml). The combined organic layers were washed with brine (60 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with (MeOH / DCM = 1:10) to give the desired product 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (240 mg, yield 72%) as a yellow solid. MS: m/z = 882.3 (M+1, ESI+). Step 2 : 3-(1-(( S )-5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4 - fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizine7a ( 5H )-yl ) methoxy ) -8- methyl -8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen - 10- yl ) ethyl ) pyridin -2- amine (Example 6- Intermediate 3 )

To a solution of 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro-10H - 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (220 mg, 0.249 mmol) in DMF (3 mL) was added CsF (379 mg, 2.490 mmol). The mixture was stirred at 25°C for 1 hour under an atmosphere of argon. The reaction mixture was purified by reverse phase flash chromatography under the following conditions to give the desired product 3-(1-(( S )-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, yield 75%) as a yellow solid: C18 silica gel; mobile phase, ACN in _H2 O solution (0.1% FA), gradient from 30% to 70% in 15 minutes; detector, UV 254 nm. MS: m/z =726.2 (M+1, ESI+). Step 3 : 4-((8 S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-8- methyl - 9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethynyl -6- fluoronaphth -2- ol (Example 6 )

To a solution of 3-(1-(( S )-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H-7 -oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 0.21 mmol) in ACN (2 mL) was added HCl/dioxane (3.3 mL, 3.224 mmol). The mixture was stirred at 25°C under argon for 2 hours. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase flash chromatography under the following conditions to give the desired product 4-(( 8S )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as _a yellow solid (118 mg, racemate): C18 silica gel; mobile phase, ACN in _H2O (0.1% _NH3H2 O), gradient from 40% to 80% in 10 min; detector, UV 254 nm. MS: m/z =682.2 (M+1, ESI+) MS: m/z =682.2 (M+H, ESI+) ¹ H NMR (400 mHz, MeOD) δ 8.04 – 7.93 (m, 1H), 7.87 – 7.75 (m, 2H), 7.35 - 7.25 (m, 2H), 7.24 – 7.10 (m, 1H), 6.86 - 6.76 (m, 1H), 6.72 – 6.55 (m, 1H), 5.32 (d, J = 53.0 Hz, 1H), 4.70 – 4.19 (m, 3H), 3.77 – 3.35 (m, 3H), 3.28 - 3.18 (m, 2H), 3.08 - 2.96 (m, 1H), 2.46 – 2.11 (m, 3H), 2.07 - 1.86 (m, 3H), 1.74 – 1.59 (m, 3H), 1.38 – 1.14 (m, 3H). Step 4 : Example 6a and Example 6b

Compound Example 6 (100 mg) was purified by SFC (column: Regis (S,S) Wilcox-O1, MeOH (+0.1% 7.0 mol/L ammonium in MeOH)/CO ₂ = 55/45) to give Example 6a (40.46 mg, 40%) and Example 6b (31.19 mg, 31%). Example 6a : 4-(( S )-10-(( R )-1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin - 7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H-7 - oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6 -fluoronaphthalen -2- ol LC-MS: (ES, m/z ): [M+H] ⁺ = 682.0 ¹ H NMR (400 MHz, MeOD) δ 8.00 (d, J = 4.8 Hz, 1H), 7.87 – 7.75 (m, 2H), 7.34 – 7.26 (m, 2H), 7.22 - 7.12 (m, 1H), 6.86 - 6.78 (m, 1H), 6.66 - 6.56 (m, 1H), 5.31 (d, J = 53.6 Hz, 1H), 4.40 - 4.17 (m, 3H), 3.68 - 3.41 (m, 3H), 3.27 - 3.16 (m, 2H), 3.07 - 2.97 (m, 1H), 2.42 - 2.11 (m, 3H), 2.06 - 1.86 (m, 3H), 1.71 - 1.58 (m, 3H), 1.25 - 1.14 (m, 3H). Example 6b : 4-(( S )-10-(( S )-1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H-7 -oxa- 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol LC-MS: (ES, m/z ): [M+H] ⁺ = 682.0 ¹ H NMR (400 MHz, MeOD) δ 8.00 - 7.92 (m, 1H), 7.87 – 7.72 (m, 2H), 7.35 – 7.25 (m, 7 - 8 (m, 2H), 7.23 - 7.12 (m, 1H), 6.84 - 6.74 (m, 1H), 6.69 - 6.57 (m, 1H), 5.33 (d, J = 55.0 Hz, 1H), 4.71 - 4.61 (m, 1H), 4.41 - 4.29 (m, 2H), 3.77 - 3.34 (m, 3H), 3.30 - 3.17 (m, 2H), 3.09 - 2.99 (m, 1H), 2.40 - 2.12 (m, 3H), 2.06 - 1.88 (m, 3H), 1.70 (d, J = 6.7 Hz, 3H), 1.37 - 1.22 (m, 3H). 7. Synthesis scheme of Example 7 Experimental procedure of Example 7 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((4,4 -difluoro -1 -methylpyrrolidin -2- yl ) methoxy )-4- fluoro -8 - methyl -9,10- dihydro - 8H -7-oxa- 1,3,6,10 - tetraazacyclohepta [ de ] naphthalen - 5 -yl )-5 -ethynyl -6- fluoronaphthalen -2- ol Step 1 : 3-(1-(( S )-2-((( S )-4,4 -difluoro -1- methylpyrrolidin -2 -yl ) methoxy )-4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-8- methyl -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 7- Intermediate 2 )

To a slurry of NaH (60%) (20 mg, 0.05 mmol) in THF (1 mL) was added a solution of ( R )-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol ( Example 7- Intermediate 1 ) (113 mg, 0.75 mmol) in THF (1 mL) at 0° C. The solution was stirred at 0° C. for 30 min. To the above mixture was added a solution of 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.25 mmol) in THF (1 mL). The mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with _NH4Cl (aq., 10 mL) and the solution was extracted with EA (2 x 20 mL). The organic _phase was washed with brine (10 mL) and dried over _Na2SO4 . The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography using DCM/MeOH = 20:1 to give 3-(1-(( S )-2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H -7 -oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (210 mg, 64%) as a yellow oil. MS: m/z = 874.3 (M+1, ESI+). Step 2 : 3-(1-(( S )-2-((( S )-4,4 -difluoro -1 -methylpyrrolidin -2- yl ) methoxy )-5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen - 1 -yl )-4 - fluoro -8- methyl - 8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 7- Intermediate 3 )

A mixture of 3-(1-(( S )-2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, 0.22 mmol), CsF (330 mg, 2.18 mmol) in DMF (2 ml) was stirred at room temperature for 2 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was then purified by preparative HPLC (column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL/min) to obtain the desired product 3-(1-(( S )-2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10 H as a yellow solid. -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (104 mg, 60%). MS: m/z =718.1 (M+1, ESI+). Step 3 : 4-((8 S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-2 - ((( S )-4,4 -difluoro -1- methylpyrrolidin -2- yl ) methoxy )-4- fluoro -8- methyl -9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5 -yl )-5- ethynyl -6- fluoronaphthalen -2- ol ( Example 7 )

To a solution of 3-(1-(( S )-2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (94 mg, 0.13 mmol) in ACN (0.5 ml) was slowly added dropwise HCl/dioxane (4 mol/L, 0.5 ml) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda, column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 18-28%; retention time: 7.9-10.8 min in 16 min) to give the desired product as a yellow solid to give Example 7 (20.08 mg, 22%). MS: m/z =673.9 (M+1, ESI+) ¹ H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.05 – 7.89 (m, 2H), 7.76 – 7.63 (m, 1H), 7.51 - 7.42 (m, 1H), 7.38 (s, 1H), 7.23 – 7.07 (m, 1H), 6.76 – 6.62 (m, 1H), 6.47 – 6.28 (m, 1H), 5.83 - 5.63 (m, 2H), 4.71 – 3.92 (m, 4H), 3.66 - 3.50 (m, 1H), 3.05 - 2.93 (m, 1H), 2.81 – 2.52 (m, 2H), 2.39 (s, 3H), 2.35 - 2.15 (m, 1H), 1.69 - 1.49 (m, 3H), 1.31 - 1.03 (m, 3H). 8. Synthesis scheme of Example 8 Experimental procedure of Example 8 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((( S )-1-(2,2 -difluoroethyl ) azetidin -2- yl ) methoxy )-4- fluoro -8- methyl -9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5 - yl )-5- ethynyl- 6- fluoronaphthalen -2- ol Step 1 : ( S ) -azetidin -2- ylmethanol (Example 8 - Intermediate 2 )

To a solution of ( S )-2-(Hydroxymethyl)azetidine-1-carboxylic acid tert- butyl ester ( Example 8- Intermediate 1 ) (1 g, 5.35 mmol) in DCM (5 mL) was added HCl/dioxane (4 mol/L, 6 mL). The reaction mixture was stirred at 25 °C for 16 h. The solvent was removed under reduced pressure to give ( S )-azetidine-2-ylmethanol (700 mg, 98%) as a colorless oil. MS: m/z = 88.2 (M+1, ESI+). Step 2 : ( S ) -(1-(2,2 -difluoroethyl ) azetidine -2- yl ) methanol (Example 8- Intermediate 3 )

To an ice-cold solution of K ₂ CO ₃ (2.4 g, 17.70 mmol) in ACN (10 ml) and ( S )-azetidin-2-ylmethoxide hydrochloride (700 mg, 8.04 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (1.7 g, 8.04 mmol). The reaction mixture was allowed to warm to room temperature. After 24 h, the reaction was diluted with water (30 ml), the mixture was extracted with EA (40 ml), and the solution was washed with brine (40 ml). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography using PE/EA=1:1 to give ( S )-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (274 mg, 22%) as a colorless oil. MS: m/z =152.1 (M+1, ESI+). Step 3 : 3-(1-(( S )-2-((( S )-1-(2,2 -difluoroethyl ) azetidin- 2- yl ) methoxy )-4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-8- methyl -8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 8- Intermediate 4 )

To a slurry of NaH (60%, oil, 37 mg, 0.56 mmol) in THF (1 mL) at 0 °C was added a solution of ( S )-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (125 mg, 0.82 mmol) in THF (1 mL). The reaction mixture was stirred at 0°C for 30 min, and to the above mixture was added a solution of 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (225 mg, 0.28 mmol) in THF (1 mL). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with concentrated _NH4Cl (aq., 5 mL), and the solution was extracted with EA (2 x 20 mL). The organic phase was washed with brine (10 ml) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography eluting with DCM/MeOH=20:1 to obtain 3-(1-(( S )-2-((( S )-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (261 mg, 36%) as a yellow oil. MS: m/z = 874.2 (M+1, ESI+) Step 4 : 3-(1-(( S )-2-((( S )-1-(2,2 -difluoroethyl ) azetidin -2- yl ) methoxy )-5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -8- methyl -8,9 - dihydro - 10H -7- oxa -1,3,6,10 - tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 8- Intermediate 5 )

A mixture of 3-(1-(( S )-2-((( S )-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (261 mg, 0.30 mmol), CsF (454 mg, 2.98 mmol) in DMF (3 ml) was stirred at 25 °C for 2 h. The residue was then purified by preparative HPLC (column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL/min) to give the desired product 3-(1-(( S )-2-((( S )-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (107 mg, 50%) as a yellow solid. MS: m/z = 718.2 (M+1, ESI+) Step 5 : 4-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((( S )-1-(2,2 -difluoroethyl ) azetidin -2- yl ) methoxy ) -4- fluoro -8- methyl -9,10 -dihydro - 8H -7 - oxa - 1,3,6,10 - tetraazacyclohepta [ de ] naphth -5- yl )-5- ethynyl- 6- fluoronaphth -2- ol (Example 8 )

To a solution of 3-(1-(( S )-2-((( S )-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (87 mg, 0.12 mmol) in DCM (1 ml) was added HCl/dioxane (4 mol/L, 0.3 ml). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with DCM/MeOH (10/1 ml). The mixture was washed with concentrated NaHCO ₃ (aqueous solution, 10 mL), then with brine (10 mL), and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda column: Pursuit XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 18-23%; retention time: 7-9.2 min in 16 min) to give Example 8 (4.49 mg, 5%) as a light yellow solid. MS: m/z =674.0 (M+1, ESI+) ¹ H NMR (400 mHz, DMSO) δ 10.38 (brs, 0.47H, FA), 8.42 (s, 1H), 8.08 – 7.88 (m, 2H), 7.76 - 7.62 (m, 1H), 7.52 - 7.34 (m, 2H), 7.25 – 7.04 (m, 1H), 6.80 – 6.61 (m, 1H), 6.46 - 6.24 (m, 1H), 6.16 - 5.82 (m, 1H), 5.80 – 5.49 (m, 2H), 4.74 – 3.77 (m, 4H), 3.74 - 3.54 (m, 2H), 3.05 – 2.70 (m, 3H), 2.16 - 2.00 (m, 2H), 1.68 – 1.52 (m, 3H), 1.34 - 1.02 (m, 3H). 9. Synthesis scheme of Example 9 Experimental procedure of Example 9 : 4-(( 8S )-2-((2- oxabicyclo [2.1.1] hexane -4- yl) methoxy )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-10-(1-(2- aminopyridin -3- yl ) ethyl)-4- fluoro - 8 - methyl - 9,10 - dihydro - 8H - 7 - oxabicyclo [ 1,3,6,10-tetraazacyclohepta [ de] naphthalen-5- yl )-5- ethynyl-6- fluoronaphthalen-2- ol Step 1 : 3-(1-(( S )-2-((2- oxabicyclo [2.1.1] hexane -4- yl ) methoxy )-4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-((triisopropylsilyl ) ethynyl ) naphthalen-1- yl )-8- methyl -8,9-dihydro-10H-7- oxabicyclo [2.1.1 ] hexane-4-yl)methoxy)-4-fluoro-5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl)ethynyl)naphthalen-1-yl)-8 -methyl -8,9- dihydro - 10H- 7 -oxabicyclo[ 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 9- Intermediate 2 )

To a solution of (2-oxabicyclo[2.1.1]hexan-4-yl)methanol (44 mg, 0.372 mmol) in THF (3 mL) was added NaH (60%, oil, 20 mg, 0.500 mmol) under argon at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the above mixture was added 3-(1-(( S )-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 4- Intermediate 8 ) (200 mg, 0.248 mmol) under argon at 0°C. The mixture was stirred at 0°C for another 1 hour. The reaction was quenched with _NH4Cl solution (40 mL) at 0°C. The mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (60 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM = 1:10) to give the desired product 3-(1-(( S )-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro- 10H -7-oxabicyclo[ 2.1.1 ]hexan-4-yl)ethyl)pyridin-2-amine (200 mg, yield 54%) as a yellow solid. MS: m/z = 837.2 (M+H, ESI+). Step 2 : 3-(1-(( S )-2-((2- oxabicyclo [2.1.1]hexane-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxabicyclo[2.1.1] hexane -4 - yl )methoxy)-5-(8- ethynyl - 7 - fluoro- 3- ( methoxymethoxy ) naphthalen-1-yl)-4- fluoro-8-methyl - 8,9 - dihydro - 10H - 7 - oxabicyclo[ 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 9- Intermediate 3 )

To a solution of 3-(1-(( S )-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro- 10H -7-oxabicyclo[ 2.1.1 ]hexan-4-yl)ethyl)pyridin-2-amine (180 mg, 0.216 mmol) in DMF (3 mL) was added CsF (324 mg, 2.160 mmol). The mixture was stirred at 25°C under argon for 1 hour. The resulting mixture was filtered, and the filter cake was washed with EA (20 ml). The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase flash chromatography under the following conditions to give the desired product 3-(1-(( S )-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro- 10H -7-oxabicyclo[ 2.1.1 ]hexan-4-yl)ethyl)pyridin-2-amine (130 mg, yield 79%) as a yellow solid: C18 silica gel; mobile phase, ACN in _H2O (0.1% FA), gradient from 10% to 50% over 15 min; detector, UV 254 nm. MS: m/z = 681.2 (M+H, ESI+). Step 3 : 4-(( 8S )-2-((2- oxabicyclo [2.1.1] hexane-4-yl)methoxy)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxabicyclo[2.1.1]hexane -4- yl ) methoxy ) -10- ( 1- (2-aminopyridin-3-yl)ethyl)-4-fluoro -8- methyl - 9,10 - dihydro - 8H - 7- oxabicyclo[ 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 9 )

To a solution of 3-(1-(( S )-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro- 10H- 7-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-( methoxymethoxy )naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxabicyclo[2.1.1]naphthalen-10-yl)ethyl)pyridin-2-amine (110 mg, 0.160 mmol) in ACN (2 mL) was added HCl/dioxane (4 mol/L, 3.3 mL, 2.910 mmol). The mixture was stirred at 25°C under argon for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters 2767 column: Exbridge C18, 19*250 mm, 10 μm, mobile phase A: 10 mmol NH ₄ HCO ₃ /H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 42-42%; retention time: 7.1-10 min in 16 min) to give the desired product ( Example 9 ) (17.69 mg, yield 17%) as a yellow solid. MS: m/z =636.9 (M+H, ESI+) ¹ H NMR (400 mHz, CD3OD_SPE) δ 8.03 - 7.90 (m, 1H), 7.85 – 7.69 (m, 2H), 7.34 – 7.13 (m, 3H), 6.85 – 6.71 (m, 1H), 6.68 – 6.54 (m, 1H), 4.74 – 4.12 (m, 3H), 3.77 – 3.63 (m, 2H), 3.57 – 3.27 (m, 3H), 2.03 – 1.90 (m, 2H), 1.72 - 1.54 (m, 5H), 1.32 - 1.13 (m, 3H). 10. Synthesis scheme of Example 10a and Example 10b Experimental Procedures of Examples 10a and 10b Step 1 : (3-(1-(( S )-5- chloro -4- fluoro -8- methyl -2-( methylsulfonyl )-8,9 - dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 10- Intermediate 1 )

To a solution of tert-butyl (3-(1-(( S )-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen- 10 -yl)ethyl)pyridin-2-yl)carbamate ( Example 3- Intermediate 6 ) (1 g, 1.920 mmol) in ACN (12 mL) and _H2O (4 mL) was added potassium hydrogen persulfate (5.9 g, 9.595 mmol) under argon at 0°C. The resulting mixture was stirred at 25°C for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NaHSO3 solution at 0°C. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (80 mL). The mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product (3-(1-(( S )-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid tert -butyl ester (1 g, yield 94%) as a yellow solid. MS: m/z =553.1 (M+H, ESI+). Step 2 : (3-(1-(( S )-5- chloro -4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 10- Intermediate 3 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol ( Example 10- Intermediate 2 ) (440 mg, 2.72 mmol) in THF (10 ml) was added NaH (160 mg, 3.60 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added tert-butyl (3-(1-(( S )-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.0 g, 1.80 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for another hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with NH ₄ Cl solution (100 mL) at 0°C. The resulting mixture was extracted with EA (3×60 mL). The combined organic layers were washed with brine (120 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with (MeOH / DCM = 1:10) to give the desired product (3-(1-(( S )-5-chloro-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid tert -butyl ester (800 mg, yield 69%) as a yellow solid. MS: m/z = 632.2 (M+H, ESI+). Step 3 : 3-(1-(( S )-5-(7,8 -difluoro -3-( methoxymethoxy ) naphthalen -1 - yl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen - 10- yl ) ethyl ) pyridin -2- amine (Example 10- Intermediate 5 )

To a solution of (3-(1-(( S )-5-chloro-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-10-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (150 mg, 0.237 mmol) in dioxane (3 mL) and H ₂ O (1 mL) was added 2-(7,8-difluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane ( Example 10- Intermediate 4 ) (84 mg, 0.237 mmol), Ruphos-Pd-G ₃ (60 mg, 0.071 mmol) and K ₃ PO ₄ (153 mg, 0.711 mmol). The mixture was stirred at 100° C. for 2 hours under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H ₂ O (40 ml). The resulting mixture was extracted with EA (20 ml). The combined organic layers were washed with brine (40 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (9%) to give the desired product 3-(1-(( S )-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, yield 83%) as a yellow solid. MS: m/z = 720.2 (M+H, ESI+). Step 4 : Example 10a and Example 10b

To a solution of 3-(1-(( S )-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (170 mg, 0.236 mmol) in ACN (2 mL) was added HCl/dioxane (4.3 mL, 4.252 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product: Preparative HPLC (Waters 2767) column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 0.05% NH ₃ H ₂ O/H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 39-39%; retention time: 8.8-12.8 minutes in 16 minutes. Example 10a : 4-(( S )-10-(( R )-1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5,6 -difluoronaphthalen -2- ol as a white solid (7.90 mg, yield 4%). MS: m/z = 676.0 (M+H, ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.27 (s, 1H), 8.01 (dd, J = 4.9, 1.5 Hz, 1H), 7.79 – 7.66 (m, 2H), 7.63 - 7.51 (m, 1H), 7.37 (s, 1H), 7.28 - 7.12 (m, 1H), 6.75 - 6.66 (m, 1H), 6.45 - 6.32 (m, 1H), 5.73 (s, 2H), 5.41 – 5.20 (m, 1H), 4.23 – 4.10 (m, 3H), 3.53 - 3.46 (m, 2H), 3.13 - 2.99 (m, 3H), 2.88 - 2.78 (m, 1H), 2.18 – 1.94 (m, 4H), 1.90 - 1.75 (m, 3H), 1.60 - 1.48 (m, 3H), 1.10 (d, J = 6.5 Hz, 3H). Example 10b : 4-(( S )-10-(( S )-1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta[ de ] naphthalen -5- yl )-5,6 -difluoronaphthalen -2- ol as a white solid (5.90 mg, yield 3%). MS: m/z = 676.0 (M+H, ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 7.96 (d, J = 4.1 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.58 - 7.44 (m, 1H), 7.30 (s, 1H), 7.18 (d, J = 34.6 Hz, 1H), 6.72 - 6.60 (m, 1H), 6.46 - 6.34 (m, 1H), 5.72 (s, 2H), 5.43 - 5.19 (m, 1H), 4.72 - 4.56 (m, 1H), 4.24 - 4.07 (m, 2H), 3.66 - 3.55 (m, 2H), 3.11 – 3.01 (m, 3H), 2.88 - 2.78 (m, 1H), 2.14 – 1.98 (m, 4H), 1.90 – 1.75 (m, 3H), 1.60 (d, J = 6.7 Hz, 3H), 1.23 – 1.20 (m, 3H). 11. Synthesis scheme of Example 11 Experimental procedure of Example 11 : 3-(( 8S )-10-(1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8- methyl -9,10- dihydro - 8H- 7 - oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- chloro -4- cyclopropylphenol Step 1 : 3-(1-(( S )-5-(3- chloro -2 - cyclopropyl -5-( methoxymethoxy ) phenyl )-4 - fluoro -2-((( 2R , 7aS ) -2-fluorotetrahydro- 1H - pyrrolizin -7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)-5-chloro-4 - cyclopropylphenol ) -yl ) methoxy )-8- methyl -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen- 10 - yl ) ethyl ) pyridin -2- amine (Example 11- Intermediate 2 )

