Novel triheterocyclic compounds

Abstract

Provided are a triheterocyclic compound, and more particularly, a triheterocyclic compound that can be used as a Hilstein rat sarcoma virus oncogene homolog protein inhibitor, and a pharmaceutical composition for treating cancer comprising the triheterocyclic compound.

Description

Technical Field

[0001] The present disclosure relates to novel triheterocyclic compounds, and more particularly to novel triheterocyclic compounds capable of serving as inhibitors of Kirsten rat sarcoma virus oncogene homolog protein and a pharmaceutical composition for treating cancer comprising the triheterocyclic compounds. Background Art

[0002] The rat sarcoma (RAS) gene is responsible for signal transduction within the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and is referred to as an oncogene due to frequent mutations. The RAS gene family is divided into the Kirsten rat sarcoma virus oncogene homolog (KRAS), the neuroblastoma RAS virus oncogene homolog (NRAS), and the Harvey rat sarcoma virus oncogene homolog (HRAS), where the three genes encode four proteins, namely the splice variants K-Ras4A, K-Ras4B, N-Ras, and H-Ras. K-Ras is the most frequently mutated isoform (86%) in Ras-induced cancers, followed by N-Ras (11%) and H-Ras (3%) (Non-Patent Document 1). For example, oncogenic changes in KRAS were 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 located mainly at codons 12, 13, and 61 constitutively activate the RAS protein and are detected in various types of human cancers. Ninety-eight percent of tumor Ras mutations are found in the active-site amino acid residues G12, G13, and Q61, and these mutations impair the intrinsic guanosine triphosphate (GTP) hydrolysis mediated by GTPase-activating protein (GAP) and abnormally activate downstream signaling (Non-Patent Document 3). K-Ras G12 mutations (89%) predominate in human cancers, followed by G13 mutations (9%) and Q61 mutations (1%). Codon 12 mutations include codon 12 Gly→Asp (G12D) (36%), codon 12 Gly→Val (G12V) (23%), and codon 12 Gly→Cys (G12C) (14%), and G12D is the most common mutation among codon 12 mutations. In addition, mutations at codon 13 Gly→Asp (G13D) (7%) and codon 61 Gln→His (Q61H) (0.6%) have also been observed (Non-Patent Document 1).

[0004] The well-known role of KRAS in malignancies and reports on KRAS mutations in various tumor types suggest that KRAS may be an effective target for cancer treatment. The present inventors have developed a new KRAS inhibitor, thereby completing the present invention.

[0005] [Prior Art Documents]

[0006] (Non-Patent Document 1) Scientific Reports 6(1):21949

[0007] (Non-Patent Document 2) J Cancer Metastasis Treat 2021;7:26

[0008] (Non-Patent Document 3) Cancer Biol Ther. August 2006;5(8):928-932 Summary of the Invention

[0009] Technical Problem

[0010] Provided are novel triheterocyclic compounds having KRAS protein inhibitory activity. The present disclosure relates to: novel triheterocyclic compounds; stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the triheterocyclic compounds; and a pharmaceutical composition for treating cancer comprising the triheterocyclic compounds and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the triheterocyclic compounds.

[0011] Technical solution

[0012] According to one aspect of an embodiment, provided is a compound selected from the compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compounds of Formula 1.

[0013] According to one aspect of another embodiment, provided is a pharmaceutical composition comprising a compound selected from the compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compounds of Formula 1.

[0014] Advantageous effects

[0015] The present disclosure relates to novel triheterocyclic compounds capable of acting as KRAS protein inhibitors and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the triheterocyclic compounds, and a pharmaceutical composition for treating cancer comprising the triheterocyclic compounds and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the triheterocyclic compounds. Detailed implementation manners

[0016] Hereinafter, the present disclosure will be described in more detail.

[0017] Unless otherwise defined, all technical terms used in the present disclosure are used with the same meaning as commonly understood by those skilled in the art associated with the present disclosure. Additionally, although preferred methods or samples are described in this specification, those similar or equivalent methods or samples are also included within the scope of the present disclosure.

[0018] In addition, unless explicitly stated, the numerical values set forth herein are to be considered as including the meaning of "about". All publications disclosed herein as references are incorporated by reference in their entirety for reference purposes.

[0019] Tricyclic heterocyclic compound

[0020] According to an aspect of an embodiment, there is provided a compound selected from the compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts of the compounds of Formula 1.

[0021] [Formula 1]

[0022]

[0023] In Formula 1,

[0024] X is N or CR 11 ;

[0025] R 1 is phenyl substituted or unsubstituted with R 1A , naphthyl substituted or unsubstituted with R 1A , or benzothienyl substituted or unsubstituted with R 1A ;

[0026] Each R 1A is independently selected from 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;

[0027] R 2 is hydrogen or halogen;

[0028] R 3 is hydrogen, -O-L-W or

[0029] L is a key or via L A substituted or unsubstituted C 1 -C 3 alkylene;

[0030] L A is hydrogen, halogen or C 1 -C 3 alkyl;

[0031] W is via R 6 substituted or unsubstituted C 1 -C 3 alkyl, via R 6 substituted or unsubstituted 3- to 10-membered monocyclic heterocycle, or via R 6 substituted or unsubstituted 6- to 14-membered bicyclic heterocycle;

[0032] Each R 6 is independently selected from 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 , side oxygen group (=O), S(C 1 -C 3 alkyl), SO 2 NH 2 , SO 2 NH(C 1 -C 3 alkyl), SO 2 (C 1 -C 3 alkyl), and SO 2 (C 1 -C 3 haloalkyl), or halo C 1 -C 3 alkoxy;

[0033] R 4 is hydrogen, via R 4A substituted or unsubstituted C 1 -C 6 haloalkyl, via R 4A substituted or unsubstituted C 1 -C 6 alkyl, via R 4ASubstituted or unsubstituted C 3 -C 10 cycloalkyl, R 4A substituted or unsubstituted C 5 -C 8 aryl, R 4A substituted or unsubstituted 3- to 10-membered heterocycle, or R 4A substituted or unsubstituted 5- to 10-membered heteroaryl;

[0034] Each R 4A independently selected from hydrogen, CN, NR 9 R 10 、=O、OR 7 、SR 8 、SO 2 R 8 、C(O)N(R 7 ) 2 、C(O)R 7 、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 substituted or unsubstituted 3- to 6-membered heterocycle, and R 4B substituted or unsubstituted 5- to 9-membered heteroaryl;

[0035] Wherein the two of R 4A together form R 4B substituted or unsubstituted C 3 -C 10 cycloalkyl, R 4B substituted or unsubstituted C 5 -C 8 aryl, R 4B substituted or unsubstituted 3- to 10-membered heterocycle, or R 4B substituted or unsubstituted 5- to 10-membered heteroaryl;

[0036] Each R 4B independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C3 -C 6 Cycloalkyl, CN, NR 9 R 10 , =O, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy, hydroxy, SCH 3 , SO 2 NH 2 , SO 2 CH 3 , C(O)NH 2 , C(O)CH 3 , 3- to 6-membered heterocycle, C 5 -C 8 Aryl, and 5- or 6-membered heteroaryl;

[0037] Each R 5 Independently selected from hydrogen, hydroxy, halogen, C 1 -C 3 Haloalkyl and C 1 -C 3 Alkyl,

[0038] Each R 7 Independently selected from hydrogen, amino, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, and 3- or 4-membered heterocycle;

[0039] Each R 8 Independently selected from hydrogen, amino and C 1 -C 3 Alkyl;

[0040] R 9 and R 10 Each independently selected from hydrogen, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C(O)NH 2 , C(O)CH 3 , and 3- to 6-membered heterocycle;

[0041] Each R 11 Independently selected from hydrogen, hydroxy, halogen, C 1 -C 3 Haloalkyl and C 1 -C 3 Alkyl,

[0042] n is an integer selected from 0 to 2; and

[0043] wherein each of the heterocycle or heteroaryl contains 1 to 3 heteroatoms independently selected from N, O, and S.

[0044] In an embodiment, L is a methylene group;

[0045] W is a substituted or unsubstituted 3- to 10-membered monocyclic heterocycle or a substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; and 6 6

[0046] Each R 6 is independently selected from halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, =CH 2 , =O, SCH 3 , SO 2 NH 2 , SO 2 NH(CH 3 ), SO 2 CH 3 and SO 2 CF 3 .

[0047] In one embodiment, W can be a substituted monocyclic or bicyclic non-aromatic ring. For example, W includes but is not limited to

[0048]

[0049] In an embodiment, wherein L is a methylene group;

[0050] Each W is independently a substituted or unsubstituted 6

[0051] and

[0052] Each R 6 is independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, =CH 2 , =O, SCH 3 , SO​​​2 NH 2 、SO 2 NH(CH 3 ), SO 2 CH 3 and SO 2 CF 3 .

[0053] In one embodiment, for example, W may be 1-methylpyrrolidinyl 1-(2,2-Difluoroethyl)azetidine 2-Fluorohexahydro-1H-pyrrolizinyl 2,6-Dimethy1hexahydro-1H-pyrrolizinyl 1-Methyloctahydro-1H-cyclopentyl[b]pyridine or 2-oxabicyclo[2.1.1]hexane But it’s not limited to this.

[0054] In one embodiment, for example, W can be a substituted 4- to 10-membered heterocyclic ring. For example, W can be morpholine But it’s not limited to this.

[0055] In an embodiment, wherein R 4 It is R 4A Substituted or unsubstituted C 1 -C 3 alkyl;

[0056] Each R 4A are independently selected from hydrogen, halogen, CN, NH 2 NH(C 1 -C 3 Alkyl), N(C 1 -C 3 alkyl) 2 , =O, through R 4C Substituted or unsubstituted C 3 -C 6 Cycloalkyl, R 4C Substituted or unsubstituted phenyl, R 4C Substituted or unsubstituted pyridyl, R 4C Substituted or unsubstituted pyrimidinyl, and R 4C a substituted or unsubstituted pyrazinyl group;

[0057] or where R 4A Together, the two of the groups form a 5- to 10-membered heteroaryl group selected from saturated or partially unsaturated isoquinoline or quinoline; and

[0058] Each R 4C are independently selected from hydrogen, halogen, C 1 -C3 alkyl, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 .

[0059] In one embodiment, R 4 may be a substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, azetidinyl, pyrazolyl or pyridyl, but not limited thereto.

[0060] In one embodiment, R 4 may be a C 4A -C 4A cycloalkyl, each substituted or unsubstituted by R 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl includes spiro C 3 -C 10 cycloalkyl. For example, R 4 may each be a substituted or unsubstituted spiro[3.3]alkyl (e.g., ), but not limited thereto.

[0061] In one embodiment, R 4 may be substituted by halogen, amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C 3 -C 10 cycloalkyl), di(C 1 -C 6 alkyl)amino(C 3 -C 10 cycloalkyl) or 1-morpholino(C 3 -C 10 cycloalkyl) (e.g., 1-morpholin-4-ylcyclobutyl ), but not limited thereto.

[0062] R 4 may be, for example, substituted by halogen, amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C3 -C 10 cycloalkyl), di(C 1 -C 6 alkyl)amino(C 3 -C 10 cycloalkyl) or 1-morpholin-4-ylcyclobutyl-substituted C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl.

[0063] R 4 may be, for example, unsubstituted azetidinyl or unsubstituted pyrrolizinyl. R 4 may be, for example, amino-substituted spiro[3.3]heptyl, amino-substituted pyridine or amino-substituted C 3 -C 10 cycloalkyl.

[0064] In an embodiment, where X is CR 11 ,

[0065] each R 11 is independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl;

[0066] R 1 is substituted or unsubstituted benzothienyl; 1A substituted by R

[0067] each R 1A is independently selected from hydrogen, halogen, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 and CN.

