Novel triheterocyclic compounds

Abstract

The present invention provides triheterocyclic compounds, specifically triheterocyclic compounds useful as KRAS protein inhibitors, and pharmaceutical compositions containing the same for treating cancer.

Description

[Technical Field]

[0001] The present invention relates to novel triheterocyclic compounds, and more specifically to novel triheterocyclic compounds useful as KRAS protein inhibitors and pharmaceutical compositions containing the same for treating cancer. [Background technology]

[0002] RAS genes are involved in signal transduction within the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and are known to be oncogenes due to frequent mutations. The RAS gene family is classified as KRAS, NRAS, and HRAS, and these three genes encode four proteins: splice variants K-Ras4A and K-Ras4B, N-Ras, and H-Ras. K-Ras is the most frequently mutated isomorph in Ras-driven cancers (86%), followed by N-Ras (11%) and H-Ras (3%) (Non-Patent Document 1). For example, oncogenic alterations of KRAS have been observed in 15.95% of cancers, including pancreatic cancer, lung cancer, colon adenocarcinoma, colorectal cancer, and rectal adenocarcinoma (Non-Patent Document 2).

[0003] Gain-of-function missense mutations, primarily located at codons 12, 13, and 61, persistently activate RAS proteins and are detected in various types of human cancers. 98% of tumor Ras mutations are found at the active site amino acid residues G12, G13, and Q61. Such mutations impair intrinsic and GAP-mediated GTP hydrolysis, resulting in abnormal activation of downstream signaling (Non-Patent Document 3). K-Ras G12 mutations (89%) are the most common in human cancers, followed by G13 mutations (9%) and Q61 mutations (1%). Codon 12 mutations include codon 12 Gly to Asp (G12D) (36%), codon 12 Gly to Val (G12V) (23%), and codon 12 Gly to Cys (G12C) (14%), with G12D being the most frequent codon 12 mutation. Mutations at codon 13 Gly→Asp (G13D) (7%) and codon 61 Gln→His (Q61H) (0.6%) were also observed (Non-Patent Document 1).

[0004] The well-known role of KRAS in malignant tumors and reports of KRAS mutations in various tumor types suggest that KRAS may be an effective target for cancer therapy. The present inventors have developed novel KRAS inhibitors to complete the present invention. [Prior art documents] [Non-patent literature]

[0005] [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 August; 5(8): 928-932 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides novel triheterocyclic compounds having KRAS protein inhibitory activity. The present invention relates to novel triheterocyclic compounds, their stereoisomers, diastereomers, enantiomers, rotamers (atropisomers), isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts, and pharmaceutical compositions containing the same for cancer treatment. [Means for solving the problem]

[0007] According to one aspect of one embodiment, there is provided a compound selected from a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof:

[0008] According to one aspect of other embodiments, there is provided a pharmaceutical composition comprising a compound selected from a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof. [Effects of the Invention]

[0009] The present invention relates to novel triheterocyclic compounds useful as KRAS protein inhibitors, their stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts, and pharmaceutical compositions containing the same for cancer treatment. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will now be described in further detail.

[0011] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. In addition, although preferred methods or samples are described herein, similar or equivalent methods are also included within the scope of the present invention.

[0012] Furthermore, unless expressly stated otherwise, numerical values ​​specified in this document are considered to include the meaning of "about." All publications disclosed as references in this document are incorporated by reference in their entirety.

[0013] Triheterocyclic Compounds According to an aspect of one embodiment, there is provided a compound selected from a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof:

[0014] [ka]

[0015] In chemical formula 1 X is N or CR 11 and; R 1 is R 1A phenyl substituted or unsubstituted with R 1A naphthyl substituted or unsubstituted by R 1A benzothiophenyl substituted or unsubstituted by; Each R 1A are independently selected from hydrogen, hydroxy, halogen, C-C haloalkyl, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, NH, NH(C-C alkyl), N(C-C alkyl) and CN; R 2 is hydrogen or halogen; R 3 is hydrogen, -OLW or [ka] and; L is a bond or L A is a substituted or unsubstituted C1-C3 alkylene; L Ais hydrogen, halogen, or C1-C3 alkyl; W is R 6 C1-C3 alkyl substituted or unsubstituted with R 6 a 3- to 10-membered monocyclic heterocycle substituted or unsubstituted by R 6 a substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; Each R 6 is independently selected from hydrogen, halogen, C-C haloalkyl, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, amino, CN, ═CH, oxo (═O), S(C-C alkyl), SONH, SONH(C-C alkyl), SO(C-C alkyl), SO(C-C haloalkyl), and haloC-C alkoxy; R 4 is hydrogen, R 4A substituted or unsubstituted C1-C6 haloalkyl, R 4A C1-C6 alkyl substituted or unsubstituted with R 4A Substituted or unsubstituted C3-C 10 Cycloalkyl, R 4A C5-C8 aryl substituted or unsubstituted with R 4A a 3- to 10-membered heterocycle substituted or unsubstituted by R 4A substituted or unsubstituted 5-10 membered heteroaryl; Each R 4A is hydrogen, CN, NR 9 R 10 , =O, OR 7 , S.R. 8 , SO2R 8 , C(O)N(R 7 )2, C(O)R 7 , R 4B substituted or unsubstituted C1-C6 haloalkyl, R 4B C1-C6 alkyl substituted or unsubstituted with R 4B Substituted or unsubstituted C3-C 10 Cycloalkyl, R 4B C5-C8 aryl substituted or unsubstituted with R 4Ba substituted or unsubstituted 3- to 6-membered heterocycle and R 4B independently selected from substituted or unsubstituted 5- to 9-membered heteroaryl; where R 4A Two of them are R 4B Substituted or unsubstituted C3-C 10 Cycloalkyl, R 4B C5-C8 aryl substituted or unsubstituted with R 4B a 3- to 10-membered heterocycle substituted or unsubstituted by R 4B forming a substituted or unsubstituted 5- to 10-membered heteroaryl; Each R 4B is hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, C3-C6 cycloalkyl, CN, NR 9 R 10 , =O, C1-C3 alkoxy, haloC1-C3 alkoxy, hydroxy, SCH3, SO2NH2, SO2CH3, C(O)NH2, C(O)CH3, 3- to 6-membered heterocycle, C5-C8 aryl, and 5- or 6-membered heteroaryl; Each R 5 are independently selected from hydrogen, hydroxy, halogen, C1-C3 haloalkyl, and C1-C3 alkyl; Each R 7 are independently selected from hydrogen, amino, C1-C3 haloalkyl, C1-C3 alkyl, C3-C6 cycloalkyl, and 3- or 4-membered heterocycle; Each R 8 are independently selected from hydrogen, amino, and C1-C3 alkyl; R 9 and R 10 are each independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C(O)NH2, C(O)CH3, and a 3- to 6-membered heterocycle; Each R 11 are independently selected from hydrogen, hydroxy, halogen, C1-C3 haloalkyl, and C1-C3 alkyl; n is an integer selected from 0 to 2; wherein the heterocycle or heteroaryl each contains 1 to 3 heteroatoms independently selected from N, O and S. In one embodiment, L is methylene; W is R 6 a 3- to 10-membered monocyclic heterocycle substituted or unsubstituted by R 6 a substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; Each R 6 are independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, CN, =CH2, =O, SCH3, SO2NH2, SO2NH(CH3), SO2CH3, and SO2CF3.

[0016] In one embodiment, W is also a substituted monocyclic or bicyclic non-aromatic ring, such as [ka] Including, but not limited to,

[0017] In one embodiment, L is methylene; Each W is independently R 6 substituted or unsubstituted [ka] and; Each R 6 are independently selected from hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, CN, =CH2, =O, SCH3, SO2NH2, SO2NH(CH3), SO2CH3, and SO2CF3.

[0018] In one embodiment, for example, W is 1-methylpyrrolidinyl. [ka] , 1-(2,2-difluoroethyl)azetidine [ka] , 2-fluorohexahydro-1H-pyrrolidinyl [ka] , 2,6-dimethylidenehexahydro-1H-pyrrolidinyl [ka] , 1-methyloctahydro-1H-cyclopenta[b]pyridine [ka] , or 2-oxabicyclo[2.1.1]hexane [ka] However, it is not limited to these.

[0019] In one embodiment, for example, W is a substituted 4- to 10-membered heterocycle, e.g., morpholine. [ka] However, it is not limited to these.

[0020] In one embodiment, R 4 is R 4A is a substituted or unsubstituted C1-C3 alkyl; Each R 4A is hydrogen, halogen, CN, NH2, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, =O, R 4C C3-C6 cycloalkyl substituted or unsubstituted with R 4C phenyl substituted or unsubstituted with R 4C pyridinyl substituted or unsubstituted by R 4C pyrimidinyl substituted or unsubstituted by R 4C and substituted or unsubstituted pyrazinyl; Or, where R 4Atwo of which together form a 5-10 membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; Each R 4C are independently selected from hydrogen, halogen, C1-C3 alkyl, NH2, NH(C1-C3 alkyl), and N(C1-C3 alkyl)2.

[0021] In one embodiment, R 4 is a substituted or unsubstituted C1-C6 alkyl, C3-C 10 It can also be, but is not limited to, cycloalkyl, azetidinyl, pyrrolidinyl or pyridinyl.

[0022] In one embodiment, R 4 Spiro C3-C 10 C3-C including cycloalkyl 10 and cycloalkyl, each of which is R 4A For example, R 4 each represents a substituted or unsubstituted spiro[3.3]alkanyl [ka] But it is not limited to that.

[0023] In one embodiment, R 4 is halogen, amino, (C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C3-C 10 cycloalkyl), di(C1-C6 alkyl)amino(C3-C 10 cycloalkyl), or 1-morpholino-(C3-C 10 cycloalkyl) (e.g., 1-morpholin-4-ylcyclobutyl [ka] ), but is not limited to them.

[0024] R 4is, for example, halogen, amino, (C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C3-C 10 cycloalkyl), di(C1-C6 alkyl)amino(C3-C 10 cycloalkyl), or C1-C6 alkyl or C3-C substituted with 1-morpholin-4-ylcyclobutyl 10 It is also a cycloalkyl.

[0025] R 4 R may also be, for example, unsubstituted azetidinyl or unsubstituted pyrrolidinyl. 4 is, for example, an amino-substituted spiro[3.3]heptanyl, an amino-substituted pyridine or an amino-substituted C3-C 10 It is also a cycloalkyl.

[0026] In one embodiment, X is CR 11 and Each R 11 are independently selected from hydrogen, halogen, C1-C3 haloalkyl, and C1-C3 alkyl; R 1 is R 1A benzothiophenyl substituted or unsubstituted by; Each R 1A are independently selected from hydrogen, halogen, NH2, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, and CN.

[0027] In one embodiment, R1 is [ka] and; each substituted or unsubstituted with one or more substituents independently selected from hydrogen, hydroxy, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, amino, and CN; R 2 is F, R 3 is hydrogen, -OLW or [ka] L is methylene.

[0028] W is [ka] Each is R 6 substituted or unsubstituted one to three times by; Each R 6 are independently selected from hydrogen, halogen, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, CN, ═CH2, and ═O; R 4 teeth, [ka] TIFF2025535294000018.tif25170, each substituted or unsubstituted with one or more substituents independently selected from hydrogen, halogen, C1-C3 alkyl, NH2, NH(C1-C3 alkyl), and N(C1-C3 alkyl)2; n is selected from 1 and 2.

[0029] In one embodiment, the compound is selected from the group consisting of the following compounds and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof: [ka] TIFF2025535294000020.tif255159TIFF2025535294000021.tif255161TIFF2025535294000022.tif255158TIFF2025535294000023.tif187162

[0030] According to an aspect of yet another embodiment, there is provided a pharmaceutical composition comprising a compound selected from a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0031] In one embodiment, the pharmaceutical composition exhibits KRAS protein inhibitory activity.

[0032] definition The term "halogen" as used herein means fluorine, chlorine, bromine or iodine, unless otherwise specified.

[0033] The term "alkyl," as used herein, unless otherwise specified, means a straight-chain or branched saturated monovalent hydrocarbon radical.

[0034] As used herein, the term "alkylene" refers to (-CH-) n and, unless otherwise specified, includes, but is not limited to, methylene, ethylene, propylene, butylene, isobutylene, and the like.

[0035] As used herein, the term "alkenyl" means a monovalent hydrocarbon group containing at least one carbon-carbon double bond, where each double bond has either the E or Z configuration, unless otherwise specified.

[0036] The term "alkynyl," as used herein, unless otherwise specified, means a monovalent hydrocarbon radical containing at least one carbon-carbon triple bond.

[0037] The term "alkoxy," as used herein, unless otherwise specified, means a straight-chain or branched hydrocarbon residue attached through an oxygen atom.

[0038] As used herein, unless otherwise specified, the term "aryl" refers to a substituted or unsubstituted aromatic group, including monocyclic or bicyclic or higher than bicyclic aromatic groups, which may also be substituted or unsubstituted, and may include unsaturated or partially saturated aryls, such as C6- 15 Aryl includes, but is not limited to, phenyl, bipenyl, naphthyl, toluyl, and the like.

[0039] As used herein, unless otherwise specified, the term "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms selected from N, O, and S, including monocyclic, bicyclic, or higher than bicyclic aromatic groups, which may be substituted or unsubstituted and may include unsaturated or partially saturated heteroaryls, such as C4- 15 Heteroaryl includes, but is not limited to, morpholinyl, piperidinyl, pyrrolidinyl, or pyrrolidinyl, and the like.

[0040] The term "fused heteroaryl," as used herein, unless otherwise specified, refers to an unsaturated or partially saturated, substituted or unsubstituted ring system in which a heteroaryl group is connected in a fused manner to another aryl, heteroaryl, or heterocycloalkyl group. For example, C8- 20Heteroaryl includes, but is not limited to, 9-, 10-, 11-, 12-, 13-, 14-, or 15-membered benzofused heteroaryl groups, such as, but not limited to, 5+5, 5+6, 5+7, 6+6, or 6+7 fused ring systems, pyrrolidine, benzothiazole, benzthiazolinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, benzothionyl, indolyl, isoindolinyl, indazolyl, indazolinyl, benzimidazolinyl, benzoxazolinyl, benzisoxazolinyl, benzothiadiazolinyl, benzoxadiazolinyl, benztriazolinyl, quinolinyl, isoquinolinyl, quinazolinyl, and the like.

[0041] As used herein, the term "partially saturated" means containing at least one site of saturation, i.e., at least one single bond, within an aryl, heteroaryl, or fused heteroaryl ring as defined above. As used herein, the term "unsaturated" refers to an aryl, heteroaryl, or fused heteroaryl ring that does not contain a site of saturation, i.e., a single bond, as defined above.

[0042] The term "cycloalkyl," as used herein, unless otherwise specified, means a substituted or unsubstituted, saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic hydrocarbon ring, and unless otherwise specified, may include bridged cycloalkyls, fused cycloalkyls, and spirocycloalkyls, for example, C3- 10Examples include, but are not limited to, cycloalkyl or C3-6 cycloalkyl, which may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. As used herein, the term "cycloalkylene" refers to a radical (divalent radical) derived from a cycloalkene. As used herein, the term "heterocycloalkyl" means a cycloalkyl containing one or more heteroatoms selected from N, O, and S, which is substituted or unsubstituted, and unless otherwise specified, includes substituted or unsubstituted monocyclic, bicyclic, or higher than bicyclic aromatic groups.

[0043] As used herein, the term "heterocycle" means a saturated, partially unsaturated, or aromatic ring, monocyclic, bicyclic, or polycyclic ring containing one or more heteroatoms selected from N, O, and S, which may be substituted or unsubstituted, and includes bridged, fused, and spiro heterocycles, unless otherwise specified. For example, it refers to C4- 15 Heterocycloalkyl includes, but is not limited to, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, imidazolidinyl, pyrrolidin-2-one, pyrrolidinyl, or pyrrolyl, etc. Heterocycles can also be carbon- or heteroatom-linked, e.g., they can be linked to the base molecule through a ring atom (either C or N). For example, a heterocycle linked to the base molecule through a nitrogen ring atom of the heterocycle can include, but is not limited to, N-morpholinyl, N-piperidinyl, N-pyrrolidinyl, or N-pyrrolyl, etc.