To a solution of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( Example 11 - Intermediate 1 ) (100 mg, 0.29 mmol) in dioxane (2 mL)/H ₂ O (0.2 mL) was added (3-(( R )-1-(( S )-5-chloro-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy]-8-methyl-8,9-dihydro-10 H -7-oxaborolane[ de ]naphth-10-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester ( Example 10 - Intermediate 3 ) (186 mg, 0.29 mmol), Cs ₂ CO ₃ (192 mg, 0.59 mmol) and Pd(dppf)Cl ₂ (21 mg, 0.03 mmol). The reaction mixture was stirred at 100 °C under N ₂ for 4 h. After completion, water (5 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The organic layer was filtered and concentrated, and dried over Na ₂ SO _4. The product was purified by silica gel chromatography using DCM/MeOH = 20:1 and preparative HPLC (Waters 2767/Qda column: Perthwaite XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 18-23%; retention time: 7-9.2 min in 16 min) The residue was purified to give 3-(1-(( S )-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-10-yl)ethyl)pyridin-2-amine (80 mg, 38%) as a yellow solid. MS: m/z =708.2 (M+H ⁺ , ESI+) Step 2 : 3-(( 8S )-10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H )-yl ) methoxy ) -8- methyl -9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- chloro -4- cyclopropylphenol (Example 11 )

To a solution of 3-(1-(( S )-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 11- Intermediate 2 ) (60 mg, 0.08 mmol) in DCM (1 ml) was added HCl/dioxane (0.3 ml). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with DCM/MeOH (10/1 ml x 2). The mixture was washed with concentrated NaHCO ₃ (aqueous solution, 10 mL), then with brine (10 mL), and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda column: Perthwaite XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.05% trifluoroacetic acid (TFA)/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 18-23%; retention time: 7.3-9.8 min in 16 min) to obtain Example 11 (4.62 mg, 8%) as a light yellow solid. MS: m/z = 664.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.97 (d, J = 4.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.75 – 6.67 (m, 2H), 6.66 - 6.56 (m, 1H), 5.92 (brs, 2H), 5.41 (d, J = 52.4 Hz, 1H), 4.61 - 4.43 (m, 3H), 3.46 – 3.08 (m, 6H), 2.60 – 2.23 (m, 3H), 2.18 - 2.04 (m, 3H), 1.893 - 1.80 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H), 0.72 - 0.55 (m, 2H), 0.18 - 0.06 (m, 2H). 12. Synthesis scheme of Example 12 Experimental procedure of Example 12 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4 -fluoro -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-9,10 - dihydro - 8H- 7- oxa -1,3,6,10- tetraazacycloheptyl [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol Step 1 : ( Z )-(3-(1-((2- hydroxyethyl ) imino ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 12- Intermediate 1 )

To a solution of (3-acetylpyridin-2-yl)carbamic acid tert- butyl ester ( Example 3- Intermediate 2 ) (20 g, 84.65 mmol) in EtOH (200 mL) at 25°C under _N2 was added 2-aminoethan-1-ol (15.5 g, 253.95 mmol). The mixture was stirred at 90°C for 2 hours. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with _H2O (200 mL), extracted with EA (120 mL), and dried over _Na2SO4 . Filtered and concentrated under reduced _pressure to obtain a residue. The residue was purified by column chromatography based on silica gel eluted with (EA/PE = 85%) to give the desired product ( Z )-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (7.6 g, crude) as a colorless oil. MS: m/z = 280.0 (M+H, ESI+). Step 2 : (3-(1-((2- hydroxyethyl ) amino ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 12- Intermediate 2 )

To _a solution of ( Z )-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (7.6 g, 27.207 mmol) in MeOH (80 mL) was added _NaBH4 (3.087 g, 81.621 mmol) under N2 at 0°C. The mixture was stirred at 25°C for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with _H2O (150 mL), extracted with EA (100 _mL ), and dried over _Na2SO4 . Filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel eluted with (MeOH/DCM = 10%) to give the desired product (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (3.0 g, yield 39%) as a colorless oil. MS: m/z = 282.1 (M+H, ESI+). Step 3 : (3-(1-((2-((7- chloro - 8- fluoro - 4- hydroxy -2-( methylthio ) pyrido [4,3- d ] pyrimidin -5- yl ) oxy ) ethyl ) amino ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 12- Intermediate 3 )

To a solution of tert -butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (4.4 g, 15.709 mmol) in THF (50 mL) was added NaH (1.89 g, 47.126 mmol) at 0°C under argon. The mixture was stirred for 0.5 h at 0°C. To the above mixture was added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (4.4 g, 15.709 mmol) at 0°C under argon. The resulting mixture was stirred for another 1 h at 0°C. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched by the addition of _H2O (30 mL) at 0°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (150 mL), extracted with EA (100 mL), and dried over Na ₂ SO _4. Filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel eluted with (MeOH/DCM=9%) to obtain the desired product (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (3.4 g, yield 41%) as a yellow solid. MS: m/z = 525.1 (M+H, ESI+). Step 4 : (3-(1-(5- chloro -4- fluoro -2-( methylthio )-8,9- dihydro - 10H -7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 12- Intermediate 4 )

To a solution of tert-butyl (3-(1-((2-((7-chloro-8-fluoro- 4 -hydroxy-2-(methylthio)pyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (3.1 g, 5.905 mmol) in THF (30 ml) was added DIEA (6.87 g, 53.145 mmol) at 0°C under argon. The mixture was stirred for 0.5 h at 0°C. To the above mixture was added BopCl (4.51 g, 17.714 mmol) at 0°C under argon. The resulting mixture was stirred for another 16 h at 25°C under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H ₂ O (150 mL), extracted with EA (100 mL), and dried over Na ₂ SO _4. Filtration and concentration under reduced pressure gave a crude product. The crude product was purified by column chromatography based on silica gel eluted with (EA/PE=82%) to give the desired product (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (1.6 g, yield 53%) as a yellow solid. Structural confirmation was confirmed by two-dimensional NMR. MS: m/z = 507.1 (M+H, ESI+). Step 5 : 3-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen- 1 -yl )-2-( methylthio )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 12- Intermediate 5 )

To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl) carbamate (1.6 g, 3.156 mmol) in dioxane (21 ml) and _H2O (7 ml) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.624 g, 3.156 mmol), _Ruphos -Pd- _G3 (792 mg, 0.947 mmol) and _K3PO4 (2 g, 9.468 mmol). The mixture was stirred at 100 °C under argon for 2 hours. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with _H2O (100 mL). The mixture was extracted with EA (60 mL). The combined organic layers were washed with brine (80 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with EA/PE (70%) to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (1.3 g, yield 54%) as a yellow solid. MS: m/z = 757.2 (M+H, ESI+). Step 6 : 3-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 -yl )-2-( methylsulfonyl )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 12- Intermediate 6 )

To a solution of SM (1.3 g, 1.717 mmol) in ACN (15 ml) and H ₂ O (5 ml) was added potassium persulfate (5.28 g, 8.587 mmol) under argon at 0°C. The mixture was stirred at 25°C for 1 hour under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with NaHSO ₃ solution at 0°C. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (80 ml). The mixture was extracted with EA (3×60 ml). The combined organic layers were washed with brine (120 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl) ethyl )pyridin-2-amine (1.20 g, crude) as a yellow solid. MS: m/z = 789.1 (M+H, ESI+). Step 7 : 3-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-2-((1-( oxolinylmethyl )cyclopropyl) methoxy ) -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 12- Intermediate 7 )

To a solution of (1-(morpholinylmethyl)cyclopropyl)methanol (65 mg, 0.380 mmol) in THF (2 ml) was added NaH (20 mg, 0.506 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.253 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for another 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding H ₂ O (4 mL) at 0°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (30 mL), extracted with EA (20 mL), and dried over Na ₂ SO _4. Filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel eluted with (MeOH / DCM = 10%) to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, yield 48%) as a yellow solid. MS: m/z = 880.3 (M+H, ESI+). Step 8 : 3-(1-(5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 12- Intermediate 8 )

To a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 0.148 mmol) in DMF (3 mL) was added CsF (225 mg, 1.48 mmol). The mixture was stirred at 25 °C under argon for 1 hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was purified by reverse phase flash chromatography under the following conditions to give the desired product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 56% yield) as a yellow solid: C18 silica gel; mobile phase, ACN in _H2O (0.1% FA), gradient 10% to 50% in 15 min; detector, UV 254 nm. MS: m/z = 723.9 (M+H, ESI+). Step 9 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((1-( oxolinylmethyl ) cyclopropyl ) methoxy )-9,10 -dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 12 )

To a solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (20 mg, 0.028 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C under argon for 2 hours. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 12 ) (2.21 mg, yield 11%) as a white solid: Preparative HPLC (Waters 2767/Qda) column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 13-23%; retention time: 8.9-9.8 min in 16 min). MS: m/z = 680.0 (M+1, ESI+) ¹ H NMR (400 mHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.70 - 7.54 (m, 2H), 7.22 - 7.10 (m, 3H), 6.78 – 6.59 (m, 2H), 5.95 (brs, 2H), 4.51 – 4.18 (m, 4H), 3.78 – 3.54 (m, 5H), 3.52 – 3.38 (m, 1H), 2.99 (d, J = 33.9 Hz, 1H), 2.64 – 2.46 (m, 6H), 1.60 (dd, J = 18.7, 6.8 Hz, 3H), 0.78 - 0.66 (m, 2H), 0.56 - 0.44 (m, 2H). 13. Synthesis scheme of Example 13 Experimental procedure of Example 13 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H )-yl ) methoxy )-9,10- dihydro - 8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen- 5 - yl )-5- ethynyl - 6 - fluoronaphthalen -2- ol carboxylate Step 1 : 3-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilane ) ethynyl)naphthalen-1-yl)-2-(((2 R ,7a S ) -2 - fluorotetrahydro -1 H -pyrrolizin- 7a(5 H )-yl )methoxy)-9,10 - dihydro -8 H -7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5 -yl )-5-ethynyl-6-fluoronaphthalen - 2-ol carboxylate ) -yl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 - tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 13- Intermediate 1 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (302 mg, 1.901 mmol) in THF (10 mL) was added NaH (60%, oil, 101 mg, 2.534 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 12- Intermediate 6 ) (1 g, 1.267 mmol) at 0°C under argon. The mixture was stirred at 0°C for another 1 hour. The reaction was quenched with _NH4Cl solution (60 mL) at 0°C. The mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (60 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with (MeOH / DCM = 1:10) to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro-10H - 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (920 mg, yield 83%) as a yellow solid. MS: m/z = 868.3 (M+H) ⁺ , ESI+ Step 2 : 3-(1-(5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-8,9- dihydro -10 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 13- Intermediate 2 )

To a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (820 mg, 0.945 mmol) in DMF (10 mL) was added CsF (1.43 g, 9.447 mmol). The mixture was stirred at 25°C under argon for 1 h. The resulting mixture was diluted with _H2O (60 mL). The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (80 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro-10H - 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (450 mg, crude) as a yellow solid. MS: m/z = 712.2 (M+H) ⁺ , ESI+ Step 3 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorohexahydro -1 H -pyrrolizin -7a- yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 13 )

To a solution of SM (450 mg, 0.632 mmol) in ACN (10 ml) was added HCl/dioxane (11 ml, 11.380 mmol). The mixture was stirred at 25 °C for 1 hour under argon. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase flash chromatography under the following conditions to give the desired product ( Example 13 ) (23.93 mg, yield 5%) as a yellow solid: C18 silica gel; mobile phase, ACN in _H2O (0.1% FA), gradient from 10% to 50% in 15 minutes; detector, UV 254 nm. MS: m/z = 667.9 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.16 (brs, 1H), 8.15 (s, 0.76H, FA), 8.01 – 7.91 (m, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (d, J = 1.3 Hz, 1H), 7.15 (s, 1H), 6.74 – 6.63 (m, 1H), 6.39 – 6.26 (m, 1H), 5.82 (s, 1H), 5.74 (s, 1H), 5.36 (d, J = 54.6 Hz, 1H), 4.53 – 4.14 (m, 4H), 4.04 (d, J = 54.6 Hz, 1H), 3.83 – 3.67 (m, 1H), 3.50 – 3.37 (m, 3H), 2.97 - 2.87 (m, 1H), 2.31 – 1.77 (m, 6H), 1.66 – 1.52 (m, 3H). Step 4 : Example 13a and Example 13b

Compound Example 13 (120 mg) was purified by SFC (column: DAICELCHIRALPAK® W, EtOH (+0.1% 7.0 mol/L ammonia in EtOH solution)/CO ₂ = 63:37) to give Example 13a (20.55 mg, 17.1%) and Example 13b (21.20 mg, 17.6%). Example 13a : 4-(10-(( R )-1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5 - yl )-5- ethynyl -6- fluoronaphthalen -2- ol MS: m/z = 668.2 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO- _d6 ) δ 10.16 (s, 1H), 8.07 – 7.87 (m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (t, J = 2.2 Hz, 1H), 6.72 – 6.64 (m, 1H), 6.40 - 6.25 (m, 1H), 5.76 (d, J = 28.3 Hz, 2H), 5.30 (d, J = 54.2 Hz, 1H), 4.45 – 4.37 (m, 1H), 4.26 - 4.08 (m, 3H), 3.80 – 3.64 (m, 1H), 3.51 - 3.44 (m, 1H), 3.15 - 3.00 (m, 3H), 2.90 – 2.78 (m, 1H), 2.19 – 1.78 (m, 6H), 1.67 – 1.54 (m, 3H). Example 13b : 4-(10-(( S )-1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5 - yl )-5- ethynyl- 6- fluoronaphthalen - 2- ol MS: m/z = 668.2 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO- _d6 ) δ 10.22 (brs, 1H), 8.16 – 7.94 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 6.72 – 6.64 (m, 1H), 6.45 – 6.24 (m, 1H), 5.76 (d, J = 30.0 Hz, 2H), 5.31 (d, J = 55.8 Hz, 1H), 4.45 – 4.37 (m, 1H), 4.27 – 4.06 (m, 3H), 3.82 - 3.74 (m, 1H), 3.72 – 3.67 (m, 1H), 3.16 - 2.99 (m, 3H), 2.90 - 2.80 (m, 1H), 2.15 – 1.78 (m, 6H), 1.69 – 1.51 (m, 3H). 14. Synthesis scheme of Example 14 Experimental procedure of Example 14 : Synthesis step 1a of 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10 - dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol * (Example 14- Intermediate 2 ) : (3- acetylpyridin - 2- yl ) carbamic acid tert- butyl ester (Example 14 - Intermediate 2b )

To a stirred solution of 1-(2-aminopyridin-3-yl)ethan-1-one ( Example 14- Intermediate 2a ) (4.00 g, 29.4 mmol) in t -BuOH (20 ml, 5 vol) at room temperature was added (Boc) _2O (10.0 ml, 44.1 mmol), and the reaction mixture was heated to 80°C and stirred for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a solid, which was filtered and dried under high vacuum to give the crude compound tert- butyl (3-acetylpyridin-2-yl)carbamate ( Example 14- Intermediate 2b ) (5.0 g, crude) as a pale yellow solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 237.28 m/z [M+H]. Step 2a : ( E )-tert-butyl(3-(1-((2- hydroxyethyl ) amino ) ethyl ) pyridin -2- yl ) carbamate (Example 14- Intermediate 2d )

To a stirred solution of (3-acetylpyridin-2-yl)carbamic acid tert -butyl ester ( Example 14- Intermediate 2b ) (5.00 g, 21.2 mmol) and 2-aminoethan-1-ol ( Example 14- Intermediate 2c ) (2.50 g, 31.8 mmol) in THF (50 mL, 10 vol) was added titanium ethoxide (14.5 g, 63.6 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (twice), the combined organic layers were washed with _brine , dried over anhydrous _Na2SO4 , filtered and evaporated under reduced pressure to give crude compound ( E ) -tert- butyl(3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate ( Example 14- Intermediate 2d ) (5.50 g, crude) as a white solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 280.33 m/z [M+H]. Step 3a : (3-(1-((2- hydroxyethyl ) amino ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 14- Intermediate 2 )

To a stirred solution of ( E )-(3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester ( Example 14- Intermediate 2d ) (5.00 g, 17.9 mmol) in MeOH (50 ml, 10 vol) at 0°C was added _NaBH4 (1.35 g, 35.8 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester ( Example 14- Intermediate 2 ) (1.80 g, crude) as a white solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 282.30 m/z [M+H]. Step 1 : tert-butyl (3-(1-((2-((7- chloro -2-( ethylthio )-8- fluoro -4- oxo -3,4- dihydropyrido [4,3- d ] pyrimidin -5- yl )oxy ) ethyl ) amino ) ethyl ) pyridin - 2- yl ) carbamate (Example 14 - Intermediate 3 )

To a stirred solution of 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3- d ]pyrimidin-4( 3H )-one ( Example 1- Intermediate 2 ) (1.80 g, 6.14 mmol) in THF (31 mL, 17 vol) was added NaH (1.00 g, 27.6 mmol) at 0°C and stirred for 30 min, followed by the addition of tert- butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate ( Example 14- Intermediate 2 ) (2.00 g, 7.37 mmol) at 0°C and the reaction mixture was stirred for 1 h at 0°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 ml), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to get a crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 5% methanol in DCM as eluent to give tert-butyl (3-(1-((2-((7-chloro-2-(ethylthio)-8-fluoro-4-oxo-3,4-dihydropyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate ( Example 14- Intermediate 3 ) (1.50 g, yield: 45%) as an off -white solid. MS (LC-MS): 539.37 m/z [M+H]. Step 2 : (3-(1-(5- chloro -2-( ethylthio )-4- fluoro -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 14- Intermediate 4 )

To a stirred solution of tert-butyl (3-(1-((2-((7-chloro-2-( ethylthio )-8-fluoro-4-oxo-3,4-dihydropyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate ( Example 14- Intermediate 3 ) (0.25 g, 0.46 mmol) in DCM (2.5 mL, 10 vol) at room temperature were added BOP-Cl (0.13 g, 1.62 mmol) and DIPEA (1.20 mL, 6.72 mmol) and the reaction mixture was heated to 60 °C and stirred for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2 x 20 mL), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 50% ethyl acetate in petroleum ether as eluent to afford tert-butyl (3-(1-(5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl) carbamate ( Example 14- Intermediate 4 ) (0.90 g, total 6 batches (6 x 250 mg), crude) as a brown solid. MS (LCMS): 521.35 m/z [M+H]. Step 3 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-2-( ethylthio )-4- fluoro - 8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 14- Intermediate 6 )

To a stirred solution of tert - butyl (3-(1-(5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate ( Example 14- Intermediate 4 ) (0.30 g, 0.58 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( Example 14- Intermediate 5 ) (0.25 g, 0.69 mmol) in a mixture of 1,4-dioxane and water (2:1, 9 ml) was added KOtBu (0.19 g, 1.73 mmol) at room temperature and heated to 40 ℃ under N ₂ atmosphere for 10 minutes. Tetrakis(triphenylphosphine)palladium (0.067 g, 0.06 mmol) was added thereto at room temperature and the reaction mixture was heated to 90°C and stirred for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 25 ml), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 5% methanol in DCM as eluent to afford 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 14- Intermediate 6 ) (0.30 g, total 3 batches (3 x 250 mg), yield: 28%) as a light yellow solid. MS (LC-MS): 619.40 m/z [M+H]. Step 4 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-2-( ethylsulfonyl )-4- fluoro - 8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 14- Intermediate 7 )

To a stirred solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 14- Intermediate 6 ) (0.30 g, 0.48 mmol) in a mixture of solvent ACN and water (2:1, 36 ml) was added potassium hydrogen persulfate (1.49 g, 4.85 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water and ethyl acetate (2 x 25 ml), the combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , concentrated under reduced pressure, and washed with n-pentane to give crude compound 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl) _-4 -fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 14- Intermediate 7 ) as a light yellow solid (0.25 g, crude). The crude compound was used as such in the next step without further purification. MS (LC-MS): 651.36 m/z [M+H]. Step 5 : 3-(1-(5-(8- ethyl -7- fluoro - 3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8,9- dihydro - 10H- 7- oxa- 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 14- Intermediate 9 )

To a stirred solution of (( 2R )-2-fluorotetrahydro- 1H -pyrrolizin- 7a ( 5H )-yl)methanol ( Example 14- Intermediate 8 ) (0.073 g, 0.46 mmol) in THF (5.0 mL, 20 vol) at 0°C was added ^NaOtBu (0.074 g, 0.77 mmol) and stirred for 15 min followed by the addition of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 14- Intermediate 7) at 0°C. ) (0.25 g, 0.38 mmol). The reaction mixture was stirred at 0°C for 15 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (twice), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin- 7a ( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 14- Intermediate 9 ) as an off-white solid (0.03 g, yield: 11%). ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 0.83 (q, J = 7.20 Hz, 3H), 1.58 (dd, J = 10.4, 7.20 Hz, 3H), 1.78-1.85 (m, 3H), 2.02-2.07 (m, 2H), 2.13-2.16 (m, 1H), 2.83 (q, J = 6.40 Hz, 1H), 3.08-3.10 (m, 2H), 3.42 (d, J = 3.20 Hz, 3H), 3.69-3.76 (m, 2H), 4.05-4.09 (m, 1H), 4.14-4.15 (m, 1H), 4.22 (dd, J = 10.4, 3.20 Hz, 1H), 4.28-4.36 (m, 4H), 5.22-5.35 (m, 3H), 5.69-5.77 (m, 1H), 6.07 (brs, 1H), 6.37 (q, J = 5.89 Hz, 1H), 6.67 (dd, J = 6.40, 5.20 Hz, 1H), 7.17 (d, J = 2.40 Hz, 1H), 7.40-7.45 (m, 1H), 7.63-7.65 (m, 2H), 7.88 (dd, J = 9.20, 6.00 Hz, 1H), 7.98 (t, J = 3.60 Hz, 1H). MS (LC-MS): 716.36 m/z [M+H]. Step 6 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7 a (5 H ) -yl ) methoxy- )9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6 -fluoronaphthalen -2- ol (Example 14 )

To a stirred solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin -7a ( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 14- Intermediate 9 ) (0.03 g, 0.042 mmol) was added 4 mol HCl in 1,4-dioxane (0.2 ml) at 0°C, and the reaction mixture was stirred at 0°C for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude compound. The crude was purified by preparative HPLC to obtain Example 14 (0.007 g, yield: 25%) as an off-white solid. MS: m/z = 672.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.01 (brs, 1H), 7.97 (s, 1H), 7.81 – 7.54 (m, 2H), 7.42 – 7.21 (m, 2H), 7.00 (s, 1H), 6.75 – 6.59 (m, 1H), 6.44 -6.30 (m, 1H), 5.72 (d, J = 26.4 Hz, 2H), 5.29 (d, J = 54.3 Hz, 1H), 4.44 - 4.04 (m, 4H), 3.80 - 3.66 (m, 2H), 3.12 - 2.96 (m, 3H), 2.88 - 2.76 (m, 1H), 2.42 - 2.24 (m, 2H), 2.18 - 1.98 (m, 3H), 1.88 - 1.70 (m, 3H), 1.64 - 1.52 (m, 3H), 0.88 - 0.72 (m, 3H).