[0068] In an embodiment, where R 1 is each independently substituted or unsubstituted by one or more substituents independently selected from hydrogen, hydroxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, amino and CN

[0069] R 2 is F;

[0070] R 3 is hydrogen, -O-L-W or

[0071] L is a methylene group;

[0072] W is each independently substituted one to three times with R 6 or unsubstituted with R 6 substituted

[0073] Each R 6 is independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, =CH 2 and =O;

[0074] R 4 is each independently substituted with one or more substituents independently selected from hydrogen, halogen, C 1 -C 3 alkyl, NH 2 , NH(C 1 -C 3 alkyl) and N(C 1 -C 3 alkyl) 2 or unsubstituted with said one or more substituents and

[0075] n is selected from 1 and 2.

[0076] In an embodiment, the compound is selected from the group consisting of the following compounds and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the following described compounds:

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] In one aspect according to another embodiment, there is provided a pharmaceutical composition comprising a compound selected from the compounds of formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compound of formula 1.

[0085] In an embodiment, the pharmaceutical composition exhibits KRAS protein inhibitory activity.

[0086] Definitions

[0087] Unless otherwise stated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

[0088] Unless otherwise stated, the term "alkyl" as used herein refers to a straight or branched chain saturated monovalent hydrocarbon group.

[0089] Unless otherwise stated, the term "alkylene" as used herein refers to a divalent straight or branched chain hydrocarbon group having (-CH 2 -) n and includes but is not limited to methylene, ethylene, propylene, butylene, isobutylene, etc.

[0090] Unless otherwise stated, the term "alkenyl" as used herein refers to a monovalent hydrocarbon group including at least one carbon-carbon double bond, wherein each double bond has an E or Z configuration.

[0091] Unless otherwise stated, the term "alkynyl" as used herein refers to a monovalent hydrocarbon group including at least one carbon-carbon triple bond.

[0092] Unless otherwise stated, the term "alkoxy" as used herein refers to a straight or branched chain hydrocarbon residue linked through oxygen.

[0093] Unless otherwise stated, the term "aryl" as used herein refers to an aromatic group which may be substituted or unsubstituted, and includes monocyclic, bicyclic or polybicyclic aromatic groups which may be substituted or unsubstituted, and may include unsaturated or partially saturated aryl. For example, aryl includes but is not limited to C 6-15 aryl, and may include but is not limited to phenyl, biphenyl, naphthyl, tolyl, etc.

[0094] Unless otherwise stated, the term "heteroaryl" as used herein refers to an aromatic group which may be substituted or unsubstituted and includes one or more heteroatoms selected from N, O and S, and includes monocyclic, bicyclic or polybicyclic aromatic groups which may be substituted or unsubstituted, and may include unsaturated or partially saturated heteroaryl. For example, heteroaryl includes but is not limited to C 4-15a heteroaryl group, and may include, but are not limited to, a morpholinyl group, a piperidinyl group, a pyrrolidinyl group, a pyrazinyl group, etc.

[0095] Unless otherwise stated, the term "fused heteroaryl" as used herein refers to an unsaturated or partially saturated, substituted or unsubstituted ring system in which a heteroaryl group is linked to another aryl group, heteroaryl group or heterocycloalkyl group in a fused manner. For example, the fused heteroaryl may include C 8-20 heteroaryl groups, and may include, but are not limited to, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered or 15-membered benzo-fused heteroaryl groups. For example, the fused heteroaryl may include, but is 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. For example, the fused heteroaryl may include, but is not limited to, pyrazine, benzothiazole, benzothiazolinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, benzothionyl, indolyl, isoindolinyl, indazolyl, indazolinyl, benzimidazolyl, benzoxazolinyl, benzisoxazolinyl, benzothiadiazolinyl, benzoxadiazolinyl, benzotriazolinyl, quinolinyl, isoquinolinyl, quinazolinyl, etc.

[0096] The term "partially saturated" as used herein refers to including at least one saturated site (i.e., at least one single bond) within an aryl group, heteroaryl group or fused heteroaryl ring as defined above. The term "unsaturated" as used herein refers to an aryl group, heteroaryl group or fused heteroaryl ring as defined above that does not include a saturated site (i.e., a single bond).

[0097] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon ring that may be substituted or unsubstituted, and unless otherwise stated, the cycloalkyl may include bridged cycloalkyl, fused cycloalkyl and spirocycloalkyl. For example, cycloalkyl includes, but is not limited to, C 3-10 cycloalkyl or C 3-6 cycloalkyl, and may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "cycloalkylidene" as used herein refers to a radical (divalent radical) derived from a cycloolefin. Unless otherwise stated, the term "heterocycloalkyl" as used herein refers to a cycloalkyl that may be substituted or unsubstituted and includes one or more heteroatoms selected from N, O and S, and includes a substituted or unsubstituted monocyclic, bicyclic or more than bicyclic aromatic group.

[0098] Unless otherwise stated, as used herein, the term "heterocycle" refers to a saturated or partially unsaturated aromatic, monocyclic, bicyclic or polycyclic ring containing one or more heteroatoms selected from N, O and S, which may be substituted or unsubstituted, and the heterocycle may include bridged heterocycles, fused heterocycles and spiro heterocycles. For example, heterocycles include but are not limited to C 4-15 heteroalkyl, and may include but are not limited to piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, imidazolidinyl, pyrrolidin-2-one, pyrazolyl or pyrrolyl, etc. The heterocycle may be carbon-linked or heteroatom-linked. For example, the heterocycle may be connected to the base molecule through a ring atom (which may be C or N). For example, heterocycles connected to the base molecule through the nitrogen of the ring atom of the heterocycle may include but are not limited to N-morpholinyl, N-piperidinyl, N-pyrrolidinyl or N-pyrrolyl, etc.

[0099] Unless otherwise stated, as used herein, the term "fused heterocycle" or "fused cycloalkyl" refers to a substituted or unsubstituted ring system, and depending on the number of rings, the fused heterocycle or fused cycloalkyl may be classified as bicyclic, tricyclic, tetracyclic or higher polycyclic fused cycloalkyl. Fused cycloalkyl is polycyclic, 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 these rings has a completely conjugated π-electron system. For example, fused cycloalkyl includes but is not limited to C 3-20 fused cycloalkyl, and depending on the number of atoms in each of the two rings that form the fusion, may 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. Bicyclic fused cycloalkyl is also referred to as "bicycloalkyl" or "bicyclic heterocycle", and as long as the valence allows, "bicycloalkyl" or "bicyclic heterocycle" includes any combination of saturated, unsaturated and aromatic bicyclics. In an exemplary embodiment, an aromatic ring (e.g., pyridinyl) may be fused with a saturated or unsaturated ring.

[0100] As used herein, the term "fused heteroalkyl" refers to a substituted or unsubstituted fused cycloalkyl containing one or more heteroatoms selected from N, O and S. For example, fused heteroalkyl includes but is not limited to C 8-20 fused heteroalkyl. For example, bicyclic fused heteroalkyl is also referred to as "heterobicycloalkyl", and depending on the number of atoms in each of the two rings that form the fusion, bicyclic fused heteroalkyl includes but is 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. For example, bicyclic fused heteroalkyl may be hexahydro-1H-pyrazine, but is not limited thereto.

[0101] As used herein, the term "stereoisomer" refers to compounds that are composed of the same atoms bonded by the same bonds but have different non-interchangeable three-dimensional structures. Stereoisomers are compounds that have the same chemical formula or molecular formula but are different optically or spatially. As used herein, the term "enantiomer" refers to the various stereoisomers and geometric isomers that may exist for the compounds of the present disclosure. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers" which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0102] The compounds described herein may have an asymmetric center, a geometric center (e.g., a double bond), or both an asymmetric center and a geometric center. Unless a specific stereochemistry or isomeric form is specifically indicated, all chiral forms, diastereomeric forms, racemic forms, and all geometric isomeric forms of the structure are contemplated.

[0103] The compound of Formula 1 according to one aspect of the present disclosure may have an asymmetric carbon center (asymmetric carbon), and thus may exist as enantiomers (R or S isomers), a racemate, diastereomers, or any mixture thereof, and all such isomers and mixtures are included within the scope of the present disclosure.

[0104] The compounds described herein may have an asymmetric center, a geometric center (e.g., a double bond), or both an asymmetric center and a geometric center. Unless a specific stereochemistry or isomeric form is specifically indicated, all chiral forms, diastereomeric forms, racemic forms, and all geometric isomeric forms of the structure are contemplated. In some embodiments, the compounds described herein have one or more chiral centers. It is understood that if the absolute stereochemistry is not explicitly indicated, each chiral center may independently be in the R-configuration or the S-configuration or a mixture thereof. Accordingly, the compounds described herein include the optical isomers that are enriched or resolved at any or all of the asymmetric atoms that are apparent by reading the depiction. Racemic mixtures of R-enantiomers and S-enantiomers, and stereoisomeric mixtures of enriched enantiomers containing R-enantiomers and S-enantiomers, as well as the individual optical isomers, may be isolated or synthesized to be substantially free of their enantiomeric or diastereomeric counterparts, and all such stereoisomers are within the scope of the present technology.

[0105] The compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active or racemic form. Methods for preparing optically active forms are well known in the art, for example, by resolution of the racemic form, by synthesis from optically active starting materials, or by using chiral auxiliaries.

[0106] As used herein, the term "configurational isomer" refers to all stereoisomers that can be separated from each other. Configurational isomers are isomers that occur when the single bonds formed between carbon and carbon among the bonds constituting a compound cannot freely rotate due to bulky substituents. Configurational isomers refer to stereoisomers generated by an axis of asymmetry and include the complete isolation of stable non-interconvertible non-mirror isomeric species (diastereomeric species) or mirror isomeric species (enantiomeric species). Additionally, configurational isomers may be caused by limited rotation around a single bond, in which the rotational barrier is high enough to distinguish isomeric species.

[0107] The compounds according to one embodiment can produce configurational isomers with a high probability.

[0108] As used herein, the term "tautomer" refers to one of two or more structural isomers that readily convert from one isomeric form to another and exist in equilibrium. The compounds according to one embodiment may also include "tautomers". Tautomers result from the exchange of a single bond with an adjacent double bond and the accompanying proton transfer. Tautomeric forms include prototropic tautomers as isomeric protonation states having the same empirical formula and total charge. Through appropriate substitution, the tautomeric forms can be in equilibrium or fixed in space as one form.

[0109] As used herein, the term "solvate" may include a molecular complex comprising a compound of Formula 1 and one or more pharmaceutically acceptable solvent molecules (such as ethanol or water). A complex in which the solvent molecule is water is also referred to as a "hydrate".

[0110] As used herein, the term "pharmaceutically acceptable salt" includes any salt as long as the salt has low toxicity to humans and does not adversely affect the biological activity and physicochemical properties of the parent compound.

[0111] Compounds according to one embodiment may include “isotope variants”. The present disclosure also encompasses isotopically labeled compounds which are identical to those 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 of the atom usually found in nature (“isotopologue”). The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, respectively, 2 H (“D”), 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, the compounds described herein may have one or more H atoms replaced by deuterium.

[0112] Generally, a reference or depiction of a particular element (such as hydrogen or H) is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, the R group also includes deuterium and tritium. Compounds containing radioactive isotopes (such as tritium, 14 C, 32 P and 35 S) are thus within the scope of the present technology. Based on the disclosure herein, the procedures for inserting such labels into the compounds of the present technology will be apparent to those skilled in the art.