[0044] As used herein, the term "fused heterocycle" or "fused cycloalkyl" refers to a substituted or unsubstituted ring system, which may be classified as a bicyclic, tricyclic, tetracyclic, or higher polycyclic fused cycloalkyl depending on the number of rings, unless otherwise specified. A fused cycloalkyl is a polycyclic ring in which each ring shares an adjacent pair of carbon atoms with another ring, and one or more rings may share one or more double bonds, but none of the rings has a fully bonded π-electron system. For example, C3- 20 Fused cycloalkyls include, but are not limited to, 5+5 fused ring systems, 5+6 fused ring systems, 5+7 fused ring systems, 6+6 fused ring systems, or 6+7 fused ring systems, depending on the number of atoms forming the two rings. Bicyclic fused cycloalkyls, also referred to as "bicycloalkyls" or "bicycloheterocycles," include all combinations of saturated, unsaturated, and aromatic bicyclic rings, valence permitting. In an exemplary embodiment, an aromatic ring, such as pyridyl, can be fused to a saturated or unsaturated ring.

[0045] The term "fused heterocycloalkyl" as used herein refers to a substituted or unsubstituted fused cycloalkyl containing one or more heteroatoms selected from N, O, and S, such as C8- 20 It includes, but is not limited to, fused heterocycloalkyl. For example, bicyclic fused heterocycloalkyl is also referred to as "heterobicycloalkyl", and herein, depending on the number of atoms forming the two rings, includes, but is not limited to, 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system. For example, it also includes, but is not limited to, hexahydro-1H-pyrrolidine.

[0046] As used herein, the term "stereoisomer" refers to compounds composed of the same atoms connected by the same bonds but with different, incompatible three-dimensional structures. These compounds have the same chemical or molecular formula but are optically or spatially distinct. The term "enantiomer" as used herein refers to the various stereoisomers and geometric isomers present in the compounds of the present invention. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers" which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0047] The compounds described therein may possess asymmetric centers, geometric centers (e.g., double bonds), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

[0048] The compounds of Formula 1 according to one aspect of the present invention may have asymmetric carbon centers (asymmetric carbons) and therefore may exist as enantiomers (R or S isomers), racemates, diastereomers or any mixtures thereof, and all such isomers and mixtures are included within the scope of the present invention.

[0049] The compounds described herein can have asymmetric centers, geometric centers (e.g., double bonds), or both. All chiral, diastereomeric, and racemic forms of a structure and all geometric isomeric forms are intended, unless a particular stereochemistry or isomeric form is specifically indicated. In some embodiments, the compounds described herein have one or more chiral centers. Unless the absolute stereochemistry is explicitly indicated, each chiral center is understood to be independently of the R-configuration, the S-configuration, or a mixture thereof. Accordingly, the compounds described herein include enantiomers enriched or resolved at some or all asymmetric atoms, as illustrated. Racemic mixtures of the R- and S-enantiomers, enantiomerically enriched stereoisomeric mixtures containing the R- and S-enantiomers, and individual enantiomers may be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and all such stereoisomers are within the scope of the present technology.

[0050] Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as by resolution of racemic forms, synthesis from optically active starting materials, or use of chiral auxiliaries, are well known in the art.

[0051] As used herein, the term "atropisomer" refers to all stereoisomers that can be separated from one another. These are isomers that arise when a single carbon-carbon bond in a compound cannot rotate freely due to bulky substituents. This refers to stereoisomers formed by an asymmetric axis, including complete separation of stable non-reversible diastereomers or enantiomeric species. They can also arise from restricted rotation about a single bond, where the rotational barrier is high enough to distinguish between isomeric species.

[0052] A compound according to one embodiment can produce rotamers with a high probability.

[0053] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium, one isomeric form readily convertible to the other isomeric form. A compound according to an embodiment may also contain "tautomers." Tautomers are formed by swapping a single bond with an adjacent double bond, thereby transferring a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Tautomeric forms may be in equilibrium or sterically locked into one form through appropriate substitution.

[0054] As used herein, the term "solvate" includes a molecular complex comprising a compound of Formula 1 and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. A complex where the solvent molecule is water is also referred to as a "hydrate."

[0055] As used herein, the term "pharmaceutically acceptable salt" includes all salts that have low toxicity to the human body and do not negatively affect the biological activity and physicochemical properties of the parent compound.

[0056] Compounds according to one embodiment may include "isotopic variations." The present invention also includes isotopically labeled compounds that are identical to the compounds described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature (an "isotope"). The compounds of the present invention contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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, e.g., 2 H("D"), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36For example, the compounds may have one or more H atoms replaced with deuterium.

[0057] Generally, references or statements about a particular element, such as hydrogen or H, are meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, tritium, 14 C. 32 P and 35 Compounds containing radioisotopes such as S are within the scope of the present technology. Procedures for inserting such labels into compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

[0058] Unless otherwise specified, compounds described herein are intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, the substitution of deuterium or tritium for hydrogen or the substitution of carbon for 13 C- or 14 Compounds having this structure, except for the substitution of a C-rich carbon, are within the scope of this invention.

[0059] In one embodiment, 3 H and 14 Certain isotopically labeled compounds, such as those labeled with 1C, are also useful for compound and / or substrate tissue distribution analysis. 3 H) and carbon-14 ( 14 C) Isotopes may be preferred because they are easy to prepare and detect. Substitution with heavier isotopes, such as deuterium, may also be preferred in some situations because they may provide certain therapeutic advantages, such as increased metabolic stability, increased in vivo half-life, or reduced dosage requirements. Isotopically labeled compounds can generally be prepared by procedures similar to those disclosed herein. For example, they may be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents in the Examples.

[0060] Deuterated starting materials are readily available, and deuterated compounds can be synthesized via the synthetic methods described herein. Deuterated reagents and building blocks can be purchased commercially in bulk from chemical supply companies such as Aldrich Chemical Co.

[0061] The term "treatment" as used herein includes the cure, amelioration, alleviation, or management of a disease. As used herein, the term "treatment" or "therapy" means inhibiting a disease, e.g., inhibiting a disease, condition, or disorder, preventing further onset of pathology and / or symptoms, ameliorating a disease, or reversing a pathology and / or symptoms, e.g., reducing the severity of a disease in a subject experiencing or exhibiting pathology or symptoms of a disease, condition, or disorder.

[0062] As used herein, the term "prevention" or "prophylaxis" refers to the prevention of a disease, e.g., the prevention of a disease, condition, or disorder in a subject who is susceptible to the disease, condition, or disorder but who does not yet experience or exhibit the pathology or symptoms of the disease.

[0063] As used herein, the term "subject" or "patient" refers to all animals, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans.

[0064] Terms such as "have," "can have," "include," and "can include" can indicate the presence of features (e.g., numbers, components such as elements) and do not exclude the presence of additional features.

[0065] KRAS protein inhibitors Kirsten Rat Sarcoma Virus Oncogene Homolog (KRAS) is a member of the small GTPase family, which includes Ras, Rho, Rab, Arf, and Ran, that integrate extracellular signals into intracellular growth and survival signals. KRAS receives signals from various receptor tyrosine kinases, particularly EGFR, at the upper level, and transmits them primarily to Raf and PI3K at the lower level through the KRAS GTPase cycle, thereby regulating various processes, including cell proliferation.

[0066] KRAS plays an important role in cancer, but its protein structure makes it difficult to inhibit its activity. Attempts to block its signaling have shown some effectiveness, but have also raised concerns about toxicity and treatment resistance. However, the discovery of compounds that bind to the switch II pocket and mutant cysteine ​​led to the development of adagrasib and sotorasib, which have been approved by the FDA for the treatment of non-small cell lung cancer.

[0067] The compounds of the present invention are novel KRAS inhibitor compounds that suppress mutations in any one of KRAS codons 12, 13, and 61, including, but not limited to, at least one of KRAS G12D, KRAS G12V, KRAS G12C, KRAS G13D, and KRAS Q61H mutations.

[0068] Pharmaceutical Compositions According to an aspect of yet another embodiment, a pharmaceutical composition comprising a compound selected from a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof is provided for the treatment of cancer.

[0069] In one embodiment, the composition can comprise a therapeutically effective amount of a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0070] In one embodiment, the composition may contain other therapeutic agents in addition to the compound selected from the compound of Formula 1 and its stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts.

[0071] In one embodiment, the composition may further comprise an additional pharmaceutically acceptable carrier or excipient.

[0072] In one embodiment, the composition comprises a compound selected from the group consisting of a compound of Formula 1 and its stereoisomers, diastereomers, enantiomers, rotamers, isotopic variations, tautomers, solvates, and pharmaceutically acceptable salts or other therapeutic agents in an amount ranging from 0.005% to 100%, with the remainder comprising a pharmaceutically acceptable carrier or excipient.

[0073] In one embodiment, a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, and solvates thereof, or a pharmaceutical composition comprising the same, may be used to treat cancer.

[0074] In one embodiment, a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, and solvates thereof, or a pharmaceutical composition comprising the same, exhibits KRAS protein inhibitory activity.

[0075] According to one aspect of yet another embodiment, there is provided a use of a compound selected from the group consisting of a compound of Formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, and solvates thereof, or a pharmaceutical composition comprising the same, for treating cancer.

[0076] Route of administration and dosage form The compounds and pharmaceutical compositions of the present invention may be provided in any suitable administration route and dosage form accepted in the pharmaceutical art.

[0077] Manufacturing method The compounds of the present invention can be synthesized using organic synthesis techniques known to those skilled in the art. Some compounds and / or intermediates of the present invention are commercially available, known in the literature, or can be prepared by those skilled in the art by selecting an appropriate synthesis method from among known organic synthesis techniques. Some compounds of the present invention can be synthesized using the reaction schemes, examples, or intermediates described herein. Those skilled in the art will recognize that reaction times, reagent equivalents, and / or temperatures may be varied from the synthesis methods described herein, and that various workup and / or purification techniques may be utilized.

[0078] The structures of the synthesized compounds may be verified by methods known to those skilled in the art, such as nuclear magnetic resonance (NMR) spectroscopy and / or mass spectroscopy.

[0079] General information Unless otherwise stated, reagents and solvents purchased from commercial suppliers were used without purification or drying. 1 H NMR was recorded using a Bruker 400 MHz and 500 MHz spectrometer, with TMS used as the internal standard. LCMS analysis was performed on a Waters UPLC equipped with an SQD-2 mass detector (single quadruple), and HPLC analysis was performed on a Waters UPLC.

[0080] Numerical values ​​described herein are considered to include the meaning of "about" unless otherwise specified. The term "about" means within 5%, preferably within 1% to 2%, of a given value or range.

[0081] In this specification, numerical ranges expressed using the term "to" include ranges that include the numerical values ​​stated before and after the term "to" as the lower and upper limits, respectively.

[0082] All references, publications, issued patents, and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes. [Example]

[0083] The present invention will be described in more detail with reference to the following examples and experimental examples. However, the examples and experimental examples are merely intended to aid in understanding the present invention and are not intended to limit the scope of the present invention.

[0084] 1. Synthesis reaction formula of Example 1 [ka]

[0085] Experimental procedure for Example 1: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0086] Step 1: 5,7-Dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate-2 of Example 1)

[0087] To a stirred solution of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one, Intermediate-1 from Example 1 (5.00 g, 18.9 mmol) dissolved in MeOH (50 mL, 10 vol) was added 0.1 M NaOH (25.0 mL, 5 vol) at room temperature and stirred for 30 minutes. After stirring, ethyl iodide (2.20 mL, 28.4 mmol) was added at room temperature and the reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and acidified with concentrated sulfuric acid. The HCl was raised to pH ∼4 to give a solid, which was filtered, washed with water, and dried under high vacuum to give crude compound 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one, Intermediate-2 of Example 1 (4.80 g, crude compound) as a light brown solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 294.12 m / z [M+H].

[0088] Step 2: 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate-5 of Example 1)

[0089] To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Intermediate-4 from Example 1) (1.17 g, 6.80 mmol) dissolved in THF (10 mL, 10 vol) was added NaH (0.67 g, 15.3 mmol) at 0°C and stirred at 0°C for 1 hour. 5,7-Dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate-2 from Example 1) (1.00 g, 3.40 mmol) was added at 0°C and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (50 mL) and extracted with 10% methanol in DCM (2 x 30 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous NaSO, 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(3H)-one, Intermediate-5 of Example 1 (1.20 g, crude compound) as a yellow liquid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 430.33 m / z [M+H].

[0090] *Synthesis of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Intermediate-4 of Example 1)

[0091] Step 1a: To a stirred solution of 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-3 of Example 1 (1.00 g, 7.80 mmol) in THF (10 mL, 10 vol), 2-bromoethan-1-ol (0.97 g, 7.80 mmol) and TEA (3.26 mL, 23.4 mmol) were added at 0°C. The reaction mixture was then warmed to room temperature and stirred for 18 hours. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with diethyl ether (20 mL) and filtered to obtain the filtrate. The filtrate was concentrated under reduced pressure to obtain crude compound 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol, Intermediate-4 of Example 1 (1.40 g, crude compound) as a yellow liquid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 173.48 m / z [M+H].

[0092] Step 3: 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-dimethylcyclobutan-1-amine (Intermediate-6 of Example 1)

[0093] 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, Intermediate-5 from Example 1 (1.00 g, 2.32 mmol) in DCM (15 mL, 15 vol) was added BOP-Cl (2.07 g, 8.14 mmol) and DIPEA (6.07 mL, 34.9 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with 10% methanol in DCM (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, 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 60% 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-dimethylcyclobutan-1-amine, Intermediate-6 of Example 1 (0.45 g, Y: 47%) as a white solid. MS (LC-MS): 412.36 m / z [M+H].

[0094] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-8 of Example 1)

[0095] To a stirred solution of 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-dimethylcyclobutan-1-amine, Intermediate-6 from Example 1 (0.45 g, 1.09 mmol), dissolved in a solvent mixture of 1,4-dioxane and water (3:1, 20 mL), was added KPO (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, Intermediate-7 from Example 1 (0.39 g, 1.09 mmol) at room temperature and degassed under argon for 15 minutes. To this was added Ruphos PdG (0.092 g, 0.11 mmol) at room temperature, and the reaction mixture was heated to 90 °C and stirred for 1 hour. The reaction progress 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 NaSO 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-8 of Example 1 (0.61 g, crude compound) as a red solid. MS (LCMS): 610.48 m / z [M+H].

[0096] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-9 of Example 1)

[0097] 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-dimethylcyclobutan-1-amine, Intermediate-8 from Example 1 (0.60 g, 0.98 mmol), dissolved in a solvent mixture of ACN and water (4:1, 20 mL) was added Oxone (3.02 g, 9.83 mmol) at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC and LC-MS. Upon completion of the reaction, the reaction mixture was diluted with ice water (30 mL), extracted with 10% methanol in DCM (2 × 30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was washed with 20% THF in hexane solution to obtain a solid, which was filtered and then dried under high vacuum to obtain 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-dimethylcyclobutan-1-amine, Intermediate-9 of Example 1 (0.30 g, crude compound) as a brown solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 642.44 m / z [M+H].

[0098] Step 6: 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-10 of Example 1)

[0099] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.099 g, 0.62 mmol) in toluene (10 mL, 30 vol) was added NaO t Bu (0.06 g, 0.62 mmol) was added at 0° C. and stirred for 15 minutes. After that, 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-dimethylcyclobutan-1-amine, Intermediate-9 of Example 1 (0.33 g, 0.51 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (30 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-10 of Example 1 (0.32 g, crude compound) as a yellow solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 707.58 m / z [M+H].

[0100] Step 7: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 1)

[0101] To a stirred solution of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-10 from Example 1 (0.32 g, 0.45 mmol) dissolved in 4 M HCl at 0° C. was added 1,4-dioxane (5.0 mL), and the reaction mixture was stirred at 0° C. for 1 hour. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to provide the crude compound. The crude compound was purified by Prep-HPLC to give Example 1 (0.037 g, Y: 12%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 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. (LC-MS): 663.47 m / z [M+H].

[0102] 2. Synthesis reaction scheme of Example 2

[0103] [ka]

[0104] Experimental Procedure for Example 2: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5 H )-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0105] Step 1: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate-2 of Example 2)

[0106] To a stirred solution of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one, Intermediate-1 from Example 2 (7.60 g, 28.69 mmol) dissolved in MeOH (477 mL, 63 vol), 0.1 M NaOH (477 mL, 240.99 mmol) and MeI (3.30 mL, 40.17 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (250 mL) and acidified with concentrated sulfuric acid. The HCl was raised to pH ∼6 to give a solid, which was filtered, washed with water, and dried under high vacuum to give crude compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, Intermediate-2 of Example 2 (4.0 g, crude compound) as a white solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 279.97 m / z [M+H].