Racemic Example 14 was purified by SFC (column: Desylapak® IE, n-hexane/EtOH (+0.1% 7.0 mol/L ammonia in MeOH) = 50/60) to give Example 14a as a white solid and Example 14b as a white solid. Example 14a : 4-(10-(( R )-1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5 -yl )-5- ethyl -6- fluoronaphthalen -2- ol MS: m/z = 672.2 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO- _d6 ) δ 8.30 (brs, 1.18H, FA), 8.03 – 7.92 (m, 1H), 7.80 – 7.64 (m, 2H), 7.44 – 7.31 (m, 2H), 7.02 (t, J = 2.5 Hz, 1H), 6.79 – 6.72 (m, 1H), 6.37 (q, J = 6.7 Hz, 1H), 5.39 (d, J = 53.9 Hz, 1H), 4.46 – 4.25 (m, 4H), 3.83 - 3.68 (m, 1H), 3.51 – 3.16 (m, 4H), 3.02 - 2.90 (m, 1H), 2.43 – 2.10 (m, 5H), 2.03 – 1.80 (m, 3H), 1.60 (t, J = 6.7 Hz, 3H), 0.88 - 0.72 (m, 3H). Example 14b : 4-(10-(( S )-1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5 -yl )-5- ethyl -6- fluoronaphthalen -2- ol MS: m/z = 672.2 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO- _d6 ) δ 8.20 (s, 0.53H, FA), 7.99 - 7.95 (m, 1H), 7.74 (dd, J = 9.0, 6.0 Hz, 7.64 (d, J = 7.5 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 6.8, 5.3 Hz, 1H), 6.43 - 6.32 (m, 1H), 5.73 (d, J = 27.4 Hz, 2H), 5.30 (d, J = 54.1 Hz, 1H), 4.45 - 4.07 (m, 4H), 3.78 - 3.73 (m, 1H), 3.19 - 3.01 (m, 4H), 2.88 - 2.78 (m, 1H), 2.43 - 2.28 (m, 2H), 1.97 (m, 3H), 1.91 – 1.71 (m, 3H), 1.65 – 1.51 (m, 3H), 0.88 - 0.76 (m, 3H). 15. Synthesis scheme of Example 15 Experimental procedure of Example 15 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((( S )-4,4 -difluoro -1 -methylpyrrolidin -2 -yl ) methoxy )-4- fluoro -9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5 - yl )-5- ethynyl- 6 - fluoronaphthalen - 2 - ol Step 1 : 3-(1-(2-((( S )-4,4 -difluoro -1 -methylpyrrolidin -2 -yl ) methoxy )-4- fluoro -5-(7- fluoro -3-( methoxymethoxy) -8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 15- Intermediate 1 )

To a slurry of NaH (60%) (25 mg, 0.63 mmol) in THF (1 mL) at 0 °C was added a solution of ( S )-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (144 mg, 0.95 mmol) in THF (1 mL). The reaction mixture was stirred at 0°C for 30 min, and to the above mixture was added a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 12- Intermediate 6 ) (250 mg, 0.32 mmol) in THF (1 ml). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with concentrated _NH4Cl (aq., 5 ml), and the solution was extracted with EA (20 ml). The organic phase was washed with brine (10 ml) and dried over Na ₂ SO _4. The residue was then purified by silica gel chromatography eluting with DCM/MeOH=20:1 to give 3-(1-(2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (148 mg, 54%) as a yellow solid. MS: m/z = 860.2 (M+H ⁺ , ESI+) Step 2 : 3-(1-(2-((( S )-4,4 -difluoro -1 -methylpyrrolidin -2 -yl ) methoxy )-5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 15- Intermediate 2 )

A mixture of 3-(1-(2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (118 mg, 0.14 mmol), CsF (209 mg, 1.37) in DMF (2 ml) was stirred at 25°C for 2 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was then purified by preparative HPLC (column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL/min) to give the desired product 3-(1-(2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (84 mg, 87%) as a yellow solid. MS: m/z = 704.1 (M+H ⁺ , ESI+) Step 3 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((( S )-4,4 -difluoro -1- methylpyrrolidin - 2- yl ) methoxy )-4- fluoro -9,10- dihydro - 8H- 7- oxa- 1,3,6,10 - tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 15 )

To a solution of 3-(1-(2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (64 mg, 0.09 mmol) in DCM (1 ml) was added HCl/dioxane (0.3 ml). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with DCM/MeOH (10/1 ml×2). The mixture was washed with concentrated NaHCO ₃ (aqueous solution, 10 mL), then with brine (10 mL), and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The HPLC was carried out by preparative HPLC (Waters 2767/Qda, column: Perthwaite XRs 10 C18, 250*21.2 mm, 10 μm; mobile phase A: 0.05% trifluoroacetic acid (TFA)/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 20-25%; retention time: 7.8-9.8 min in 16 min) and preparative HPLC (Waters 2767/Qda, column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 0.05% NH ₃ H ₂ O/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 39% to 39%; retention time: 8-11.1 min in 16 min) to give Example 15 (2.42 mg, 4%) as a light yellow solid. MS: m/z = 660.4 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.67 - 7.47 (m, 2H), 7.23 - 7.06 (m, 3H), 6.80 - 6.53 (m, 2H), 5.89 – 5.36 (m, 2H), 4.68 – 4.11 (m, 4H), 3.67 - 3.30 (m, 3H), 3.10 - 2.87 (m, 2H), 2.82 - 2.63 (m, 1H), 2.55 - 2.30 (m, 5H), 1.65 - 1.45 (m, 3H). 16. Synthesis scheme of Example 16 Experimental procedure of Example 16 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H )-yl ) methoxy ) -9,10 - dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5,6 - difluoronaphthalen -2- ol Step 1 : (3-(1-(5- chloro -4- fluoro -2-( methylsulfonyl )-8,9- dihydro -10 H -7- Oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 16- Intermediate 1 )

To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate ( Example 12- Intermediate 4 ) (400 mg, 0.789 mmol) in ACN (6 mL) and _H2O (2 mL) was added potassium hydrogen persulfate (2.42 g, 3.945 mmol) under argon at 0 °C. The resulting mixture was stirred at 0°C for 1 hour under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NaHSO3 solution at 0°C. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (50 mL). The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (360 mg, yield 84%) as a yellow solid. MS: m/z = 538.9 (M+H+, ESI+) Step 2 : (3-(1-(5- chloro -4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-8,9- dihydro -10 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphth -10- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 16- Intermediate 2 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (137 mg, 0.863 mmol) in THF (3 ml) was added NaH (46 mg, 1.15 mmol) under argon at 0°C. The mixture was stirred for 0.5 h at 0°C. To the above mixture was added tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl) carbamate (310 mg, 0.575 mmol) under argon at 0°C. The resulting mixture was stirred for another 1 h at 0°C. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched with NH ₄ Cl (20 mL) solution at 0°C. The mixture was extracted with EA (3×10 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with (MeOH / DCM = 1:10) to give the desired product (3-(1-(5-chloro-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (290 mg, 70% yield) as a yellow solid. MS: m/z = 618.2 (M+H+, ESI+) Step 3 : 3-(1-(5-(7,8- difluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-8,9- dihydro -10 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 16- Intermediate 3 )

To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-10-yl)ethyl)pyridin-2-yl) carbamate (120 mg, 0.194 mmol) in dioxane (3 mL) and H ₂ O (1 mL) were added 2-(7,8-difluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (68 mg, 0.194 mmol), Ruphos-Pd-G ₃ (48 mg, 0.058 mmol) and K ₃ PO ₄ (124 mg, 0.582 mmol). The mixture was stirred at 100° C. for 2 hours under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H ₂ O (40 ml). The resulting mixture was extracted with EA (20 ml). The combined organic layers were washed with brine (40 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (9%) to give the desired product 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, yield 53%) as a yellow solid. MS: m/z = 706.2 (M+H+, ESI+) Step 4 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorohexahydro -1 H -pyrrolizin -7a -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5,6- difluoronaphth -2- ol (Example 16 )

To a solution of 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 0.113 mmol) in ACN (2 mL) was added HCl/dioxane (2 mL, 2.040 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 16 ) (21.89 mg, yield 29%) as a white solid: preparative HPLC (Waters 2767/Qda) column: Sanfar C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 15-23%; retention time: 7.5-9.3 min in 16 min). MS: m/z = 662.0 (M+H+, ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.23 (s, 0.81H, FA), 7.98 (d, J = 4.3 Hz, 1H), 7.77 – 7.51 (m, 3H), 7.39 (s, 1H), 7.22 (d, J = 1.9 Hz, 1H), 6.72 (dd, J = 7.3, 5.0 Hz, 1H), 6.45 - 6.33 (m, 1H), 5.35 (d, J = 54.4 Hz, 1H), 4.58 – 3.99 (m, 4H), 3.50 - 3.35 (m, 1H), 3.26 - 3.10 (m, 3H), 2.96 - 2.85 (m, 1H), 2.28 – 1.78 (m, 6H), 1.59 (d, J = 4.6 Hz, 3H). 17. Synthesis scheme of Example 17 Experimental procedure of Example 17 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- methoxytetrahydro -1 H -pyrrolizin -7a(5 H )-yl ) methoxy ) -9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol Step 1 : 3-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl)ethynyl )naphthalen-1-yl ) -2-(((2 R ,7a S )-2 - methoxytetrahydro -1 H -pyrrolizin-7a(5 H )-yl) methoxy )-9,10 -dihydro -8 H -7 -oxa-1,3,6,10 -tetraazacyclohepta[de]naphthalen-5- yl )-5 - ethyl- 6- fluoronaphthalen - 2-ol ) -yl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 - tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 17- Intermediate 1 )

To a solution of (( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (250 mg, 0.32 mmol) in THF (1 mL) at 0 °C was added NaH (25 mg, 0.63 mmol). The reaction mixture was stirred at 0°C for 30 min under _N2 , and a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 12- Intermediate 6 ) SM1 (250 mg, 0.32 mmol) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature under _N2 for 2 h. The reaction mixture was quenched with concentrated _NH4Cl (aq., 5 mL), and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 ml) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM/MeOH = 10:1 to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (156 mg, 56%) as a yellow solid. MS: m/z = 880.3 (M+H+, ESI+) Step 2 : 3-(1-(5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-(((2 R ,7a S )-2- methoxytetrahydro -1 H -pyrrolazin -7a(5 H ) -yl ) methoxy )-8,9- dihydro -10 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 17- Intermediate 2 )

To a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (136 mg, 0.15 mmol) in DMF (2 mL) was added CsF (235 mg, 1.54 mmol). The reaction mixture was stirred at room temperature under _N2 for 2 h. The reaction mixture was quenched with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 ml) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure to give 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2 R ,7a S )-2-methoxytetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (136 mg, 121%) as a yellow solid. MS: m/z = 724.2 (M+H+, ESI+) Step 3 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- methoxytetrahydro -1 H -pyrrolizine -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 17- Intermediate 3 )

To a solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (136 mg, 0.19 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was concentrated under reduced pressure to give the desired product 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as a yellow solid (136 mg, 106%). MS: m/z = 680.2 (M+H+, ESI+) Step 4 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- methoxytetrahydro -1 H -pyrrolizine -7a(5 H ) -yl ) methoxy )9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphth -2- ol (Example 17 )

To a solution of 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (136 mg, 0.20 mmol) in MeOH (2 mL) was added Pd/C (60 mg). The reaction mixture was stirred at 25 °C under _H2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was concentrated and purified by preparative HPLC (Waters 2767/Qda, column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 16-26%; retention time: 8.7-10.2 min in 16 min) to give Example 17 (26.31 mg, 19%) as a light yellow solid. MS: m/z = 684.0 (M+H+, ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.28 (s, 1.8H, FA), 7.98 (s, 1H), 7.81 – 7.73 (m, 1H), 7.70 - 7.62 (m, 1H), 7.43 – 7.29 (m, 2H), 7.07 - 6.97 (m, 1H), 6.78 – 6.68 (m, 1H), 6.42 – 6.31 (m, 1H), 4.55 – 4.29 (m, 4H), 4.23 - 4.12 (m, 1H), 3.58 - 3.40 (m, 3H), 3.35 - 3.24 (m, 4H), 3.20 - 3.10 (m, 1H), 2.46 - 2.25 (m, 3H), 2.21 - 1.86 (m, 5H), 1.68 - 1.52 (m, 3H), 0.90 - 0.75 (m, 3H). 18. Synthesis scheme of Example 18 Experimental procedure of Example 18 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 4R )-4- fluoro -1 -methylpyrrolidin -2- yl ) methoxy )-9,10- dihydro - 8H -7- oxa- 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5 - yl )-5- ethynyl- 6 -fluoronaphthalen -2- ol Step 1 : 3-(1-(4- fluoro -2-(((2S,4R)-4 - fluoro -1 -methylpyrrolidin -2- yl ) methoxy )-5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1- yl )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 18- Intermediate 1 )

To a slurry of NaH (60%) (20 mg, 0.51 mmol) in THF (1 mL) at 0 °C was added a solution of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (101 mg, 0.76 mmol) in THF (1 mL). The reaction mixture was stirred at 0°C for 30 min, and to the above mixture was added a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 12- Intermediate 6 ) (200 mg, 0.25 mmol) in THF (1 ml). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with concentrated _NH4Cl (aq., 5 ml), and the solution was extracted with EA (20 ml). The organic phase was washed with brine (10 ml) and dried over Na ₂ SO _4. The residue was then purified by silica gel chromatography eluting with DCM/MeOH=20:1 to give 3-(1-(4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (87 mg, 40%) as a yellow solid. MS: m/z = 842.3 (M+H+, ESI+) Step 2 : 3-(1-(5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-(((2S,4R)-4- fluoro -1- methylpyrrolidin -2- yl ) methoxy )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 18- Intermediate 2 )

To a solution of 3-(1-(4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (67 mg, 0.08 mmol) in DMF (1 mL) was added CsF (121 mg, 0.79 mmol). The reaction mixture was stirred at room temperature under _N2 for 2 h. The reaction mixture was quenched with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL x 3) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure to give the desired crude product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (52 mg, 95%) as a yellow solid. MS: m/z = 686.2 (M+H+, ESI+) Step 3 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((2S,4R)-4- fluoro -1- methylpyrrolidin -2- yl ) methoxy )-9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 18 )

To a solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (42 mg, 0.06 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda, column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 13-23%; retention time: 7.3-9.3 min in 16 min) to give the desired product as a white solid to give Example 18 (7.28 mg, 18%). MS: m/z = 642.1 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, MeOD) δ 8.33 (s, 0.38H, FA), 7.98 (d, J = 4.9 Hz, 1H), 7.90 – 7.74 (m, 2H), 7.39 – 7.26 (m, 2H), 7.19 (s, 1H), 6.89 - 6.77 (m, 1H), 6.68 – 6.55 (m, 1H), 5.30 (d, J = 54.4 Hz, 1H), 4.55 - 4.25 (m, 4H), 3.86 – 3.45 (m, 4H), 3.12 – 2.96 (m, 1H), 2.85 - 2.70 (m, 3H), 2.55 - 2.35 (m, 1H), 2.30 - 2.04 (m, 1H), 1.75 - 1.62 (m, 3H). 19. Synthesis scheme of Example 19 Experimental procedure of Example 19 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((2,6 -dimethyltetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-4- fluoro -9,10- dihydro - 8H -7- oxa - 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5 - ethyl -6 - fluoronaphthalen -2- ol Step 1 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-( methylthio )-8,9 - dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 19- Intermediate 1 )

To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-yl) carbamate ( Example 12- Intermediate 4 ) (1.0 g, 1.972 mmol) in dioxane (12 ml) and _H2O (4 ml) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (715 mg, 1.972 mmol), Ruphos-Pd- _G3 (495 mg, 0.592 mmol) and _{K3PO4 .} (1.25 g, 5.916 mmol). The mixture was stirred at 100 °C under argon for 2 hours. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with _H2O (80 mL). The resulting mixture was extracted with EA (40 mL). The combined organic layers were washed with brine (60 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with EA/PE (75%) to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (590 mg, yield 49%) as a yellow solid. MS: m/z = 605.1 (M+H ⁺ , ESI+) Step 2 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-( methylsulfonyl )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 19- Intermediate 2 )

To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (300 mg, 0.496 mmol) in ACN (3 mL) and _H2O (1 mL) was added potassium persulfate (1.52 g, 5.481 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for 1 hour under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NaHSO3 solution at 0°C. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (50 mL). The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (210 mg, crude) as a yellow solid. MS: m/z = 637.1 (M+H ⁺ , ESI+) Step 3 : 3-(1-(2-((2,6- dimethylentetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 19- Intermediate 3 )

To a solution of (2,6-dimethylentetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (66 mg, 0.401 mmol) in THF (2 ml) was added NaH (21 mg, 0.534 mmol) under argon at 0°C. The mixture was stirred for 0.5 h at 0°C. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (170 mg, 0.267 mmol) under argon at 0°C. The resulting mixture was stirred for another 1 h at 0°C. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched with NH ₄ Cl solution (60 mL) at 0°C. The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with (MeOH / DCM = 1:20) to give the desired product 3-(1-(2-((2,6-dimethylentetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, yield 46%) as a yellow solid. MS: m/z = 722.2 (M+H ⁺ , ESI+) Step 4 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((2,6 -dimethyltetrahydro - 1H - pyrrolizin -7a( 5H )-yl ) methoxy ) -4- fluoro -9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth - 5- yl )-5- ethyl -6- fluoronaphthalen -2- ol (Example 19 )

To a solution of 3-(1-(2-((2,6-dimethylentetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 0.097 mmol) in ACN (2 mL) was added HCl/dioxane (1.8 mL, 1.745 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 19 ) (17.98 mg, yield 27%) as a yellow solid: preparative HPLC (Waters 2767 column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH ₄ HCO ₃ /H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 55-55%; retention time: 9.2-10.8 min in 16 min). MS: m/z = 678.0 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.09 – 7.94 (m, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.40 – 7.26 (m, 2H), 6.99 (t, J = 2.5 Hz, 1H), 6.68 (dd, J = 7.3, 5.0 Hz, 1H), 6.40 - 6.28 (m, 1H), 5.70 (d, J = 28.4 Hz, 2H), 4.95 (d, J = 12.0 Hz, 4H), 4.50 – 4.09 (m, 4H), 3.82 – 3.58 (m, 3H), 3.26 -3.14 (m, 3H), 2.75 – 2.62 (m, 2H), 2.49 – 2.15 (m, 4H), 1.67 – 1.50 (m, 3H), 0.90 - 0.75 (m, 3H). 20. Synthesis scheme of Example 20 Experimental procedure of Example 20 : 4-(10-(1-(2- aminophenyl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen - 5 - yl )-5- ethynyl -6- fluoronaphthalen -2- ol Step 1 : ( Z )-(2-(1-((2- hydroxyethyl ) imino ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 2 )

To a solution of tert- butyl (2-acetylphenyl)carbamate ( Example 20- Intermediate 1 ) (11 g, 46.81 mmol) in EtOH (110 ml) was added 2-aminoethan-1-ol (8.5 g, 140.42 mmol ₎ . The mixture was stirred at 90 °C for 4 hours. After completion, water (100 ml) was added to the reaction mixture and extracted with EA (100 ml). The organic layer was filtered and concentrated, and dried over _Na2SO4 . The residue was purified by silica gel chromatography using PE/EA = 2:1 for elution to give ( Z ) -tert- butyl (2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (5.3 g, 40%) as a colorless oil. MS: m/z = 279.0 (M+H ⁺ , ESI+) Step 2 : tert-butyl (2-(1-((2- hydroxyethyl ) amino ) ethyl ) phenyl ) carbamate (Example 20- Intermediate 3 )