[0113] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention but with hydrogen replaced by deuterium or tritium or carbon replaced by carbon enriched in 13 C or 14 C are within the scope of the present disclosure.

[0114] In some embodiments, certain isotopically labeled compounds (such as compounds labeled with 3 H and 14 C) may be useful in compound distribution assays and / or substrate tissue distribution assays. Tritiation ( 3H) and carbon-14 ( 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavier isotopes (e.g., deuterium) can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may thus be preferred in certain cases. Isotopically labeled compounds can generally be prepared by substituting non-isotopically labeled reagents with isotopically labeled reagents by procedures similar to those disclosed herein (e.g., in the Examples section).

[0115] Deuterated starting materials are readily available and are subjected to the synthetic methods set forth herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0116] As used herein, the term "treatment" includes the treatment, amelioration, improvement, or management of a disease. As used herein, the terms "treating / treatment" refer to inhibiting a disease (e.g., inhibiting a disease, disorder, or condition), preventing the further development of a 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 that is experiencing or displaying the pathology or symptoms of a disease, disorder, or condition.

[0117] As used herein, the term "preventing / prevention" refers to preventing a disease, e.g., preventing a disease, disorder, or condition in a subject that may be susceptible to the disease, disorder, or condition but has not yet experienced or displayed the pathology or symptoms of the disease.

[0118] As used herein, the term "subject" or "patient" refers to any animal, including mammals (e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans).

[0119] The terms "having", "may have", "including", or "may include" may refer to the presence of a feature (e.g., a component (e.g., a number, a component, etc.)), and do not exclude the presence of additional features.

[0120] KRAS protein inhibitor

[0121] Kirsten rat sarcoma viral oncogene homolog (KRAS) is a GTPase that integrates signals from outside the cell into intracellular proliferation and survival signals and is a member of the small GTPase family consisting of Ras, Rho, Rab, Arf, and Ran. KRAS receives signals from various receptor tyrosine kinases (especially the epidermal growth factor receptor (EGFR) at the upper level) and mainly transmits the signals to Raf and PI3K at the lower level through the GTPase cycle of KRAS, thereby regulating various processes including cell proliferation.

[0122] KRAS plays an important role in cancer, but due to the structure of the protein, inhibiting its activity has been challenging. Attempts to block signal transmission have shown some promise but have also presented problems of toxicity and treatment resistance. However, the discovery of the switch II pocket and compounds that bind to mutant cysteine has led to the development of adagrasib and sotorasib, which have been approved by the Food and Drug Administration (FDA) for non-small cell lung cancer.

[0123] The compounds disclosed herein are novel KRAS inhibitor compounds that inhibit mutations in any of codons 12, 13, and 61 of KRAS, such mutations being at least one of, for example but not limited to, the KRAS G12D, KRAS G12V, KRAS G12C, KRAS G13D, and KRAS Q61H mutations.

[0124] Pharmaceutical composition

[0125] According to an aspect of another embodiment, there is provided a pharmaceutical composition for treating cancer, the pharmaceutical composition comprising a compound selected from the compounds of formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts of the compound of formula 1.

[0126] In one embodiment, the composition may comprise a therapeutically effective amount of a compound selected from the compounds of formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts of the compound of formula 1.

[0127] In one embodiment, in addition to compounds selected from the compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compounds of Formula 1, the composition may also contain other therapeutic drugs.

[0128] In one embodiment, the composition may further comprise a pharmaceutically acceptable carrier or excipient.

[0129] In one embodiment, the composition may contain, in the range of 0.005% to 100%, a compound selected from the compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compounds of Formula 1 or other therapeutic drugs, and may contain a pharmaceutically acceptable carrier or excipient in the remaining range.

[0130] In one embodiment, a compound selected from the compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates of the compounds of Formula 1 or a pharmaceutical composition containing the compound can be used for cancer treatment.

[0131] In one embodiment, a compound selected from the compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates of the compounds of Formula 1 or a pharmaceutical composition containing the compound may exhibit KRAS protein inhibitory activity.

[0132] According to an aspect of another embodiment, there is provided the use of a compound selected from the compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates of the compounds of Formula 1 or a pharmaceutical composition containing the compound for treating cancer.

[0133] Route and form of administration

[0134] The compounds and pharmaceutical compositions of the present disclosure can be provided by any suitable route of administration and dosage form acceptable in pharmaceutical technology.

[0135] Manufacturing method

[0136] The compounds of the present disclosure can be synthesized using organic synthesis techniques known to those skilled in the art. Some compounds and / or intermediates of the present disclosure are commercially available, known in the literature, or can be prepared by those skilled in the art by selecting suitable synthetic methods among known organic synthesis techniques. Some compounds of the present disclosure can be synthesized using the protocols, examples, or intermediates set forth herein. Those skilled in the art will recognize that reaction times, reagent equivalents, and / or temperatures can be modified according to the synthetic methods set forth herein, and different work-up techniques and / or purification techniques can be utilized.

[0137] The structure of the synthesized compounds can be verified by methods known to those skilled in the art, such as nuclear magnetic resonance (NMR) spectroscopy and / or mass spectroscopy.

[0138] General Information

[0139] Unless otherwise stated, reagents and solvents obtained from commercial suppliers were used without purification or drying. 1H NMR was recorded using a Bruker 400 and 500 megahertz, and TMS was used as the internal standard. Liquid chromatography-mass spectrometry (LCMS) analysis was performed on a Waters Ultra Performance Liquid Chromatography (UPLC) with an SQD-2 mass detector (Single quadruple), and HPLC analysis was performed on an Acquity UPLC H CLASS (Waters). 1 H NMR was recorded using a Bruker 400 and 500 megahertz, and TMS was used as the internal standard. Liquid chromatography-mass spectrometry (LCMS) analysis was performed on a Waters Ultra Performance Liquid Chromatography (UPLC) with an SQD-2 mass detector (Single quadruple), and HPLC analysis was performed on an Acquity UPLC H CLASS (Waters).

[0140] Even if not specifically stated, the numerical values set forth in this specification are also considered to include the meaning of "about". The term "about" means within 5% of a predetermined value or range, preferably within 1% to 2%.

[0141] In this specification, a numerical range expressed using the term "to" includes the range that includes the values written before and after the term "to" as the lower and upper limits, respectively.

[0142] All references, publications, issued patents, and patent applications cited in the text of this specification are incorporated herein by reference for all purposes.

[0143] Example

[0144] In the following, the present disclosure will be described in more detail with reference to the following examples and experimental examples. However, the examples and experimental examples are intended to assist in understanding the present disclosure, and the scope of the present disclosure is not limited in any sense thereto.

[0145] 1. Synthesis Scheme of Example 1

[0146]

[0147] Experimental Procedure of Example 1: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0148] Step 1: 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 2)

[0149] To a stirred solution of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 1) (5.00 g, 18.9 mmol) in MeOH (50 mL, 10 volumes) at room temperature was added 0.1 molar (M) NaOH (25.0 mL, 5 volumes) and stirred for 30 minutes, then ethyl iodide (2.20 mL, 28.4 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with water and acidified with concentrated hydrochloric acid (conc. HCl) up to pH ~ 4 to obtain a solid, which was filtered, washed with water and dried under high vacuum to obtain the crude compound 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 2) (4.80 g, crude) as a light brown solid. The crude compound was used as such without further purification in the next step. MS (LC-MS): 294.12 m / z [M+H].

[0150] Step 2: 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 5)

[0151] At 0 °C, NaH (0.67 g, 15.3 mmol) was added to a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Example 1 - Intermediate 4) (1.17 g, 6.80 mmol) in tetrahydrofuran (THF) (10 mL, 10 volumes), and the mixture was stirred at 0 °C for 1 hour. To this was added 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 2) (1.00 g, 3.40 mmol) at 0 °C, and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with a 10% methanol in dichloromethane (DCM) solution (2 × 30 mL). The combined organic layers were washed with a brine solution (50 mL) and dried over anhydrous Na 2 SO 4 dried, filtered, and evaporated under reduced pressure to obtain the crude compound 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 5) (1.20 g, crude). The crude compound was used as such in the next step without further purification. MS (LC-MS): 430.33 m / z [M+H].

[0152] Synthesis of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Example 1 - Intermediate 4)

[0153] Step 1a: To a stirred solution of 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 3) (1.00 g, 7.80 mmol) in THF (10 mL, 10 volumes) at 0 °C was added 2-bromoethan-1-ol (0.97 g, 7.80 mmol) and triethanolamine (TEA) (3.26 mL, 23.4 mmol) and the reaction mixture was allowed to warm to room temperature and the reaction mixture was stirred for 18 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with diethyl ether (20 mL) and the reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give the crude compound 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Example 1 - Intermediate 4) (1.40 g, crude) as a yellow liquid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 173.48 m / z [M+H].

[0154] 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 (Example 1 - Intermediate 6)

[0155] To a stirred solution of 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 5) (1.00 g, 2.32 mmol) in DCM (15 mL, 15 volumes) at 0 °C was added bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOP-Cl) (2.07 g, 8.14 mmol) and N,N-diisopropylethylamine (DIPEA) (6.07 mL, 34.9 mmol) and the reaction mixture was allowed to warm to room temperature and the reaction mixture was stirred for 18 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with a DCM solution of 10% methanol (2 × 50 mL), the combined organic layers were washed with brine solution (100 mL), by anhydrous Na 2 SO 4Drying was carried out, filtration and vacuum evaporation were carried out to obtain the crude compound. The crude compound was purified by reverse phase column chromatography using a C18 column eluted with an aqueous solution of 60% acetonitrile (ACN) to obtain 1-((5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 1 - Intermediate 6) (0.45 g, yield (Y): 47%) as a white solid. MS (LC-MS): 412.36 m / z [M+H].

[0156] 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[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 1 - Intermediate 8)

[0157] To a stirred solution of 1-((5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 1 - Intermediate 6) (0.45 g, 1.09 mmol) in a mixture of solvent 1,4-dioxane and water (3:1, 20 mL) at room temperature was added K 3 PO 4 (0.81 g, 3.82 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 1 - Intermediate 7) (0.39 g, 1.09 mmol), and the mixture was degassed under argon for 15 minutes. To this was added 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (Ruphos) PdG 3 (0.092 g, 0.11 mmol), and the reaction mixture was heated to 90 °C and stirred for 1 hour. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with a 10% methanol in DCM solution (2 × 50 mL), and dried over anhydrous Na 2 SO 4The combined organic layer was dried and concentrated under reduced pressure to afford the 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-tetraazacyclotetradecino[5,4,3-cd]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 8) (0.61 g, crude) as a reddish solid. MS (LCMS): 610.48 m / z [M+H].

[0158] 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-tetraazacyclotetradecino[5,4,3-cd]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 9)

[0159] 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-tetraazacyclotetradecino[5,4,3-cd]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 8) (0.60 g, 0.98 mmol) in a mixture of solvent ACN and water (4:1, 20 mL) at 0 °C was added Oxone (3.02 g, 9.83 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with a 10% methanol in DCM solution (2 × 30 mL), dried over anhydrous Na 2 SO 4 dried and concentrated under reduced pressure to afford a residue. The residue was washed with a 20% THF in hexane solution to give a solid, which was filtered and dried under high vacuum to afford the 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-tetraazacyclotetradecino[5,4,3-cd]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 9) (0.30 g, crude) as a brown solid. The crude compound was used as such without further purification in the next step. MS (LC-MS): 642.44 m / z [M+H].