[0107] Step 2: 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate-3 of Example 2)

[0108] To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Intermediate-4 from Example 1) (0.37 g, 2.16 mmol) dissolved 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. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate-2 from Example 2) (0.50 g, 1.80 mmol) was added at 0°C and the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous NaSO, 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, Intermediate-3 of Example 2 (0.40 g, crude compound) as a yellow liquid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 416.29 m / z [M+H].

[0109] Step 3: 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-dimethylcyclobutan-1-amine (Intermediate-4 of Example 2)

[0110] 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, Intermediate-3 from Example 2 (0.40 g, 0.96 mmol) in DCM (10 mL, 25 vol) was added BOP-Cl (0.86 g, 3.36 mmol) and DIPEA (2.51 mL, 14.42 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice 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 NaSO, 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 60% ACN in water to give 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-dimethylcyclobutan-1-amine, intermediate-4 of Example 2 (0.30 g, Y: 78%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) 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].

[0111] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-6 of Example 2)

[0112] 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-dimethylcyclobutan-1-amine, Intermediate-4 from Example 2 (0.28 g, 0.71 mmol), dissolved in a solvent mixture of 1,4-dioxane and water (4:1, 5.0 mL), KPO (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, Intermediate-5 from Example 2 (0.36 g, 0.71 mmol) were added at room temperature and degassed with argon gas for 15 minutes. To this mixture, Ruphos PdG3 (0.06 g, 0.07 mmol) was added at room temperature, and the reaction mixture was heated to 100 °C and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by reverse-phase column chromatography using a C18 column and an eluent containing 80% ACN and HO to give 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-6 of Example 2 (0.30 g, Y: 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 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].

[0113] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-7 of Example 2)

[0114] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-6 from Example 2 (0.29 g, 0.39 mmol) dissolved in a mixture of ACN and water (4:1, 10 mL) was added Oxone (1.19 g, 3.88 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 18 hours. Reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL), extracted with 10% methanol in DCM (2 x 20 mL), dried over anhydrous NaSO, 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-dimethylcyclobutan-1-amine, Intermediate-7 of Example 2 (0.35 g, crude compound) as a yellow solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 780.63 m / z [M+H].

[0115] Step 6: 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-8 of Example 2)

[0116] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolidin-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 minutes, 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-dimethylcyclobutan-1-amine, Intermediate-7 from Example 2 (0.32 g, 0.41 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and then stirred for 1.5 hours. The reaction progress was monitored via TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by reverse-phase column chromatography using a C18 column, eluting with 70% ACN and HO to give 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-8 of Example 2 (0.30 g, crude compound) as a yellow solid. MS (LC-MS): 859.89 m / z [M+H].

[0117] Step 7: 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Intermediate-9 of Example 2)

[0118] To a stirred solution of 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-8 from Example 2 (0.29 g, 0.34 mmol) dissolved in THF (3.0 mL, 10 vol) was added 1 M TBAF in THF (0.35 mL, 0.34 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. Reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with 10% MeOH in DCM (2x20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered and evaporated under reduced pressure to give the crude compound. The crude compound was purified by reverse-phase column chromatography using a C18 column, eluting with 70% ACN in HO to give 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-9 of Example 2 (0.23 g, Y: 96%) as a yellow solid. MS (LC-MS): 703.64 m / z [M+H].

[0119] Step 8: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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)

[0120] To a solution of 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine, Intermediate-9 from Example 2 (0.22 g, 0.31 mmol) dissolved in 1,4-dioxane (2.0 mL) was added 4 M HCl at 0° C., and the reaction mixture was stirred at 0° C. for 1 hour. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with NaHCO3 solution (20 mL) and extracted with ethyl acetate (20 mL). The separated organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by Prep-HPLC to obtain Example 2 (0.053 g, Y: 26%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) 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].

[0121] 3. Synthesis Reaction Scheme of Example 3

[0122] [ka]

[0123] Experimental procedure for Example 3: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0124] Step 1: tert-butyl (3-acetylpyridin-2-yl)carbamate (Intermediate-2 of Example 3)

[0125] To a mixture of 1-(2-aminopyridin-3-yl)ethan-1-one, Intermediate-1 of Example 3 (25.0 g, 183 mmol) dissolved in t-BuOH (200 mL) was added BocO (59.8 g, 274 mmol), and the mixture was stirred at 90° C. for 16 hours. LCMS showed that the starting material had been consumed and the desired mass had formed. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EA=2 / 1) to give a white solid, tert-butyl (3-acetylpyridin-2-yl)carbamate (30 g, 69.4% yield). MS: m / z = 237.2 (M+H+, ESI+).

[0126] Step 2: tert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (Intermediate-3 of Example 3)

[0127] To a solution of tert-butyl (3-acetylacetylpyridin-2-yl)carbamate (30 g, 127 mmol) dissolved in EtOH (150 mL) was added (S)-1-aminopropan-2-ol (28.5 g, 381 mmol) and stirred at 90 °C for 3 h. LCMS showed that 39% of the starting material remained and 51% of the desired mass was formed. The reaction mixture was diluted with water and extracted with EA (100 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE / EA = 1 / 1) to give tert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (25 g, 67.2% yield) as a white solid. MS: m / z = 294.2 (M+H+, ESI+).

[0128] Step 3: tert-butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (Intermediate-4 of Example 3)

[0129] To a solution of tert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (25 g, 85.3 mmol) dissolved in MeOH (100 mL) was added NaBH (4.19 g, 110 mmol) at 0 °C, followed by stirring at 25 °C for 1 h. TLC (EA / MeOH = 10 / 1) showed that SM1 (Rf = 0.4) had been consumed and a new spot (Rf = 0.2) had formed. The reaction mixture was diluted with water and extracted with EA (100 mL × 2). The combined organic layer was dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (DCM / MeOH=10 / 1) to give a white solid, tert-butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (12 g, 47.6% yield). MS: m / z =296.2 (M+H+, ESI+).

[0130] 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 (Intermediate-5 of Example 3)

[0131] To a mixture of tert-butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (9.00 g, 30.5 mmol) dissolved in THF (100 mL) was added NaH (4.88 g, 122 mmol, 60% suspension in mineral oil), followed by stirring at 0 °C for 0.5 h. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (8.5 g, 30.5 mmol) was added, and the mixture was further stirred at 25 °C for 1 h. TLC (EA / MeOH = 15 / 1) showed that SM2 (Rf = 0.2) had been consumed and a new spot (Rf = 0.4) had formed. The reaction mixture was treated with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with 60 mL of brine, dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE / EA=0 / 1) to give 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, 73.1% yield) as a yellow solid. MS: m / z = 539.1 (M+H+, ESI+).

[0132] Step 5: 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 (Intermediate-6 of Example 3)

[0133] 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) dissolved in DCM (70 mL) was added BoPCl (9.95 g, 39.0 mmol) and DIEA (15.1 g, 117 mmol). The mixture was then stirred at 25 °C for 12 h. TLC (PE / EA = 0 / 1) showed that SM2 (Rf = 0.2) had been consumed and a new spot (Rf = 0.5) had formed. The reaction mixture was diluted with water (100 mL) and extracted with DCM (60 mL × 2). The combined organic layers were washed with 60 mL of brine, dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE / EA=1 / 1) to give 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 (4.00 g, 59.2% yield) as a yellow solid. Structural confirmation was determined via 2D NMR. MS: m / z = 521.2 (M+H+, ESI+).

[0134] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-7 of Example 3)

[0135] A mixture 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 (1 g, 1.92 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.69 g, 1.92 mmol), RuPhos-Pd-G (0.40 g, 0.47 mmol), and KPO (1.22 g, 5.75 mmol) dissolved in dioxane / HO (30 mL / 10 mL) was stirred at 100 °C under N atmosphere for 4 h. TLC (PE / EA = 0 / 1) showed that approximately 10% of SM1 (Rf = 0.5) remained, and a new main spot (Rf = 0.6) had formed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (40 mL × 2). The combined organic layers were washed with 60 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 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, 38.8% yield) as a yellow solid. MS: m / z =619.2 (M+H+, ESI+)

[0136] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-8 of Example 3)

[0137] 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 CAN / HO (10 mL / 10 mL) was added oxone (2.28 g, 3.72 mmol) and the mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material had been consumed and the desired mass had been obtained. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with 20 mL of brine, dried over NaSO, 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 compound) as a yellow oil. MS: m / z = 651.1 (M+H+, ESI+).

[0138] Step 8: 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-9 of Example 3)

[0139] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, 0.77 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-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 had been consumed and the desired mass had been detected. The reaction mixture was diluted with water (40 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with 20 mL of brine, dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by MPLC (FA conditions) to give 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (250 mg, 44.5% yield) as a white solid. MS: m / z = 730.3 (M+H+, ESI+).

[0140] Step 9: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 3)

[0141] 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-pyrrolidin-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 M HCl / dioxane (2 mL) and stirred at 0 °C for 1 h. LCMS indicated that the starting material had been consumed and the desired mass had formed. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by pre-HPLC (NH H O condition) to give Example 3 (100 mg, 53%) as a white solid. MS: m / z =686.2 (M+H+, ESI+)

[0142] Step 10: Example 3a and Example 3b

[0143] [ka]

[0144] The compound of Example 3 (100 mg) was purified by SFC (column: REGIS (S,S) WHELK-O1, MeOH (+0.1% ammonia dissolved in 7.0 mol / L MeOH) / CO2 = 50 / 50) to give Example 3a (30.43 mg, 30.43%) and Example 3b (20.87 mg, 20.87%).

[0145] Example 3a: 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0146] LC-MS: (ES, m / z): [M+H]+=686.2

[0147] 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).

[0148] Example 3b: 4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0149] LC-MS: (ES, m / z): [M+H] + =686.3

[0150] 1H 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).

[0151] 4. Synthesis Reaction Scheme of Example 4

[0152] [ka]

[0153] Experimental procedure for Example 4: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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

[0154] Step 1: Ethyl (E)-2-((4-bromobenzylidene)amino)acetate (Intermediate-2 of Example 4)

[0155] To a solution of 4-bromobenzaldehyde (Example 4, Intermediate-1) (5 g, 27.024 mmol) dissolved in DCM (75 mL) was added ethylglycine hydrochloride (3.77 g, 27.024 mmol), MgSO (3.74 g, 31.078 mmol), and TEA (5.47 g, 54.048 mmol). The mixture was stirred at 25 °C under an argon atmosphere 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 H0 (50 mL) and extracted with MTBE (50 mL). The organic phase was washed with brine (50 mL) and dried over NaSO. Filtration and concentration under reduced pressure gave the desired product, ethyl (E)-2-((4-bromobenzylidene)amino)acetate (6 g, 82% yield) as a colorless liquid. MS: m / z = 288.0 (M+H+, ESI+).

[0156] Step 2: Ethyl (E)-2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (Intermediate-3 of Example 4)

[0157] To a solution of ethyl (E)-2-((4-bromobenzylidene)amino)acetate (5.0 g, 18.510 mmol) dissolved 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 3-chloro-2-(chloromethyl)prop-1-ene (6.95 g, 55.530 mmol) dropwise at 25 °C under N2. The resulting mixture was further stirred at 65 °C under N2 for 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 gave the desired product, ethyl (E)-2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (6.5 g, 78% yield) as a brown liquid. MS: m / z = 447.8 (M+H+, ESI+).

[0158] Step 3: Ethyl 2,6-dimethylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate-4 of Example 4)

[0159] To a solution of ethyl (E)-2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (1.5 g, 3.354 mmol) dissolved in THF (15 mL) was added 1 M HCl (10 mL, 10.063 mmol). The mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with HO (60 mL). The aqueous layer was extracted with EA (40 mL) to give the desired crude 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+).

[0160] Step 4: Ethyl 2,6-dimethylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate-5 of Example 4)

[0161] 1M NaOH (12 mL, 11.572 mmol) was added dropwise to the upper aqueous layer to adjust the pH to 9-10. The resulting mixture was stirred at 25°C for 0.5 h. The reaction was monitored by LCMS. LCMS confirmed the presence of the desired product. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluted with DCM / MeOH (10:1) to give the desired product, ethyl 2,6-dimethylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (140 mg, 20% yield for two steps) as a brown liquid. MS: m / z = 208.0 (M+H+, ESI+).

[0162] Step 5: (2,6-dimethylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate-6 of Example 4)

[0163] To a solution of ethyl 2,6-dimethylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (680 mg, 3.278 mmol) in THF (7 mL) was added LiAlH (6.6 mL, 6.562 mmol) at 0 °C under N 2 . The mixture was stirred at 25 °C for 14 h. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction was quenched by adding H 2 O (0.3 mL), 15% NaOH solution (0.3 mL), and H 2 O (0.6 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H 2 O (80 mL). The aqueous layer was extracted with DCM (60 mL). The organic layer was concentrated under reduced pressure to give a colorless liquid (2,6-dimethylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (420 mg, 77% yield). MS: m / z = 166.0 (M+H+, ESI+).

[0164] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-7 of Example 4)

[0165] 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) dissolved in dioxane (42 mL) and HO (14 mL) To the solution were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.765 g, 5.373 mmol), RuPhos-Pd-G3 (1.343 g, 1.607 mmol), and K3PO4 (3.416 g, 16.094 mmol). The mixture was stirred at 100 °C under an argon atmosphere for 4 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (2.4 g, 57% yield) as a yellow solid. MS: m / z =771.1 (M+H+, ESI+).

[0166] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-8 of Example 4)

[0167] 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) dissolved in THF (10 mL) and HO (10 mL) was added oxone (4 g, 6.483 mmol) at 0 °C under argon. The resulting mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. LCMS indicated the presence of the desired product. The reaction was quenched with NaHSO solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (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 NaSO. 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, 96% yield) as a yellow solid. MS: m / z = 803.2 (M+H+, ESI+).

[0168] Step 8: 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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 (Intermediate-9 of Example 4)

[0169] To a solution of (2,6-dimethylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (61 mg, 0.372 mmol) dissolved in THF (3 mL) was added NaH (20 mg, 0.500 mmol) under an argon atmosphere 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 resulting mixture was further stirred at 0° C. for 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched with NH4Cl (60 mL) solution 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography from silica gel (MeOH / DCM=1:20) eluting with 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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 (180 mg, 65% yield) as a yellow solid. MS: m / z = 888.3 (M+H+, ESI+).

[0170] Step 9: 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-10 of Example 4)

[0171] To a solution of 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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) dissolved in DMF (3 mL) was added CsF (274 mg, 1.800 mmol). The mixture was stirred under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase, ACN (0.1% FA) in HO, 10% to 50% gradient over 15 min; UV at 254 nm to obtain the desired product, 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 53% yield) as a yellow solid. MS: m / z = 732.3 (M+H+, ESI+).

[0172] Step 10: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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 (Example 4)

[0173] To a solution of 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, 0.082 mmol) dissolved in ACN (1 mL) was added HCl / dioxane (1.5 mL, 1.476 mmol). The mixture was stirred under argon at 25° C. for 2 hours. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC using the following conditions: Waters 2767 / Qda, column: XBridge C18 19*250mm, 10μm; mobile phase A: 10mmol NH4HCO3 / H2O, B: ACN; flow rate: 20mL / min; gradient: 50%-50%; retention time: 6.4-11 min out of 16 min to give the desired product, Example 4 (13.40mg, 23% yield) as a yellow solid.

[0174] MS: m / z =688.2 (M+H+, ESI+)

[0175] 1H 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).

[0176] 5. Synthesis Reaction Scheme of Example 5

[0177] [ka]

[0178] Experimental procedure for Example 5: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0179] Step 1: 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 5)

[0180] To a solution of (1-(morpholinomethyl)cyclopropyl)methanol (64 mg, 0.372 mmol) dissolved in THF (3 mL) was added NaH (20 mg, 0.500 mmol) under an argon atmosphere at 0° C. The mixture was stirred at 0° C. for 0.5 hours. 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, Intermediate-8 of Example 4 (200 mg, 0.248 mmol) under argon at 0° C. The resulting mixture was further stirred at 0° C. for 1 hour. The reaction was monitored by LCMS. LCMS showed the desired product. The reaction was quenched with NH4Cl (60 mL) solution 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (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-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 71% yield) as a yellow solid. MS: m / z =894.4 (M+1, ESI+).