To a solution of ( Z ) -tert -butyl(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (5.3 g, 19.06 mmol) in MeOH (50 mL) was added _NaBH4 (2.2 g, 57.19 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography eluting with PE/EA = 2:1 to give the desired product, tert -butyl(2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (2.1 g, 39%) as a colorless oil. MS: m/z = 281.0 (M+H ⁺ , ESI+) Step 3 : (2-(1-((2-((7- chloro -8- fluoro -4- hydroxy -2-( methylthio ) pyrido [4,3 -d ] pyrimidin -5- yl ) oxy ) ethyl ) amino ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 4 )

To a solution of tert- butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (1.6 g, 5.70 mmol) in THF (5 mL) was added NaH (685 mg, 17.14 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 min under _N2 , and to the above mixture was added dropwise a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (1.6 g, 5.70 mmol). The reaction mixture was stirred at room temperature for 2 h under _N2 . The reaction mixture was quenched with concentrated _NH4Cl (aq., 10 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE/EA = 3:1 as eluent to give tert-butyl (2-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)phenyl)carbamate (2.2 g, 73%) as a yellow solid. MS: m/z = 524.1 (M+H ⁺ , ESI+) Step 4 : (2-(1-(5- chloro -4- fluoro -2-( methylthio )-8,9- dihydro - 10H -7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 5 )

To a solution of tert-butyl (2-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)phenyl) carbamate (2.2 g, 4.20 mmol) in DCM (20 mL) were added BOPCl (3.2 g, 12.59 mmol), DIEA (4.9 g, 37.79 mmol). The reaction mixture was stirred at 25 ° _C under _N2 for 16 h. The reaction mixture was diluted with DCM (40 mL). The organic phase was washed with brine (40 mL) and dried over _Na2SO4 . The organic phase was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography eluting with PE/EA = 4:1 to give tert-butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl)carbamate ( 1.4 g, 65%) as a white solid. MS: m/z = 506.0 (M+H ⁺ , ESI+) Step 5 : (2-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen-1- yl ) -2- ( methylthio )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 6 )

To a solution of tert-butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)phenyl) carbamate (700 mg, 1.39 mmol) in dioxane (7 ml)/ _H2O (0.7 ml) was added (( ₂ -fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (709 mg, 1.39 mmol), _K3PO4 (890 mg, 4.16 mmol) and Ruphos-Pd- _G3 (116 mg, 0.14 mmol). The reaction mixture was stirred at 100° C. for 2 hours under N _2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE/EA = 3:1 to give the desired product (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl)carbamic acid tert- butyl ester (750 mg, 63%) as a yellow solid. MS: m/z = 856.1 (M+H ⁺ , ESI+) Step 6 : (2-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen- 1 - yl ) -2-( methylsulfonyl )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 7 )

To (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl)carbamic acid tert- butyl ester (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacycloheptyl[de]naphthalen-10-yl)ethyl)phenyl)carbamate was added at 0°C. To a solution of tert-butyl-7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl) carbamate (650 mg, 0.76 mmol) in THF (6 ml)/H ₂ O (3 ml) was added potassium persulfate (2.33 g, 3.79 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with concentrated NaHSO ₃ (aq., 20 ml), extracted with EA (10 ml), and dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure to give tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)phenyl) carbamate (670 mg, crude) as a yellow solid. MS: m/z = 872.3 (M+H ⁺ , ESI+) Step 7 : (2-(1-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen - 1- yl )-2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolazin -7a( 5H )-yl ) methoxy ) -8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 8 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (167 mg, 1.047 mmol) in THF (7 mL) was added NaH (56 mg, 1.396 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl) carbamate (620 mg, 0.698 mmol) under argon at 0°C. The mixture was stirred at 0°C for another 1 hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NH4Cl solution (60 mL) at 0°C. The mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product, (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl)carbamic acid tert- butyl ester (600 mg, crude) as a yellow solid. MS: m/z = 967.6 (M+H ⁺ , ESI+) Step 8 : (2-(1-(5-(8- ethynyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolazin -7a( 5H ) -yl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) phenyl ) carbamic acid tert- butyl ester (Example 20- Intermediate 9 )

To a solution of tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl) carbamate (600 mg, 0.624 mmol) in DMF (1 mL) was added CsF (948 mg, 6.240 mmol). The mixture was stirred at 25°C under argon for 1 hour. The reaction was monitored by LCMS. LCMS detected the desired product. The mixture was diluted with H ₂ O (80 mL). The mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (120 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen-10-yl)ethyl)phenyl)carbamic acid tert- butyl ester (150 mg, yield 29%) as a yellow solid. MS: m/z = 811.5 (M+H ⁺ , ESI+) Step 9 : 4-(10-(1-(2- aminophenyl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol (Example 20 )

To a solution of tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-methoxytetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacycloheptyl[ de ]naphthalen- 10 -yl)ethyl)phenyl)carbamate (50 mg, 0.062 mmol) in ACN (2 mL) was added HCl/dioxane (1.2 mL, 1.110 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 20 ) (8.15 mg, yield 19%) as a white solid: Preparative HPLC (Waters 2767) column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH ₄ HCO ₃ /H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 55-55%; retention time: 9.2-10.8 min in 16 min. MS: m/z = 667.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 7.95 (dd, J = 9.0, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.15 (dd, J = 7.7, 2.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.78 - 6.65 (m, 2H), 6.47 - 6.30 (m, 1H), 5.30 (d, J = 54.6 Hz, 1H), 5.00 - 4.80 (m, 2H), 4.45 - 4.30 (m, 1H), 4.25 – 4.07 (m, 3H), 3.78 - 3.65 (m, 1H), 3.27 - 3.22 (m, 1H), 3.15 - 3.00 (m, 3H), 2.89 – 2.81 (m, 1H), 2.18 – 1.79 (m, 6H), 1.68 - 1.55 (m, 3H). 21. Synthesis scheme of Example 21 Experimental procedure of Example 21 : 4-(10-(1-(2- aminophenyl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphth -2- ol Step 1 : 4-(10-(1-(2- aminophenyl ) ethyl )-4 - fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro - 8 H -7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5 -yl ) -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol (Example 21 )

To a solution of 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy) _-9,10 -dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (70 mg, 0.105 mmol) in MeOH (2 mL) at 25°C was added Pd/C (15 mg) under H2. The mixture was stirred at 25°C under _H2 for 16 h. The reaction was monitored by LCMS. LCMS detected the desired product. The resulting mixture was filtered and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 21 ) (21.45 mg, yield 28%) as a white solid: Preparative HPLC (Waters 2767/Qda) column: Sanfar C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 13-21%; retention time: 9.8-12.2 minutes in 17 minutes. MS: m/z = 671.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 8.14 (s, 0.23H, FA), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.40 - 7.27 (m, 3H), 7.10 (t, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.79 – 6.66 (m, 2H), 6.50 - 6.35 (m, 1H), 5.47 (d, J = 54.4 Hz, 1H), 4.54 – 4.38 (m, 3H), 4.33 - 4.20 (m, 1H), 3.80 - 3.65 (m, 4H), 3.20 - 3.00 (m, 2H), 2.45 - 2.15 (m, 5H), 2.10 - 1.85 (m, 3H), 1.67 – 1.50 (m, 3H), 0.90 - 0.75 (m, 3H). 22. Synthesis scheme of Example 22 Experimental procedure of Example 22 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-(((4 R )-4- fluoro -1 -methylpyrrolidin -2- yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6 - fluoronaphth -2- ol Step 1 : 4-(10-(( R )-1-(2- aminopyridin -3 - yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H )-yl ) methoxy ) -9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol (Example 22 )

To a solution of 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10- _dihydro - 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (40 mg, 0.062 mmol) in MeOH (2 mL) at 25 °C was added Pd/C (5 mg). The mixture was stirred at ₂₅ °C under H for 16 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was filtered and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 22 ) (16.37 mg, yield 40%) as a white solid: preparative HPLC (Waters 2767/Qda) column: Sanfar C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 13-21%; retention time: 9.8-12.2 minutes in 17 minutes. MS: m/z = 646.0 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.17 (s, 0.61H, FA), 7.98 (brs, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.02 (s, 1H), 6.77 – 6.65 (m, 1H), 6.45 – 6.32 (m, 1H), 5.21 (d, J = 55.9 Hz, 1H), 4.60 – 4.24 (m, 4H), 3.82 - 3.74 (m, 1H), 3.57 – 3.32 (m, 3H), 3.07 - 2.95 (m, 1H), 2.47 – 2.27 (m, 5H), 2.24 – 2.10 (m, 1H), 2.04 – 1.85 (m, 1H), 1.66 – 1.52 (m, 3H), 0.90 - 0.75 (m, 3H). 23. Synthesis scheme of Example 23 Experimental procedure of Example 23 : 4-(10-(1-(2- amino -5- methylpyridin -3 -yl ) ethyl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol Step 1 : 3-(1- ethoxyvinyl )-5- methylpyridin -2- amine (Example 23- Intermediate 2 )

To a solution of 3-bromo-5-methylpyridin-2-amine (10 g, 53.46 mol) and ethoxyvinyltri-n-butyltin (18 ml, 53.44 mmol) in 100 ml of dioxane was added Pd(PPh ₃ )Cl ₂ (1.87 g, 2.66 mmol). The solution was purged three times with N ₂ and stirred at 100° C. under N ₂ for 4 hours. The reaction mixture was concentrated to dryness in vacuo to give a yellow oil, which was purified by silica gel chromatography eluting with DCM/MeOH=10:1. The desired fractions were collected and concentrated to dryness in vacuo to give the desired product 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (7.1 g, crude) as a yellow oil. MS: m/z = 179.0 (M+H ⁺ , ESI+) Step 2 : 1-(2- amino -5- methylpyridin -3- yl ) ethan -1- one (Example 23- Intermediate 3 )

To a mixture of 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (8.8 g, 49.44 mmol) in DCM (45 ml) was slowly added 4 mol HCl/dioxane (45 ml) dropwise at 25°C. The reaction mixture was stirred at 25°C for 16 _hours . The reaction mixture was concentrated under reduced pressure. The residue was dissolved in _H2O (40 ml), and the pH was adjusted to 8 with _Na2CO3 solution, and then the mixture was extracted with DCM (150 ml x 3). The combined organic layers were concentrated to dryness in vacuo to give a black oil. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate = 5:1 to obtain the desired product 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (4.08 g, yield 55%) as a yellow solid. MS: m/z = 151.0 (M+H ⁺ , ESI+) Step 3 : (3- acetyl -5- methylpyridin -2- yl ) carbamic acid tert- butyl ester (Example 23- Intermediate 4 )

To a mixture of 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (4.08 g, 27.17 mmol) in t-BuOH (40 ml) was added (Boc) ₂ O (12.4 ml, 54.07 mmol). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate = 10:1 to give the desired product (3-acetyl-5-methylpyridin-2-yl)carbamic acid tert- butyl ester (4.06 g, yield 60%) as a yellow solid. MS: m/z = 251.1 (M+H ⁺ , ESI+) Step 4 : ( Z )-(3-(1-((2- hydroxyethyl ) imino ) ethyl )-5- methylpyridin -2- yl ) carbamic acid tert -butyl ester (Example 23- Intermediate 5 )

To a solution of tert- butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (4 g, 15.98 mmol) in EtOH (40 mL) was added 2-aminoethan-1-ol (2.9 g, 47.94 mmol). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE/EA = 1:3 for elution to give tert-butyl ( Z )-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamate (2.3 g, 49%) as a yellow solid. MS: m/z = 294.1 (M+H ⁺ , ESI+) Step 5 : (3-(1-((2- hydroxyethyl ) amino ) ethyl )-5- methylpyridin -2- yl ) carbamic acid tert- butyl ester (Example 23- Intermediate 6 )

To a solution of ( Z )-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamic acid tert- butyl ester (2.3 g, 7.84 mmol) in MeOH (20 ml) was added _NaBH4 (890 mg, 23.54 mmol) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated. The residue was purified by silica gel chromatography eluting with DCM/MeOH = 20:1 to give the desired product, (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamic acid tert- butyl ester (2.2 g, 95%) as a yellow solid. MS: m/z = 296.2 (M+H ⁺ , ESI+) Step 6 : (3-(1-((2-((7- chloro -8- fluoro -4- hydroxy -2-( methylthio ) pyrido [4,3 -d ] pyrimidin -5- yl ) oxy ) ethyl ) amino ) ethyl )-5- methylpyridin -2- yl ) carbamic acid tert- butyl ester (Example 23- Intermediate 7 )

To a solution of tert- butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1 g, 3.39 mmol) in THF (10 mL) was added NaH (406 mg, 10.17 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min under _N2 , and to the above mixture was added dropwise a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (949 mg, 3.39 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature under _N2 for 2 h. The reaction mixture was quenched with concentrated _NH4Cl (aq., 20 mL), and the solution was extracted with EA (30 mL). The organic phase was washed with brine (20 ml) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE/EA = 1:9 to give the desired crude product (tert-butyl 3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1.3 g, 71%) as a yellow solid. MS: m/z = 539.2 (M+H ⁺ , ESI+) Step 7 : (3-(1-(5- chloro -4- fluoro -2-( methylthio )-8,9- dihydro - 10H- 7- oxa -1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl )-5- methylpyridin -2- yl ) carbamic acid tert- butyl ester (Example 23- Intermediate 8 )

To a solution of tert-butyl (3-(1-((2-((7-chloro-8-fluoro- 4 -hydroxy-2-(methylthio)pyrido[4,3- d ]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1.3 g, 2.41 mmol) in DCM (15 mL) were added BOPCl (1.8 g, 7.23 mmol), DIEA (2.8 g, 21.71 mmol). The reaction mixture was stirred at 25 °C under _N2 for 16 h. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL) and dried over _Na2SO4 . _The organic phase was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography eluting with PE/EA = 1:1 to give tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl) carbamate (580 mg, 46%) as a yellow solid. MS: m/z = 521.3 (M+H ⁺ , ESI+) Step 8 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-( methylthio )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl )-5- methylpyridin -2- amine (Example 23- Intermediate 9 )

To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl) carbamate (500 mg, 0.96 mmol) in dioxane (5 mL)/ _H2O (0.5 mL) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- _1,3,2 -dioxaborolane (345 mg, 0.96 mmol), _K3PO4 (610 mg, 2.88 mmol) and Ruphos-Pd- _G3 (241 mg, 0.29 mmol). The reaction mixture was stirred at 100° C. for 2 hours under N _2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM/MeOH = 50:1 to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (175 mg, 29%) as a yellow solid. MS: m/z = 619.4 (M+H ⁺ , ESI+) Step 9 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-( methylsulfonyl )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl )-5- methylpyridin -2- amine (Example 23- Intermediate 10 )

To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, 0.20 mmol) in ACN (3 ml)/H ₂ O (1 ml) was added potassium persulfate (621 mg, 1.01 mmol) at 0°C. The mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with concentrated NaHSO ₃ (aq., 5 ml), extracted with EA (5 ml), and dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, crude) as a yellow solid. MS: m/z = 651.3 (M+H ⁺ , ESI+) Step 10 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl )-5- methylpyridin -2- amine (Example 23- Intermediate 11 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (92 mg, 0.58 mmol) in THF (1 mL) was added NaH (15 mg, 0.38 mmol) at 0°C. The reaction mixture was stirred under _N2 at 0°C for 30 min, and to the above mixture was added dropwise a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, 0.19 mmol) in THF (1 mL). The reaction mixture was stirred at rt for 1 h under N _2. The reaction mixture was quenched with concentrated NH ₄ Cl (aq., 5 mL), and the solution was extracted with EA (5 mL). _The organic phase was washed with brine (5 ml), and dried over _Na2SO4 to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (55 mg, crude) as a yellow solid. MS: m/z = 730.4 (M+H ⁺ , ESI+) Step 11 : 4-(10-(1-(2- amino -5- methylpyridin -3- yl ) ethyl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 - tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6 -fluoronaphthalen -2- ol (Example 23 )

To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (55 mg, 0.07 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda, column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 0.05% NH ₃ H ₂ O/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 47%~47%; retention time: 9.2-11.2 min in 16 min) to give the desired product as a white solid to give Example 23 (3.82 mg, 7%). MS: m/z = 686.5 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, MeOD-d ₄ ) δ 7.81 (s, 1H), 7.69 – 7.59 (m, 2H), 7.30 – 7.18 (m, 2H), 7.06 - 7.01 (m, 1H), 6.67 - 6.56 (m, 1H), 5.41 - 5.23 (m, 1H), 4.57 – 4.30 (m, 4H), 3.84 – 3.68 (m, 1H), 3.64 - 3.46 (m, 1H), 3.28 - 2.96 (m, 4H), 2.61 - 2.33 (m, 3H), 2.27 (s, 3H), 2.23 - 2.10 (m, 2H), 2.03 - 1.86 (m, 3H), 1.71 - 1.61 (m, 3H), 0.92 - 0.81 (m, 3H). 24. Synthesis scheme of Example 24 Experimental procedure of Example 24 : 4-(((10-(1-(2- aminopyridin -3- yl ) ethyl )-5-(8- ethyl -7- fluoro -3- hydroxynaphthalen -1- yl )-4- fluoro -9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -2 -yl ) oxy ) methyl ) tetrahydro - 2H - pyran -4- carbonitrile Step 1 : 4-(((10-(1-(2- aminopyridin -3- yl ) ethyl )-5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen-1 - yl )-4 - fluoro -9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro - 2H - pyran - 4-carbonitrile -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -2- yl ) oxy ) methyl ) tetrahydro - 2H - pyran -4- carbonitrile (Example 24- Intermediate 1 )

To a solution of 4-(hydroxymethyl)tetrahydro- 2H -pyran-4-carbonitrile (44 mg, 0.306 mmol) in THF (2 ml) was added NaH (17 mg, 0.408 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 0.204 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for another 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched with NH ₄ Cl solution (50 mL) at 0°C. The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-2-yl)oxy)methyl)tetrahydro- 2H -pyran-4-carbonitrile (70 mg, yield 49%) as a yellow solid. MS: m/z = 698.4 (M+H ⁺ , ESI+) Step 2 : 4-(((10-(1-(2- aminopyridin -3- yl ) ethyl )-5-(8- ethyl -7- fluoro - 3-hydroxynaphthalen - 1- yl )-4- fluoro -9,10- dihydro - 8H- 7- oxa - 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -2- yl ) oxy ) methyl ) tetrahydro - 2H - pyran -4- carbonitrile (Example 24 )

To a solution of 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl - 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-2-yl)oxy)methyl)tetrahydro- 2H -pyran-4-carbonitrile (70 mg, 0.100 mmol) in ACN (2 mL) was added HCl/dioxane (1.8 mL, 1.806 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 24 ) (17.05 mg, 25% yield) as a white solid: Preparative HPLC (Waters 2767/Qda) column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 26-36%; retention time: 8.9-9.9 min in 16 min). MS: m/z = 654.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.19 (s, 0.56H, FA), 7.97 (s, 1H), 7.80 - 7.57 (m, 2H), 7.42 – 7.27 (m, 2H), 7.00 (s, 1H), 6.75 – 6.64 (m, 1H), 6.40 - 6.30 (m, 1H), 5.68 (d, J = 23.8 Hz, 2H), 4.61 – 4.31 (m, 4H), 3.97 - 3.90 (m, 2H), 3.80 – 3.68 (m, 4H), 2.45 - 2.25 (m, 2H), 2.07 – 1.89 (m, 2H), 1.85 - 1.70 (m, 2H), 1.65 - 1.50 (m, 3H), 0.88 - 0.75 (m, 3H). 25. Synthesis scheme of Example 25 Experimental procedure of Example 25 : 4-(10-(1-(2- aminopyridin -3 -yl ) ethyl )-4- fluoro -2-(((6 S ,8a S ) -hexahydro -1 H -pyrrolo [2,1- c ][1,4] oxazin -6- yl ) methoxy )-9,10 - dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5 - ethyl -6 - fluoronaphthalen -2- ol Step 1 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-(((6 S ,8a S ) -hexahydro -1 H -pyrrolo [2,1- c [1,4] oxazin -6- yl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 25- Intermediate 1 )

To a solution of (( 6S , 8aS )-hexahydro- 1H -pyrrolo[2,1- c ][1,4]oxazin-6-yl)methanol (48 mg, 0.282 mmol) in THF (1 mL) was added NaH (18 mg, 0.372 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine ( Example 19- Intermediate 2 ) (120 mg, 0.186 mmol) at 0°C under argon. The resulting mixture was stirred at 0°C for another 1 hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with _NH4Cl solution (60 mL) at 0°C. The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layer was washed with brine (80 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6 S ,8a S )-hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, yield 38%) as a yellow solid. MS: m/z = 714.5 (M+H ⁺ , ESI+) Step 2 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((( 6S , 8aS ) -hexahydro - 1H - pyrrolo [2,1- c ][1,4] oxazin -6- yl ) methoxy )-9,10 - dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphth -2- ol (Example 25 )

To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 6S , 8aS )-hexahydro- 1H -pyrrolo[2,1- c ][1,4]oxazin-6-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (50 mg, 0.070 mmol) in ACN (2 mL) was added HCl/dioxane (1.3 mL, 1.261 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 25 ) (10.38 mg, yield 22%, FA salt) as a white solid: Preparative HPLC (Waters 2767/Qda) column: Sanfar C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 15-23%; retention time: 7.7-9.1 min in 16 min). MS: m/z = 670.2 (M+H ⁺ , ESI+). Step 3 : Example 25- free form