[0160] Step 6: 1-((5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 10)

[0161] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Example 1 - Intermediate 9) (0.099 g, 0.62 mmol) in toluene (10 mL, 30 volumes) at 0 °C was added NaO t Bu (0.06 g, 0.62 mmol) and the mixture was stirred for 15 minutes, then 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 (0.33 g, 0.51 mmol) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with ethyl acetate (EA) (2 × 15 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na 2 SO 4 and filtered and evaporated under reduced pressure to give the crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1 - Intermediate 10) (0.32 g, crude). The crude compound was used as such without further purification in the next step. MC (LC-MS): 707.58 m / z [M+H].

[0162] Step 7: 4-(10-((1-(Dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 1)

[0163] To a stirred solution of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 1 - Intermediate 10) (0.32 g, 0.45 mmol) at 0 °C was added a 1,4-dioxane solution of 4 M HCl (5.0 mL), and the reaction mixture was stirred at 0 °C for 1 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude was purified by preparative HPLC (Prep-HPLC) to give Example 1 as a white solid (0.037 g, yield (Y): 12%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.80 (t, J = 7.38 Hz, 3H), 1.65 - 1.85 (m, 7H), 1.96 (brs, 1H), 2.03 - 2.13 (m, 4H), 2.23 (s, 6H), 2.26 - 2.30 (m, 1H), 2.36 - 2.42 (m, 1H), 2.79 - 2.85 (m, 1H), 3.01 (brs, 1H), 3.08 (d, J = 6.50 Hz, 2H), 3.97 - 4.25 (m, 6H), 4.57 (t, J = 4.88 Hz, 2H), 5.21 - 5.34 (m, 1H), 7.01 (d, J = 2.50 Hz, 1H), 7.30 (d, J = 2.50 Hz, 1H), 7.34 (t, J = 9.38 Hz, 1H), 7.74 (dd, J = 9.01, 6.00 Hz, 1H), 9.91 (s, 1H). MS (LC-MS): 663.47 m / z [M + H].

[0164] 2. Synthetic Scheme of Example 2

[0165]

[0166] Experimental Procedure for Example 2: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0167] Step 1: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2 - Intermediate 2)

[0168] To a stirred solution of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-one (Example 2 - Intermediate 1) (7.60 g, 28.69 mmol) in MeOH (477 mL, 63 volumes) at room temperature was added 0.1 M NaOH (477 mL, 240.99 mmol) and MeI (3.30 mL, 40.17 mmol), and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (250 mL) and acidified with concentrated hydrochloric acid (conc.HCl) up to pH ~ 6 to obtain a solid, which was filtered, washed with water and dried under high vacuum to afford the crude compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2 - Intermediate 2) (4.0 g, crude) as an off-white solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 279.97 m / z [M+H].

[0169] Step 2: 7-Chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2 - Intermediate 3)

[0170] To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Example 1 - Intermediate 4) (0.37 g, 2.16 mmol) in THF (10 mL, 20 volumes) at 0 °C was added NaH (0.35 g, 8.09 mmol), and the mixture was stirred at 0 °C for 1 h. To this was added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2 - Intermediate 2) (0.50 g, 1.80 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature and stirred for 18 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with ethyl acetate (2 × 30 mL), the combined organic layers were washed with brine solution (30 mL), and passed through anhydrous Na 2 SO 4Drying was carried out, filtration and vacuum evaporation were performed to obtain crude compound 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2-Intermediate 3) (0.40 g, crude). The crude compound was used as such without further purification in the next step. MS (LC-MS): 416.29 m / z [M+H].

[0171] 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 (Example 2-Intermediate 4)

[0172] To a stirred solution of 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2-Intermediate 3) (0.40 g, 0.96 mmol) in DCM (10 mL, 25 volumes) at 0 °C was added BOP-Cl (0.86 g, 3.36 mmol) and DIPEA (2.51 mL, 14.42 mmol) and the reaction mixture was allowed to warm to room temperature and the reaction mixture was stirred for 2 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with ethyl acetate (2 × 20 mL), the combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na 2 SO 4 dried, filtered and vacuum evaporated to obtain a crude compound. The crude compound was purified by reverse-phase column chromatography using a C18 column eluting with an aqueous solution of 60% ACN to obtain 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 (Example 2-Intermediate 4) as a yellow solid (0.30 g, yield: 78%). 1 H NMR (400 MHz, DMSO-d 6)δ 1.65 - 1.69 (m, 2H), 1.80 (brs, 2H), 2.08 (brs, 2H), 2.27 (brs, 3H), 2.54 (s, 6H), 3.17 (d, J = 5.00 Hz, 2H), 4.00 - 4.11 (m, 2H), 4.20 (brs, 2H). MS(LC - MS): 398.32 m / z [M + H].

[0173] 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 - tetraazacyclotetradec[de]naphthalen - 10 - yl)methyl) - N,N - dimethylcyclobutan - 1 - amine (Example 2 - Intermediate 6)

[0174] To a stirred solution of 1 - ((5 - chloro - 4 - fluoro - 2 - (methylthio) - 8,9 - dihydro - 10H - 7 - oxa - 1,3,6,10 - tetraazacyclotetradec[de]naphthalen - 10 - yl)methyl) - N,N - dimethylcyclobutan - 1 - amine (Example 2 - Intermediate 4) (0.28 g, 0.71 mmol) in a mixture of the solvents 1,4 - dioxane and water (4:1, 5.0 mL) at room temperature was added K 3 PO 4 (0.53 g, 2.47 mmol) and ((2 - fluoro - 6 - (methoxymethoxy) - 8 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)naphthalen - 1 - yl)ethynyl)triisopropylsilane (Example 2 - Intermediate 5) (0.36 g, 0.71 mmol), and the mixture was degassed under argon for 15 minutes. To this was added Ruphos PdG 3 (0.06 g, 0.07 mmol), and the reaction mixture was heated to 100 °C and stirred for 1 hour. The progress of the reaction was monitored by TLC and LC - MS. After completion of the reaction, the reaction mixture was diluted with ice - cold water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with a brine solution (20 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude compound. By using a mixture of 80% ACN and H 2Purification of the crude compound was carried out by reversed-phase column chromatography on a C18 column eluted with O to give 1-((4-chloro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2-Intermediate 6) (0.30 g, yield: 56%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.86 (dd, J = 7.38, 3.63 Hz, 18H), 1.13 - 1.18 (m, 3H), 1.67 - 1.87 (m, 4H), 2.06 - 2.15 (m, 2H), 2.24 (s, 6H), 2.53 (s, 3H), 3.42 - 3.44 (m, 3H), 3.91 - 4.02 (m, 3H), 4.40 - 4.48 (m, 2H), 4.59 - 4.63 (m, 1H), 5.34 (d, J = 10.81 Hz, 2H), 7.31 (d, J = 2.75 Hz, 1H), 7.54 - 7.59 (m, 1H), 7.72 (d, J = 2.50 Hz, 1H), 8.07 - 8.12 (m, 1H). MS (LCMS): 748.62 m / z [M+H].

[0175] 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[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2-Intermediate 7)

[0176] 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[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2-Intermediate 6) (0.29 g, 0.39 mmol) in a mixture of solvents ACN and water (4:1, 10 mL) at 0 °C was added potassium peroxymonosulfate (1.19 g, 3.88 mmol) and the reaction mixture was allowed to warm to room temperature and the reaction mixture was stirred for 18 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with a 10% methanol in DCM solution (2 × 20 mL), dried over anhydrous Na2 SO 4 It was dried and concentrated under reduced pressure to obtain 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[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2 - Intermediate 7) (0.35 g, crude). The crude compound was used as such in the next step without further purification. MS (LC-MS): 780.63 m / z [M+H].

[0177] Step 6: 1-((4-Fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2 - Intermediate 8)

[0178] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.32 g, 0.41 mmol) in THF (5 mL, 16 volumes) at 0 °C was added NaH (0.02 g, 0.49 mmol) and the mixture was stirred for 30 minutes, then at 0 °C was added 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[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2 - Intermediate 7) (0.32 g, 0.41 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with a 10% MeOH in DCM solution (2 × 20 mL), the combined organic layers were washed with brine solution (20 mL), and dried over anhydrous Na 2 SO 4 It was dried, filtered and evaporated under reduced pressure to obtain the crude compound. By using 70% ACN and H 2The crude compound was purified by reverse-phase column chromatography on a C18 column eluted with O to obtain 1-((4-chloro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[dec]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2-Intermediate 8) (0.30 g, crude) as a yellow solid. MS (LC-MS): 859.89 m / z [M+H].

[0179] Step 7: 1-((5-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[dec]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2-Intermediate 9)

[0180] 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-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[dec]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2-Intermediate 8) (0.29 g, 0.34 mmol) in THF (3.0 mL, 10 volumes) at 0 °C was added a 1 M solution of tetrabutylammonium fluoride (TBAF) in THF (0.35 mL, 0.34 mmol), and the reaction mixture was stirred at 0 °C for 1 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with a 10% MeOH in DCM solution (2 × 20 mL), the combined organic layers were washed with a brine solution (20 mL), dried over anhydrous Na 2 SO 4 and filtered and evaporated under reduced pressure to give the crude compound. By using a solution of 70% ACN and H 2The crude compound was purified by reversed-phase column chromatography on a C18 column with precipitation to obtain 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2 - Intermediate 9) as a yellow solid (0.23 g, yield: 96%). MS (LC-MS): 703.64 m / z [M+H].

[0181] Step 8: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 2)

[0182] To 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutane-1-amine (Example 2 - Intermediate 9) (0.22 g, 0.31 mmol) was added a 1,4-dioxane solution of 4 M HCl (2.0 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with an NaHCO 3 solution (20 mL), and extracted with ethyl acetate (20 mL). The separated organic layer was washed with an aqueous brine solution (20 mL), dried over anhydrous Na 2 SO 4 and filtered and evaporated under reduced pressure to obtain the crude compound. The crude product was purified by preparative HPLC (Prep-HPLC) to obtain Example 2 as a light brown solid (0.053 g, yield: 26%). 1 1H NMR (400 MHz, DMSO-d 6) δ 1.67 - 1.91 (m, 8H), 2.05 - 2.10 (m, 4H), 2.26 (brs, 6H), 2.85 (d, J = 6.01 Hz, 1H), 3.03 - 3.11 (m, 4H), 3.93 - 4.17 (m, 6H), 4.45 (dd, J = 14.13, 4.88 Hz, 1H), 4.56 (brs, 2H), 5.22 - 5.35 (m, 1H), 7.15 (d, J = 2.25 Hz, 1H), 7.37 (d, J = 2.50 Hz, 1H), 7.46 (t, J = 9.01 Hz, 1H), 7.96 (dd, J = 9.13, 5.88 Hz, 1H), 10.14 (brs, 1H). MS (LC - MS): 659.39 m / z [M + H].