[0181] Step 2: 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-3 of Example 5)

[0182] To a solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(morpholinomethyl)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) dissolved in DMF (3 mL) was added CsF (306 mg, 1.98 mmol). The mixture was stirred under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase, ACN (0.1% FA) in HO, 10% to 50% gradient over 15 min; detector, UV at 254 nm to obtain the desired product, 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (100 mg, 60% yield) as a yellow solid. MS: m / z = 738.2 (M+1, ESI+).

[0183] Step 3: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)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)

[0184] To a solution of 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)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 CAN (1 mL) was added HCl / dioxane (2 mL, 1.944 mmol). The mixture was stirred under an argon atmosphere at 25° C. for 2 hours. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC using the following conditions: Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 46%-46%; retention time: 9.8-12.3 min or 18 min to give the desired product, Example 5 (14.13 mg, 18% yield), as a yellow solid. MS: m / z = 694.0 (M+1, ESI+).

[0185] 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).

[0186] 6. Synthesis Reaction Scheme of Example 6

[0187] [ka]

[0188] Experimental procedure for Example 6: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0189] Step 1: 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-2 of Example 6)

[0190] To 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, Intermediate-8 from Example 4 (300 mg, 0.374 mmol), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, Intermediate-1 from Example 6 (89 mg, 0.560 mmol) dissolved in THF (3 mL) was added t-BuONa (72 mg, 0.748 mmol) under argon at −78° C. The mixture was stirred at −78° C. for 1 hour. The reaction was quenched with NH4Cl (60 mL) solution at -78 °C. The resulting mixture was extracted with EA (3 x 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 give a residue. The residue was purified by column chromatography on silica gel (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-pyrrolidin-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, 72% yield) as a yellow solid. MS: m / z =882.3 (M+1, ESI+).

[0191] Step 2: 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-3 of Example 6)

[0192] 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-pyrrolidin-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 under argon at 25° C. for 1 h. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase, ACN in HO (0.1% FA), 15 min 30% to 70% gradient; detector, UV 254 nm, to obtain the desired product, 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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, 75% yield) as a yellow solid. MS: m / z = 726.2 (M+1, ESI+).

[0193] Step 3: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 6)

[0194] 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-pyrrolidin-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) dissolved in ACN (2 mL) was added HCl / dioxane (3.3 mL, 3.224 mmol). The mixture was stirred under argon at 25° C. for 2 hours. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase, ACN in HO (0.1% NH3HO), 10 min 40% to 80% gradient; detector, UV 254 nm, to obtain the desired product, 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (118 mg, racemic) as a yellow solid. MS: m / z = 682.2 (M+1, ESI+).

[0195] 1H 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).

[0196] Step 4: Example 6a and Example 6b

[0197] [ka]

[0198] The compound of Example 6 (100 mg) was purified by SFC (column: REGIS (S,S) WHELK-O1, MeOH (+0.1% ammonia dissolved in 7.0 mol / L MeOH) / CO2 = 55 / 45) to give Example 6a (40.46 mg, 40%) and Example 6b (31.19 mg, 31%).

[0199] Example 6a: 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0200] LC-MS: (ES, m / z): [M+H]+ = 682.0

[0201] 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).

[0202] Example 6b: 4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0203] LC-MS: (ES, m / z): [M+H]+ = 682.0

[0204] 1H 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).

[0205] 7. Synthesis Reaction Scheme of Example 7

[0206] [ka]

[0207] Experimental procedure for 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

[0208] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 7)

[0209] To a slurry of NaH (60%) (20 mg, 0.05 mmol) dissolved in THF (1 mL) was added (R)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (Intermediate-1 of Example 7) (113 mg, 0.75 mmol) in THF (1 mL) at 0° C. The solution was stirred at 0° C. for 30 minutes. The above mixture was added to 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) dissolved in THF (1 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was treated with NH4Cl (aqueous, 10 mL) and the solution was extracted with EA (2 × 20 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography eluting with 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+).

[0210] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-3 of Example 7)

[0211] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, 0.22 mmol) and CsF (330 mg, 2.18 mmol) dissolved 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 Prep-HPLC (column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; gradient: 5%-95%B; flow rate: 50 mL / min) to give 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (104 mg, 60%) as a yellow solid. MS: m / z = 718.1 (M+1, ESI+).

[0212] Step 3: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-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 (Example 7)

[0213] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (94 mg, 0.13 mmol) dissolved in ACN (0.5 mL) was added HCl / dioxane (4 M, 0.5 mL) dropwise 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 Prep-HPLC (Waters 2767 / Qda, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 18-28%; retention time: 7.9-10.8 min out of 16 min) to give the desired product Example 7 (20.08 mg, 22%) as a yellow solid. MS: m / z = 673.9 (M+1, ESI+)

[0214] 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).

[0215] 8. Synthesis Reaction Scheme of Example 8

[0216] [ka]

[0217] Experimental procedure for 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

[0218] Step 1: (S)-Azetidin-2-ylmethanol (Intermediate-2 of Example 8)

[0219] To a solution of tert-butyl (S)-2-(hydroxymethyl)azetidine-1-carboxylate (Intermediate-1 from Example 8) (1 g, 5.35 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 6 mL). The reaction mixture was stirred at 25° C. for 16 hours. The solvent was removed under reduced pressure to give (S)-azetidin-2-ylmethanol (700 mg, 98%) as a colorless oil. MS: m / z = 88.2 (M+1, ESI+).

[0220] Step 2: (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (Intermediate-3 of Example 8)

[0221] To an ice-cooled solution of K2CO3 (2.4 g, 17.70 mmol) and (S)-azetidin-2-ylmethanol hydrochloride (700 mg, 8.04 mmol) in ACN (10 mL) 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), and the resulting mixture was extracted with EA (40 mL), followed by washing with brine (40 mL). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography eluting with 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+).

[0222] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-4 of Example 8)

[0223] To a slurry of NaH (60% in oil, 37 mg, 0.56 mmol) dissolved in THF (1 mL) was added a solution of (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (125 mg, 0.82 mmol) in THF (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and 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) dissolved in THF (1 mL) was added to the mixture. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with concentrated NH4Cl (aqueous, 5 mL) and the solution was extracted with EA (2×20 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography eluting with DCM / MeOH=20:1 to give 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+).

[0224] 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 (Intermediate-5 of Example 8)

[0225] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (261 mg, 0.30 mmol) and CsF (454 mg, 2.98 mmol) dissolved in DMF (3 mL) was stirred at 25 °C for 2 h. The residue was then purified by Prep-HPLC (column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, 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-10H-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+).

[0226] 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]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 8)

[0227] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (87 mg, 0.12 mmol) dissolved in DCM (1 mL) was added HCl / dioxane (4 M, 0.3 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with DCM / MeOH (10 / 1 mL). The mixture was washed with concentrated NaHCO (aq, 10 mL), followed by brine (10 mL) and dried over NaSO(s). The organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 18-23%; retention time: 7-9.2 min of 16 min) to give Example 8 (4.49 mg, 5%) as a pale yellow solid. MS: m / z = 674.0 (M+1, ESI+)

[0228] 1H 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).

[0229] 9. Synthesis Reaction Scheme of Example 9

[0230] [ka]

[0231] Experimental procedure for Example 9: 4-((8S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-10-(1-(2-aminopyridin-3-yl)ethyl)-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

[0232] Step 1: 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-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 9)

[0233] To a solution of (2-oxabicyclo[2.1.1]hexan-4-yl)methanol (44 mg, 0.372 mmol) dissolved in THF (3 mL) was added NaH (60% in oil, 20 mg, 0.500 mmol) under an argon atmosphere at 0° C. The mixture was stirred at 0° C. for 0.5 hours. 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, Intermediate-8 of Example 4 (200 mg, 0.248 mmol) under argon at 0° C. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was quenched with NH4Cl (40 mL) solution at 0° C. The resulting mixture was extracted with EA (3×20 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 give a residue. The residue was purified by column chromatography on silica gel (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-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 54% yield) as a yellow solid. MS: m / z =837.2 (M+H, ESI+).

[0234] Step 2: 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-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-3 of Example 9)

[0235] 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-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-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 under argon at 25 °C 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 give a residue. The residue was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase, ACN in HO (0.1% FA), 10% to 50% gradient over 15 min; detector, UV at 254 nm to obtain 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-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 79% yield) as a yellow solid. MS: m / z = 681.2 (M+H, ESI+).

[0236] Step 3: 4-((8S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-10-(1-(2-aminopyridin-3-yl)ethyl)-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 (Example 9)

[0237] 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-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (110 mg, 0.160 mmol) in ACN (2 mL) was added HCl / dioxane (4 M, 3.3 mL, 2.910 mmol). The mixture was stirred under argon at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (Waters 2767 column: Xbridge C18, 19*250 mm, 10 μ, mobile phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 42-42%; retention time: 7.1-10 min out of 16 min) to give the desired product Example 9 (17.69 mg, 17% yield) as a yellow solid. MS: m / z = 636.9 (M+H, ESI+).

[0238] 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).

[0239] 10. Synthesis Reaction Schemes of Examples 10a and 10b

[0240] [ka]

[0241] Experimental Procedures for Examples 10a and 10b

[0242] Step 1: 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 (Intermediate-1 of Example 10)

[0243] 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-tetranaphthaleneazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate, Intermediate-6 from Example 3 (1 g, 1.920 mmol) dissolved in ACN (12 mL) and HO (4 mL) was added oxone (5.9 g, 9.595 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 solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the desired product, 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 g, 94% yield) as a yellow solid. MS: m / z = 553.1 (M+H, ESI+).

[0244] Step 2: tert-butyl (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Intermediate-3 of Example 10)

[0245] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate-2 of Example 10) (440 mg, 2.72 mmol) dissolved in THF (10 mL) was added NaH (160 mg, 3.60 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 0.5 hours. 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) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 hour. The reaction was monitored by LCMS. LCMS showed the desired product. The reaction was quenched with NH4Cl (100 mL) solution 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography from silica gel (MeOH / DCM=1:10) eluting with tert-butyl (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (800 mg, 69% yield) as a yellow solid. MS: m / z =632.2 (M+H, ESI+).

[0246] Step 3: 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-5 of Example 10)

[0247] To a solution of tert-butyl (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetranaphthaleneazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (150 mg, 0.237 mmol) in dioxane (3 mL) and HO (1 mL) was added 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate-4 from Example 10) (84 mg, 0.237 mmol). RuPhos-Pd-G3 (60 mg, 0.071 mmol) and K3PO4 (153 mg, 0.711 mmol) were added. The mixture was stirred at 100 °C under an argon atmosphere for 2 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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-pyrrolidin-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, 83% yield) as a yellow solid. MS: m / z =720.2 (M+H, ESI+).

[0248] Step 4: Examples 10a and 10b

[0249] [ka]

[0250] To a solution of 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 an argon atmosphere for 2 hours. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC under the following conditions: Prep-HPLC (Waters 2767 column: Xbridge C18, 19*250 mm, 10 μm; mobile phase A: 0.05% NH3H2O / H2O, B: ACN; flow rate: 20 mL / min; gradient: 39-39%; retention time: 8.8-12.8 min or 16 min) to give the desired product.

[0251] Example 10a: 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (7.90 mg, 4% yield) is a white solid.

[0252] MS: m / z =676.0 (M+H, ESI+)

[0253] 1H NMR (400 MHz, DMSO-d6) 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).

[0254] Example 10b: 4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (5.90 mg, 3%) is a white solid.

[0255] MS: m / z =676.0 (M+H, ESI+)

[0256] 1H NMR (400 MHz, DMSO-d6) 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).

[0257] 11. Synthesis reaction scheme of Example 11

[0258] [ka]

[0259] Experimental Procedure for Example 11: 3-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-chloro-4-cyclopropylphenol

[0260] Step 1: 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-2 of Example 11)

[0261] To a solution of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate-1 from Example 11) (100 mg, 0.29 mmol) in dioxane (2 mL) / HO (0.2 mL) was added tert-butyl (3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H To the reaction mixture was added 186 mg (0.29 mmol) of 1-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Intermediate-3 from Example 10), CsCO (192 mg, 0.59 mmol), and Pd(dppf)Cl (21 mg, 0.03 mmol). The reaction mixture was stirred at 100° C. under N for 4 hours. Upon completion, water (5 mL) was added to the reaction mixture and extracted with ethyl acetate (3×10 mL). The organic layer was filtered, concentrated, and then dried over NaSO. The residue was purified by silica gel chromatography (eluting with DCM / MeOH = 20:1) and Prep-HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 18-23%; retention time: 7-9.2 min out of 16 min) to afford 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (80 mg, 38%) as a yellow solid.

[0262] MS: m / z =708.2 (M+H+, ESI+)

[0263] Step 2: 3-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-chloro-4-cyclopropylphenol (Example 11)

[0264] To a solution of 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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, intermediate-2 of Example 11 (60 mg, 0.08 mmol) dissolved in DCM (1 mL) was added HCl / dioxane (0.3 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with DCM / MeOH (10 / 1 mL × 2). The mixture was washed with concentrated NaHCO (aq, 10 mL), followed by brine (10 mL) and dried over NaSO(s). The organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.05% TFA / HO, B: ACN; flow rate: 20 mL / min; gradient: 18-23%; retention time: 7.3-9.8 min of 16 min) to give Example 11 (4.62 mg, 8%) as a pale yellow solid. MS: m / z = 664.2 (M+H+, ESI+).

[0265] 1H NMR (400 MHz, CDCl3) 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).

[0266] 12. Synthesis reaction scheme of Example 12

[0267] [ka]

[0268] Experimental Procedure for Example 12: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0269] Step 1: tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (Intermediate-1 of Example 12)

[0270] To a solution of tert-butyl (3-acetylpyridin-2-yl)carbamate, Intermediate-2 of Example 3 (20 g, 84.65 mmol) dissolved in EtOH (200 mL) was added 2-aminoethan-1-ol (15.5 g, 253.95 mmol) at 25 °C under N. The mixture was stirred at 90 °C for 2 h. The reaction was monitored by LCMS. LCMS indicated the desired product. 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. Filtration and concentration under reduced pressure gave the residue. The residue was purified by column chromatography on silica gel eluted with (EA / PE=85%) to give the desired product tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (7.6 g, crude compound) in the form of a colorless oil. MS: m / z = 280.0 (M+H, ESI+).

[0271] Step 2: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Intermediate-2 of Example 12)

[0272] To a solution of tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (7.6 g, 27.207 mmol) dissolved in MeOH (80 mL) was added NaBH (3.087 g, 81.621 mmol) at 0 °C under N. The mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H0 (150 mL), extracted with EA (100 mL), and dried over NaSO. Filtration and concentration under reduced pressure gave the crude compound prepared. The crude compound was purified by column chromatography from silica gel eluting with MeOH / DCM=10% to give the desired product tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (3.0 g, 39% yield) in the form of a colorless oil. MS: m / z = 282.1 (M+H, ESI+).

[0273] Step 3: 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 (Intermediate-3 of Example 12)

[0274] To a solution of tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (4.4 g, 15.709 mmol) dissolved in THF (50 mL) was added NaH (1.89 g, 47.126 mmol) at 0 °C under argon atmosphere. The mixture was stirred at 0 °C for 0.5 h. 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 further stirred at 0 °C for 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched by adding HO (30 mL) at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (150 mL), extracted with EA (100 mL), and dried over NaSO. Filtration and concentration under reduced pressure gave the crude compound. The crude compound was purified by column chromatography on silica gel eluting with MeOH / DCM=9% to give the desired 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)pyridin-2-yl)carbamate (3.4 g, 41% yield) as a yellow solid. MS: m / z = 525.1 (M+H, ESI+).

[0275] Step 4: 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 (Intermediate-4 of Example 12)

[0276] 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) dissolved in THF (30 mL) was added DIEA (6.87 g, 53.145 mmol) at 0 °C under argon atmosphere. The mixture was stirred at 0 °C for 0.5 h. To the above mixture was added BopCl (4.51 g, 17.714 mmol) under argon at 0 °C. The resulting mixture was further stirred at 25 °C under argon atmosphere for 16 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with HO (150 mL) and extracted with EA (100 mL). The crude compound was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography on silica gel eluting with EA / PE = 82% to give the desired product, 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 (1.6 g, 53% yield) as a yellow solid. Structural confirmation was determined via 2D NMR. MS: m / z = 507.1 (M+H, ESI+).

[0277] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-5 of Example 12)

[0278] 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 (1.6 g, 3.156 mmol) dissolved in dioxane (21 mL) and HO (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 an argon atmosphere for 2 hours. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with HO (100 mL). The resulting mixture was extracted with EA (60 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (1.3 g, 54% yield) as a yellow solid. MS: m / z = 757.2 (M+H, ESI+).