A solution of 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 6S , 8aS )-hexahydro- 1H -pyrrolo[2,1- c ][1,4]oxazin- ₆ -yl)methoxy)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (20 mg, 0.030 mmol, FA salt) in DCM (10 mL) was washed with concentrated NaHCO3 (aq) (5 mL x 3 ). The organic phase was concentrated to give the desired product ( Example 25- free ) (10.16 mg, 51% yield) as a white solid. MS: m/z = 670.2 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 9.93 (d, J = 2.0 Hz, 1H), 8.01 -7.92 (m, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (d, J = 2.1 Hz, 1H), 6.72 – 6.62 (m, 1H), 6.42 - 6.30 (m, 1H), 5.72 (dd, J = 27.4, 10.6 Hz, 2H), 4.55 – 4.14 (m, 4H), 3.80 - 3.68 (m, 1H), 3.65 - 3.43 (m, 6H), 3.20 - 3.10 (m, 1H), 3.03 - 2.84 (m, 3H), 2.44 - 2.26 (m, 2H), 2.14 - 2.02 (m, 1H), 1.85 - 1.71 (m, 1H), 1.69 - 1.53 (m, 4H), 1.36 - 1.26 (m, 1H), 0.88 - 0.76 (m, 3H). 26. Synthesis scheme of Example 26 Experimental procedure of Example 26 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((1-((( R )-3 -fluoropyrrolidin -1 -yl ) methyl ) cyclopropyl ) methoxy )-9,10- dihydro - 8H- 7- oxa- 1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol Step 1 : ( R )-1-(3- fluoropyrrolidine -1- carbonyl ) cyclopropane -1- carboxylic acid methyl ester (Example 26- Intermediate 1 )

To a solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (1.5 g, 10.353 mmol) in DCM (20 mL) at 0°C under argon was added (COCl) ₂ (1.72 g, 13.551 mmol) and DMF (12 mg, 0.080 mmol). The resulting mixture was stirred at 25°C under argon for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. To a stirred solution of ( R )-3-fluoropyrrolidine hydrochloride (1.5 g, 10.353 mmol) and DIEA (1.5 g, 10.353 mmol) in DCM (20 mL) at 25°C under argon atmosphere was added the residue. The resulting mixture was stirred at 25 °C under an argon atmosphere for 16 hours. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give the desired product ( R )-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylic acid methyl ester (1.5 g, crude) as a yellow solid. MS: m/z = 216.1 (M+H ⁺ , ESI+) Step 2 : ( R )-(1-((3- fluoropyrrolidine -1- yl ) methyl ) cyclopropyl ) methanol (Example 26- Intermediate 2 )

To a solution of ( R )-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1 _- carboxylic acid methyl ester (1.5 g, 6.970 mmol) in THF (20 mL) was added lithium aluminum hydride (LAH) (14 mL, 13.939 mmol) at 0°C under N2. The mixture was stirred at 25°C for 3 hours. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched by adding _H2O (0.14 mL), 15% NaOH solution (0.14 mL) and _H2O (0.3 mL) at 0°C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with MeOH:DCM (6%) to give ( R )-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (710 mg, yield 58%) as a colorless liquid. MS: m/z = 174.3 (M+H ⁺ , ESI+) Step 3 : 3-(1-(5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -2-((1-((( R )-3 -fluoropyrrolidin -1 -yl ) methyl ) cyclopropyl ) methoxy )-8,9 - dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 26- Intermediate 3 )

To a solution of ( R )-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (61 mg, 0.353 mmol) in THF (4 ml) was added NaH (28 mg, 0.706 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 0.236 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for another 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched with NH ₄ Cl solution (50 mL) at 0°C. The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the desired product, 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, crude) as a yellow solid. MS: m/z = 730.4 (M+H ⁺ , ESI+) Step 4 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-4- fluoro -2-((1-((( R )-3- fluoropyrrolidin -1- yl ) methyl ) cyclopropyl ) methoxy )-9,10 - dihydro - 8H - 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl- 6- fluoronaphth -2- ol (Example 26 )

To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (140 mg, 0.192 mmol) in ACN (2 mL) was added HCl/dioxane (3.5 mL, 3.453 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product ( Example 26 ) (3.10 mg, yield 2%) as a white solid: preparative HPLC (Waters 2767/Qda) column: Sanfar C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 13-23%; retention time: 8.9-9.8 min in 16 min). MS: m/z = 686.2 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (s, 1.52 H, FA), 7.97 (s, 1H), 7.79 – 7.60 (m, 2H), 7.43 – 7.26 (m, 2H), 6.99 (s, 1H), 6.77 – 6.61 (m, 1H), 6.40 - 6.30 (m, 1H), 5.70 (dd, J = 27.6, 5.6 Hz, 2H), 5.17 (d, J = 56.5 Hz, 1H), 4.48 - 4.20 (m, 4H), 3.80 – 3.68 (m, 4H), 2.90 - δ 0.14 - 0.13 (m, 2H), 0.25 - 0.25 (m, 4H), 0.25 - 0.30 (m, 2H), 0.40 - 0.60 (m, 2H). 27. Synthesis scheme of Example 27 Experimental procedure of Example 27 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((( S )-1-(2,2 -difluoroethyl ) pyrrolidin -2- yl ) methoxy )-4- fluoro -9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl )-5- ethyl -6- fluoronaphthalen -2- ol Step 1 : (S) -Pyrrolidin -2 -ylmethoxide hydrochloride (Example 27- Intermediate 2 )

To a solution of ( S )-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert- butyl ester (5 g, 24.84 mmol) was slowly added 4 mol HCl/dioxane (62 mL) at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The solvent was removed under reduced pressure to give ( S )-pyrrolidin-2-ylmethanol hydrochloride (3.2 g, 93%) as a colorless oil. MS: m/z = 102.1 (M+H ⁺ , ESI+) Step 2 : ( S ) -(1-(2,2 -difluoroethyl ) pyrrolidin -2- yl ) methanol (Example 27- Intermediate 3 )

To an ice-cold solution of K ₂ CO ₃ (7.1 g, 51.16 mmol) in ACN (30 mL) and ( S )-pyrrolidin-2-ylmethoxide hydrochloride (3.2 mg, 23.25 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (4.97 g, 23.25 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at 25° C. for 16 h. The reaction was diluted with water (30 mL), the mixture was extracted with EA (40 mL), and the solution was washed with brine (30 mL). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography eluting with PE/EA = 2:1 to give ( S )-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (1.2 g, 31%) as a colorless oil. MS: m/z = 166.1 (M+H ⁺ , ESI+) Step 3 : 3-(1-(2-((( S )-1-(2,2 -difluoroethyl ) pyrrolidin - 2- yl ) methoxy )-5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1 -yl )-4- fluoro -8,9- dihydro - 10H -7- oxa - 1,3,6,10 - tetraazacycloheptyl [ de ] naphthalen -10- yl ) ethyl ) pyridin -2- amine (Example 27- Intermediate 4 )

To a solution of ( S )-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (174 mg, 1.05 mmol) in THF (2 mL) was added NaH (28 mg, 0.70 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min under _N2 , and a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (224 mg, 0.35 mmol) in THF (2 mL) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was quenched with concentrated NH ₄ Cl (aq., 5 mL) and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL) and dried over Na ₂ SO ₄ to give 3-(1-(2-((( S )-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 12%) as a yellow solid. MS: m/z = 722.4 (M+H ⁺ , ESI+) Step 4 : 4-(10-(1-(2- aminopyridin -3- yl ) ethyl )-2-((( S )-1-(2,2 -difluoroethyl ) pyrrolidin -2- yl ) methoxy )-4- fluoro -9,10- dihydro - 8H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl )-5- ethyl -6- fluoronaphth -2- ol (Example 27 )

To a solution of 3-(1-(2-((( S )-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 0.12 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda, column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 18-28%; retention time: 7.9-10.8 min in 16 min) and preparative HPLC (Waters 2767/Qda, column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 0.05% NH ₃ H ₂ O/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 53%~53%; retention time: 9.4-11.4 min in 16 min) to obtain the desired product as a white solid to obtain Example 27. (14.55 mg, 17%). MS: m/z = 678.4 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 7.98 (s, 1H), 7.75 (dd, J = 8.8, 6.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.41 – 7.24 (m, 2H), 6.99 (s, 1H), 6.74 – 6.63 (m, 1H), 6.42 - 6.30 (m, 1H), 6.08 (t, J = 56.4 Hz, 1H), 5.76 - 5.60 (m, 2H), 4.48 - 4.16 (m, 4H), 3.80 - 3.66 (m, 1H), 3.48 - 3.38 (m, 2H), 3.16 - 2.98 (m, 2H), 2.93 - 2.75 (m, 1H), 2.44 - 2.26 (m, 3H), 2.02 - 1.89 (m, 1H), 1.81 - 1.50 (m, 6H), 0.90 - 0.78 (m, 3H). 28. Synthesis scheme of Example 28 Experimental procedure of Example 28 : 5- ethyl -6- fluoro -4-(4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-10- methyl -9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphth -5- yl ) naphth -2- ol Step 1 : 7- chloro -8- fluoro -5-(2-( methylamino ) ethoxy )-2-( methylthio ) pyrido [4,3- d ] pyrimidin -4- ol (Example 28- Intermediate 2 )

To a solution of 2-(methylamino)ethan-1-ol (3 g, 10.71 mmol) in THF (30 mL) was added NaH (1.28 g, 32.13 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min under _N2 , and a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (804 mg, 10.71 mmol) in THF (30 mL) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1 h under _N2 . The reaction mixture was quenched with concentrated _NH4Cl (aq., 30 mL), and the solution was extracted with EA (30 mL). Filtration was performed and then washed with EA, and the filter cake was collected to give the desired crude product 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (2.1 g, 61%) as a yellow solid. MS: m/z = 319.0 (M+H ⁺ , ESI+) Step 2 : 5- Chloro -4- fluoro -10- methyl -2-( methylthio )-9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalene (Example 28- Intermediate 3 )

To a solution of 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (1.9 g, 5.96 mmol) in DCM (20 mL) was added BOPCl (4.6 g, 17.88 mmol), DIEA (6.9 g, 53.65 mmol). The reaction mixture was stirred at 25 °C under _N2 for 16 h. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL) and dried over _Na2SO4 . _The organic phase was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography eluting with PE/EA = 1:4 to give 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (220 mg, 12%) as a yellow solid. MS: m/z = 301.0 (M+H ⁺ , ESI+) Step 3 : 5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -10- methyl -2-( methylthio )-9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalene (Example 28- Intermediate 4 )

To a solution of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (220 mg, 0.73 mmol) in dioxane (3 mL)/ _H2O (0.3 mL) was added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (263 mg, 0.73 mmol), _K3PO4 ( ₄₆₅ mg, 2.19 mmol) and Ruphos-Pd- _G3 (61 mg, 0.07 mmol). The reaction mixture was stirred at 100°C under _N2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE/EA = 1:1 to give the desired product 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (80 mg, 22%) as a white solid. MS: m/z = 499.2 (M+H ⁺ , ESI+) Step 4 : 5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -10- methyl -2-( methylsulfonyl )-9,10- dihydro - 8H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalene (Example 28- Intermediate 5 )

To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene SM1 (80 mg, 0.16 mmol) in THF (3 ml)/H ₂ O (1 ml) was added potassium persulfate (493 mg, 0.80 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with concentrated NaHSO ₃ (aq., 5 ml), extracted with EA (5 ml), and dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure to give 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (56 mg, 65%) as a yellow solid. MS: m/z = 515.3/531.2 (M+H ⁺ , ESI+) Step 5 : 5-(8- ethyl -7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-10- methyl -9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalene (Example 28- Intermediate 6 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (50 mg, 0.32 mmol) in THF (1 mL) was added NaH (8 mg, 0.21 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min under _N2 , and to the above mixture was added dropwise a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (56 mg, 0.11 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was quenched with concentrated NH ₄ Cl (aq., 5 mL) and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL) and dried over Na ₂ SO ₄ to give 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolazin-7a(5 H )-yl)methoxy)-10-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (63 mg, 97%) as a yellow solid. MS: m/z = 610.5 (M+H ⁺ , ESI+) Step 6 : 5- ethyl -6- fluoro -4-(4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-10- methyl -9,10- dihydro -8 H -7- oxa - 1,3,6,10- tetraazacyclohepta [ de ] naphth -5- yl ) naphth -2- ol (Example 28 )

To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-10-methyl-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (63 mg, 0.10 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature under _N2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda), column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 23-31%; retention time: 7.9-9.6 min in 16 min) to give the desired product as a white solid to give Example 28 (5.78 mg, 9%). MS: m/z = 566.3 (M+H ⁺ , ESI+) ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.22 (s, 0.48 H, FA), 7.75 (dd, J = 8.6, 6.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.01 (s, 1H), 5.29 (d, J = 54.1 Hz, 1H), 4.63 – 4.48 (m, 2H), 4.11 (dd, J = 42.3, 10.3 Hz, 2H), 4.02 - 3.92 (m, 2H), 3.36 (s, 2H), 3.16 – 2.97 (m, 4H), 2.90 - 2.78 (m, 1H), 2.39 – 1.99 (m, 5H), 1.88 - 1.74 (m, 3H), 0.86 - 0.76 (m, 3H). 29. Synthesis scheme of Example 29 (Example 29a and Example 29b ) Experimental Procedure of Example 29 (Example 29a and Example 29b ) Step 1 : (3-(1-((2-((7- bromo -6- chloro -8- fluoro -4- hydroxy -2-( methylthio ) quinazolin -5- yl ) oxy ) ethyl ) amino ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 29- Intermediate 1 )

To a solution of tert -butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (824 mg, 2.928 mmol) in THF (10 mL) was added NaH (60%, oil, 351 mg, 8.793 mmol) at 0°C under argon. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added 7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-ol (1.0 g, 2.928 mmol) at 0°C under argon. The resulting mixture was stirred at 0°C for another 1 h. The reaction was quenched by the addition of NH ₄ Cl (30 mL) at 0°C, and the solution was extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the desired product (3-(1-((2-((7-bromo-6-chloro-8-fluoro-4-hydroxy-2-(methylthio)quinazolin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (1.26 g, yield 58%) as a yellow solid. MS: m/z = 604.0 (M+H ⁺ , ESI+) Step 2 : (3-(1-(9- bromo -8- chloro -10- fluoro -2-( methylthio )-5,6- dihydro - 4H- [1,4] oxazolidinone [5,6,7- de ] quinazolin -4- yl ) ethyl ) pyridin -2- yl ) carbamic acid tert- butyl ester (Example 29- Intermediate 2 )

To a solution of tert-butyl (3-(1-((2-((7-bromo-6-chloro- 8 -fluoro-4-hydroxy-2-(methylthio)quinazolin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (1.26 g, 2.090 mmol) in THF (20 mL) was added DIEA (2.43 g, 18.810 mmol) at 0°C under argon. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added BopCl (1.60 g, 6.270 mmol) at 0°C under argon. The resulting mixture was stirred at 25°C under argon for another 16 h. The reaction mixture was diluted with H ₂ O (80 mL) and the solution was extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (ethyl acetate in petroleum ether = 82%) to give the desired product (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (840 mg, yield 68%) as a yellow solid. MS: m/z = 586.1 (M+H ⁺ , ESI+) Step 3 : (4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8- chloro -10- fluoro -2-( methylthio )-5,6- dihydro - 4H- [1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-3- cyano -7- fluorobenzo [ b ] thiophene -2- yl ) carbamic acid tert- butyl ester (Example 29- Intermediate 3 )

3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamic acid tert- butyl ester (240 mg, 0.410 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[ b ]thiophen- 2 -yl)carbamate (332 mg, 0.821 mmol), Pd(DPEPhos) _Cl2 (30 mg, 0.041 mmol), KF (48 mg, 0.821 mmol) and _{K3PO4 were reacted} at 105°C under argon. (261 mg, 1.230 mmol) in dioxane (3 ml) was stirred for 3 hours. The reaction mixture was diluted with H ₂ O (40 ml) and the solution was extracted with EA (20 ml). The combined organic layers were washed with brine (30 ml) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (75%) to give the desired product (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamic acid tert- butyl ester (154 mg, 53% yield) as a yellow solid. MS: m/z = 696.2 (M+H ⁺ , ESI+) Step 4 : (4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8- chloro -10- fluoro -2-( methylsulfonyl )-5,6 - dihydro - 4H- [1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-3- cyano -7- fluorobenzo [ b ] thiophene -2- yl ) carbamic acid tert- butyl ester (Example 29- Intermediate 4 )

To a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl) carbamate (130 mg, 0.187 mmol) in THF (3 mL) and _H2O (1 mL) was added potassium persulfate (575 mg, 0.934 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for 1 h under argon. The reaction was quenched with _NaHSO3 solution at 0°C. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure to give the desired product (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro- 4H- [1,4]oxazolidin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamic acid tert- butyl ester (90 mg, crude) as a yellow solid. MS: m/z = 712.3 (M+H ⁺ , ESI+). The crude product was used directly in the next step. Step 5 : (4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8- chloro -10- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-5,6- dihydro -4 H -[1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-3- cyano -7- fluorobenzo [ b ] thiophene -2- yl ) carbamic acid tert- butyl ester (Example 29- Intermediate 5 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (30 mg, 0.190 mmol) in THF (2 mL) was added NaH (60%, oil, 10 mg, 0.252 mmol) under argon at 0°C. The mixture was stirred at 0°C for 0.5 h. To the above mixture was added tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamate (90 mg, 0.126 mmol) under argon at 0°C. The resulting mixture was stirred at 0°C for another 1 hour. The reaction was quenched by the addition of _NH4Cl solution (4 mL) at 0°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H ₂ O (30 mL), and the solution was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol in dichloromethane (9%) to give the desired product (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamic acid tert- butyl ester (30 mg, yield 29%) as a yellow solid. MS: m/z = 807.4 (M+H ⁺ , ESI+) Step 6 : Example 29a and Example 29b

A solution of tert _- butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5,6-dihydro-4 H -[1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamate (70 mg , 0.097 mmol) in HCl/dioxane (3 mL) was stirred at 25° C. under N 2 atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda, column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 13-23%; retention time: 4.6-6 min in 16 min) to give Example 29a (2.62 mg, 9%) as a white solid and Example 29b (3.31 mg, 12%) as a white solid. Example 29a : (4R)-2- amino -4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8 - chloro -10- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H)-yl ) methoxy ) -5,6- dihydro -4H-[1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-7- fluorobenzo [b] thiophene -3- carbonitrile MS: m/z = 707.1 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, MeOD) δ 7.96 (d, J = 4.8 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.17 (dd, J = 8.3, 7.7 – 7.6 Hz, 1H), 3.21 (m, 3H), 3.09 (t, J = 11.7, 5.8 Hz, 1H), 3.72 (t, J = 12.7, 7.6 Hz, 1H), 3.12 (m, 3H), 3.52 (t, J = 14.9, 5.9 Hz, 1H), 3.54 (t, J = 15.7, 7.6 Hz, 1H), 3.26 (t, J = 15.7, 5.8 Hz, 1H), 3.10 (t, J = 14.9, 5.9 Hz, 1H), 3.28 (t, J = 15.7, 7.6 Hz, 1H), 3.30 (t, J = 15.7, 5.8 Hz, 1H), 3.11 (m, 3H), 3.29 (t, J = 15.7, 7.6 Hz, 1H), – 1.87 (m, 3H), 1.66 (d, J = 6.8 Hz, 3H). Example 29b : (4S)-2- amino -4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8 - chloro -10- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H)-yl ) methoxy ) -5,6- dihydro -4H-[1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-7- fluorobenzo [b] thiophene -3- carbonitrile MS: m/z = 707.1 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 0.84 H, FA), 8.08 (s, 2H), 8.00 - 7.95 (m, 1H), 7.64 δ 5.71 - 5.97 ( m, 3H), 3.54 - 3.70 (m, 2H), 3.59 - 3.81 (m, 1H), 3.30 - 3.97 (m, 3H), 3.70 - 3.81 ( m , 2H), 3.13 - 3.91 (m, 3H) , 3.54 - 3.70 ( m , 1H), 3.12 - 3.81 (m, 3H), 3.53 - 3.97 (m, 3H), 3.82 - 3.81 (m, 1H), 3.10 - 3.11 (m, 3H), 3. (m, 3H), 1.58 (d, J = 6.8 Hz, 3H). 30. Synthesis scheme of Example 30 Experimental procedure of Example 30 : 4-(10-(1- amino -5,6,7,8- tetrahydroisoquinolin -8- yl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H )-yl ) methoxy ) -9,10 - dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -5- yl ) -5- ethynyl - 6- fluoronaphthalen -2- ol Step 1 : 8- oxo -5,6,7,8 - tetrahydroisoquinoline -2- oxide (Example 30- Intermediate 2 )

To a solution of 6,7-dihydroisoquinolin-8(5H)-one ( Example 30- Intermediate 1 ) (6.7 g, 45.58 mmol) in DCM (100 mL) was added m-CPBA (13.4 g, 77.48 mmol). The reaction mixture was stirred at 25 °C under _N2 for 16 h. The reaction mixture was quenched with concentrated _NaHSO3 (aq., 60 mL) and concentrated under reduced pressure. The residue was triturated with DCM (80 mL)/MeOH (8 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM/MeOH = 10:1 to give the desired product 8-oxo-5,6,7,8-tetrahydroisoquinoline-2-oxide (8 g, 89%) as a slightly yellow solid. MS: m/z = 164.1 (M+H ⁺ , ESI+). Step 2 : 1-( Benzylamino )-6,7- dihydroisoquinolin -8(5H) -one (Example 30- Intermediate 3 )

To a solution of 8-oxo-5,6,7,8-tetrahydroisoquinoline-2-oxide (7 g, 42.94 mmol) in dichloroethane (DCE) (70 mL) were added _BnNH2 (11.5 g, 107.36 mmol), TEA (13 g, 128.83 mmol), PyBrOP (26 g, 55.83 mmol). The reaction mixture was stirred at 25 °C under _N2 for 4 h. The reaction mixture was quenched with DCM (70 mL) and the solution was washed with brine (100 mL). The organic phase was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography using PE/EA = 10:1 to give 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (3.8 g, 35%) as a yellow solid. MS: m/z = 252.9 (M+H ⁺ , ESI+). Step 3 : ( E )-2-((1-( benzylamino )-6,7- dihydroisoquinolin -8(5H) -yl ) amino ) ethan -1- ol (Example 30- Intermediate 4 )