[0183] 3. Synthetic Scheme of Example 3

[0184]

[0185] Experimental Procedure of Example 3: 4 - ((8S) - 10 - (1 - (2 - aminopyridin - 3 - yl)ethyl) - 4 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H) - yl)methoxy) - 8 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 5 - yl) - 5 - ethyl - 6 - fluoronaphthalen - 2 - ol

[0186] Step 1: tert - Butyl (3 - acetylpyridin - 2 - yl)carbamate (Example 3 - Intermediate 2)

[0187] To a mixture of 1 - (2 - aminopyridin - 3 - yl)ethan - 1 - one (Example 3 - Intermediate 1) (25.0 g, 183 mmol) in t - BuOH (200 mL) was added Boc 2 O (59.8 g, 274 mmol), and the mixture was stirred at 90 °C for 16 h. LCMS indicated consumption of the starting material and formation of the desired mass. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (polyethylene (PE) / ethyl acetate (EA) = 2 / 1) to give tert - butyl (3 - acetylpyridin - 2 - yl)carbamate (30 g, yield 69.4%) as a white solid. MS: m / z = 237.2 (M + H + , ESI+)

[0188] Step 2: (S,Z) - tert - Butyl (3 - (1 - ((2 - hydroxypropyl)imino)ethyl)pyridin - 2 - yl)carbamate (Example 3 - Intermediate 3)

[0189] To a solution of tert-butyl (3-acetylpyridin-2-yl)carbamate (30 g, 127 mmol) in EtOH (150 mL) was added (S)-1-aminopropan-2-ol (28.5 g, 381 mmol), and the mixture was stirred at 90 °C for 3 h. LCMS indicated 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). By Na 2 SO 4 The combined organic layers were dried, 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+)

[0190] Step 3: tert-Butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (Example 3 - Intermediate 4)

[0191] To a solution of tert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (25 g, 85.3 mmol) in MeOH (100 mL) at 0 °C was added NaBH 4 (4.19 g, 110 mmol), and the mixture was stirred at 25 °C for 1 h. TLC (EA / MeOH = 10 / 1) indicated consumption of SM1 (Rf = 0.4) and formation of a new spot (Rf = 0.2). The reaction mixture was diluted with water and extracted with EA (100 mL × 2). By Na 2 SO 4 The combined organic layers were dried, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give tert-butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (12 g, 47.6% yield) as a white solid. MS: m / z = 296.2 (M+H + ,ESI+).

[0192] Step 4: tert-Butyl (3-(1-(((S)-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (Example 3 - Intermediate 5)

[0193] To a mixture of tert-Butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (9.00 g, 30.5 mmol) in THF (100 mL) was added NaH (4.88 g, 122 mmol, 60% mineral oil suspension), and the mixture was stirred at 0 °C for 0.5 h. After adding 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (8.5 g, 30.5 mmol) to the mixture, the mixture was stirred at 25 °C for an additional 1 h. TLC (EA / MeOH = 15 / 1) indicated consumption of SM2 (Rf = 0.2) and formation of a new spot (Rf = 0.4). The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE / EA = 0 / 1) to afford tert-Butyl (3-(1-(((S)-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (12 g, yield 73.1%) as a yellow solid. MS: m / z = 539.1 (M+H + ,ESI+)

[0194] 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 (Example 3 - Intermediate 6)

[0195] A solution of tert-butyl ((3-(1-(((S)-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (7 g, 13.0 mmol) in DCM (70 mL) was added with BoPCl (9.95 g, 39.0 mmol) and N,N-diisopropylethylamine (DIEA) (15.1 g, 117 mmol). The mixture was then stirred at 25 °C for 12 h. TLC (PE / EA = 0 / 1) indicated consumption of SM2 (Rf = 0.2) and formation of a new spot (Rf = 0.5). The reaction mixture was diluted with water (100 mL) and extracted with DCM (60 mL × 2). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 , 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-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (4.00 g, yield 59.2%) as a yellow solid. Structural confirmation was determined by 2D NMR. MS: m / z = 521.2 (M+H + , ESI+)

[0196] 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-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3 - Intermediate 7)

[0197] Under N 2 atmosphere at 100 °C, tert-butyl ((3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[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 3 (0.40 g, 0.47 mmol) and K 3 PO4 (1.22 g, 5.75 mmol) in a mixture of dioxane / H 2 O (30 mL / 10 mL) was stirred for 4 h. TLC (PE / EA = 0 / 1) indicated that about 10% of SM1 (Rf = 0.5) was retained and a new main spot (Rf = 0.6) was formed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (40 mL × 2). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 filtered and concentrated in vacuo to 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (460 mg, yield 38.8%) as a yellow solid. MS: m / z = 619.2 (M+H + , ESI+)

[0198] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3 - Intermediate 8)

[0199] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (460 mg, 0.74 mmol) in ammonium ceric nitrate (CAN) / H 2 O (10 mL / 10 mL) was added potassium peroxymonosulfate (2.28 g, 3.72 mmol), and the mixture was stirred at 25 °C for 1 h. LCMS indicated consumption of the starting material and detection of the desired mass. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4Drying was carried out, filtration and vacuum concentration were carried out to obtain 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, crude) as a yellow oil. MS: m / z = 651.1 (M+H + , ESI+)

[0200] Step 8: 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3 - Intermediate 9)

[0201] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, 0.77 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 hour. LCMS indicated consumption of the starting material and detection of the desired mass. The reaction mixture was diluted with water (40 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (20 mL), passed through Na 2 SO 4Drying was carried out, filtration and vacuum concentration were carried out to obtain a residue. The residue was purified by medium pressure liquid chromatography (MPLC) (fatty acid (FA) conditions) to obtain 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine as a white solid (250 mg, yield 44.5%). MS: m / z = 730.3 (M+H + ,ESI+)

[0202] Step 9: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 3)

[0203] To a solution of 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]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 the mixture was stirred at 0 °C for 1 h. LCMS indicated consumption of the starting material and formation of the desired mass. The reaction mixture was vacuum concentrated to obtain a residue. The residue was purified by preparative HPLC (NH 3 ·H 2 O conditions) to obtain Example 3 as a white solid (100 mg, 53%). MS: m / z = 686.2 (M+H + ,ESI+)

[0204] Step 10: Example 3a and Example 3b

[0205]

[0206] Compound Example 3 (100 mg) was purified by supercritical fluid chromatography (SFC) (column: REGIS (S,S) WHELK - O1, MeOH (+0.1% MeOH solution of 7.0 mol / L ammonium) / CO 2 = 50 / 50) to obtain Example 3a (30.43 mg, 30.43%) and Example 3b (20.87 mg, 20.87%).

[0207] Example 3a: 4 - ((S)-10 - ((R)-1-(2 - aminopyridin - 3 - yl)ethyl)-4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-8 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 5 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol

[0208] LC - MS: (ES, m / z): [M + H] + = 686.2

[0209] 1 1H 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).

[0210] Example 3b: 4 - ((S)-10 - ((S)-1-(2 - aminopyridin - 3 - yl)ethyl)-4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-8 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 5 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol

[0211] LC-MS: (ES, m / z): [M+H] + = 686.3

[0212] 1 H NMR (400 MHz, MeOD) δ 7.96 (s, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.31 - 7.17 (m, 2H), 7.03 (d, J = 23.2 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.72 - 6.62 (m, 1H), 5.31 (d, J = 54.4 Hz, 1H), 4.69–4.53 (m, 2H), 4.34 (dd, J = 23.5, 10.5 Hz, 2H), 3.75 - 3.64 (m, 1H), 3.27 - 3.17 (m, 2H), 3.06 - 2.97 (m, 1H), 2.57–2.12 (m, 5H), 2.05 - 1.85 (m, 3H), 1.76 - 1.64 (m, 3H), 1.36 - 1.22 (m, 3H), 0.96 - 0.79 (m, 3H).

[0213] 4. Synthetic Scheme of Example 4

[0214]

[0215] Experimental Procedure of Example 4: 4 - ((8S)-10-(1-(2 - aminopyridin - 3 - yl)ethyl)-2((2,6 - dimethylenetetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-4 - fluoro - 8 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 5 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol

[0216] Step 1: Ethyl (E)-2 - ((4 - bromobenzylidene)amino)acetate (Example 4 - Intermediate 2)

[0217] To a solution of 4 - bromobenzaldehyde (Example 4 - Intermediate 1) (5 g, 27.024 mmol) in DCM (75 mL) was added glycine ethyl ester hydrochloride (3.77 g, 27.024 mmol), Mg 2 SO 4 (3.74 g, 31.078 mmol) and TEA (5.47 g, 54.048 mmol). The mixture was stirred at 25 °C under argon for 14 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the cake was washed with DCM (25 mL). The filtrate was concentrated under reduced pressure to give a residue. Using H 2O (50 mL) was used to dilute the residue, and extraction was carried out using methyl tert-butyl ether (MTBE) (50 mL). The organic phase was washed with brine (50 mL) and dried over Na 2 SO 4 . Filtration and concentration under reduced pressure were carried out to obtain 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+)

[0218] Step 2: Ethyl (E)-2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (Example 4-Intermediate 3)

[0219] Under N 2 , at 25 °C, NaH (1.63 g, 8.144 mmol) was added to a solution of ethyl (E)-2-((4-bromobenzylidene)amino)acetate (5.0 g, 18.510 mmol) in THF (125 mL). The mixture was stirred at 25 °C for 5 minutes. Under N 2 , at 25 °C, 3-chloro-2-(chloromethyl)prop-1-ene (6.95 g, 55.530 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at 65 °C for an additional 5 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with H 2 O (250 mL), and extraction was carried out using EA (150 mL). The organic phase was washed with brine (250 mL) and dried over Na 2 SO 2 SO 4 . Filtration and concentration under reduced pressure were carried out to obtain 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+)

[0220] Step 3: Ethyl 2,6-dimethylenetetrahydro-1H-pyrrolo[3,4-c]pyrrole-7a(5H)-carboxylate (Example 4-Intermediate 4)

[0221] 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) 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 H 2 O (60 mL). The aqueous layer was extracted with EA (40 mL) to afford the crude desired product, ethyl 2-amino-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate, in the aqueous layer. MS: m / z = 280.0 (M+H + , ESI+)

[0222] Step 4: Ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Example 4 - Intermediate 5)

[0223] To the above aqueous layer was added dropwise 1 M NaOH (12 mL, 11.572 mmol) to adjust the pH = 9 - 10. The resulting mixture was stirred at 25 °C for 0.5 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was extracted with EA (2 × 40 mL). The combined organic layers were washed with brine (90 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with (DCM / MeOH = 10:1) to afford the desired product, ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate, as a brown liquid (140 mg, 2 steps, 20% yield). MS: m / z = 208.0 (M+H + , ESI+)

[0224] Step 5: (2,6-Dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (Example 4 - Intermediate 6)

[0225] Under N 2 at 0 °C, to a solution of ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (680 mg, 3.278 mmol) in THF (7 mL) was added LiAlH 4 (6.6 mL, 6.562 mmol). The mixture was stirred at 25 °C for 14 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. At 0 °C, by the addition of H 2O (0.3 mL), 15% NaOH solution (0.3 mL) and H 2 O (0.6 mL) quenched the reaction. 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 (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (420 mg, 77% yield) as a colorless liquid. MS: m / z = 166.0 (M+H + , ESI+)

[0226] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Intermediate 7)

[0227] To a solution of tert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (2.8 g, 5.373 mmol) in dioxane (42 mL) and H 2 O (14 mL) was 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-G 3 (1.343 g, 1.607 mmol) and K 3 PO 4 (3.416 g, 16.094 mmol). The mixture was stirred at 100 °C under argon for 4 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H 2 O (140 mL). The resulting mixture was extracted with EA (100 mL). The combined organic layers were washed with brine (120 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography with elution using EA / PE (78%) to obtain 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (2.4 g, yield 57%). MS: m / z = 771.1 (M+H + ,ESI+)

[0228] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4 - Intermediate 8)

[0229] Under argon at 0 °C, potassium peroxymonosulfate (4 g, 6.483 mmol) 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-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, 1.297 mmol) in THF (10 mL) and H 2 O (10 mL). The resulting mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with a NaHSO 3 solution at 0 °C. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H 2 O (100 mL). The mixture was extracted with EA (3×40 mL). The combined organic layers were washed with brine (80 mL), and passed through anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, yield 96%) as a yellow solid. MS: m / z = 803.2 (M+H + ,ESI+)

[0230] Step 8: 3-(1-((S)-2-((2,6-Dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4 - Intermediate 9)

[0231] Under argon at 0 °C, NaH (20 mg, 0.500 mmol) was added to a solution of (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (61 mg, 0.372 mmol) in THF (3 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.248 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with NH 4 Cl solution (60 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with (MeOH / DCM = 1:20) to afford the desired product 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, 65% yield). MS: m / z = 888.3 (M+H + ,ESI+)

[0232] Step 9: 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Intermediate 10)

[0233] To a solution of 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (160 mg, 0.180 mmol) in N,N-dimethylformamide (DMF) (3 mL) was added CsF (274 mg, 1.800 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was purified by reversed-phase flash chromatography under the following conditions to afford the desired product 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 53% yield) as a yellow solid: C18 silica gel; mobile phase, H 2 O solution of ACN (0.1% FA), gradient from 10% to 50% in 15 min; detector, ultraviolet (UV) 254 nm. MS: m / z = 732.3 (M+H + , ESI+)

[0234] Step 10: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 4)

[0235] To a solution of 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, 0.082 mmol) in ACN (1 mL) was added HCl / dioxane (1.5 mL, 1.476 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a yellow solid (Example 4) (13.40 mg, yield 23%): Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 10 mmol NH 4 HCO 3 / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 50% - 50%; retention time: 6.4 - 11 min out of 16 min.