[0279] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-6 of Example 12)

[0280] To a solution of SM (1.3 g, 1.717 mmol) dissolved in ACN (15 mL) and H2O (5 mL) was added oxone (5.28 g, 8.587 mmol) under argon atmosphere at 0 °C. The resulting mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was monitored by LCMS. The reaction was quenched with NaHSO3 solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (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 Na2SO4. 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 compound) as a yellow solid. MS: m / z = 789.1 (M+H, ESI+).

[0281] Step 7: 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-7 of Example 12)

[0282] To a solution of (1-(morpholinomethyl)cyclopropyl)methanol (65 mg, 0.380 mmol) dissolved in THF (2 mL) was added NaH (20 mg, 0.506 mmol) under an argon atmosphere 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) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of HO (4 mL) at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (30 mL), extracted with EA (20 mL), and dried over NaSO. Filtration and concentration under reduced pressure gave the crude compound. The crude compound was purified by column chromatography on silica gel (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-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 48% yield) as a yellow solid. MS: m / z = 880.3 (M+H, ESI+).

[0283] Step 8: 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-8 of Example 12)

[0284] To a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)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) dissolved in DMF (3 mL) was added CsF (225 mg, 1.48 mmol). The mixture was stirred under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction mixture was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase, ACN (0.1% FA) in HO, 10% to 50% gradient over 15 min; detector, UV at 254 nm to obtain the desired product, 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 56% yield) as a yellow solid. MS: m / z = 723.9 (M+H, ESI+).

[0285] Step 9: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)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)

[0286] To a solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)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 an argon atmosphere for 2 hours. The reaction was monitored by LCMS. LCMS confirmed the presence of the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC using the following conditions. Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; retention time: 8.9-9.8 min out of 16 min to give the desired product, Example 12 (2.21 mg, 11% yield), as a white solid. MS: m / z = 680.0 (M+1, ESI+).

[0287] 1 H NMR (400 MHz, CDCl3) 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).

[0288] 13. Synthesis reaction scheme of Example 13

[0289] [ka]

[0290] Experimental Procedure for Example 13: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 formate

[0291] Step 1: 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-1 of Example 13)

[0292] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (302 mg, 1.901 mmol) dissolved in THF (10 mL) was added NaH (60% in oil, 101 mg, 2.534 mmol) under an argon atmosphere at 0° C. The mixture was stirred at 0° C. for 0.5 hours. 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, Intermediate-6 of Example 12 (1 g, 1.267 mmol) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was quenched with NH4Cl (60 mL) solution 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography from silica gel (MeOH / DCM=1:10) eluting with 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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, 83% yield) as a yellow solid. MS: m / z = 868.3 (M+H), ESI

[0293] Step 2: 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 13)

[0294] To a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 under argon at 25 °C for 1 h. The resulting mixture was diluted with HO (60 mL). The resulting mixture was extracted with EA (3 × 40 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. The desired product, 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 compound) was obtained as a yellow solid. MS: m / z = 712.2 (M+H)+, ESI+

[0295] Step 3: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 13)

[0296] 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 under argon at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography using the following conditions: C18 silica gel; mobile phase: ACN (0.1% FA) in HO, 10% to 50% gradient over 15 min; detector: UV at 254 nm to give the desired product, Example 13 (23.93 mg, 5% yield), as a yellow solid. MS: m / z = 667.9 (M+H+, ESI+).

[0297] 1 H NMR (400 MHz, DMSO-d6) 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).

[0298] Step 4: Example 13a and Example 13b

[0299] [ka]

[0300] Compound Example 13 (120 mg) was purified by SFC (column: DAICELCHIRALPAK (registered trademark) W, EtOH (+0.1% ammonia dissolved in 7.0 mol / L EtOH) / CO2 = 63:37) to give Example 13a (20.55 mg, 17.1%) and Example 13b (21.20 mg, 17.6%).

[0301] Example 13a: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0302] MS: m / z = 668.2 (M+H+, ESI+)

[0303] 1H 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).

[0304] Example 13b: 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0305] MS: m / z = 668.2 (M+H+, ESI+)

[0306] 1H 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).

[0307] 14. Synthesis reaction scheme of Example 14

[0308] [ka]

[0309] [ka]

[0310] Experimental procedure for Example 14: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0311] Synthesis of Intermediate-2 in Example 14

[0312] Step 1a: tert-butyl (3-acetylpyridin-2-yl)carbamate (Intermediate-2b of Example 14)

[0313] To a stirred solution of 1-(2-aminopyridin-3-yl)ethan-1-one, Intermediate-2a of Example 14 (4.00 g, 29.4 mmol) dissolved in t-BuOH (20 mL, 5 vol.), (Boc)2O (10.0 mL, 44.1 mmol) was added at room temperature, and the reaction mixture was heated to 80 °C and stirred for 5 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a solid. The solid was filtered and dried under high vacuum to give crude compound tert-butyl (3-acetylpyridin-2-yl)carbamate, Intermediate-2b of Example 14 (5.0 g, crude compound) as a pale yellow solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 237.28 m / z [M+H].

[0314] Step 2a: tert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate (Intermediate-2d of Example 14)

[0315] To a stirred solution of tert-butyl (3-acetylpyridin-2-yl)carbamate 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) dissolved in THF (50 mL, 10 vol) at room temperature was added titanium ethoxide (14.5 g, 63.6 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. Upon 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 NaSO, filtered, and evaporated under reduced pressure to give crude compound tert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate Example 14 Intermediate-2d (5.50 g, crude compound) as a white solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 280.33 m / z [M+H].

[0316] Step 3a: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Intermediate-2 of Example 14)

[0317] To a stirred solution of tert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate Example 14 Intermediate-2d (5.00 g, 17.9 mmol) in MeOH (50 mL, 10 vol) was added NaBH4 (1.35 g, 35.8 mmol) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude compound tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate Example 14 Intermediate-2 (1.80 g, crude compound) as a white solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 282.30 m / z [M+H]

[0318] 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 (Intermediate-3 of Example 14)

[0319] To a stirred solution of 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one, Intermediate-2 from Example 1 (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 minutes. After that, tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate, Intermediate-2 from Example 14 (2.00 g, 7.37 mmol) was added at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give the 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, Y: 45%) as a white solid. MS (LC-MS): 539.37 m / z [M+H].

[0320] Step 2: 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 (Intermediate-4 of Example 14)

[0321] 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, Intermediate-3 from Example 14 (0.25 g, 0.46 mmol), dissolved in DCM (2.5 mL, 10 vol) was added BOP-Cl (0.13 g, 1.62 mmol) and DIPEA (1.20 mL, 6.72 mmol) at room temperature, and the reaction mixture was then heated to 60° C. and stirred for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give 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 give 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 Intermediate-4 of Example 14 (0.90 g, total 6-configuration (6x250 mg) yield, crude compound) as a brown solid. MS (LCMS): 521.35 m / z [M+H].

[0322] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-6 of Example 14)

[0323] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate Intermediate-4 from Example 14 (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 Intermediate-5 from Example 14 (0.25 g, 0.69 mmol) dissolved in a solvent mixture of 1,4-dioxane and water (2:1, 9 mL) was added KOtBu (0.19 g, 1.73 mmol) at room temperature and degassed under N gas for 10 minutes. To this was added tetrakis (0.067 g, 0.06 mmol) at room temperature, and the reaction mixture was heated to 90 °C and stirred for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 25 mL). The combined organic layer was washed with brine solution, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 5% methanol in DCM as the eluent to give 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, intermediate-6 of Example 14 (0.30 g, total yield of 3 configurations (3 x 250 mg), Y: 28%) as a pale yellow solid. MS (LC-MS): 619.40 m / z [M+H].

[0324] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-7 of Example 14)

[0325] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine, Intermediate-6 from Example 14 (0.30 g, 0.48 mmol) dissolved in a solvent mixture of ACN and water (2:1, 36 mL) was added Oxone (1.49 g, 4.85 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and ethyl acetate (2 x 25 mL), and the combined organic layer was washed with brine, dried over anhydrous NaSO, 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, Intermediate-7 of Example 14 (0.25 g, crude compound) as a pale yellow solid. The crude compound was used directly in the next step without further purification. MS (LC-MS): 651.36 m / z [M+H].

[0326] Step 5: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-9 of Example 14)

[0327] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol Intermediate-8 from Example 14 (0.073 g, 0.46 mmol) in THF (5.0 mL, 20 vol) was added NaO tBu (0.074 g, 0.77 mmol) was added at 0° C. and stirred for 15 minutes, 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, Intermediate-7 of Example 14 (0.25 g, 0.38 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. The reaction progress 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 solution, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by Prep-HPLC to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine, intermediate-9 of Example 14 (0.03 g, Y: 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 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].

[0328] Step 6: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 14)

[0329] 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-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine, Intermediate-9 of Example 14 (0.03 g, 0.042 mmol) was added 4 M HCl in 1,4-dioxane (0.2 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give Example 14 (0.007 g, Y: 25%) as a white solid. MS: m / z = 672.2 (M+H+, ESI+) 1 H NMR (400 MHz, DMSO-d6) 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).

[0330] Racemic Example 14 was purified by SFC (column: DAICELCHIRALPAK® IE, n-hexane / EtOH (+0.1% 7.0 mol / L ammonia dissolved in MeOH) = 50 / 60) to give Example 14a as a white solid and Example 14b as a white solid.

[0331] Example 14a: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0332] MS: m / z = 672.2 (M+H+, ESI+)

[0333] 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).

[0334] Example 14b: 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0335] MS: m / z = 672.2 (M+H+, ESI+)

[0336] 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, 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).

[0337] 15. Synthesis reaction scheme of Example 15

[0338] [ka]

[0339] Experimental Procedure for 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

[0340] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-1 of Example 15)

[0341] To a slurry of NaH (60%) (25 mg, 0.63 mmol) in THF (1 mL) was added a solution of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (144 mg, 0.95 mmol) in THF (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, after which 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, Intermediate-6 from Example 12 (250 mg, 0.32 mmol) in THF (1 mL) was added. The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with concentrated NH4Cl (aqueous, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4(s). 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-10H-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+).

[0342] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 15)

[0343] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (118 mg, 0.14 mmol) and CsF (209 mg, 1.37) dissolved 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 Prep-HPLC (column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (84 mg, 87%) as a yellow solid. MS: m / z = 704.1 (M+H+, ESI+).

[0344] 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)

[0345] 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-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (64 mg, 0.09 mmol) dissolved in DCM (1 mL) was added HCl / dioxane (0.3 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with DCM / MeOH (10 / 1 mL × 2). The mixture was washed with concentrated NaHCO (aq, 10 mL), then brine (10 mL) and dried over NaSO(s). The organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.05% TFA / HO, B: ACN; flow rate: 20 mL / min; gradient: 20-25%; retention time: 7.8-9.8 min over 16 min) and Prep-HPLC (Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.05% NH3HO / HO, B: ACN; flow rate: 20 mL / min; gradient: 39%-39%; retention time: 8-11.1 min over 16 min) to give Example 15 (2.42 mg, 4%) as a pale yellow solid. MS: m / z = 660.4 (M+H+, ESI+)

[0346] 1 H NMR (400 MHz, CDCl3) 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).

[0347] 16. Synthesis reaction scheme of Example 16

[0348] [ka]

[0349] Experimental procedure for Example 16: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol

[0350] Step 1: 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 (Intermediate-1 of Example 16)

[0351] 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 of Intermediate-4 of Example 12 (400 mg, 0.789 mmol) dissolved in ACN (6 mL) and HO (2 mL) was added oxone (2.42 g, 3.945 mmol) at 0 °C under argon. The resulting mixture was stirred at 0 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was monitored by LCMS. The reaction was quenched with NaHSO solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the desired product, 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 (360 mg, 84% yield) as a yellow solid. MS: m / z = 538.9 (M+H+, ESI+).

[0352] Step 2: tert-butyl (3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Intermediate-2 of Example 16)

[0353] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (137 mg, 0.863 mmol) dissolved in THF (3 mL) was added NaH (46 mg, 1.15 mmol) at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 0.5 h. 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) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction was quenched with NH4Cl (20 mL) solution at 0 °C. The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with MeOH / DCM = 1:10 to give the desired product, tert-butyl (3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (290 mg, 70% yield) as a yellow solid. MS: m / z = 618.2 (M+H+, ESI+)

[0354] Step 3: 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-3 of Example 16)

[0355] tert-Butyl(3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridine-2- To a solution of 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (68 mg, 0.194 mmol), RuPhos-Pd-G3 (48 mg, 0.058 mmol), and K3PO4 (124 mg, 0.582 mmol) were added. The mixture was stirred at 100 °C under an argon atmosphere for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H2O (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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 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-pyrrolidin-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, 53% yield) as a yellow solid. MS: m / z = 706.2 (M+H+, ESI+).

[0356] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol (Example 16)

[0357] To a solution of 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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) dissolved in ACN (2 mL) was added HCl / dioxane (2 mL, 2.040 mmol). The mixture was stirred under an argon atmosphere at 25° C. for 2 hours. The reaction was monitored by LCMS. LCMS confirmed the presence of the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC using the following conditions. Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 15-23%; retention time: 7.5-9.3 min out of 16 min to give the desired product, Example 16 (21.89 mg, 29% yield), as a white solid. MS: m / z = 662.0 (M+H+, ESI+).

[0358] 1 H NMR (400 MHz, DMSO-d6) 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).

[0359] 17. Synthesis reaction scheme for Example 17

[0360] [ka]

[0361] Experimental Procedure for Example 17: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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

[0362] Step 1: 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-1 of Example 17)

[0363] To a solution of ((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (250 mg, 0.32 mmol) dissolved in THF (1 mL) was added NaH (25 mg, 0.63 mmol) at 0° C. The reaction mixture was stirred under N at 0° C. for 30 minutes, 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine, Intermediate-6SM1 of Example 12 (250 mg, 0.32 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature under N for 2 hours. The reaction mixture was quenched with concentrated NH4Cl (aqueous, 5 mL), and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 10:1 elution) 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-pyrrolidin-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+)

[0364] Step 2: 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 17)

[0365] To a solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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 N for 2 h. The reaction mixture was treated 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 NaSO(s). 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-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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, 121%) as a yellow solid. MS: m / z = 724.2 (M+H+, ESI+).

[0366] Step 3: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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 (Intermediate-3 of Example 17)

[0367] To a solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N 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-pyrrolidin-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, 106%) as a yellow solid. MS: m / z = 680.2 (M+H+, ESI+).

[0368] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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 (Example 17)

[0369] To a solution of 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-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 under H at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was concentrated and purified by Prep-HPLC (Waters 2767 / Qda). Column: SunFire C18, 19*250 mm, 10 μm; Mobile phase A: 0.1% FA / HO, B: ACN; Flow rate: 20 mL / min; Gradient: 16-26%; Retention time: 8.7-10.2 min of 16 min. Purification gave Example 17 (26.31 mg, 19%) as a pale yellow solid. MS: m / z = 684.0 (M+H+, ESI+).

[0370] 1 H NMR (400 MHz, DMSO-d6) 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).

[0371] 18. Synthesis reaction scheme for Example 18

[0372] [ka]

[0373] Experimental procedure for 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

[0374] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-1 of Example 18)

[0375] To a slurry of NaH (60%) (20 mg, 0.51 mmol) in THF (1 mL) was added a solution of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (101 mg, 0.76 mmol) in THF (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, and then 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, Intermediate-6 of Example 12 (200 mg, 0.25 mmol) in THF (1 mL) was added to the mixture. The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with concentrated NH4Cl (aqueous, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4(s). 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-10H-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+).

[0376] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 18)

[0377] 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 N for 2 hours. The reaction mixture was treated with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL × 3) and dried over NaSO(s). 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-10H-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+).

[0378] 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)

[0379] 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 and 4 M HCl in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature under N for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; retention time: 7.3-9.3 min of 16 min to give the desired product Example 18 (7.28 mg, 18%) as a white solid. MS: m / z = 642.1 (M+H+, ESI+).

[0380] 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).