To a solution of 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (1.0 g, 3.968 mmol) in MeOH (10 ml)/DMF (10 ml) were added 2-aminoethan-1-ol (720 mg, 11.905 mmol), TEA (1.2 g, 11.905 mmol), AcOH (240 mg, 3.968 mmol). The reaction mixture was stirred at 60°C for 2 hours, and NaBH ₃ CN (740 mg, 11.905 mmol) was added to the above solution. The reaction mixture was then stirred at 60°C for 48 hours. The reaction mixture was diluted with DCM (100 ml), and the solution was washed with water (150 ml×3). The organic phase was washed with brine ( ₁₀₀ mL), dried over _Na2SO4 , and concentrated to give the crude product ( E )-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-yl)amino)ethan-1-ol (1.0 g, 100%) as a slightly yellow oil. MS: m/z = 296.0 (M+H ⁺ , ESI+). Step 4 : 2-((1-( benzylamino )-5,6,7,8- tetrahydroisoquinolin -8- yl ) amino ) ethan -1- ol (Example 30- Intermediate 5 )

To a solution of ( E )-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-yl)amino)ethan-1-ol (1.5 g, 5.078 mmol) in MeOH (10 mL) was added _NaBH4 (576 mg, 15.234 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography using PE/EA = 1:1 to give the desired product 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (440 mg, yield 29%) as a colorless oil. MS: m/z = 298.0 (M+H ⁺ , ESI+) Step 5 : 5-(2-((1-( benzylamino )-5,6,7,8- tetrahydroisoquinolin - 8 - yl ) amino ) ethoxy )-7- chloro -8- fluoro -2-( methylthio ) pyrido [4,3- d ] pyrimidin -4- ol (Example 30- Example 6 )

To a solution of 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (400 mg, 1.342 mmol) in THF (2 mL) was added NaH (60%, oil, 215 mg, 5.346 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min under _N2 , and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (374 mg, 1.342 mmol) was added to the above solution. The reaction mixture was stirred at 25°C for 16 h under _N2 . The reaction mixture was quenched with concentrated _NH4Cl (aq) (5 mL), and the solution was extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography using PE/EA = 3:1 to give the desired product 5-(2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4-ol (185 mg, 25% yield) as a colorless oil. MS: m/z = 541.1 (M+H ⁺ , ESI+). Step 6 : N- benzyl -8-(5- chloro -4- fluoro -2-( methylthio )-8,9 -dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl )-5,6,7,8- tetrahydroisoquinolin -1- amine (Example 30- Intermediate 7 )

To a solution of 5-(2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3 -d ]pyrimidin-4-ol (185 mg, 0.343 mmol) in DCM (5 mL) were added BOPCl (262 mg, 1.028 mmol), DIEA (398 mg, 3.087 mmol). The reaction mixture was stirred at 25 °C under _N2 for 16 h. The reaction mixture was diluted with DCM (10 mL). The organic phase was washed with brine (20 mL) and dried over _Na2SO4 . _The organic phase was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography eluting with PE/EA = 3:1 to give the desired product N-benzyl-8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (90 mg, yield 50%) as a colorless oil. MS: m/z = 523.1 (M+H ⁺ , ESI+). Step 7 : 8-(5- chloro -4- fluoro -2-( methylthio )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl )-5,6,7,8 -tetrahydroisoquinolin -1- amine (Example 30- Intermediate 8 )

To a solution of N-benzyl-8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8- _{tetrahydroisoquinolin} -1-amine (90 mg, 0.172 mmol) in TFA (2.5 mL) was added _CF3SO3H (0.5 mL). The reaction mixture was stirred at 25°C under _N2 for 5 h. The reaction mixture was quenched with _{concentrated Na2CO3} (50 mL), and the solution was extracted with DCM (50 mL x 3). _The organic phase was washed with brine (50 mL) and dried over _Na2SO4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE/EA = 3:1 to give the desired product 8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (50 mg, yield 67%) as a yellow solid. MS: m/z = 433.0 (M+H ⁺ , ESI+). Step 8 : 8-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 -yl )-2-( methylthio )-8,9- dihydro - 10H- 7- oxa - 1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen - 10- yl )-5,6,7,8- tetrahydroisoquinolin -1- amine (Example 30- Intermediate 9 )

To a solution of 8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (40 mg, 0.092 mmol) in dioxane (3 mL)/ _H2O (0.3 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl ₎ triisopropylsilane (48 mg, 0.092 mmol), _K3PO4 (60 mg, 0.276 mmol) and Ruphos-Pd- _G3 (16 mg, 0.0184 mmol). The reaction mixture was stirred at 100 °C for 2 h under _N2 . The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE/EA = 3:1 to give the desired product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (20 mg, yield 27%) as a yellow solid. MS: m/z = 783.3 (M+H ⁺ , ESI+). Step 9 : 8-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilyl ) ethynyl ) naphthalen -1 -yl )-2-( methylsulfonyl ) -8,9- dihydro - 10H- 7- oxa - 1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl )-5,6,7,8- tetrahydroisoquinolin -1- amine (Example 30- Intermediate 10 )

To a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (20 mg, 0.025 mmol) in ACN (1 mL)/ _H2O (1 mL) was added potassium persulfate (78 mg, 0.128 mmol) at 0°C. The reaction mixture was stirred at room temperature under _N2 for 2 h. The reaction mixture was quenched with concentrated _NaHSO3 (aq., 5 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure to give the desired crude product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (15 mg, 72% yield) as a yellow solid. MS: m/z = 815.2 (M+H ⁺ , ESI+). Step 10 : 8-(4- fluoro -5-(7- fluoro -3-( methoxymethoxy )-8-(( triisopropylsilane ) ethynyl ) naphthalen - 1 - yl )-2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H )-yl ) methoxy ) -8,9- dihydro - 10H- 7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen -10- yl ) -5,6,7,8- tetrahydroisoquinolin -1- amine (Example 30- Intermediate 1 )

To a solution of (( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (14 mg, 0.090 mmol) in THF (1 mL) at 0°C was added NaH (60%, oil, 2 mg, 0.128 mmol). The reaction mixture was stirred at 0°C for 20 min under _N2 , and a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (15 mg, 0.018 mmol) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 2 h under _N2 . The reaction mixture was quenched with concentrated _NH4Cl (aq., 5 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 ml) and dried over Na ₂ SO _4. The organic phase was concentrated under reduced pressure to give the desired crude product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolazin-7a(5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, yield 60%) as a yellow solid. MS: m/z = 849.3 (M+H ⁺ , ESI+). Step 11 : 8-(5-(8- ethynyl- 7- fluoro -3-( methoxymethoxy ) naphthalen -1- yl )-4- fluoro -2-((( 2R , 7aS )-2- fluorotetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-8,9- dihydro - 10H -7- oxa -1,3,6,10 -tetraazacycloheptyl [ de ] naphthalen -10- yl )-5,6,7,8 -tetrahydroisoquinolin -1- amine (Example 30- Intermediate 12 )

To a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane)ethynyl)naphthalen-1-yl)-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, 0.011 mmol) in DMF (1 mL) was added CsF (17 mg, 0.110 mmol). The reaction mixture was stirred at room temperature under _N2 for 2 h. The reaction mixture was quenched with water (10 mL), and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL x 3), and dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure to give the desired crude product 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolazin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, yield 100%) as a colorless oil. MS: m/z = 738.2 (M+H ⁺ , ESI+). Step 12 : 4-(10-(1- amino -5,6,7,8- tetrahydroisoquinolin -8- yl )-4- fluoro -2-(((2 R ,7a S )-2- fluorotetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-9,10- dihydro -8 H -7- oxa -1,3,6,10 -tetraazacyclohepta [ de ] naphthalen - 5 - yl )-5- ethynyl -6- fluoronaphthalen -2- ol ( Example 30 )

To a solution of 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8,9-dihydro- 10H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, 0.013 mmol) in ACN (1 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature under _N2 for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sanfal C18, 19*250 mm, 10 μm; mobile phase A: 0.1% NH ₄ HCO ₃ /H ₂ O, B: ACN; gradient: 5%-95% B; flow rate: 50 ml/min) to obtain the desired product ( Example 30 ) as a white solid (1.07 mg, yield 11%). MS: m/z = 694.4 (M+H ⁺ , ESI+). 31. Synthesis scheme of Example 36 Experimental procedure for Example 36 : 2- amino -4-(4-(1-(2- aminopyridin -3 -yl ) ethyl )-8- chloro -10- fluoro -2-((( S )-2- methylenetetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-5,6- dihydro - 4H- [1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-7- fluorobenzo [ b ] thiophene -3- carbonitrile Step 1 : (4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8- chloro -10- fluoro -2-((( S )-2- methylenetetrahydro - 1H - pyrrolizin -7a( 5H ) -yl ) methoxy )-5,6- dihydro-4H-[1,4]oxazolidinone[5,6,7-de] quinazolin -9- yl ) -[1,4] oxaza-nitro- [5,6,7- de ] quinazolin -9- yl )-3- cyano -7- fluorobenzo [ b ] thiophen -2- yl ) carbamic acid tert- butyl ester (Example 36- Intermediate 1 )

To a solution of ( S )-(2-methylenetetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (13 mg, 0.082 mmol) in THF (1 ml) was added NaH (60%, oil, 10 mg, 0.41 mmol) under argon at 0°C. The mixture was stirred at 0°C for 10 min under argon. Then, to the above mixture was added tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen- 2 -yl)carbamate (60 mg, 0.082 mmol). The reaction mixture was stirred under argon at 0°C to room temperature for 1 hour. The mixture was quenched with H ₂ O (10 mL). The mixture was extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (30 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography using dichloromethane:methanol (10:1) as an elution to obtain the desired product (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( S )-2-methylene-tetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophene-2-yl)carbamic acid tert- butyl ester (50 mg, yield 75%). MS: m/z = 801.4 (M+H ⁺ , ESI+) Step 2 : 2- amino -4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8- chloro -10- fluoro -2-((( S )-2 - methylenetetrahydro -1 H -pyrrolazin -7a(5 H ) -yl ) methoxy )-5,6- dihydro -4 H -[1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-7- fluorobenzo [ b ] thiophene -3- carbonitrile (Example 36 )

To a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( S )-2-methylene-tetrahydro- 1H -pyrrolizin- 7a ( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamate (50 mg, 0.062 mmol) in DCM (0.5 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767/Qda, column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mM NH ₄ HCO ₃ , B: ACN; flow rate: 20 ml/min; gradient: 57%~57%). Retention time: 5.6-7.1 min in 16 min to obtain the desired product ( Example 36a ) (1.34 mg, 3%) as a white solid; retention time: 9.5-11 min in 16 min to obtain the desired product ( Example 36b ) (6.06 mg, 14%) as a white solid. Example 36a : MS: m/z = 701.3 (M+H ⁺ , ESI+). ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.08 (brs, 1.87 H, FA), 7.97 (d, J = 4.3 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.24 – 7.08 (m, 2H), 6.68 (dd, J = 7.4, 5.0 Hz, 1H), 6.30 - 6.20 (m, 1H), 5.67 (d, J = 15.6 Hz, 2H), 4.90 (d, J = 11.1 Hz, 2H), 4.45 - 4.25 (m, 2H), 4.10 – 3.98 (m, 2H), 3.60 - 3.50 (m, 2H), 3.25 - 3.13 (m, 2H), 3.05 - 2.95 (m, 1H), 2.70 - 2.56 (m, 1H), 2.40 - 2.30 (m, 2H), 2.03 - 1.70 (m, 4H), 1.66 - 1.55 (m, 3H). Example 36b : MS: m/z = 701.3 (M+H ⁺ , ESI+). ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.09 (brs, 2H), 7.97 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.25 - 7.09 (m, 2H), 6.68 (dd, J = 7.4, 4.9 Hz, 1H), 6.35 - 6.25 (m, 1H), 5.81 (d, J = 16.5 Hz, 2H), 4.90 (d, J = 9.9 Hz, 2H), 4.52 (dd, J = 11.8, 6.1 Hz, 1H), 4.21 (dd, J = 11.0, 7.0 Hz, 1H), 4.13 - 3.97 (m, 3.70 (dd, J = 15.7, 6.4 Hz, 1H), 3.56 (d, J = 14.0 Hz, 1H), 3.18 (d, J = 13.7 Hz, 2H), 3.02 – 2.98 (m, 1H), 2.67 - 2.59 (m, 1H), 2.36 (d, J = 15.2 Hz, 2H), 1.99 – 1.68 (m, 4H), 1.58 (d, J = 6.6 Hz, 3H) . 32. Synthesis Scheme of Example 37 Experimental procedure for Example 37 : 2- amino -4-(4-(1-(2- aminopyridin -3 -yl ) ethyl )-8- chloro -10- fluoro -2-(((2 R ,7a S )-2- methoxytetrahydro -1 H -pyrrolizin -7a(5 H ) -yl ) methoxy )-5,6- dihydro -4 H -[1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-7 - fluorobenzo [ b ] thiophene -3- carbonitrile Step 1 : (4-(4-(1-(2- aminopyridin -3 -yl ) ethyl )-8- chloro -10- fluoro -2-(((7a S )-2- methoxytetrahydro -1 H -pyrrolizin- 7a(5 H ) -yl ) methoxy )-5,6- dihydro - 4 H -[1,4]oxazolidinone[5,6,7-de] quinazolin -9-yl) -[1,4] oxaza -1,2 - dihydro -1- nitro -2 - nitro - 3 - nitro -7- fluorobenzo [ b ] thiophen -2- yl ) carbamic acid tert- butyl ester (Example 37- Intermediate 1 )

To a solution of (( 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methanol (14 mg, 0.082 mmol) in THF (1 ml) was added NaH (10 mg, 0.41 mmol) under argon at 0°C. The mixture was stirred at 0°C for 10 min under argon. Then, to the above solution was added tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro- 10 -fluoro-2-(methylsulfonyl)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamate (60 mg, 0.082 mmol). The reaction mixture was stirred under argon at 0°C to room temperature for 1 hour. The mixture was quenched with H ₂ O (10 mL). The mixture was extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (30 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography using dichloromethane:methanol (10:1) as an elution to obtain the desired product (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-3-cyano-7-fluorobenzo[ b ]thiophene-2-yl)carbamic acid tert- butyl ester (40 mg, yield 60%). MS: m/z = 819.4 (M+H ⁺ , ESI+) Step 2 : 2- amino -4-(4-(1-(2- aminopyridin -3- yl ) ethyl )-8- chloro -10- fluoro -2-(((2 R ,7a S )-2- methoxytetrahydro -1 H -pyrrolazin -7a(5 H ) -yl ) methoxy )-5,6- dihydro -4 H -[1,4] oxazolidinone [5,6,7- de ] quinazolin -9- yl )-7- fluorobenzo [ b ] thiophene -3- carbonitrile (Example 37 )

To a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl) -3 -cyano-7-fluorobenzo[ b ]thiophen-2-yl)carbamate (40 mg, 0.048 mmol) in DCM (0.5 mL) was added 4 mol HCl/dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: Waters 2767/Qda, column: Exbridge C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 ml/min; gradient: 19%~28%; retention time: 7.9-9.7 min in 16 min to obtain the desired product ( Example 37a ) (4.34 mg, 13%) as a white solid; retention time: 11.6-12.9 min in 16 min to obtain the desired product ( Example 37b ) (4.88 mg, 14%) as a white solid. Example 37a : MS: m/z = 719.4 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (brs, 3.59 H, FA), 8.09 (s, 2H), 8.00 - 7.92 (m, 1H), 7.64 (d, J = 6.7 Hz, 1H), 7.26 - 7.08 (m, 2H), 6.71 – 6.65 (m, 1H), 6.29 - 6.20 (m, 1H), 5.69 (s, 2H), 4.46 - 4.36 (m, 1H), 4.34 - 4.26 (m, 1H), 4.10 -4.02 (m, 3H), 4.00 - 3.94 (m, 2H), 3.20 (s, 3H), 3.08 - 2.96 (m, 2H), 2.76 - 2.66 (m, 2H), 2.18 - 2.08 (m, 1H), 1.94 - 1.70 (m, 5H), 1.66 - 1.54 (m, 3H). Example 37b : MS: m/z = 719.4 (M+H ⁺ , ESI+) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (brs, 2.72 H, FA), 8.09 (s, 2H), 7.97 (d, J = 3.5 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.25 - 7.08 (m, 2H), 6.73 – 6.62 (m, 1H), 6.40 - 6.25 (m, 1H), 5.83 (s, 2H), 4.60 - 4.47 (m, 1H), 4.25 - 4.16 (m, 1H), 4.10 - 3.95 (m, 3H), 3.74 – 3.68 (m, 2H), 3.20 (s, 3H), 3.10 - 2.92 (m, 2H), 2.75 – 2.68 (m, 2H), 2.15 (dd, J = 12.8, 5.6 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.80 - 1.70 (m, 3H), 1.58 (d, J = 6.8 Hz, 3H).