[0236] MS: m / z = 688.2 (M+H + ,ESI+)

[0237] 1 H NMR (400 MHz, MeOD) δ 8.03 - 7.90 (m, 1H), 7.86–7.74 (m, 2H), 7.36–7.25 (m, 2H), 7.23–7.11 (m, 1H), 6.85–6.75 (m, 1H), 6.68 - 6.54 (m, 1H), 5.12–4.91 (m, 4H), 4.68–4.19 (m, 3H), 3.83–3.34 (m, 6H), 2.88 - 2.76 (m, 2H), 2.66 - 2.54 (m, 2H), 1.74–1.59 (m, 3H), 1.37 - 1.14 (m, 3H).

[0238] 5. Synthetic Scheme of Example 5

[0239]

[0240] 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

[0241] 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 (Example 5-Intermediate 2)

[0242] Under argon at 0 °C, NaH (20 mL, 0.500 mmol) was added to a solution of (1-(morpholinomethyl)cyclopropyl) alcohol (64 mg, 0.372 mmol) in THF (3 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Intermediate 8) (200 mg, 0.248 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with NH 4 Cl solution (60 mL). The resulting mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to 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-((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, yield 71%). MS: m / z = 894.4 (M+1, ESI+).

[0243] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 5 - Intermediate 3)

[0244] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, 0.198 mmol) in DMF (3 mL) was added CsF (306 mg, 1.98 mmol). The mixture was stirred under argon at 25 °C for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions to afford 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (100 mg, 60% yield) as a yellow solid: C18 silica gel; mobile phase, ACN in H 2 O solution (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. MS: m / z = 738.2 (M+1, ESI+).

[0245] 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[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 5)

[0246] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 0.108 mmol) in ACN (1 mL) was added HCl / dioxane (2 mL, 1.944 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a yellow solid (Example 5) (14.13 mg, yield 18%): Waters 2767 / Qda, column: XBridge C18 19*250 mm, 10 μm; mobile phase A: 10 mmol NH 4 HCO 3 / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 46% - 46%; retention time: 9.8 - 12.3 min out of 18 min. MS: m / z = 694.0 (M+1, ESI+).

[0247] MS: m / z = 694.0 (M+1, ESI+).

[0248] 1 1H 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).

[0249] 6. Synthetic Scheme for Example 6

[0250]

[0251] Experimental procedure for Example 6: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0252] Step 1: 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 6 - Intermediate 2)

[0253] Under argon at -78 °C, t-BuONa (72 mg, 0.748 mmol) 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 (Example 4 - Intermediate 8) (300 mg, 0.374 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Example 6 - Intermediate 1) (89 mg, 0.560 mmol) in THF (3 mL). The mixture was stirred at -78 °C for 1 hour. The reaction was quenched at -78 °C with NH 4 Cl solution (60 mL). The resulting mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel using precipitation with (MeOH / DCM = 1:10) to obtain 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-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (240 mg, yield 72%). MS: m / z = 882.3 (M+1, ESI+).

[0254] Step 2: 3-(1-((S)-5-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 6 - Intermediate 3)

[0255] To a solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]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 under the following conditions 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-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, yield 75%): C18 silica gel; mobile phase, H 2 O solution of ACN (0.1% FA), gradient from 30% to 70% in 15 min; detector, UV 254 nm. MS: m / z = 726.2 (M+1, ESI+).

[0256] Step 3: 4-((8S)-10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 6)

[0257] HCl / dioxane (3.3 mL, 3.224 mmol) was added to a solution of 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 0.21 mmol) in ACN (2 mL). The mixture was stirred at 25 °C under argon for 2 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography under the following conditions to give the desired product 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (118 mg, racemate): C18 silica gel; mobile phase, H 2 O solution of ACN (0.1% NH 3 H 2 O), gradient from 40% to 80% in 10 min; detector, UV 254 nm. MS: m / z = 682.2 (M+1, ESI+)

[0258] MS: m / z = 682.2 (M+H, ESI+)

[0259] 11H 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).

[0260] Step 4: Example 6a and Example 6b

[0261]

[0262] Compound Example 6 (100 mg) was purified by SFC (column: Regis (S,S) Whelk - O1, MeOH (+0.1% MeOH solution of 7.0 mol / L ammonium) / CO 2 = 55 / 45) to obtain Example 6a (40.46 mg, 40%) and Example 6b (31.19 mg, 31%).

[0263] Example 6a: 4 - ((S)-10 - ((R)-1-(2 - aminopyridin - 3 - yl)ethyl)-4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolo[3,4 - c]pyridin - 7a(5H)-yl)methoxy)-8 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclotetradecino[5,6 - b]naphthalen - 5 - yl)-5 - ethynyl - 6 - fluoronaphthalen - 2 - ol

[0264] LC - MS: (ES, m / z): [M + H] + = 682.0

[0265] 11H 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).

[0266] Example 6b: 4-((S)-10-((S)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0267] LC-MS: (ES, m / z): [M+H] + = 682.0

[0268] 1 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).

[0269] 7. Synthetic Scheme of Example 7

[0270]

[0271] 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

[0272] 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 (Example 7-Intermediate 2)

[0273] To a slurry of NaH (60%) (20 mg, 0.05 mmol) in THF (1 mL) at 0 °C was added a solution of (R)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (Example 7-Intermediate 1) (113 mg, 0.75 mmol) in THF (1 mL). The solution was stirred at 0 °C for 30 minutes. To the above mixture was added a solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.25 mmol) in THF (1 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with NH 4 Cl (aqueous solution, 10 mL), and the solution was extracted with EA (2 × 20 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. Then, the residue was 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+).

[0274] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 7 - Intermediate 3)

[0275] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, 0.22 mmol) and CsF (330 mg, 2.18 mmol) in DMF (2 mL) was stirred at room temperature for 2 h. Then filtration was carried out and the filtrate was concentrated under reduced pressure. Then the residue was purified by preparative HPLC (column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; gradient: 5% - 95% B; flow rate: 50 mL / min) to 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (104 mg, 60%) as a yellow solid. MS: m / z = 718.1 (M+1, ESI+).

[0276] 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-tetraazacyclotetradec[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 7)

[0277] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (94 mg, 0.13 mmol) in ACN (0.5 mL) was slowly added HCl / dioxane (4 M, 0.5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: Sunfire C18, 19*250 mm, 10 µm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 18 - 28%; retention time: 7.9 - 10.8 min out of 16 min) to afford the desired product as a yellow solid to give Example 7 (20.08 mg, 22%). MS: m / z = 673.9 (M+1, ESI+)

[0278] 1 1H 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).

[0279] 8. Synthetic Scheme of Example 8

[0280]

[0281] 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[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0282] Step 1: (S)-azetidin-2-ylmethanol (Example 8 - Intermediate 2)

[0283] To a solution of (S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (Example 8 - Intermediate 1) (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 h. The solvent was removed under reduced pressure to afford (S)-azetidin-2-ylmethanol (700 mg, 98%) as a colorless oil. MS: m / z = 88.2 (M+1, ESI+).

[0284] Step 2: (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (Example 8 - Intermediate 3)

[0285] To a cold solution of K 2 CO 3 (2.4 g, 17.70 mmol) in ACN (10 mL) and (S)-azetidin-2-ylmethanol hydrochloride (700 mg, 8.04 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (1.7 g, 8.04 mmol). The reaction mixture was warmed to room temperature. After 24 h, the reaction was diluted with water (30 mL), the resulting mixture was extracted with EA (40 mL), and the solution was washed with brine (40 mL). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography eluting with PE / EA = 1:1 to afford (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (274 mg, 22%) as a colorless oil. MS: m / z = 152.1 (M+1, ESI+).

[0286] 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 (Example 8 - Intermediate 4)

[0287] A solution of (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (125 mg, 0.82 mmol) in THF (1 mL) was added to a slurry of NaH (60%, oily, 37 mg, 0.56 mmol) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (225 mg, 0.28 mmol) in THF (1 mL) was added to the above mixture. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 5 mL), and the solution was extracted with EA (2 × 20 mL). The organic phase was washed with brine (10 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography eluting with DCM / MeOH = 20:1 to 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (261 mg, 36%) as a yellow oil. MS: m / z = 874.2 (M+1, ESI+)

[0288] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 8 - Intermediate 5)

[0289] 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), CsF (454 mg, 2.98 mmol) in DMF (3 mL) was stirred for 2 h. Then the residue was purified by preparative HPLC (column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL / min) to afford 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+)

[0290] 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)

[0291] 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) 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 3 (aqueous solution, 10 mL), then washed with brine (10 mL), passed through Na 2 SO 4Drying was carried out. The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18 (250 * 21.2 mm, 10 μm); mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 18 - 23%; retention time: 7 - 9.2 minutes out of 16 minutes) to obtain Example 8 as a pale yellow solid (4.49 mg, 5%). MS: m / z = 674.0 (M+1, ESI+)

[0292] 1 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).

[0293] 9. Synthetic Scheme of Example 9

[0294]

[0295] 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

[0296] 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 (Example 9 - Intermediate 2)

[0297] Under argon at 0 °C, NaH (60%, oily, 20 mg, 0.500 mmol) was added to a solution of (2-oxabicyclo[2.1.1]hexan-4-yl)methanol (44 mg, 0.372 mmol) in THF (3 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Intermediate 8) (200 mg, 0.248 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched at 0 °C with NH 4 Cl solution (40 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with (MeOH / DCM = 1:10) to give the desired product 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 54% yield) as a yellow solid. MS: m / z = 837.2 (M+H, ESI+).

[0298] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 9-Intermediate 3)

[0299] 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-tetraazacyclotetradecino[dec]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 at 25 °C under argon for 1 h. The resulting mixture was filtered and the 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 under the following conditions to give the desired product 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradecino[dec]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 79% yield) as a yellow solid: C18 silica gel; mobile phase, ACN in H 2 O solution (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. MS: m / z = 681.2 (M+H, ESI+).

[0300] 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-tetraazacyclotetradecino[dec]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 9)

[0301] 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-tetraazacyclotetradecino[dec]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 at 25 °C under argon for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. By preparative HPLC (Waters 2767 column: XBridge C18, 19*250 mm, 10 μm, mobile phase A: 10 mmol NH4 HCO 3 / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 42 - 42%; Retention time: 7.1 - 10 minutes out of 16 minutes) The residue was purified to obtain the desired product as a yellow solid (Example 9) (17.69 mg, 17% yield). MS: m / z = 636.9 (M+H, ESI+)

[0302] 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).