[0381] 19. Synthesis reaction scheme for Example 19

[0382] [ka]

[0383] Experimental Procedure for Example 19: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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

[0384] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-1 of Example 19)

[0385] 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 Intermediate-4 from Example 12 (1.0 g, 1.972 mmol) dissolved in dioxane (12 mL) and HO (4 mL) was added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (715 mg, 1.972 mmol), RuPhos-Pd-G (495 mg, 0.592 mmol), and KPO (1.25 g, 5.916 mmol). The mixture was stirred at 100° C. under an argon atmosphere for 2 hours. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction mixture was diluted with HO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 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, 49% yield) as a yellow solid. MS: m / z = 605.1 (M+H+, ESI+)

[0386] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-2 of Example 19)

[0387] 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) dissolved in ACN (3 mL) and HO (1 mL) was added oxone (1.52 g, 5.481 mmol) at 0 °C under argon. The resulting mixture was stirred at 0 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was monitored by LCMS. The reaction was quenched with NaHSO solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (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 NaSO. 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 compound) as a yellow solid. MS: m / z = 637.1 (M+H+, ESI+).

[0388] Step 3: 3-(1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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 (Intermediate-3 of Example 19)

[0389] To a solution of (2,6-dimethylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (66 mg, 0.401 mmol) dissolved in THF (2 mL) was added NaH (21 mg, 0.534 mmol) under argon atmosphere at 0° C. The mixture was stirred at 0° C. for 0.5 hours. 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) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction was quenched with NH4Cl (60 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 30 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 give a residue. The residue was purified by column chromatography on silica gel eluting with MeOH / DCM = 1:20 to give the desired product, 3-(1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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 (90 mg, 46% yield) as a yellow solid. MS: m / z = 722.2 (M+H+, ESI+)

[0390] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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 (Example 19)

[0391] To a solution of 3-(1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolidin-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) dissolved in ACN (2 mL) was added HCl / dioxane (1.8 mL, 1.745 mmol). The mixture was stirred under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC under the following conditions: Prep-HPLC (Waters 2767 column: Xbridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 55-55%; retention time: 9.2-10.8 min out of 16 min) gave the desired product Example 19 (17.98 mg, 27% yield) in the form of a yellow solid. MS: m / z = 678.0 (M+H+, ESI+).

[0392] 1H NMR (400 MHz, DMSO-d6) 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).

[0393] 20. Synthesis reaction scheme for Example 20

[0394] [ka]

[0395] Experimental Procedure for Example 20: 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0396] Step 1: tert-butyl (Z)-(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (Intermediate-2 of Example 20)

[0397] To a solution of tert-butyl (2-acetylphenyl)carbamate, Intermediate-1 from Example 20 (11 g, 46.81 mmol) dissolved 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 h. Upon completion, water (100 mL) was added to the reaction mixture and extracted with EA (100 mL). The organic layer was filtered, concentrated, and dried over Na2SO4. The residue was purified by silica gel chromatography eluting with PE / EA = 2:1 to give tert-butyl (Z)-(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (5.3 g, 40%) as a colorless oil. MS: m / z = 279.0 (M+H+, ESI+).

[0398] Step 2: tert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (Intermediate-3 of Example 20)

[0399] To a solution of tert-butyl (Z)-(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 h. 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%) in the form of a colorless oil. MS: m / z = 281.0 (M+H+, ESI+).

[0400] Step 3: 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 (Intermediate-4 of Example 20)

[0401] To a solution of tert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (1.6 g, 5.70 mmol) dissolved in THF (5 mL) was added NaH (685 mg, 17.14 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 20 min, and then a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.6 g, 5.70 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature under N for 2 h. The reaction mixture was quenched with concentrated NH Cl (aqueous, 10 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na SO (s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA=3:1 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+).

[0402] Step 4: 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 (Intermediate-5 of Example 20)

[0403] 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) dissolved in DCM (20 mL) was added BOPCl (3.2 g, 12.59 mmol) and DIEA (4.9 g, 37.79 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. The reaction mixture was diluted with DCM (40 mL). The organic phase was washed with brine (40 mL) and dried over NaSO(s). 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (1.4 g, 65%) as a white solid. MS: m / z = 506.0 (M+H+, ESI+).

[0404] Step 5: tert-butyl (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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Intermediate-6 of Example 20)

[0405] 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) dissolved in dioxane (7 mL) / HO (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), KPO (890 mg, 4.16 mmol), and RuPhos-Pd-G (116 mg, 0.14 mmol). The reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA=3:1 elution) to give the desired product, tert-butyl (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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (750 mg, 63%) as a yellow solid. MS: m / z = 856.1 (M+H+, ESI+).

[0406] Step 6: 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 (Intermediate-7 of Example 20)

[0407] tert-Butyl (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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate tert-butyl (2-(1 To a solution of -(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)ethyl)phenyl)carbamate (650 mg, 0.76 mmol) was added oxone (2.33 g, 3.79 mmol) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with concentrated NaHSO (aqueous, 20 mL), extracted with EA (10 mL), and dried over NaSO. 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-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (670 mg, crude compound) as a yellow solid. MS: m / z = 872.3 (M+H+, ESI+).

[0408] Step 7: tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Intermediate-8 of Example 20)

[0409] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (167 mg, 1.047 mmol) dissolved in THF (7 mL) was added NaH (56 mg, 1.396 mmol) under an argon atmosphere 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-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (620 mg, 0.698 mmol) under argon at 0° C. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was monitored by LCMS. LCMS detected the desired product. The reaction was quenched with NH4Cl (60 mL) solution 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product, tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (600 mg, crude compound) as a yellow solid. MS: m / z = 967.6 (M+H+, ESI+).

[0410] Step 8: tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Intermediate-9 of Example 20)

[0411] 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-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (600 mg, 0.624 mmol) dissolved in DMF (1 mL) was added CsF (948 mg, 6.240 mmol). The mixture was stirred under argon at 25 °C for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was diluted with HO (80 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (120 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the desired product, tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (150 mg, 29% yield) as a yellow solid. MS: m / z = 811.5 (M+H+, ESI+).

[0412] Step 9: 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 20)

[0413] To a solution of tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (50 mg, 0.062 mmol) dissolved in ACN (2 mL) was added HCl / dioxane (1.2 mL, 1.110 mmol). The mixture was stirred under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC under the following conditions: Prep-HPLC (Waters 2767 column: Xbridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 55-55%; retention time: 9.2-10.8 min out of 16 min) to give the desired product, Example 20 (8.15 mg, 19% yield) as a white solid. MS: m / z = 667.2 (M+H+, ESI+).

[0414] 1H NMR (400 MHz, DMSO-d6) 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).

[0415] 21. Synthesis reaction scheme of Example 21

[0416] [ka]

[0417] Experimental Procedure for Example 21: 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0418] Step 1: 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 21)

[0419] To a solution of 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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) dissolved in MeOH (2 mL) was added Pd / C (15 mg) under H2 at 25 °C. The mixture was stirred under H2 at 25 °C 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 give the residue. The residue was purified by prep-HPLC under the following conditions. Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 13-21%; retention time: 9.8-12.2 min or 17 min to give the desired product, Example 21 (21.45 mg, 28% yield), as a white solid. MS: m / z = 671.2 (M+H+, ESI+).

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.14 (s, 0.23H, FA), 7.75 (d, 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).

[0421] 22. Synthesis reaction scheme for Example 22

[0422] [ka]

[0423] Experimental procedure for Example 22: 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-ethyl-6-fluoronaphthalen-2-ol

[0424] Step 1: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 22)

[0425] 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) dissolved in MeOH (2 mL) was added Pd / C (5 mg) under H at 25 °C. The mixture was stirred under H at 25 °C 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 give a residue. The residue was purified by preparative HPLC using the following conditions: Preparative HPLC (Waters 2767 / Qda) Column: SunFire C18, 19*250 mm, 10 μm; Mobile phase A: 0.1% FA / HO, B: ACN; Flow rate: 20 mL / min; Gradient: 13-21%; Retention time: 9.8-12.2 min or 17 min to give the desired product, Example 22 (16.37 mg, 40% yield) as a white solid. MS: m / z = 646.0 (M+H+, ESI+).

[0426] 1 H NMR (400 MHz, DMSO-d6) 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).

[0427] 23. Synthesis reaction scheme of Example 23

[0428] [ka]

[0429] Experimental procedure for Example 23: 4-(10-(1-(2-amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0430] Step 1: 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (Intermediate-2 of Example 23)

[0431] 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(PPh3)Cl2 (1.87 g, 2.66 mmol). The solution was purged with N2 three times and then stirred under N2 at 100 °C for 4 h. The reaction 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 compound) as a yellow oil. MS: m / z = 179.0 (M+H+, ESI+).

[0432] Step 2: 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (Intermediate-3 of Example 23)

[0433] To a mixture of 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (8.8 g, 49.44 mmol) in DCM (45 mL) was slowly added dropwise 4 M HCl / dioxane (45 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in HO (40 mL). After adjusting the pH to 8 with NaCO solution, 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 (petroleum ether / ethyl acetate = 5:1) to give the desired product, 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (4.08 g, 55% yield), as a yellow solid. MS: m / z = 151.0 (M+H+, ESI+).

[0434] Step 3: tert-butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (Intermediate-4 of Example 23)

[0435] To a mixture of 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (4.08 g, 27.17 mmol) dissolved in t-BuOH (40 mL) was added (Boc)2O (12.4 mL, 54.07 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1) to give the desired product, tert-butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (4.06 g, 60% yield) as a yellow solid. MS: m / z = 251.1 (M+H+, ESI+).

[0436] Step 4: tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamate (Intermediate-5 of Example 23)

[0437] 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 was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA=1:3 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+).

[0438] Step 5: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (Intermediate-6 of Example 23)

[0439] To a solution of tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamate (2.3 g, 7.84 mmol) in MeOH (20 mL) was added NaBH (890 mg, 23.54 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (DCM / MeOH = 20:1 elution) to give the desired product, tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (2.2 g, 95%) as a yellow solid. MS: m / z = 296.2 (M+H+, ESI+).

[0440] Step 6: 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 (Intermediate-7 of Example 23)

[0441] To a solution of tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1 g, 3.39 mmol) dissolved in THF (10 mL) was added NaH (406 mg, 10.17 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 30 min, and then a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (949 mg, 3.39 mmol) dissolved in THF (10 mL) was added dropwise to the mixture. The reaction mixture was stirred at room temperature under N for 2 h. The reaction mixture was quenched with concentrated NH Cl (aqueous, 20 mL), and the solution was extracted with EA (30 mL). The organic phase was washed with brine (20 mL) and dried over Na SO (s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA=1:9 to give the crude desired compound 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+).

[0442] Step 7: 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 (Intermediate-8 of Example 23)

[0443] 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) dissolved in DCM (15 mL) was added BOPCl (1.8 g, 7.23 mmol) and DIEA (2.8 g, 21.71 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL) and dried over NaSO(s). 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+).

[0444] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Intermediate-9 of Example 23)

[0445] 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) dissolved in dioxane (5 mL) / HO (0.5 mL) was 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), KPO (610 mg, 2.88 mmol), and RuPhos-Pd-G (241 mg, 0.29 mmol). The reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH=50:1 elution) 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)-5-methylpyridin-2-amine (175 mg, 29%) as a yellow solid. MS: m / z = 619.4 (M+H+, ESI+).

[0446] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Intermediate-10 of Example 23)

[0447] 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) dissolved in ACN (3 mL) / HO (1 mL) was added oxone (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 (aqueous, 5 mL), extracted with EA (5 mL), and dried over NaSO. 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 compound) as a yellow solid. MS: m / z = 651.3 (M+H+, ESI+).

[0448] Step 10: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Intermediate-11 of Example 23)

[0449] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (92 mg, 0.58 mmol) dissolved in THF (1 mL) was added NaH (15 mg, 0.38 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 30 min, and then 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) dissolved in THF (1 mL) was added dropwise to the mixture. The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was quenched with concentrated NH4Cl (aqueous, 5 mL) and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL) and dried over Na2SO4(s) to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 compound) as a yellow solid. MS: m / z = 730.4 (M+H+, ESI+).

[0450] Step 11: 4-(10-(1-(2-amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Example 23)

[0451] To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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) dissolved in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.05% NH3H2O / H2O, B: ACN; flow rate: 20 mL / min; gradient: 47%-47%; retention time: 9.2-11.2 min out of 16 min) to give the desired product Example 23 (3.82 mg, 7%) as a white solid. MS: m / z = 686.5 (M+H+, ESI+).

[0452] 1 H NMR (400 MHz, MeOD-d4) 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).

[0453] 24. Synthesis reaction scheme of Example 24

[0454] [ka]

[0455] Experimental Procedure for 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

[0456] 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 (Intermediate-1 of Example 24)

[0457] To a solution of 4-(hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile (44 mg, 0.306 mmol) dissolved in THF (2 mL) was added NaH (17 mg, 0.408 mmol) at 0 °C under an argon atmosphere. 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) at 0 °C under argon. The resulting mixture was further stirred at 0 °C for 1 h. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction was quenched with NH4Cl solution (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 30 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 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, 49% yield) as a yellow solid. MS: m / z = 698.4 (M+H+, ESI+).

[0458] 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)

[0459] 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) dissolved in ACN (2 mL) was added HCl / dioxane (1.8 mL, 1.806 mmol). The mixture was stirred under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC under the following conditions: Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 26-36%; retention time: 8.9-9.9 min out of 16 min to give the desired product, Example 24 (17.05 mg, 25% yield), as a white solid. MS: m / z = 654.2 (M+H+, ESI+).

[0460] 1 H NMR (400 MHz, DMSO-d6) 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).

[0461] 25. Synthesis reaction scheme for Example 25

[0462] [ka]

[0463] Experimental Procedure for Example 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]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0464] Step 1: 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 (Intermediate-1 of Example 25)

[0465] To a solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (48 mg, 0.282 mmol) dissolved in THF (1 mL) was added NaH (18 mg, 0.372 mmol) at 0° C. under an argon atmosphere. 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, intermediate-2 of Example 19 (120 mg, 0.186 mmol) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was monitored by LCMS. LCMS confirmed the presence of the desired product. The reaction was quenched with NH4Cl (60 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 40 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 give the desired product, 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 (60 mg, 38% yield) as a yellow solid. MS: m / z = 714.5 (M+H+, ESI+)

[0466] 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]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 25)

[0467] 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 under argon at 25 °C for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC using the following conditions. Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 15-23%; retention time: 7.7-9.1 min out of 16 min to give the desired product, Example 25 (10.38 mg, 22% yield, FA salt) as a white solid. MS: m / z = 670.2 (M+H+, ESI+).

[0468] Step 3: Example 25 - Free form

[0469] 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) dissolved in DCM (10 mL) was washed with concentrated NaHCO3 (aqueous, 5 mL x 3). The organic phase was concentrated to give the desired product Example 25-free form (10.16 mg, 51% yield) as a white solid. MS: m / z = 670.2 (M+H+, ESI+).

[0470] 1 H NMR (400 MHz, DMSO-d6) 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).

[0471] 26. Synthesis reaction scheme of Example 26

[0472] [ka]

[0473] Experimental procedure for 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

[0474] Step 1: Methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (Intermediate-1 of Example 26)

[0475] To a solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (1.5 g, 10.353 mmol) in DCM (20 mL) was added (COCl) (1.72 g, 13.551 mmol) and DMF (12 mg, 0.080 mmol) under an argon atmosphere at 0 °C. The resulting mixture was stirred under argon at 25 °C 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) under an argon atmosphere at 25 °C, the residue was added. The resulting mixture was stirred at 25 °C for 16 h under an argon atmosphere. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give the desired product, methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (1.5 g, crude compound) as a yellow solid. MS: m / z = 216.1 (M+H+, ESI+).

[0476] Step 2: (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (Intermediate-2 of Example 26)

[0477] To a solution of methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (1.5 g, 6.970 mmol) in THF (20 mL) was added LAH (14 mL, 13.939 mmol) at 0 °C under N 2 . The mixture was stirred at 25 °C for 3 h. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction was quenched by adding HO (0.14 mL), 15% NaOH solution (0.14 mL), and HO (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, 58% yield) as a colorless liquid. MS: m / z = 174.3 (M+H+, ESI+)

[0478] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-3 of Example 26)

[0479] To a solution of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (61 mg, 0.353 mmol) dissolved in THF (4 mL) was added NaH (28 mg, 0.706 mmol) at 0° C. under an argon atmosphere. 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) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was monitored by LCMS. LCMS indicated the desired product. The reaction was quenched with NH4Cl solution (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 30 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 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 compound) as a yellow solid. MS: m / z = 730.4 (M+H+, ESI+).