In a similar manner, the compounds of Examples 1 to 37 in the following Table 1 were prepared using samples suitable for preparing the compounds described in each Example. [Table 1] No. Structure IUPAC name Mass (ESI+) m/z (M+H) 1 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 663.47 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 0.80 (t, J = 7.38 Hz, 3H), 1.65-1.85 (m, 7H), 1.96 (brs, 1H), 2.03-2.13 (m, 4H), 2.23 (s, 6H), 2.26-2.30 (m, 1H), 2.36-2.42 (m, 1H), 2.79-2.85 (m, 1H), 3.01 (brs, 1H), 3.08 (d, J = 6.50 Hz, 2H), 3.97-4.25 (m, 6H), 4.57 (t, J = 4.88 Hz, 2H), 5.21-5.34 (m, 1H), 7.01 (d, J = 2.50 Hz, 1H), 7.30 (d, J = 2.50 Hz, 1H), 7.34 (t, J = 9.38 Hz, 1H), 7.74 (dd, J = 9.01, 6.00 Hz, 1H), 9.91 (s, 1H). 2 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 659.39 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 1.67-1.91 (m, 8H), 2.05-2.10 (m, 4H), 2.26 (brs, 6H), 2.85 (d, J = 6.01 Hz, 1H), 3.03-3.11 (m, 4H), 3.93-4.17 (m, 6H), 4.45 (dd, J = 14.13, 4.88 Hz, 1H), 4.56 (brs, 2H), 5.22-5.35 (m, 1H), 7.15 (d, J = 2.25 Hz, 1H), 7.37 (d, J = 2.50 Hz, 1H), 7.46 (t, J = 9.01 Hz, 1H), 7.96 (dd, J = 9.13, 5.88 Hz, 1H), 10.14 (brs, 1H). 3 4-((8 S )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 686.2 N/A 3a (hypothetical) 4-(( S )-10-(( R )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 686.2 ¹ H NMR (400 mHz, MeOD) δ 7.91 (d, J = 4.7 Hz, 1H), 7.70 (d, J = 7.1 Hz, 1H), 7.55 (dd, J = 8.9, 5.9 Hz, 1H), 7.25 – 7.07 (m, 2H), 6.99 - 6.87 (m, 1H), 6.78 – 6.65 (m, 1H), 6.57 - 6.48 (m, 1H), 5.24 (d, J = 54.6 Hz, 1H), 4.53 - 4.45 (m, 1H), 4.29 – 4.15 (m, 2H), 3.54 – 3.40 (m, 2H), 3.20 - 3.11 (m, 2H), 3.04 - 2.92 (m, 1H), 2.53 – 2.06 (m, 5H), 2.01 - 1.73 (m, 3H), 1.62 - 1.48 (m, 3H), 1.20 - 1.06 (m, 3H), 0.78 (t, J = 7.3 Hz, 3H). 3b (hypothetical) 4-(( S )-10-(( S )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 686.3 ¹ H NMR (400 mHz, MeOD) δ 7.96 (s, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.31 - 7.17 (m, 2H), 7.03 (d, J = 23.2 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.72 - 6.62 (m, 1H), 5.31 (d, J = 54.4 Hz, 1H), 4.69 – 4.53 (m, 2H), 4.34 (dd, J = 23.5, 10.5 Hz, 2H), 3.75 - 3.64 (m, 1H), 3.27 - 3.17 (m, 2H), 3.06 - 2.97 (m, 1H), 2.57 – 2.12 (m, 5H), 2.05 - 1.85 (m, 3H), 1.76 - 1.64 (m, 3H), 1.36 - 1.22 (m, 3H), 0.96 - 0.79 (m, 3H). 4 4-(( 8S )-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethyltetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 688.2 ¹ H NMR (400 mHz, MeOD) δ 8.03 - 7.90 (m, 1H), 7.86 - 7.74 (m, 2H), 7.36 - 7.25 (m, 2H), 7.23 - 7.11 (m, 1H), 6.85 - 6.75 (m, 1H), 6.68 - 6.54 (m, 1H), 5.12 - 4.91 (m, 4H), 4.68 - 4.19 (m, 3H), 3.83 - 3.34 (m, 6H), 2.88 - 2.76 (m, 2H), 2.66 - 2.54 (m, 2H), 1.74 - 1.59 (m, 3H), 1.37 - 1.14 (m, 3H). 5 4-(( 8S )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 694.0 ¹ H NMR (400 mHz, MeOD) δ 8.04 - 7.94 (m, 1H), 7.87 - 7.74 (m, 2H), 7.36 - 7.25 (m, 2H), 7.24 - 7.11 (m, 1H), 6.86 - 6.74 (m, 1H), 6.71 - 6.56 (m, 1H), 4.71 - 4.18 (m, 3H), 3.70 - 3.65 (m, 4H), 3.62 - 3.40 (m, 2H), 2.62 - 2.36 (m, 6H), 1.77 - 1.60 (m, 3H), 1.36 - 1.15 (m, 3H), 0.80 - 0.68 (m, 2H), 0.56 - 0.46 (m, 2H). 6 4-((8 S )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 682.2 ¹ H NMR (400 mHz, MeOD) δ 8.04 – 7.93 (m, 1H), 7.87 – 7.75 (m, 2H), 7.35 - 7.25 (m, 2H), 7.24 – 7.10 (m, 1H), 6.86 - 6.76 (m, 1H), 6.72 – 6.55 (m, 1H), 5.32 (d, J = 53.0 Hz, 1H), 4.70 – 4.19 (m, 3H), 3.77 – 3.35 (m, 3H), 3.28 - 3.18 (m, 2H), 3.08 - 2.96 (m, 1H), 2.46 – 2.11 (m, 3H), 2.07 - 1.86 (m, 3H), 1.74 – 1.59 (m, 3H), 1.38 – 1.14 (m, 3H). 6a (hypothetical) 4-(( S )-10-(( R )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 682.0 ¹ H NMR (400 mHz, MeOD) δ 8.00 (d, J = 4.8 Hz, 1H), 7.87 – 7.75 (m, 2H), 7.34 - 7.26 (m, 2H), 7.22 - 7.12 (m, 1H), 6.86 – 6.78 (m, 1H), 6.66 - 6.56 (m, 1H), 5.31 (d, J = 53.6 Hz, 1H), 4.40 – 4.17 (m, 3H), 3.68 – 3.41 (m, 3H), 3.27 - 3.16 (m, 2H), 3.07 – 2.97 (m, 1H), 2.42 – 2.11 (m, 3H), 2.06 – 1.86 (m, 3H), 1.71 – 1.58 (m, 3H), 1.25 - 1.14 (m, 3H). 6b (hypothetical) 4-(( S )-10-(( S )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 682.0 ¹ H NMR (400 mHz, MeOD) δ 8.00 - 7.92 (m, 1H), 7.87 - 7.72 (m, 2H), 7.35 - 7.25 (m, 2H), 7.23 - 7.12 (m, 1H), 6.84 - 6.74 (m, 1H), 6.69 - 6.57 (m, 1H), 5.33 (d, J = 55.0 Hz, 1H), 4.71 - 4.61 (m, 1H), 4.41 - 4.29 (m, 2H), 3.77 - 3.34 (m, 3H), 3.30 - 3.17 (m, 2H), 3.09 - 2.99 (m, 1H), 2.40 - 2.12 (m, 3H), 2.06 - 1.88 (m, 3H), 1.70 (d, J = 6.7 Hz, 3H), 1.37 - 1.22 (m, 3H). 7 4-(( 8S )-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 673.9 ¹ H NMR (400 mHz, DMSO) δ 10.15 (s, 1H), 8.05 – 7.89 (m, 2H), 7.76 – 7.63 (m, 1H), 7.51 - 7.42 (m, 1H), 7.38 (s, 1H), 7.23 – 7.07 (m, 1H), 6.76 – 6.62 (m, 1H), 6.47 – 6.28 (m, 1H), 5.83 - 5.63 (m, 2H), 4.71 – 3.92 (m, 4H), 3.66 - 3.50 (m, 1H), 3.05 - 2.93 (m, 1H), 2.81 – 2.52 (m, 2H), 2.39 (s, 3H), 2.35 - 2.15 (m, 1H), 1.69 - 1.49 (m, 3H), 1.31 - 1.03 (m, 3H). 8 4-(( 8S )-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((( S )-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 674.0 ¹ H NMR (400 mHz, DMSO) δ 10.38 (brs, 0.47H, FA), 8.42 (s, 1H), 8.08 – 7.88 (m, 2H), 7.76 - 7.62 (m, 1H), 7.52 - 7.34 (m, 2H), 7.25 – 7.04 (m, 1H), 6.80 – 6.61 (m, 1H), 6.46 - 6.24 (m, 1H), 6.16 - 5.82 (m, 1H), 5.80 – 5.49 (m, 2H), 4.74 – 3.77 (m, 4H), 3.74 - 3.54 (m, 2H), 3.05 – 2.70 (m, 3H), 2.16 - 2.00 (m, 2H), 1.68 - 1.52 (m, 3H), 1.34 - 1.02 (m, 3H). 9 4-(( 8S )-2-((2-oxabicyclo[2.1.1]hex-4-yl)methoxy)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-9,10-dihydro- 8H -7-oxabicyclo[1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 636.9 ¹ H NMR (400 mHz, CD3OD_SPE) δ 8.03 - 7.90 (m, 1H), 7.85 - 7.69 (m, 2H), 7.34 - 7.13 (m, 3H), 6.85 - 6.71 (m, 1H), 6.68 - 6.54 (m, 1H), 4.74 - 4.12 (m, 3H), 3.77 - 3.63 (m, 2H), 3.57 - 3.27 (m, 3H), 2.03 - 1.90 (m, 2H), 1.72 - 1.54 (m, 5H), 1.32 - 1.13 (m, 3H). 10a (hypothetical) 4-(( S )-10-(( R )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-8-methyl-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5,6-difluoronaphth-2-ol 676.0 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.27 (s, 1H), 8.01 (dd, J = 4.9, 1.5 Hz, 1H), 7.79 – 7.66 (m, 2H), 7.63 - 7.51 (m, 1H), 7.37 (s, 1H), 7.28 - 7.12 (m, 1H), 6.75 - 6.66 (m, 1H), 6.45 - 6.32 (m, 1H), 5.73 (s, 2H), 5.41 – 5.20 (m, 1H), 4.23 – 4.10 (m, 3H), 3.53 - 3.46 (m, 2H), 3.13 - 2.99 (m, 3H), 2.88 - 2.78 (m, 1H), 2.18 – 1.94 (m, 4H), 1.90 - 1.75 (m, 3H), 1.60 - 1.48 (m, 3H), 1.10 (d, J = 6.5 Hz, 3H). 10b (hypothetical) 4-(( S )-10-(( S )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5,6-difluoronaphth-2-ol 676.0 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 7.96 (d, J = 4.1 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.58 - 7.44 (m, 1H), 7.30 (s, 1H), 7.18 (d, J = 34.6 Hz, 1H), 6.72 – 6.60 (m, 1H), 6.46 - 6.34 (m, 1H), 5.72 (s, 2H), 5.43 – 5.19 (m, 1H), 4.72 – 4.56 (m, 1H), 4.24 – 4.07 (m, 2H), 3.66 - 3.55 (m, 2H), 3.11 – 3.01 (m, 3H), 2.88 - 2.78 (m, 1H), 2.14 – 1.98 (m, 4H), 1.90 – 1.75 (m, 3H), 1.60 (d, J = 6.7 Hz, 3H), 1.23 – 1.20 (m, 3H). 11 3-((8 S )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-chloro-4-cyclopropylphenol 664.2 ¹ H NMR (400 mHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.97 (d, J = 4.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.75 – 6.67 (m, 2H), 6.66 - 6.56 (m, 1H), 5.92 (brs, 2H), 5.41 (d, J = 52.4 Hz, 1H), 4.61 - 4.43 (m, 3H), 3.46 – 3.08 (m, 6H), 2.60 – 2.23 (m, 3H), 2.18 - 2.04 (m, 3H), 1.893 - 1.80 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H), 0.72 - 0.55 (m, 2H), 0.18 - 0.06 (m, 2H). 12 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(oxolinemethyl)cyclopropyl)methoxy)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 680.0 ¹ H NMR (400 mHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.70 - 7.54 (m, 2H), 7.22 - 7.10 (m, 3H), 6.78 – 6.59 (m, 2H), 5.95 (brs, 2H), 4.51 – 4.18 (m, 4H), 3.78 – 3.54 (m, 5H), 3.52 – 3.38 (m, 1H), 2.99 (d, J = 33.9 Hz, 1H), 2.64 – 2.46 (m, 6H), 1.60 (dd, J = 18.7, 6.8 Hz, 3H), 0.78 - 0.66 (m, 2H), 0.56 - 0.44 (m, 2H). 13 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 667.9 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.16 (brs, 1H), 8.15 (s, 0.76H, FA), 8.01 – 7.91 (m, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (d, J = 1.3 Hz, 1H), 7.15 (s, 1H), 6.74 – 6.63 (m, 1H), 6.39 – 6.26 (m, 1H), 5.82 (s, 1H), 5.74 (s, 1H), 5.36 (d, J = 54.6 Hz, 1H), 4.53 – 4.14 (m, 4H), 4.04 (d, J = 54.6 Hz, 1H), 3.83 – 3.67 (m, 1H), 3.50 – 3.37 (m, 3H), 2.97 - 2.87 (m, 1H), 2.31 – 1.77 (m, 6H), 1.66 – 1.52 (m, 3H). 13a (hypothetical) 4-(10-(( R )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 668.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 8.07 – 7.87 (m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (t, J = 2.2 Hz, 1H), 6.72 – 6.64 (m, 1H), 6.40 - 6.25 (m, 1H), 5.76 (d, J = 28.3 Hz, 2H), 5.30 (d, J = 54.2 Hz, 1H), 4.45 – 4.37 (m, 1H), 4.26 - 4.08 (m, 3H), 3.80 – 3.64 (m, 1H), 3.51 - 3.44 (m, 1H), 3.15 - 3.00 (m, 3H), 2.90 – 2.78 (m, 1H), 2.19 – 1.78 (m, 6H), 1.67 – 1.54 (m, 3H). 13b (hypothetical) 4-(10-(( S )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 668.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.22 (brs, 1H), 8.16 – 7.94 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 6.72 – 6.64 (m, 1H), 6.45 – 6.24 (m, 1H), 5.76 (d, J = 30.0 Hz, 2H), 5.31 (d, J = 55.8 Hz, 1H), 4.45 – 4.37 (m, 1H), 4.27 – 4.06 (m, 3H), 3.82 - 3.74 (m, 9 – 2.80 (m, 1H), 2.15 – 1.78 (m, 6H), 1.69 – 1.51 (m, 3H). 14 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 672.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.01 (brs, 1H), 7.97 (s, 1H), 7.81 – 7.54 (m, 2H), 7.42 – 7.21 (m, 2H), 7.00 (s, 1H), 6.75 – 6.59 (m, 1H), 6.44 -6.30 (m, 1H), 5.72 (d, J = 26.4 Hz, 2H), 5.29 (d, J = 54.3 Hz, 1H), 4.44 - 4.04 (m, 4H), 3.80 - 3.66 (m, 2H), 3.12 - 2.96 (m, 3H), 2.88 - 2.76 (m, 1H), 2.42 - 2.24 (m, 2H), 2.18 - 1.98 (m, 3H), 1.88 - 1.70 (m, 3H), 1.64 - 1.52 (m, 3H), 0.88 - 0.72 (m, 3H). 14a (hypothetical) 4-(10-(( R )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 672.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.30 (brs, 1.18H, FA), 8.03 – 7.92 (m, 1H), 7.80 – 7.64 (m, 2H), 7.44 – 7.31 (m, 2H), 7.02 (t, J = 2.5 Hz, 1H), 6.79 – 6.72 (m, 1H), 6.37 (q, J = 6.7 Hz, 1H), 5.39 (d, J = 53.9 Hz, 1H), 4.46 – 4.25 (m, 4H), 3.83 - 3.68 (m, 1H), 3.51 – 3.16 (m, 4H), 3.02 - 2.90 (m, 1H), 2.43 – 2.10 (m, 5H), 2.03 – 1.80 (m, 3H), 1.60 (t, J = 6.7 Hz, 3H), 0.88 - 0.72 (m, 3H). 14b (hypothetical) 4-(10-(( S )-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 672.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.20 (s, 0.53H, FA), 7.99 - 7.95 (m, 1H), 7.74 (dd, J = 9.0, 6.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 6.8, 5.3 Hz, 1H), 6.43 - 6.32 (m, 1H), 5.73 (d, J = 27.4 Hz, 2H), 5.30 (d, J = 54.1 Hz, 1H), 4.45 - 4.07 (m, 4H), 3.78 – 3.73 (m, 1H), 3.19 – 3.00 (m, 4H), 2.88 - 2.78 (m, 1H), 2.43 – 2.28 (m, 2H), 2.19 – 1.97 (m, 3H), 1.91 – 1.71 (m, 3H), 1.65 – 1.51 (m, 3H), 0.88 - 0.76 (m, 3H). 15 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((( S )-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 660.4 ¹ H NMR (400 mHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.67 - 7.47 (m, 2H), 7.23 - 7.06 (m, 3H), 6.80 - 6.53 (m, 2H), 5.89 - 5.36 (m, 2H), 4.68 - 4.11 (m, 4H), 3.67 - 3.30 (m, 3H), 3.10 - 2.87 (m, 2H), 2.82 - 2.63 (m, 1H), 2.55 - 2.30 (m, 5H), 1.65 - 1.45 (m, 3H). 16 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5,6-difluoronaphth-2-ol 662.0 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.23 (s, 0.81H, FA), 7.98 (d, J = 4.3 Hz, 1H), 7.77 – 7.51 (m, 3H), 7.39 (s, 1H), 7.22 (d, J = 1.9 Hz, 1H), 6.72 (dd, J = 7.3, 5.0 Hz, 1H), 6.45 - 6.33 (m, 1H), 5.35 (d, J = 54.4 Hz, 1H), 4.58 – 3.99 (m, 4H), 3.50 - 3.35 (m, 1H), 3.26 - 3.10 (m, 3H), 2.96 - 2.85 (m, 1H), 2.28 – 1.78 (m, 6H), 1.59 (d, J = 4.6 Hz, 3H). 17 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-methoxytetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 684.0 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.28 (s, 1.8H, FA), 7.98 (s, 1H), 7.81 – 7.73 (m, 1H), 7.70 - 7.62 (m, 1H), 7.43 – 7.29 (m, 2H), 7.07 - 6.97 (m, 1H), 6.78 – 6.68 (m, 1H), 6.42 – 6.31 (m, 1H), 4.55 – 4.29 (m, 4H), 4.23 - 4.12 (m, 1H), 3.58 - 3.40 (m, 3H), 3.35 - 3.24 (m, 4H), 3.20 - 3.10 (m, 1H), 2.46 – 2.25 (m, 3H), 2.21 – 1.86 (m, 5H), 1.68 - 1.52 (m, 3H), 0.90 - 0.75 (m, 3H). 18 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((4 R )-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 642.1 ¹ H NMR (400 mHz, MeOD) δ 8.33 (s, 0.38H, FA), 7.98 (d, J = 4.9 Hz, 1H), 7.90 – 7.74 (m, 2H), 7.39 – 7.26 (m, 2H), 7.19 (s, 1H), 6.89 - 6.77 (m, 1H), 6.68 – 6.55 (m, 1H), 5.30 (d, J = 54.4 Hz, 1H), 4.55 - 4.25 (m, 4H), 3.86 – 3.45 (m, 4H), 3.12 – 2.96 (m, 1H), 2.85 - 2.70 (m, 3H), 2.55 - 2.35 (m, 9 (m, 1H), 2.30 – 2.04 (m, 1H), 1.75 - 1.62 (m, 3H). 19 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-methylenetetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-4-fluoro-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 678.0 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.09 – 7.94 (m, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.40 – 7.26 (m, 2H), 6.99 (t, J = 2.5 Hz, 1H), 6.68 (dd, J = 7.3, 5.0 Hz, 1H), 6.40 - 6.28 (m, 1H), 5.70 (d, J = 28.4 Hz, 2H), 4.95 (d, J = 12.0 Hz, 4H), 4.50 – 4.09 (m, 4H), 3.82 – 3.58 (m, 3H), 3.26 -3.14 (m, 3H), 2.75 – 2.62 (m, 2H), 2.49 – 2.15 (m, 4H), 1.67 – 1.50 (m, 3H), 0.90 - 0.75 (m, 3H). 20 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 667.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 7.95 (dd, J = 9.0, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.15 (dd, J = 7.7, 2.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.78 - 6.65 (m, 2H), 6.47 - 6.30 (m, 1H), 5.30 (d, J = 54.6 Hz, 1H), 5.00 - 4.80 (m, 2H), 4.45 - 4.30 (m, 1H), 4.25 – 4.07 (m, 3H), 3.78 - 3.65 (m, 1H), 3.27 - 3.22 (m, 1H), 3.15 - 3.00 (m, 3H), 2.89 – 2.81 (m, 1H), 2.18 – 1.79 (m, 6H), 1.68 - 1.55 (m, 3H). twenty one 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 671.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 8.14 (s, 0.23H, FA), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.40 - 7.27 (m, 3H), 7.10 (t, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.79 – 6.66 (m, 2H), 6.50 - 6.35 (m, 1H), 5.47 (d, J = 54.4 Hz, 1H), 4.54 – 4.38 (m, 3H), 4.33 - 4.20 (m, 1H), 3.80 - 3.65 (m, 4H), 3.20 - 3.00 (m, 2H), 2.45 - 2.15 (m, 5H), 2.10 - 1.85 (m, 3H), 1.67 – 1.50 (m, 3H), 0.90 - 0.75 (m, 3H). twenty two 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((4 R )-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 646.0 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.17 (s, 0.61H, FA), 7.98 (brs, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.02 (s, 1H), 6.77 – 6.65 (m, 1H), 6.45 – 6.32 (m, 1H), 5.21 (d, J = 55.9 Hz, 1H), 4.60 – 4.24 (m, 4H), 3.82 - 3.74 (m, 1H), 3.57 – 3.32 (m, 3H), 3.07 - 2.95 (m, 1H), 2.47 – 2.27 (m, 5H), 2.24 – 2.10 (m, 1H), 2.04 – 1.85 (m, 1H), 1.66 – 1.52 (m, 3H), 0.90 - 0.75 (m, 3H). twenty three 4-(10-(1-(2-amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 686.5 ¹ H NMR (400 mHz, MeOD-d ₄ ) δ 7.81 (s, 1H), 7.69 – 7.59 (m, 2H), 7.30 – 7.18 (m, 2H), 7.06 - 7.01 (m, 1H), 6.67 - 6.56 (m, 1H), 5.41 - 5.23 (m, 1H), 4.57 – 4.30 (m, 4H), 3.84 – 3.68 (m, 1H), 3.64 - 3.46 (m, 1H), 3.28 - 2.96 (m, 4H), 2.61 - 2.33 (m, 3H), 2.27 (s, 3H), 2.23 - 2.10 (m, 2H), 2.03 - 1.86 (m, 3H), 1.71 - 1.61 (m, 3H), 0.92 – 0.81 (m, 3H). twenty four 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile 654.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.19 (s, 0.56H, FA), 7.97 (s, 1H), 7.80 - 7.57 (m, 2H), 7.42 – 7.27 (m, 2H), 7.00 (s, 1H), 6.75 – 6.64 (m, 1H), 6.40 - 6.30 (m, 1H), 5.68 (d, J = 23.8 Hz, 2H), 4.61 – 4.31 (m, 4H), 3.97 - 3.90 (m, 2H), 3.80 – 3.68 (m, 4H), 2.45 - 2.25 (m, 2H), 2.07 – 1.89 (m, 2H), 1.85 - 1.70 (m, 2H), 1.65 - 1.50 (m, 3H), 0.88 - 0.75 (m, 3H). 25 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( 6S , 8aS )-hexahydro-1H-pyrrolo[2,1- c ][1,4]oxazin-6-yl)methoxy)-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 670.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 9.93 (d, J = 2.0 Hz, 1H), 8.01 -7.92 (m, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (d, J = 2.1 Hz, 1H), 6.72 – 6.62 (m, 1H), 6.42 - 6.30 (m, 1H), 5.72 (dd, J = 27.4, 10.6 Hz, 2H), 4.55 – 4.14 (m, 4H), 3.80 - 3.68 (m, 1H), 3.65 – 3.43 (m, 6H), 3.20 - 3.10 (m, 1H), 3.03 - 2.84 (m, 3H), 2.44 - 2.26 (m, 2H), 2.14 - 2.02 (m, 1H), 1.85 - 1.71 (m, 1H), 1.69 - 1.53 (m, 4H), 1.36 - 1.26 (m, 1H), 0.88 - 0.76 (m, 3H). 26 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 686.2 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.38 (s, 1.52 H, FA), 7.97 (s, 1H), 7.79 – 7.60 (m, 2H), 7.43 – 7.26 (m, 2H), 6.99 (s, 1H), 6.77 – 6.61 (m, 1H), 6.40 - 6.30 (m, 1H), 5.70 (dd, J = 27.6, 5.6 Hz, 2H), 5.17 (d, J = 56.5 Hz, 1H), 4.48 - 4.20 (m, 4H), 3.80 – 3.68 (m, 4H), 2.90 - 2.75 (m, 2H), 2.44 – 2.26 (m, 4H), 2.20 - 1.96 (m, 1H), 1.95 - 1.75 (m, 1H), 1.65 - 1.50 (m, 3H), 0.88 - 0.75 (m, 3H), 0.70 - 0.60 (m, 2H), 0.50 - 0.40 (m, 2H). 27 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((( S )-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 678.4 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 7.98 (s, 1H), 7.75 (dd, J = 8.8, 6.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.41 – 7.24 (m, 2H), 6.99 (s, 1H), 6.74 – 6.63 (m, 1H), 6.42 - 6.30 (m, 1H), 6.08 (t, J = 56.4 Hz, 1H), 5.76 - 5.60 (m, 2H), 4.48 - 4.16 (m, 4H), 3.80 - 3.66 (m, 1H), 3.48 - 3.38 (m, 9 - 1.54 (m, 6H), 0.90 - 0.78 (m, 3H). 28 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-10-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)naphth-2-ol 566.3 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.22 (s, 0.48 H, FA), 7.75 (dd, J = 8.6, 6.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.01 (s, 1H), 5.29 (d, J = 54.1 Hz, 1H), 4.63 – 4.48 (m, 2H), 4.11 (dd, J = 42.3, 10.3 Hz, 2H), 4.02 - 3.92 (m, 2H), 3.36 (s, 2H), 3.16 – 2.97 (m, 4H), 2.90 - 2.78 (m, 1H), 2.39 – 1.99 (m, 5H), 1.88 - 1.74 (m, 3H), 0.86 - 0.76 (m, 3H). 29a (hypothetical) (4R)-2-amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazolidinone[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 707.1 ¹ H NMR (400 mHz, MeOD) δ 7.96 (d, J = 4.8 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.17 (dd, J = 8.3, 5.1 Hz, 1H), 7.01 (t, J = 8.9 Hz, 1H), 6.83 – 6.73 (m, 1H), 6.48 (q, J = 6.6 Hz, 1H), 5.30 (d, J = 51.5 Hz, 1H), 4.44 (dd, J = 11.7, 5.4 Hz, 1H), 4.33 – 4.21 (m, 3H), 3.69 (dd, J = 15.7, 7.6 Hz, 1H), 3.50 (dd, J = 15.1, 4.7 Hz, 1H), 3.26 – 3.11 (m, 3H), 3.05 – 2.95 (m, 1H), 2.39 – 2.12 (m, 3H), 2.04 – 1.87 (m, 3H), 1.66 (d, J = 6.8 Hz, 3H). 29b (hypothetical) (4S)-2-amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazolidinone[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 707.1 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.30 (s, 0.84 H, FA), 8.08 (s, 2H), 8.00 - 7.95 (m, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.27 – 7.09 (m, 2H), 6.67 (dd, J = 7.5, 4.9 Hz, 1H), 6.37 - 6.23 (m, 1H), 5.84 (s, 2H), 5.29 (d, J = 54.5 Hz, 1H), 4.53 (dd, J = 11.3, 6.2 Hz, 1H), 4.25 – 3.99 (m, 3H), 3.72 (dd, J = 15.0, 6.3 Hz, 2H), 3.12 – 2.96 (m, 3H), 2.89 - 2.78 (m, 1H), 2.21 – 1.98 (m, 3H), 1.91 – 1.74 (m, 3H), 1.58 (d, J = 6.8 Hz, 3H). 30 4-(10-(1-amino-5,6,7,8-tetrahydroisoquinolin-8-yl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol 694.4 N/A 31 2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-2-((1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-10-fluoro-5,6-dihydro- 4H- [1,4]oxazolo[5,6,7- de ]quinazolin-9-yl)-7-fluorobenzo[ b ]thiophene-3-carbonitrile N/A N/A 32 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( S )-2-methylenetetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol N/A N/A 33 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-methoxytetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol N/A N/A 34 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-9,10-dihydro- 8H- 7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethynyl-6-fluoronaphth-2-ol N/A N/A 35 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((( S )-2-methylenetetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-9,10-dihydro- 8H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol N/A N/A 36a (hypothetical) 2-Amino-4-(4-(( R )-1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( S )-2-methylenetetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[ b ]thiophene-3-carbonitrile 701.3 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.08 (brs, 1.87 H, FA), 7.97 (d, J = 4.3 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.24 – 7.08 (m, 2H), 6.68 (dd, J = 7.4, 5.0 Hz, 1H), 6.30 - 6.20 (m, 1H), 5.67 (d, J = 15.6 Hz, 2H), 4.90 (d, J = 11.1 Hz, 2H), 4.45 - 4.25 (m, 2H), 4.10 – 3.98 (m, 2H), 3.60 - 3.50 (m, 2H), 3.25 - 3.13 (m, 2H), 3.05 - 2.95 (m, 1H), 2.70 - 2.56 (m, 1H), 2.40 - 2.30 (m, 2H), 2.03 - 1.70 (m, 4H), 1.66 - 1.55 (m, 3H). 36b (assumed) 2-Amino-4-(4-(( S )-1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( S )-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5,6-dihydro-4 H -[1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-7-fluorobenzo[ b ]thiophene-3-carbonitrile 701.3 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.09 (brs, 2H), 7.97 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.25 - 7.09 (m, 2H), 6.68 (dd, J = 7.4, 4.9 Hz, 1H), 6.35 - 6.25 (m, 1H), 5.81 (d, J = 16.5 Hz, 2H), 4.90 (d, J = 9.9 Hz, 2H), 4.52 (dd, J = 11.8, 6.1 Hz, 1H), 4.21 (dd, J = 11.0, 7.0 Hz, 1H), 4.13 - 3.97 (m, 3.70 (dd, J = 15.7, 6.4 Hz, 1H), 3.56 (d, J = 14.0 Hz, 1H), 3.18 (d, J = 13.7 Hz, 2H), 3.02 – 2.98 (m, 1H), 2.67 - 2.59 (m, 1H), 2.36 (d, J = 15.2 Hz, 2H), 1.99 – 1.68 (m, 4H), 1.58 (d, J = 6.6 Hz, 3H). 37a (hypothetical) 2-Amino-4-(4-(( R )-1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-7-fluorobenzo[ b ]thiophene-3-carbonitrile 719.4 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.38 (brs, 3.59 H, FA), 8.09 (s, 2H), 8.00 - 7.92 (m, 1H), 7.64 (d, J = 6.7 Hz, 1H), 7.26 - 7.08 (m, 2H), 6.71 – 6.65 (m, 1H), 6.29 - 6.20 (m, 1H), 5.69 (s, 2H), 4.46 - 4.36 (m, 1H), 4.34 - 4.26 (m, 1H), 4.10 -4.02 (m, 3H), 4.00 - 3.94 (m, 2H), 3.20 (s, 3H), 3.08 - : 2.96 (m, 2H), 2.76 - 2.66 (m, 2H), 2.18 - 2.08 (m, 1H), 1.94 - 1.70 (m, 5H), 1.66 - 1.54 (m, 3H). 37b 2-Amino-4-(4-(( S )-1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-((( 7aS )-2-methoxytetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)-5,6-dihydro- 4H- [1,4]oxazolidinone[5,6,7- de ]quinazolin-9-yl)-7-fluorobenzo[ b ]thiophene-3-carbonitrile 719.4 ¹ H NMR (400 mHz, DMSO-d ₆ ) δ 8.40 (brs, 2.72 H, FA), 8.09 (s, 2H), 7.97 (d, J = 3.5 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.25 - 7.08 (m, 2H), 6.73 – 6.62 (m, 1H), 6.40 - 6.25 (m, 1H), 5.83 (s, 2H), 4.60 - 4.47 (m, 1H), 4.25 - 4.16 (m, 1H), 4.10 - 3.95 (m, 3H), 3.74 – 3.68 (m, 2H), 3.20 (s, 3H), 3.10 - 2.92 (m, 2H), 2.75 – 2.68 (m, 2H), 2.15 (dd, J = 12.8, 5.6 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.80 - 1.70 (m, 3H), 1.58 (d, J = 6.8 Hz, 3H). Test Example < Test Example 1 : KRAS Nucleotide Exchange Assay > Objective To evaluate the inhibitory effect of compounds on SOS1-mediated nucleotide exchange activity of KRAS ^WT , KRAS ^G12D , KRAS ^G12V , KRAS ^G12C and KRAS ^G13D mutants