[0303] 10. Synthetic schemes for Example 10a and Example 10b

[0304]

[0305] Experimental procedures for Example 10a and Example 10b

[0306] 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-tetraazacyclotetra[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 10 - Intermediate 1)

[0307] Under argon at 0 °C, potassium peroxymonosulfate (5.9 g, 9.595 mmol) was added 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-tetraazacyclotetra[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 3 - Intermediate 6) (1 g, 1.920 mmol) in ACN (12 mL) and H 2 O (4 mL). The resulting mixture was stirred at 25 °C for 2 hours under argon. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with a NaHSO 3 solution at 0 °C. The resulting mixture was concentrated under reduced pressure to obtain a residue. Using H 2O (80 mL) diluted the residue. The mixture was extracted with EA (3 × 50 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain 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-tetraazacycloundec[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate) as a yellow solid (1 g, yield 94%). MS: m / z = 553.1 (M+H, ESI+).

[0308] Step 2: (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundec[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 10 - Intermediate 3)

[0309] Under argon at 0 °C, NaH (160 mg, 3.60 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Example 10 - Intermediate 2) (440 mg, 2.72 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, tert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundec[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.0 g, 1.80 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with NH 4 Cl solution (100 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 60 mL). The combined organic layer was washed with brine (120 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with (MeOH / DCM = 1:10) to give the desired product as a yellow solid, tert-butyl (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (800 mg, yield 69%). MS: m / z = 632.2 (M+H, ESI+).

[0310] Step 3: 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 10 - Intermediate 5)

[0311] To a solution of tert-butyl (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (150 mg, 0.237 mmol) in dioxane (3 mL) and H 2 O (1 mL) was added 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 10 - Intermediate 4) (84 mg, 0.237 mmol), Ruphos-Pd-G 3 (60 mg, 0.071 mmol) and K 3 PO 4 (153 mg, 0.711 mmol). The mixture was stirred under argon at 100 °C for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H 2 O (40 mL). The resulting mixture was extracted with EA (20 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography with elution using MeOH / DCM (9%) to obtain the desired product 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, yield 83%) as a yellow solid. MS: m / z = 720.2 (M+H, ESI+).

[0312] Step 4: Example 10a and Example 10b

[0313]

[0314] To a solution of 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (170 mg, 0.236 mmol) in ACN (2 mL) was added HCl / dioxane (4.3 mL, 4.252 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product: Preparative HPLC (Waters 2767) Column: XBridge C18, 19*250 mm, 10 μm; Mobile phase A: 0.05% NH 3 H 2 O / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 39 - 39%; Retention time: 8.8 - 12.8 min out of 16 min.

[0315] Example 10a: 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol as a white solid (7.90 mg, yield 4%).

[0316] MS: m / z = 676.0 (M+H, ESI+)

[0317] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 8.01 (dd, J = 4.9, 1.5 Hz, 1H), 7.79–7.66 (m, 2H), 7.63 - 7.51 (m, 1H), 7.37 (s, 1H), 7.28 - 7.12 (m, 1H), 6.75 - 6.66 (m, 1H), 6.45 - 6.32 (m, 1H), 5.73 (s, 2H), 5.41–5.20 (m, 1H), 4.23–4.10 (m, 3H), 3.53 - 3.46 (m, 2H), 3.13 - 2.99 (m, 3H), 2.88 - 2.78 (m, 1H), 2.18–1.94 (m, 4H), 1.90 - 1.75 (m, 3H), 1.60 - 1.48 (m, 3H), 1.10 (d, J = 6.5 Hz, 3H).

[0318] Example 10b: 4-((S)-10-((S)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol as a white solid (5.90 mg, yield 3%).

[0319] MS: m / z = 676.0 (M+H, ESI+)

[0320] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.96 (d, J = 4.1 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.58 - 7.44 (m, 1H), 7.30 (s, 1H), 7.18 (d, J = 34.6 Hz, 1H), 6.72–6.60 (m, 1H), 6.46 - 6.34 (m, 1H), 5.72 (s, 2H), 5.43–5.19 (m, 1H), 4.72–4.56 (m, 1H), 4.24–4.07 (m, 2H), 3.66 - 3.55 (m, 2H), 3.11–3.01 (m, 3H), 2.88 - 2.78 (m, 1H), 2.14–1.98 (m, 4H), 1.90–1.75 (m, 3H), 1.60 (d, J = 6.7 Hz, 3H), 1.23–1.20 (m, 3H).

[0321] 11. Synthetic Scheme of Example 11

[0322]

[0323] Experimental Procedure of Example 11: 3 - ((8S)-10-(1-(2 - aminopyridin - 3 - yl)ethyl)-4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-8 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 5 - yl)-5 - chloro - 4 - cyclopropylphenol

[0324] Step 1: 3-(1 - ((S)-5-(3 - chloro - 2 - cyclopropyl - 5 - (methoxymethoxy)phenyl)-4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy)-8 - methyl - 8,9 - dihydro - 10H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 10 - yl)ethyl)pyridin - 2 - amine (Example 11 - Intermediate 2)

[0325] To a solution of 2-(3 - chloro - 2 - cyclopropyl - 5 - (methoxymethoxy)phenyl)-4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane (Example 11 - Intermediate 1) (100 mg, 0.29 mmol) in dioxane (2 mL) / H 2 O (0.2 mL) was added (3 - ((R)-1 - ((S)-5 - chloro - 4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolizin - 7a(5H)-yl)methoxy]-8 - methyl - 8,9 - dihydro - 10H - 7 - oxa - 1,3,6,10 - tetraazacycloheptane[de]naphthalen - 10 - yl)ethyl)pyridin - 2 - yl)amine tert - butyl carbonate (Example 10 - Intermediate 3) (186 mg, 0.29 mmol), Cs 2 CO 3 (192 mg, 0.59 mmol) and Pd(dppf)Cl 2 (21 mg, 0.03 mmol). The reaction mixture was stirred at 100 °C for 4 h under N 2 . After completion, water (5 mL) was added to the reaction mixture, and extraction was carried out with ethyl acetate (3 × 10 mL). The organic layer was filtered and concentrated, and passed through Na 2 SO 4Drying was carried out. The residue was purified by silica gel chromatography with precipitation using DCM / MeOH = 20:1 and preparative HPLC (Waters 2767 / Qda column: Perseptive XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 18 - 23%; retention time: 7 - 9.2 minutes out of 16 minutes) to obtain 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[3,4-c]pyrrol-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradec[5,6,7,8-def]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 38%) as a yellow solid.

[0326] MS: m / z = 708.2 (M+H + , ESI+)

[0327] Step 2: 3-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[3,4-c]pyrrol-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradec[5,6,7,8-def]naphthalen-5-yl)-5-chloro-4-cyclopropylphenol (Example 11)

[0328] To a solution of 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[3,4-c]pyrrol-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradec[5,6,7,8-def]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 11 - Intermediate 2) (60 mg, 0.08 mmol) in DCM (1 mL) was added HCl / dioxane (0.3 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with DCM / MeOH (10 / 1 mL × 2). The mixture was washed with concentrated NaHCO 3 (aqueous solution, 10 mL), then washed with brine (10 mL), and passed through Na 2 SO 4Drying was carried out. The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18 250*21.2 mm, 10 μm; mobile phase A: 0.05% trifluoroacetic acid (TFA) / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 18 - 23%; retention time: 7.3 - 9.8 minutes out of 16 minutes) to obtain Example 11 as a pale yellow solid (4.62 mg, 8%). MS: m / z = 664.2 (M+H + , ESI+)

[0329] 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (s, 1H), 7.97 (d, J = 4.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.75–6.67 (m, 2H), 6.66 - 6.56 (m, 1H), 5.92 (brs, 2H), 5.41 (d, J = 52.4 Hz, 1H), 4.61 - 4.43 (m, 3H), 3.46–3.08 (m, 6H), 2.60–2.23 (m, 3H), 2.18 - 2.04 (m, 3H), 1.893 - 1.80 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H), 0.72 - 0.55 (m, 2H), 0.18 - 0.06 (m, 2H).

[0330] 12. Synthetic Scheme of Example 12

[0331]

[0332] 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

[0333] Step 1: tert-Butyl (Z)-(3-(1-((2-Hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (Example 12-Intermediate 1)

[0334] In N 2To a solution of tert-butyl (3-acetylpyridin-2-yl)carbamate (Example 3 - Intermediate 2) (20 g, 84.65 mmol) in EtOH (200 mL) at below 25 °C was added 2-aminoethanol (15.5 g, 253.95 mmol). The mixture was stirred at 90 °C for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (200 mL), extracted with EA (120 mL), and dried over Na 2 SO 4 . Filtration and concentration under reduced pressure were carried out to obtain a residue. The residue was purified by column chromatography on silica gel eluting with (EA / PE = 85%) to afford the desired product (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamic acid tert-butyl ester (7.6 g, crude) as a colorless oil. MS: m / z = 280.0 (M+H,ESI+).

[0335] Step 2: (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert-butyl ester (Example 12 - Intermediate 2)

[0336] To a solution of (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamic acid tert-butyl ester (7.6 g, 27.207 mmol) in MeOH (80 mL) at 0 °C under N 2 was added NaBH 4 (3.087 g, 81.621 mmol). The mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H 2 O (150 mL), extracted with EA (100 mL), and dried over Na 2 SO 4 . Filtration and concentration under reduced pressure were carried out to obtain a crude product. The crude product was purified by column chromatography on silica gel eluting with (MeOH / DCM = 10%) to afford the desired product (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamic acid tert-butyl ester (3.0 g, 39% yield) as a colorless oil. MS: m / z = 282.1 (M+H,ESI+).

[0337] 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 (Example 12 - Intermediate 3)

[0338] Under argon at 0 °C, NaH (1.89 g, 47.126 mmol) was added to a solution of tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (4.4 g, 15.709 mmol) in THF (50 mL). The mixture was stirred at 0 °C for 0.5 h. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (4.4 g, 15.709 mmol) was added to the above mixture under argon at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C by adding H 2 O (30 mL). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H 2 O (150 mL), extracted with EA (100 mL), and dried over Na 2 SO 4 . Filtration and concentration under reduced pressure were carried out to give a crude product. The crude product was purified by column chromatography on silica gel eluting with (MeOH / DCM = 9%) to give the desired product as a yellow solid, 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, yield 41%). MS: m / z = 525.1 (M+H, ESI+).

[0339] Step 4: tert-Butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 12 - Intermediate 4)

[0340] Under argon at 0 °C, DIEA (6.87 g, 53.145 mmol) was added to a solution of tert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (3.1 g, 5.905 mmol) in THF (30 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, BopCl (4.51 g, 17.714 mmol) was added to the above mixture. The resulting mixture was stirred at 25 °C under argon for an additional 16 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H 2 O (150 mL), extracted with EA (100 mL), and dried over Na 2 SO 4 . Filtration and concentration under reduced pressure were carried out to obtain a crude product. The crude product 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-tetraazacycloundec[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.6 g, 53% yield) as a yellow solid. The structural confirmation was determined by two-dimensional NMR. MS: m / z = 507.1 (M+H, ESI+).

[0341] 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-tetraazacycloundec[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 5)

[0342] To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundec[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.6 g, 3.156 mmol) in dioxane (21 mL) and H 2 O (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-G 3 (792 mg, 0.947 mmol), and K 3 PO 4(2 g, 9.468 mmol). The mixture was stirred at 100 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H 2 O (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 Na 2 SO 4 . 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 afford 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-tetraazacyclotetradeca[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+).