[0480] 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]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 26)

[0481] 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 under argon at 25° C. for 1 hour. The reaction was monitored by LCMS. LCMS indicated the desired product. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC under the following conditions: Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; retention time: 8.9-9.8 min out of 16 min to give the desired product, Example 26 (3.10 mg, 2% yield), as a white solid. MS: m / z = 686.2 (M+H+, ESI+).

[0482] 1H NMR (400 MHz, DMSO-d6) 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).

[0483] 27. Synthesis reaction scheme for Example 27

[0484] [ka]

[0485] Experimental procedure for 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

[0486] Step 1: (S)-Pyrrolidin-2-ylmethanol hydrochloride (Intermediate-2 of Example 27)

[0487] To a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.84 mmol), 4 M HCl / dioxane (62 mL) was added dropwise slowly at 25° C. The reaction mixture was stirred at 25° C. for 16 h. 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+).

[0488] Step 2: (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (Intermediate-3 of Example 27)

[0489] To an ice-cooled solution of K2CO3 (7.1 g, 51.16 mmol) and (S)-pyrrolidin-2-ylmethanol hydrochloride (3.2 mg, 23.25 mmol) in ACN (30 mL) 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), and the resulting mixture was extracted with EA (40 mL), after which 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+).

[0490] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate-4 of Example 27)

[0491] To a solution of (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (174 mg, 1.05 mmol) dissolved in THF (2 mL) was added NaH (28 mg, 0.70 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 30 min, and then 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) dissolved in THF (2 mL) was added dropwise to the mixture. The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was quenched with concentrated NH Cl (aqueous, 5 mL), and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL) and dried over Na2SO4(s) 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-10H-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+).

[0492] 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]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 27)

[0493] 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-10H-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 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Waters 2767 / Qda, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 18-28%; retention time: 7.9-10.8 min over 16 min) and Prep-HPLC (Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.05% NH3HO / HO, B: ACN; flow rate: 20 mL / min; gradient: 53%-53%; retention time: 9.4-11.4 min over 16 min) to give the desired product Example 27 (14.55 mg, 17%) as a white solid. MS: m / z = 678.4 (M+H+, ESI+)

[0494] 1H NMR (400 MHz, DMSO-d6) 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).

[0495] 28. Synthesis reaction scheme for Example 28

[0496] [ka]

[0497] Experimental Procedure for Example 28: 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0498] Step 1: 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate-2 of Example 28)

[0499] To a solution of 2-(methylamino)ethan-1-ol (3 g, 10.71 mmol) dissolved in THF (30 mL) was added NaH (1.28 g, 32.13 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 30 min, and then a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (804 mg, 10.71 mmol) dissolved in THF (30 mL) was added dropwise. The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was quenched with concentrated NH Cl (aqueous, 30 mL), and the solution was extracted with EA (30 mL). After filtration and washing with EA, 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+).

[0500] Step 2: 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Intermediate-3 of Example 28)

[0501] 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) and DIEA (6.9 g, 53.65 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL) and dried over NaSO(s). 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+).

[0502] 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 (Intermediate-4 of Example 28)

[0503] 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) dissolved in dioxane (3 mL) / HO (0.3 mL) was added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 mg, 0.73 mmol), KPO (465 mg, 2.19 mmol), and RuPhos-Pd-G (61 mg, 0.07 mmol). The reaction mixture was stirred at 100 °C under N 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+).

[0504] 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-tetraazacyclohepta[de]naphthalene (Intermediate-5 of Example 28)

[0505] 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) dissolved in THF (3 mL) / HO (1 mL) was added oxone (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 (aqueous, 5 mL), extracted with EA (5 mL), and dried over NaSO. 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+).

[0506] Step 5: 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Intermediate-6 of Example 28)

[0507] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (50 mg, 0.32 mmol) dissolved in THF (1 mL) was added NaH (8 mg, 0.21 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 30 min, and then 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) dissolved in THF (1 mL) was added dropwise. The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was quenched with concentrated NH Cl (aqueous, 5 mL), and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL) and dried over Na2SO4(s) to give 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (63 mg, 97%) as a yellow solid. MS: m / z = 610.5 (M+H+, ESI+).

[0508] Step 6: 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Example 28)

[0509] To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda) column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 23-31%; retention time: 7.9-9.6 min of 16 min to give Example 28 (5.78 mg, 9%) as a white solid. MS: m / z = 566.3 (M+H+, ESI+).

[0510] 1 H NMR (400 MHz, DMSO-d6) 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).

[0511] 29. Synthesis Reaction Scheme of Example 29 (Examples 29a and 29b)

[0512] [ka]

[0513] Experimental Procedure for Example 29 (Examples 29a and 29b)

[0514] Step 1: 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 (Intermediate-1 of Example 29)

[0515] To a solution of tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (824 mg, 2.928 mmol) dissolved in THF (10 mL) was added NaH (60% in oil, 351 mg, 8.793 mmol) at 0 °C under argon atmosphere. 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 further stirred at 0 °C for 1 h. The reaction was quenched by adding NH Cl (30 mL) at 0 °C. The solution was then extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the desired product 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, 58% yield) as a yellow solid. MS: m / z = 604.0 (M+H+, ESI+).

[0516] Step 2: tert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (Intermediate-2 of Example 29)

[0517] 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) dissolved in THF (20 mL) was added DIEA (2.43 g, 18.810 mmol) at 0 °C under argon atmosphere. The mixture was stirred at 0 °C for 0.5 h. To the above mixture was added BopCl (1.60 g, 6.270 mmol) under argon at 0 °C. The resulting mixture was further stirred at 25 °C under argon for 16 h. The reaction mixture was diluted with HO (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 NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether=82%) to give the desired product tert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (840 mg, 68% yield) as a yellow solid. MS: m / z = 586.1 (M+H+, ESI+).

[0518] Step 3: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate-3 of Example 29)

[0519] tert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (240 mg, 0.410 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl)pyridin-2-yl)carbamate ( ... A solution of (ethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (332 mg, 0.821 mmol), Pd(DPEPhos)Cl (30 mg, 0.041 mmol), KF (48 mg, 0.821 mmol), and KPO (261 mg, 1.230 mmol) was stirred at 105 °C under argon for 3 h. The reaction mixture was diluted with HO (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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with petroleum ether (75%) and ethyl acetate to give the desired product tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (154 mg, 53% yield) as a yellow solid. MS: m / z = 696.2 (M+H+, ESI+).

[0520] Step 4: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfinyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate-4 of Example 29)

[0521] 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]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (130 mg, 0.187 mmol) dissolved in THF (3 mL) and HO (1 mL) was added oxone (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 NaHSO solution at 0 °C. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired product, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfinyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (90 mg, crude compound) as a yellow solid. MS: m / z = 712.3 (M+H+, ESI+). The crude material was used directly in the next step.

[0522] Step 5: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate-5 of Example 29)

[0523] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (30 mg, 0.190 mmol) dissolved in THF (2 mL) was added NaH (60% in oil, 10 mg, 0.252 mmol) at 0° C. under an argon atmosphere. 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-(methylsulfinyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (90 mg, 0.126 mmol) at 0° C. under argon. The resulting mixture was further stirred at 0° C. for 1 h. The reaction was terminated by the addition of NH4Cl (4 mL) at 0 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (30 mL), and the solution was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography from silica gel eluting with dichloromethane (9%) in methanol to give the desired product, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (30 mg, 29% yield) as a yellow solid. MS: m / z = 807.4 (M+H+, ESI+).

[0524] Step 6: Examples 29a and 29b

[0525] [ka]

[0526] A solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (70 mg, 0.097 mmol) dissolved in HCl / dioxane (3 mL) was stirred at 25° C. for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / HO, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; retention time: 4.6-6 min out of 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.

[0527] Example 29a: (4R)-2-amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0528] MS: m / z = 707.1 (M+H+, ESI+)

[0529] 1H 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).

[0530] Example 29b: (4S)-2-amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0531] MS: m / z = 707.1 (M+H+, ESI+)

[0532] 1H NMR (400 MHz, DMSO-d6) 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).

[0533] 30. Synthesis reaction scheme of Example 30

[0534] [ka]

[0535] Experimental Procedure for Example 30: 4-(10-(1-amino-5,6,7,8-tetrahydroisoquinolin-8-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

[0536] Step 1: 8-Oxo-5,6,7,8-tetrahydroisoquinoline 2-oxide (Intermediate-2 of Example 30)

[0537] To a solution of 6,7-dihydroisoquinolin-8(5H)-one, Intermediate-1 of Example 30 (6.7 g, 45.58 mmol) dissolved in DCM (100 mL) was added m-CPBA (13.4 g, 77.48 mmol). The reaction mixture was stirred under N at 25 °C for 16 h. The reaction mixture was quenched with concentrated NaHSO (aqueous, 60 mL), and the mixture was 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 eluting with DCM / MeOH = 10:1 to give the desired product, 8-oxo-5,6,7,8-tetrahydroisoquinoline 2-oxide (8 g, 89%) as a pale yellow solid. MS: m / z = 164.1 (M+H+, ESI+).

[0538] Step 2: 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (Intermediate-3 of Example 30)

[0539] To a solution of 8-oxo-5,6,7,8-tetrahydroisoquinoline 2-oxide (7 g, 42.94 mmol) in DCE (70 mL) was added BnNH (11.5 g, 107.36 mmol), TEA (13 g, 128.83 mmol), and PyBrOP (26 g, 55.83 mmol). The reaction mixture was stirred at 25 °C under N for 4 h. The reaction mixture was diluted 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 eluting with 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+).

[0540] Step 3: (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-ylidene)amino)ethan-1-ol (Intermediate-4 of Example 30)

[0541] To a solution of 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (1.0 g, 3.968 mmol) dissolved in MeOH (10 mL) / DMF (10 mL) was added 2-aminoethan-1-ol (720 mg, 11.905 mmol), TEA (1.2 g, 11.905 mmol), and AcOH (240 mg, 3.968 mmol). The reaction mixture was stirred at 60° C. for 2 hours, and then NaBHCN (740 mg, 11.905 mmol) was added to the 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 x 3). The organic phase was washed with brine (100 mL), dried over NaSO(s), and concentrated to give crude (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-ylidene)amino)ethan-1-ol (1.0 g, 100%) as a pale yellow oil. MS: m / z = 296.0 (M+H+, ESI+).

[0542] Step 4: 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (Intermediate-5 of Example 30)

[0543] To a solution of (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-ylidene)amino)ethan-1-ol (1.5 g, 5.078 mmol) dissolved in MeOH (10 mL) was added NaBH4 (576 mg, 15.234 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was concentrated and purified by silica gel chromatography eluting with 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, 29% yield) in the form of a colorless oil. MS: m / z = 298.0 (M+H+, ESI+).

[0544] 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 (Intermediate-6 of Example 30)

[0545] To a solution of 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (400 mg, 1.342 mmol) dissolved in THF (2 mL) was added NaH (60% in oil, 215 mg, 5.346 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 30 min, and then 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (374 mg, 1.342 mmol) was added to the solution. The reaction mixture was stirred at 25 °C for 16 h under N. The reaction mixture was quenched with concentrated NH Cl (aq) (5 mL), and the solution was extracted with EA (10 mL × 3). The organic phase was washed with brine (20 mL) and dried over Na SO (s). 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 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) in the form of a colorless oil. MS: m / z = 541.1 (M+H+, ESI+).

[0546] Step 6: 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 (Intermediate-7 of Example 30)

[0547] 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) was added BOPCl (262 mg, 1.028 mmol) and DIEA (398 mg, 3.087 mmol). The reaction mixture was stirred at 25 °C under N for 16 h. The reaction mixture was diluted with DCM (10 mL). The organic phase was washed with brine (20 mL) and dried over NaSO(s). 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, 50% yield) in the form of a colorless oil. MS: m / z = 523.1 (M+H+, ESI+).

[0548] Step 7: 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 (Intermediate-8 of Example 30)

[0549] 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) dissolved in TFA (2.5 mL) was added CFSOH (0.5 mL). The reaction mixture was stirred at 25 °C under N for 5 h. The reaction mixture was quenched with concentrated NaCO (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 NaSO(s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 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, 67% yield) as a yellow solid. MS: m / z = 433.0 (M+H+, ESI+).

[0550] 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-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (Intermediate-9 of Example 30)

[0551] 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) dissolved in dioxane (3 mL) / HO (0.3 mL) was 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), KPO (60 mg, 0.276 mmol), and RuPhos-Pd-G (16 mg, 0.0184 mmol). The reaction mixture was stirred under N at 100° C. for 2 hours. 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, 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, 27% yield) as a yellow solid. MS: m / z = 783.3 (M+H+, ESI+).

[0552] 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-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (Intermediate-10 of Example 30)

[0553] 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) dissolved in ACN (1 mL) / HO (1 mL) was added oxone (78 mg, 0.128 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N for 2 h. The reaction mixture was quenched with concentrated NaHSO (aqueous, 5 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over NaSO(s). 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-10H-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+).

[0554] Step 10: 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-11 of Example 30)

[0555] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (14 mg, 0.090 mmol) dissolved in THF (1 mL) was added NaH (60% in oil, 2 mg, 0.128 mmol) at 0 °C. The reaction mixture was stirred under N at 0 °C for 20 min, and then 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 mixture. The reaction mixture was stirred at room temperature under N for 2 h. The reaction mixture was quenched with concentrated NH4Cl (aqueous, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4(s). 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-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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, 60% yield) as a yellow solid. MS: m / z = 849.3 (M+H+, ESI+).

[0556] Step 11: 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 (Intermediate-12 of Example 30)

[0557] To a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 N for 2 h. The reaction mixture was treated with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL × 3) and dried over NaSO(s). 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-pyrrolidin-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, 100% yield) as a colorless oil. MS: m / z = 738.2 (M+H+, ESI+).

[0558] Step 12: 4-(10-(1-amino-5,6,7,8-tetrahydroisoquinolin-8-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 30)

[0559] To a solution of 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: SunFire C18, 19*250 mm, 10 μm; Mobile phase A: 0.1% NH4HCO3 / H2O, B: ACN; Gradient: 5%-95% B; Flow rate: 50 mL / min) to give the desired product, Example 30 (1.07 mg, 11% yield) as a white solid. MS: m / z = 694.4 (M+H+, ESI+).

[0560] 31. Synthesis reaction scheme of Example 36

[0561] [ka]

[0562] Experimental Procedure for Example 36: 2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0563] Step 1: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methyl-enetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate-1 of Example 36)

[0564] To a solution of (S)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (13 mg, 0.082 mmol) dissolved in THF (1 mL) was added NaH (60% in oil, 10 mg, 0.41 mmol) under argon at 0° C. The mixture was stirred under argon at 0° C. for 10 minutes. Then, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (60 mg, 0.082 mmol) was added to the mixture. The reaction mixture was stirred under argon at 0° C. and room temperature for 1 hour. The resulting mixture was treated with HO (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with dichloromethane:methanol (10:1) to give the desired product, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylene-tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, 75% yield) as a yellow solid. MS: m / z = 801.4 (M+H+, ESI+)

[0565] Step 2: 2-Amino - 4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 36)

[0566] To a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methyl-enetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, 0.062 mmol) dissolved in DCM (0.5 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 10 mmol NH4HCO3, B: ACN; flow rate: 20 mL / min; gradient: 57%-57%). Retention time: 5.6-7.1 min out of 16 min gave the desired product, Example 36a (1.34 mg, 3%) as a white solid; retention time: 9.5-11 min out of 16 min gave the desired product, Example 36b (6.06 mg, 14%) as a white solid.

[0567] Example 36a:

[0568] MS: m / z = 701.3 (M+H + , ESI+).

[0569] 11H NMR (400 MHz, DMSO-d6) 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).

[0570] Example 36b:

[0571] MS: m / z = 701.3 (M+H + , ESI+).

[0572] 1H NMR (400 MHz, DMSO-d6) 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, 7.0Hz, 1H), 4.13 - 3.97 (m, 2H), 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).