The assay monitors the SOS1-mediated exchange of unlabeled GDP bound to KRAS for fluorescently labeled GTP. Detection is based on the energy transfer between the two fluorophores when they are in close proximity. The donor is an anti-GST antibody labeled with Tb cryptate, and the acceptor is DY-647P1 GTP. Test conditions and procedures Materials KRAS wild-type (WT) or mutant protein (amino acids 2-169), SOS1 (amino acids 564-1049) labeled with GST, labeled with GTP (GTP-DY-647P1), assay buffer (20 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) pH 7.4, 150 mM NaCl, 5 mM MgCl ₂ , 1 mM dithiothreitol (DTT), 0.05% bovine serum albumin (BSA), 0.0025% NP40) Test procedures

1. KRAS protein was diluted to 1.5 times the final concentration in assay buffer, mixed with Tb cryptate anti-GST antibody, and added to each assay well at 10 μl (the final concentration of KRAS ^WT , KRAS ^G12D , and KRAS ^G12V was 20 nM).

2. Compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted to prepare 100-fold the final concentration.

3. Compounds were dispensed into assay wells using an ECHO acoustic dispenser (Beckman), gently mixed with the KRAS/Ab mixture, and incubated for up to 60 minutes.

4. Mix SOS1 and labeled GTP, dilute to 3 times the final concentration with assay buffer, and add 5 μl of the solution to the assay wells to initiate the reaction (the final concentration of labeled GTP is 0.15 μl, the final concentration of SOS1 is 7.5 nmol/L in WT, 12.5 nmol/L in G12D, and 50 nmol/L in G12V). Add only assay buffer and labeled GTP to blank wells.

5. The reaction was monitored using a Pherastar Plate Reader (BMG) at Ex/Em = (337/665; 337/620).

6. The homogenous time-resolved fluorescence (HTRF) signal was analyzed approximately 25 minutes after the start of the reaction (60 minutes for the G12V reaction).

7. Nucleotide exchange activity was expressed as a percentage difference relative to the DMSO response value, and _IC50 values were calculated based on a four-parameter logic equation in GraphPad 4.0 software. HTRF signal = ems 665/ ems 620*10000

The test results are shown in Table 2. [Table 2] Test results Examples G12D IC ₅₀ （nM） G12V IC ₅₀ (nM) G12C IC ₅₀ (nM) G13D IC ₅₀ （nM） WT _IC50 (nM) 1 1.26 33.4 - - 6.22 2 1.34 - - - - 3 8.69 3.25 - - - 3a 5.76 2.19 - - - 3b 176 62.1 - - - 10a 3.67 1.59 0.608 6.97 - 13 1.65 1.38 0.609 3.69 - 14 3.79 2.79 1.78 8.71 - 16 2.35 2.30 0.916 4.94 - < Test Example 2 : KRAS Nano Bioluminescence Resonance Energy Transfer ( NanoBRET ) Assay > Purpose To evaluate the binding of compounds to the nanoBRET target of KRAS (WT, G12D or G12V) HEK293 cells Test conditions and procedures Compound preparation

Test compounds were dissolved in 10 mmol/L stock, and reference compounds BI-2582 and MRTX1133 (MedChemExpress) were dissolved in DMSO at 10 mmol/L and 1 mmol/L stock, respectively. Cell culture

NanoBRET KRAS (WT, G12D, or G12V)-NanoLuc Fusion vector and tracer K-2 were purchased from Promega, and HEK293 cell line was purchased from American Type Culture Collection (ATCC). HEK293 cells were cultured in Eagle's Minimal Essential Medium (EMEM) supplemented with 10% FBS and 100 μg/mL penicillin-streptomycin at 37°C in a humidified atmosphere of 5% CO ₂ and 95% air. Assay Procedure

1. Transfect HEK293 cells with nanoBRET KRAS (WT, G12D, or G12V)-nanoluc fusion vector.

2. Adjust the density of transfected cells to 2 × 10 ⁵ cells/mL in Opti-MEM without phenol red and mix 20x K-2 tracer with the cells.

3. Dispense the cell and tracer mixture into 384 wells, place in a 5% CO ₂ incubator at 37°C for one hour, and then leave at room temperature for 15 minutes.

4. Add the substrate and test compound solutions to the 384 wells containing cells and tracers and react at room temperature for 15 minutes.

5. Measurements were performed using an Envision 2104 plate reader at donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm).

6. Calculate the BRET ratio by dividing the acceptor emission value (600 nm) by the donor emission value (460 nm) and correct for background by eliminating the BRET ratio that does not include the tracer.

6. Calculate the BRET response as the ratio of the BRET ratio when treated with compound*100 compared to the BRET ratio when treated with DMSO.

7. _IC50 values were calculated based on the sigmoidal dose-response equation in GraphPad Prism 4. < Test Example 3 : Cell Proliferation Assay > Objective Test Compounds in AsPC-1 Pancreatic Cancer (KRAS G12D Mutation) or SW480 Colon Cancer (KRAS G12V Mutation) Cells for 72 hours Test Conditions and Procedure Materials

The reference compound staurosporine was purchased from Sigma-Aldrich (St. Louis, MO), and CellTiter-Glo® 2.0 Luminescent Cell Viability Assay Reagent (Catalog No. G9243) was purchased from Promega (Madison, WI). AsPC-1 and SW480 cell lines were purchased from the American Type Culture Collection (Manassas, VA). AsPC-1 cells were cultured using RPMI-1640 (ATCC, catalog no. 30-2001), and SW480 cells were cultured using Dulbecco's minimum essential medium (DMEM) (ATCC catalog no. 30-2002). Medium supplemented with 10% FBS (Sigma-Aldrich, catalog no. F2442) and 100 μg/ml penicillin-streptomycin (Sigma-Aldrich, catalog no. P4333) was used. Cells were cultured at 37°C in a humidified atmosphere of 5% CO ₂ and 95% air. Assay Procedure

1. The test compound and reference compound staurosporine were dissolved in DMSO solution to prepare 20 mmol/L (test compound) and 10 mmol/L (reference compound, staurosporine) in the source plate, and diluted 3-fold and 10 doses with DMSO.

2. Use an Echo 655 to dispense 10 volumes of 125 nanoliters of test compound or 25 nanoliters of reference compound from the source plate into the wells of a 384-well culture plate (VWR, catalog number 82050-076).

3. Dispense 25 μl of medium containing 2000 AsPC-1 or SW480 cells into each well of a 384-well cell culture plate.

4. Incubate cells with compounds at 37°C and 5% CO ₂ for up to 72 hours.

5. Add 25 μl of Cell Titer Luminescence 2.0 Reagent to each well of the plate.

6. Mix the contents on an orbital shaker for 2 minutes and allow the luminescence signal to stabilize for 15 minutes at room temperature.

7. Luminescence signals were measured using an Emerson 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA), and the number of viable cells was determined by quantifying the ATP present in each culture.

8. _IC50 values were calculated based on the sigmoidal dose-response equation in the GraphPad Prism 4 program.

The test results are shown in Table 3. [Table 3] Test results Examples AsPC-1 SW480 1 C - 2 B - 3 C - 3a C - 4 C - 5 C - 6 B - 6a B B 6b C - 7 C - 8 C - 9 B - 10a C - 10b C - 11 C - 12 B A 13 A A 13a A A 13b C - 14 A A 14a A A 14b B - 15 B - 16 A A 17 A A 18 B A 19 B - 20 - A twenty one C - twenty two B A twenty three B A twenty four C B 25 B A 26 B - 27 C - 28 C - 29a A A 29b B - (IC ₅₀ < 1 μM = A; IC ₅₀ ≧ 1 μM, < 10 μM = B; IC ₅₀ > 10 μM = C)

Although the present disclosure has been specifically shown and described with reference to the exemplary embodiments of the present disclosure, it should be understood that various changes in form and details may be made thereto without departing from the spirit and scope of the present disclosure as defined by the appended claims. The exemplary embodiments should be considered to be merely illustrative and not for limiting purposes. Therefore, the scope of the present disclosure is defined not by the specific description of the present disclosure but by the appended claims, and all differences within the said scope should be understood to be included in the present disclosure.

Claims (9)

A compound selected from the group consisting of a compound of Formula 1 and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts thereof: [Formula 1] In Formula 1, X is N or CR ¹¹ ; R ¹ is phenyl substituted or unsubstituted by R ^1A , naphthyl substituted or unsubstituted by R ^1A , benzothiophenyl substituted or unsubstituted by R ^1A ; each R ^1A is independently selected from hydrogen, hydroxyl, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ and CN; R ² is hydrogen or halogen; R ³ is hydrogen, -OLW or ; L is a bond or a C ₁ -C ₃ alkylene group which is substituted or unsubstituted by ^LA ; ^LA is hydrogen, halogen or C ₁ -C ₃ alkyl; W is a C ₁ -C ₃ alkyl group which is substituted or unsubstituted by R ⁶ , a 3- to 10-membered monocyclic heterocyclic ring which is substituted or unsubstituted by R ⁶ , or a 6- to 14-membered bicyclic heterocyclic ring which is substituted or unsubstituted by R ⁶ ; each R ⁶ is independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, amine, CN, =CH ₂ , pendoxy (=O), S(C ₁ -C ₃ alkyl), SO ₂ NH ₂ , SO ₂ NH(C ₁ -C ₃ alkyl), SO ₂ (C ₁ -C ₃ alkyl), SO ₂ (C ₁ -C ₃ halogenated alkyl), or halogenated C ₁ -C ₃ alkoxy; R ⁴ is hydrogen, C ₁ -C ₆ halogenated alkyl substituted or unsubstituted by R ^4A , C ₁ -C ₆ alkyl substituted or unsubstituted by R ^4A , C ₃ -C ₁₀ cycloalkyl substituted or unsubstituted by R ^4A , C ₅ -C ₈ aryl substituted or unsubstituted by R 4A, 3- to 10-membered heterocyclic substituted or unsubstituted ^by R ^4A , or 5- to 10-membered heteroaryl substituted or unsubstituted by R ^4A ; each R ^4A is independently selected from hydrogen, CN, NR ⁹ R ¹⁰ , =O, OR ⁷ , SR ⁸ , SO ₂ R ⁸ , C(O)N(R ⁷ ) ₂ , C(O)R ⁷ , C ₁ -C ₆ halogenated alkyl substituted or unsubstituted by R ^4B , C ₁ -C ₆ alkyl substituted or unsubstituted by R ^4B , C ₃ -C ₁₀ cycloalkyl substituted or unsubstituted by R ^4B , C ₅ -C ₈ aryl substituted or unsubstituted by R ^4B , 3 to 6 membered heterocyclic ring substituted or unsubstituted by R ^4B , and 5 to 9 membered heteroaryl substituted or unsubstituted by R ^4B ; wherein two of R ^4A together form C ₃ -C ₁₀ cycloalkyl substituted or unsubstituted by R ^4B , C ₅ -C ₈ aryl substituted or unsubstituted by R ^4B , 3 to 10 membered heterocyclic ring substituted or unsubstituted by R ^{4B, or 5 to 9 membered heteroaryl substituted or unsubstituted by R 4B} . R ^{4B is} independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl _, CN, NR ⁹ R ¹⁰ , =O, C 1 -C 3 alkoxy, halogenated C ₁ -C ₃ alkoxy, hydroxy, SCH ₃ , SO ₂ NH ₂ , SO ₂ CH ₃ , C(O)NH ₂ , C(O)CH ₃ , 3- to 6-membered heterocyclic, C ₅ -C ₈ aryl, and 5- or 6-membered heteroaryl; each R ⁵ is independently selected from hydrogen, _hydroxy , halogen, C ₁ -C ₃ halogenated alkyl and C ₁ -C ₃ alkyl, each R ^R7 is independently selected from hydrogen, amino, _C1 - _C3 halogenated alkyl, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, and 3- or 4-membered heterocyclic ring; each ^R8 is independently selected from hydrogen, amino and _C1 - _C3 alkyl; ^R9 and ^R10 are each independently selected from hydrogen, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, C(O) _NH2 , C(O) _CH3 , and 3- to 6-membered heterocyclic ring; each ^R11 is independently selected from hydrogen, hydroxyl, halogen, _C1 - _C3 halogenated alkyl and _C1 - _C3 alkyl, n is an integer selected from 0 to 2; and wherein the heterocyclic ring or the heteroaryl group each comprises 1 to 3 heteroatoms independently selected from N, O and S. The compound as described in claim 1, wherein L is methylene; W is a 3- to 10-membered monocyclic heterocycle which is unsubstituted or substituted by R ⁶ , or a 6- to 14-membered bicyclic heterocycle which is unsubstituted or substituted by R ⁶ ; and each R ⁶ is independently selected from halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CN, =CH ₂ , =O, SCH ₃ , SO ₂ NH ₂ , SO ₂ NH(CH ₃ ), SO ₂ CH ₃ and SO ₂ CF ₃ . The compound as claimed in claim 1, wherein L is methylene; each W is independently substituted or unsubstituted by R ⁶ , , , , , , , , , , , , , , , , or ; and each R ⁶ is independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CN, =CH ₂ , =O, SCH ₃ , SO ₂ NH ₂ , SO ₂ NH(CH ₃ ), SO ₂ CH ₃ and SO ₂ CF ₃ . The compound of claim 1, wherein R ⁴ is C ₁ -C ₃ alkyl substituted or unsubstituted by R ^4A ; each R ^4A is independently selected from hydrogen, halogen, CN, NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ , =O, C ₃ -C ₆ cycloalkyl substituted or unsubstituted by R ^4C , phenyl substituted or unsubstituted by R ^4C , pyridinyl substituted or unsubstituted by R ^4C , pyrimidinyl substituted or unsubstituted by R ^4C , and pyrazinyl substituted or unsubstituted by R ^4C ; or wherein two of R ^4A together form a 5- to 10-membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; and each R ^4C is independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, NH ₂ , NH(C ₁ -C ₃ alkyl) and N(C ₁ -C ₃ alkyl) ₂ . The compound of claim 1, wherein X is CR ¹¹ , each R ¹¹ is independently selected from hydrogen, halogen, C ₁ -C ₃ halogenated alkyl and C ₁ -C ₃ alkyl; R ¹ is benzothienyl which may be substituted by R ^1A ; each R ^1A is independently selected from hydrogen, halogen, NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ and CN. The compound of claim 1, wherein R ¹ is each substituted or unsubstituted by one or more substituents independently selected from hydrogen, hydroxyl, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, amino and CN. , or ; R ² is F; R ³ is hydrogen, -OLW or ; L is methylene; W is each substituted 1 to 3 times by R ⁶ or not substituted by R ⁶ , , , , , , , , , , , , , , , , or ; each R ⁶ is independently selected from hydrogen, halogen, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CN, =CH ₂ and =O; R ⁴ is each substituted or unsubstituted with one or more substituents independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, NH ₂ , NH(C ₁ -C ₃ alkyl) and N(C ₁ -C ₃ alkyl) ₂ , , , , , , , , , , , , , , , or ; and n is selected from 1 and 2. The compound as claimed in claim 1, wherein the compound is selected from the group consisting of the following compounds and stereoisomers, non-mirror isomers, mirror isomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . A pharmaceutical composition for treating cancer, comprising as an active ingredient a compound selected from the group consisting of a compound as described in any one of claims 1 to 7 and a stereoisomer, non-mirror isomer, mirror isomer, configurational isomer, isotopic variant, tautomer, solvate and pharmaceutically acceptable salt of the compound as described in any one of claims 1 to 7. A pharmaceutical composition as described in claim 9, wherein the pharmaceutical composition exhibits Hirschstern rat sarcoma viral oncogene homolog protein inhibitory activity.