[0573] 32. Synthesis reaction scheme of Example 37

[0574] [ka]

[0575] Experimental Procedure for Example 37: 2-amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0576] Step 1: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate-1 of Example 37)

[0577] To a solution of ((7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (14 mg, 0.082 mmol) dissolved in THF (1 mL) was added NaH (10 mg, 0.41 mmol) under argon at 0° C. The mixture was stirred under argon at 0° C. for 10 minutes. Then, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (60 mg, 0.082 mmol) was added to the solution. The reaction mixture was stirred under argon at 0° C. and room temperature for 1 hour. The resulting mixture was treated with HO (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with dichloromethane:methanol (10:1) to give the desired product, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (40 mg, 60% yield) as a yellow solid. MS: m / z = 819.4 (M+H+, ESI+)

[0578] Step 2: 2-Amino - 4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 37)

[0579] To a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-methoxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (40 mg, 0.048 mmol) dissolved in DCM (0.5 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC under the following conditions: Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 μm; Mobile phase A: 0.1% FA / HO, B: ACN; Flow rate: 20 mL / min; Gradient: 19%-28%; Retention time: 7.9-9.7 min out of 16 min to give the desired product Example 37a (4.34 mg, 13%) as a white solid; Retention time: 11.6-12.9 min out of 16 min to give the desired product Example 37b (4.88 mg, 14%) as a white solid.

[0580] Example 37a:

[0581] MS: m / z = 719.4 (M+H+, ESI+)

[0582] 11H NMR (400 MHz, DMSO-d6) 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).

[0583] Example 37b:

[0584] MS: m / z = 719.4 (M+H+, ESI+)

[0585] 1 1H NMR (400 MHz, DMSO-d6) 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).

[0586] In a similar manner, the compounds of Examples 1 to 37 in Table 1 below were prepared using samples appropriate for the preparation of the compounds described in each example.

[0587] [Table 1] TIFF2025535294000063.tif255164TIFF2025535294000064.tif255164TIFF2025535294000065.tif255164TIFF202 5535294000066.tif252168TIFF2025535294000067.tif255168TIFF2025535294000068.tif255168TIFF20255352940 00069.tif255168TIFF2025535294000070.tif229168TIFF2025535294000071.tif255167TIFF2025535294000072.t if255167TIFF2025535294000073.tif255167TIFF2025535294000074.tif237168TIFF2025535294000075.tif255165 TIFF2025535294000076.tif255165TIFF2025535294000077.tif255165TIFF2025535294000078.tif255168TIFF202 5535294000079.tif255165TIFF2025535294000080.tif243168TIFF2025535294000081.tif255167TIFF20255352940 00082.tif255167TIFF2025535294000083.tif255167TIFF2025535294000084.tif255167TIFF2025535294000085.t if223168TIFF2025535294000086.tif247168TIFF2025535294000087.tif255166TIFF2025535294000088.tif180168

[0588] Test Example <Test Example 1: KRAS Nucleotide Exchange Assay> the purpose KRAS WT , KRAS G12D , KRAS G12V , KRAS G12C and KRAS G13D Evaluation of the inhibitory effects of compounds on SOS1-mediated nucleotide exchange activity of mutants

[0589] principle This assay monitors the SOS1-mediated exchange of unlabeled GDP bound to KRAS with fluorescently labeled GTP. Sensing is based on energy transfer between two fluorophores when they are in close proximity. The donor is a Tb cryptate-labeled anti-GST antibody, and the acceptor is DY-647P1 GTP.

[0590] Testing conditions and procedures material GST-tagged KRAS WT or mutant proteins (amino acids 2–169); SOS1 (amino acids 564-1049), Displayed as GTP (GTP-DY-647P1) Black buffer (20mM HEPES pH 7.4, 150mM NaCl, 5mM MgCl2, 1mM DTT, 0.05% BSA, 0.0025% NP40)

[0591] Exam Procedures 1. KRAS protein was diluted with assay buffer to 1.5 times the final concentration, then mixed with Tb cryptate anti-GST antibody and added in an amount of 10 μL to each assay well (KRAS WT , KRAS G12D and KRAS G12V All final concentrations were 20 nM). 2. The compounds were dissolved in DMSO and then diluted to 100 times the final concentration. 3. Compounds were dispensed into assay wells using an ECHO acoustic dispenser (Beckman) and gently mixed with the KRAS / Ab mixture, followed by incubation for 60 minutes. 4. SOS1 and labeled GTP were mixed and diluted to 3x the final concentration with assay buffer. 5 μL of the solution was added to assay wells to initiate the reaction (the final concentration of labeled GTP was 0.15 μM, and the final concentrations of SOS1 were 7.5 nM for WT, 12.5 nM for G12D, and 50 nM for G12V). Empty wells contained only assay buffer and labeled GTP. 5. The reaction was monitored using a Pherastar Plate Reader (BMG) with Ex / Em = (337 / 665; 337 / 620). 6. HTRF signals were analyzed approximately 25 minutes after the start of the reaction (for G12V, the reaction time was 60 minutes). 7. Nucleotide exchange activity is expressed as a percentage difference compared to the DMSO reaction value and is given as IC 50 Values ​​were calculated based on a four-parameter logistic equation in GraphPad 4.0 software.

[0592]

number

[0593] [Table 2]

[0594] <Test Example 2: KRAS NanoBRET Assay> the purpose Evaluation of NanoBRET target binding of compounds to KRAS (WT, G12D, or G12V) HEK293 cells

[0595] Testing conditions and procedures Compound production Test compounds were dissolved in 10 mM stocks, and reference compounds BI-2582 and MRTX1133 (MedChemExpress) were dissolved in DMSO at 10 mM and 1 mM stocks, respectively.

[0596] Cell culture NanoBRET KRAS (WT, G12D, or G12V)-NanoLuc Fusion vector and tracer K-2 were purchased from Promega, and the HEK293 cell line was purchased from ATCC. HEK293 cells were cultured in EMEM medium supplemented with 10% FBS and 100 μg / mL penicillin-streptomycin at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0597] Exam Procedures 1. HEK293 cells are transfected with NanoBRET KRAS (WT, G12D, or G12V)-NanoLuc fusion vectors. 2. Transformed cells were cultured in Opti-MEM without phenol red at a density of 2 x 10 5 Adjust the concentration to cells / mL and mix 20x K-2 tracer with the cells. 3. The cell and tracer mixture is dispensed into 384 wells, and the plate is placed in a 37°C, 5% CO2 incubator for 1 hour, and then left at room temperature for 15 minutes. 4. The substrate and test compound solution are applied to the 384 wells containing the cells and tracer, and the reaction is allowed to proceed at room temperature for 15 minutes. 5. Measurements are performed at the donor emission wavelength (460 nm) and the acceptor emission wavelength (600 nm) using an Envision 2104 plate reader. 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 subtracting the BRET ratio without tracer. 6. The BRET response is calculated as the BRET ratio when treated with DMSO and the BRET ratio when treated with the compound * 100. 7.IC 50 Values ​​are calculated based on a sigmoidal dose-response equation in the GraphPad Prism 4 program.

[0598] <Test Example 3: Cell proliferation assay> the purpose Cell viability assay of test compounds for 72 hours in AsPC-1 pancreatic cancer (KRAS G12D mutation) or SW480 colon cancer (KRAS G12V mutation) cells

[0599] Testing conditions and procedures material The reference compound, staurosporine, was purchased from Sigma-Aldrich (Saint Louis, MI), and CellTiter-Glo® Luminescent Cell Viability Assay Reagent (Cat. No. G9243) was purchased from Promega (Madison, WI). AsPC-1 and SW480 cell lines were purchased from American Type Culture Collection (Manassas, VA). AsPC-1 cells were cultured in RPMI-1640 (ATCC, Cat. No. 30-2001), and SW480 cells were cultured in DMEM (ATCC, Cat. No. 30-2002). Media supplemented with 10% FBS (Sigma-Aldrich, Cat. No. F2442) and 100 μg / mL penicillin-streptomycin (Sigma-Aldrich, Cat. No. P4333) was used. Cells were cultured at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0600] Exam Procedures 1. Test compounds and the reference compound staurosporine were dissolved in DMSO solution to prepare 20 mM (test compound) and 10 mM (reference compound, staurosporine) in a source plate, and then diluted 3-fold and 10-fold with DMSO. 2. In the source plate, 125 nL of 10-fold volume of test compound or 25 nL of 10-fold volume of reference compound was dispensed into wells of a 384-well culture plate (VWR, catalog number 82050-076) using an Echo 655. 3. 25 μL of culture medium containing 2000 AsPC-1 or SW480 cells was dispensed into each 384-well cell culture plate. 4. The cells were cultured with the compound for 72 hours at 37°C and 5% CO2. 5. 25 μL of CellTiter-Glo 2.0 reagent was added to each well of the plate. 6. The contents were mixed on an orbital shaker for 2 minutes, after which the luminescence signal was allowed to stabilize at room temperature for 15 minutes. 7. Luminescence signals were measured using an Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA), and the number of viable cells was determined by quantifying the ATP present in each culture medium. 8.IC 50 Values ​​were calculated based on the sigmoidal dose-response equation in the GraphPad Prism 4 program.

[0601] The test results are shown in Table 3.

[0602] [Table 3] TIFF2025535294000092.tif212163

[0603] Although the present invention has been particularly shown and described with reference to examples thereof, those skilled in the art will recognize that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. The illustrated embodiments are to be considered in an illustrative sense only and not for limiting purposes. Accordingly, the scope of the present invention is to be determined by the appended claims, not the following detailed description, and all variations within such scope are to be construed as being included within the present invention.

Claims

1. A compound selected from compounds of formula 1 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variations, tautomers, solvates, and pharmaceutically acceptable salts thereof: 【Chemical 1】 In chemical formula 1 X is N or CR １１ and R １ is R １Ａ phenyl substituted or unsubstituted with R １Ａ naphthyl substituted or unsubstituted by R １Ａ benzothiophenyl substituted or unsubstituted by Each R １Ａ is hydrogen, hydroxy, halogen, C １ -C ３ Haloalkyl, 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 【Chemistry 2】 and L is a bond or L Ａ substituted or unsubstituted C １ -C ３ alkylene; L Ａ is hydrogen, halogen, or C １ -C ３ is alkyl; W is R ６ substituted or unsubstituted C １ -C ３ Alkyl, R ６ a 3- to 10-membered monocyclic heterocycle substituted or unsubstituted by R ６ a substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; Each R ６ is hydrogen, halogen, C １ -C ３ Haloalkyl, 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, amino, CN, =CH ２ , oxo (=O), S(C １ -C ３ alkyl), SO ２ NH ２ , S.O. ２ NH (C １ -C ３ alkyl), SO ２ (C １ -C ３ alkyl), SO ２ (C １ -C ３ haloalkyl), and haloC １ -C ３ independently selected from: alkoxy; R ４ is hydrogen, R ４Ａ substituted or unsubstituted C １ -C ６ Haloalkyl, R ４Ａ substituted or unsubstituted C １ -C ６ Alkyl, R ４Ａ substituted or unsubstituted C ３ -C １０ Cycloalkyl, R ４Ａ substituted or unsubstituted C ５ -C ８ Aryl, R ４Ａ a 3- to 10-membered heterocycle substituted or unsubstituted by R ４Ａ is a 5-10 membered heteroaryl substituted or unsubstituted by Each R ４Ａ is hydrogen, CN, NR ９ R １０ , = O, OR ７ , S.R. ８ , S.O. ２ R ８ , C(O)N(R ７ ) ２ , C(O)R ７ , R ４Ｂ substituted or unsubstituted C １ -C ６ Haloalkyl, R ４Ｂ substituted or unsubstituted C １ -C ６ Alkyl, R ４Ｂ substituted or unsubstituted C ３ -C １０ Cycloalkyl, R ４Ｂ substituted or unsubstituted C ５ -C ８ Aryl, R ４Ｂ a substituted or unsubstituted 3- to 6-membered heterocycle and R ４Ｂ substituted or unsubstituted 5- to 9-membered heteroaryl; Here, R ４Ａ Two of them are R ４Ｂ substituted or unsubstituted C ３ -C １０ Cycloalkyl, R ４Ｂ substituted or unsubstituted C ５ -C ８ Aryl, R ４Ｂ a 3- to 10-membered heterocycle substituted or unsubstituted by R ４Ｂ forming a substituted or unsubstituted 5-10 membered heteroaryl; Each R ４Ｂ is hydrogen, halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, C ３ -C ６ Cycloalkyl, CN, NR ９ R １０ , =O,C １ -C ３ Alkoxy, HaloC １ -C ３ Alkoxy, hydroxy, SCH ３ , S.O. ２ NH ２ , S.O. ２ CH ３ , C(O)NH ２ , C(O)CH ３ , 3- to 6-membered heterocycle, C ５ -C ８ aryl, and 5- or 6-membered heteroaryl; Each R ５ is hydrogen, hydroxy, halogen, C １ -C ３ Haloalkyl and C １ -C ３ independently selected from alkyl; Each R ７ is hydrogen, amino, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, C ３ -C ６ independently selected from cycloalkyl and a 3- or 4-membered heterocycle; Each R ８ is hydrogen, amino and C １ -C ３ alkyl; R ９ and R １０ are each independently hydrogen, C １ -C ３ Alkyl, C ３ -C ６ Cycloalkyl, C(O)NH ２ , C(O)CH ３ and a 3- to 6-membered heterocycle; Each R １１ is hydrogen, hydroxy, halogen, C １ -C ３ Haloalkyl and C １ -C ３ independently selected from alkyl; n is an integer selected from 0 to 2; wherein the heterocycle or heteroaryl each contains 1 to 3 heteroatoms independently selected from N, O and S.

2. L is methylene; W is R ６ or a 3- to 10-membered monocyclic heterocycle substituted or unsubstituted by R ６ a substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; Each R ６ is a halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, CN, =CH ２ , = O, SCH ３ , S.O. ２ NH ２ , S.O. ２ NH (CH ３ ), SO ２ CH ３ and SO ２ CF ３ 2. The compound of claim 1, independently selected from:

3. L is methylene; Each W is independently R ６ substituted or unsubstituted 【Chemistry 3】 and Each R ６ is hydrogen, halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, CN, =CH ２ , = O, SCH ３ , S.O. ２ NH ２ , S.O. ２ NH (CH ３ ), SO ２ CH ３ and SO ２ CF ３ 2. The compound of claim 1, independently selected from:

4. R ４ is R ４Ａ substituted or unsubstituted C １ -C ３ is alkyl; Each R ４Ａ is hydrogen, halogen, CN, NH ２ , NH(C １ -C ３ alkyl), N(C １ -C ３ alkyl) ２ , = O, R ４Ｃ substituted or unsubstituted C ３ -C ６ Cycloalkyl, R ４Ｃ phenyl substituted or unsubstituted with R ４Ｃ pyridinyl substituted or unsubstituted by R ４Ｃ pyrimidinyl substituted or unsubstituted by R ４Ｃ and substituted or unsubstituted pyrazinyl; or where R ４Ａ two of which together form a 5-10 membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; Each R ４Ｃ is hydrogen, halogen, C １ -C ３ Alkyl, NH ２ , NH(C １ -C ３ alkyl), and N(C １ -C ３ alkyl) ２ 2. The compound of claim 1, independently selected from:

5. X is CR １１ and Each R １１ is hydrogen, halogen, C １ -C ３ Haloalkyl and C １ -C ３ alkyl; R １ is R １Ａ benzothiophenyl substituted or unsubstituted by Each R １Ａ is hydrogen, halogen, NH ２ , NH(C １ -C ３ alkyl), N(C １ -C ３ alkyl) ２ 2. The compound of claim 1, wherein the compound is independently selected from the group consisting of CN and CN.

6. R １ teeth, 【Chemistry 4】 and Hydrogen, hydroxy, halogen, C respectively １ -C ３ Alkyl, C ３ -C ６ substituted or unsubstituted with one or more substituents independently selected from cycloalkyl, amino, and CN; R ２ is F; R ３ is hydrogen, -OLW or 【Chemistry 5】 and L is methylene; W is 【Chemistry 6】 and Each is R ６ is substituted 1 to 3 times with or unsubstituted; Each R ６ is hydrogen, halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, CN, =CH ２ and =O; R ４ teeth, 【Chemistry 7】 and Hydrogen, halogen, and C, respectively １ -C ３ Alkyl, NH ２ , NH(C １ -C ３ alkyl), and N(C １ -C ３ alkyl) ２ and is substituted or unsubstituted with one or more substituents independently selected from:

2. The compound of claim 1, wherein n is selected from the group consisting of 1 and 2.

7. The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variations, tautomers, solvates, and pharmaceutically acceptable salts thereof: 【Chemistry 8】 【change】 【change】 【change】 【change】

8. A pharmaceutical composition for cancer treatment, comprising as an active ingredient a compound selected from the group consisting of the compound according to any one of claims 1 to 7 and stereoisomers, diastereomers, enantiomers, rotamers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts thereof.

9. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition exhibits KRAS protein inhibitory activity.

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