[0343] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Intermediate 6)

[0344] To a solution of SM (1.3 g, 1.717 mmol) in ACN (15 mL) and H 2 O (5 mL) at 0 °C under argon was added potassium peroxymonosulfate (5.28 g, 8.587 mmol). The resulting mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with NaHSO 3 solution 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 mixture was extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (120 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (1.20 g, crude) as a yellow solid. MS: m / z = 789.1 (M+H, ESI+).

[0345] 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 7)

[0346] Under argon at 0 °C, NaH (20 mg, 0.506 mmol) was added to a solution of (1-(morpholinomethyl)cyclopropyl)methanol (65 mg, 0.380 mmol) in THF (2 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.253 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The reaction was quenched at 0 °C by adding H 2 O (4 mL). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H 2 O (30 mL), extracted with EA (20 mL), and passed through Na 2 SO 4Drying was carried out. Filtration and concentration under reduced pressure were carried out to obtain a crude product. The crude product was purified by column chromatography on silica gel based on elution using (MeOH / DCM = 10%) to obtain 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, yield 48%) as a yellow solid. MS: m / z = 880.3 (M+H, ESI+).

[0347] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 8)

[0348] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 0.148 mmol) in DMF (3 mL) was added CsF (225 mg, 1.48 mmol). The mixture was stirred under argon at 25 °C for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was purified by reverse phase flash chromatography under the following conditions to 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, yield 56%): C18 silica gel; mobile phase, H 2 O solution of ACN (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. MS: m / z = 723.9 (M+H, ESI+).

[0349] 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[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 12)

[0350] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (20 mg, 0.028 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a white solid (Example 12) (2.21 mg, yield 11%): Preparative HPLC (Waters 2767 / Qda) Column: Sunfire C18, 19*250 mm, 10 μm; Mobile phase A: 0.1% FA / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 13 - 23%; Retention time: 8.9 - 9.8 min out of 16 min). MS: m / z = 680.0 (M+1, ESI+)

[0351] 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.70 - 7.54 (m, 2H), 7.22 - 7.10 (m, 3H), 6.78–6.59 (m, 2H), 5.95 (brs, 2H), 4.51–4.18 (m, 4H), 3.78–3.54 (m, 5H), 3.52–3.38 (m, 1H), 2.99 (d, J = 33.9 Hz, 1H), 2.64–2.46 (m, 6H), 1.60 (dd, J = 18.7, 6.8 Hz, 3H), 0.78 - 0.66 (m, 2H), 0.56 - 0.44 (m, 2H).

[0352] 13. Synthetic Scheme of Example 13

[0353]

[0354] Experimental procedure for Example 13: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-yl alcohol formate

[0355] Step 1: 3-(1-(4-Fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 13 - Intermediate 1)

[0356] Under argon at 0 °C, NaH (60%, oil, 101 mg, 2.534 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (302 mg, 1.901 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 6) (1 g, 1.267 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched at 0 °C with NH 4 Cl solution (60 mL). The resulting mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel using (MeOH / DCM = 1:10) for elution to obtain the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (920 mg, yield 83%). MS: m / z = 868.3 (M+H) + ,ESI+

[0357] Step 2: 3-(1-(5-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 13 - Intermediate 2)

[0358] 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-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (820 mg, 0.945 mmol) in DMF (10 mL) was added CsF (1.43 g, 9.447 mmol). The mixture was stirred at 25 °C under argon for 1 h. The resulting mixture was diluted with H 2 O (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 Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (450 mg, crude). MS: m / z = 712.2 (M+H)+ , ESI+

[0359] Step 3: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolizin-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)

[0360] To a solution of SM (450 mg, 0.632 mmol) in ACN (10 mL) was added HCl / dioxane (11 mL, 11.380 mmol). The mixture was stirred at 25 °C under argon for 1 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography under the following conditions to give the desired product as a yellow solid (Example 13) (23.93 mg, 5% yield): C18 silica gel; mobile phase, H 2 O solution of ACN (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. MS: m / z = 667.9 (M+H + , ESI+)

[0361] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (brs, 1H), 8.15 (s, 0.76H, FA), 8.01–7.91 (m, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (d, J = 1.3 Hz, 1H), 7.15 (s, 1H), 6.74–6.63 (m, 1H), 6.39–6.26 (m, 1H), 5.82 (s, 1H), 5.74 (s, 1H), 5.36 (d, J = 54.6 Hz, 1H), 4.53–4.14 (m, 4H), 4.04 (d, J = 54.6 Hz, 1H), 3.83–3.67 (m, 1H), 3.50–3.37 (m, 3H), 2.97 - 2.87 (m, 1H), 2.31–1.77 (m, 6H), 1.66–1.52 (m, 3H).

[0362] Step 4: Example 13a and Example 13b

[0363]

[0364] By SFC (column: W( W), EtOH (+0.1% EtOH solution of 7.0 M ammonia) / CO 2 = 63:37) The compound Example 13 (120 mg) was purified to obtain Example 13a (20.55 mg, 17.1%) and Example 13b (21.20 mg, 17.6%).

[0365] Example 13a: 4-(10-((R)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0366] MS: m / z = 668.2 (M+H + ,ESI+)

[0367] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.07–7.87 (m, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (t, J = 2.2 Hz, 1H), 6.72–6.64 (m, 1H), 6.40 - 6.25 (m, 1H), 5.76 (d, J = 28.3 Hz, 2H), 5.30 (d, J = 54.2 Hz, 1H), 4.45–4.37 (m, 1H), 4.26 - 4.08 (m, 3H), 3.80–3.64 (m, 1H), 3.51 - 3.44 (m, 1H), 3.15 - 3.00 (m, 3H), 2.90–2.78 (m, 1H), 2.19–1.78 (m, 6H), 1.67–1.54 (m, 3H).

[0368] Example 13b: 4-(10-((S)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0369] MS: m / z = 668.2 (M+H + ,ESI+)

[0370] 1 H NMR (400 MHz, DMSO-d 6)δ 10.22 (brs, 1H), 8.16–7.94 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 6.72–6.64 (m, 1H), 6.45–6.24 (m, 1H), 5.76 (d, J = 30.0 Hz, 2H), 5.31 (d, J = 55.8 Hz, 1H), 4.45–4.37 (m, 1H), 4.27–4.06 (m, 3H), 3.82 - 3.74 (m, 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).

[0371] 14. Synthetic Scheme of Example 14

[0372]

[0373] Experimental Procedure of Example 14: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0374] *(Synthesis of Example 14 - Intermediate 2)

[0375] Step 1a: tert-Butyl (3-acetylpyridin-2-yl)carbamate (Example 14 - Intermediate 2b)

[0376] To a stirred solution of 1-(2-aminopyridin-3-yl)ethan-1-one (Example 14 - Intermediate 2a) (4.00 g, 29.4 mmol) in t-BuOH (20 mL, 5 volumes) at room temperature was added (Boc) 2 O (10.0 mL, 44.1 mmol), and the reaction mixture was heated to 80 °C and stirred for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a solid, which was filtered and dried under high vacuum to give the crude compound tert-butyl (3-acetylpyridin-2-yl)carbamate (Example 14 - Intermediate 2b) (5.0 g, crude) as a pale yellow solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 237.28 m / z [M + H].

[0377] Step 2a: tert-Butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 2d)

[0378] To a stirred solution of tert-butyl (3-acetylpyridin-2-yl)carbamate (Example 14 - Intermediate 2b) (5.00 g, 21.2 mmol) and 2-aminoethanol (Example 14 - Intermediate 2c) (2.50 g, 31.8 mmol) in THF (50 mL, 10 volumes) at room temperature was added titanium(IV) ethoxide (14.5 g, 63.6 mmol), and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (twice), the combined organic layers were washed with brine solution, dried over anhydrous Na 2 SO 4 and filtered and evaporated under reduced pressure to give crude tert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 2d) (5.50 g, crude) as a white solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 280.33 m / z [M+H].

[0379] Step 3a: tert-Butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 2)

[0380] 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 volumes) at 0 °C was added NaBH 4 (1.35 g, 35.8 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 2) (1.80 g, crude) as a white solid. The crude compound was used as such in the next step without further purification. MS (LC-MS): 282.30 m / z [M+H].

[0381] Step 1: tert-Butyl (3-(1-((2-((7-chloro-2-(ethylthio)-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 3)

[0382] To a stirred solution of 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1 - Intermediate 2) (1.80 g, 6.14 mmol) in THF (31 mL, 17 volumes) at 0 °C was added NaH (1.00 g, 27.6 mmol) and the mixture was stirred for 30 minutes. Then at 0 °C was added tert-Butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 2) (2.00 g, 7.37 mmol), and the reaction mixture was stirred at 0 °C for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na 2 SO 4 and 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 a DCM solution of 5% methanol as the eluent to give tert-Butyl (3-(1-((2-((7-chloro-2-(ethylthio)-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 3) (1.50 g, yield: 45%) as an off-white solid. MS (LC-MS): 539.37 m / z [M + H].

[0383] Step 2: tert-Butyl (3-(1-(5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[def]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 4)

[0384] At room temperature, BOP-Cl (0.13 g, 1.62 mmol) and DIPEA (1.20 mL, 6.72 mmol) were added to a stirred solution of tert-butyl (3-(1-((2-((7-chloro-2-(ethylthio)-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 3) (0.25 g, 0.46 mmol) in DCM (2.5 mL, 10 volumes), and the reaction mixture was heated to 60 °C and stirred for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (100 - 200 mesh) column chromatography using a petroleum ether solution of 50% ethyl acetate as the eluent to obtain tert-butyl (3-(1-(5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 14 - Intermediate 4) (0.90 g, total harvest 6 batches (6 × 250 mg), crude). MS (LCMS): 521.35 m / z [M+H].

[0385] 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 (Example 14 - Intermediate 6)

[0386] At room temperature, KOtBu (0.19 g, 1.73 mmol) was added 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 (Example 14 - Intermediate 4) (0.30 g, 0.58 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 14 - Intermediate 5) (0.25 g, 0.69 mmol) in a mixture of the solvents 1,4-dioxane and water (2:1, 9 mL), and in N 2The gas degassing was carried out for 10 minutes. At room temperature, tetrakis(triphenylphosphine)palladium (0.067 g, 0.06 mmol) was added thereto and the reaction mixture was heated to 90 °C and stirred for 4 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL), the combined organic layers were washed with brine solution, and dried over anhydrous Na 2 SO 4 and 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 a DCM solution of 5% methanol as the eluent to obtain 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14 - Intermediate 6) as a pale yellow solid (0.30 g, total harvest 3 batches (3×250 mg), yield: 28%). MS (LC-MS): 619.40 m / z [M+H].

[0387] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14 - Intermediate 7)

[0388] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14 - Intermediate 6) (0.30 g, 0.48 mmol) in a mixture of solvents ACN and water (2:1, 36 mL) at room temperature was added potassium peroxymonosulfate (1.49 g, 4.85 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water and ethyl acetate (2×25 mL), the combined organic layers were washed with brine solution, and dried over anhydrous Na 2 SO 4It was dried, concentrated under reduced pressure, and washed with n-pentane to obtain the 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-tetraazacycloundeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Intermediate 7) (0.25 g, crude). The crude compound was used as such in the next step without further purification. MS (LC-MS): 651.36 m / z [M+H].

[0389] Step 5: 3-(1-(5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Intermediate 9)

[0390] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Example 14-Intermediate 8) (0.073 g, 0.46 mmol) in THF (5.0 mL, 20 volumes) at 0 °C was added NaO t Bu (0.074 g, 0.77 mmol) and the mixture was stirred for 15 minutes, then 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-tetraazacycloundeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Intermediate 7) (0.25 g, 0.38 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (twice), and the combined organic layers were washed with brine solution, dried over anhydrous Na 2 SO 4 filtered and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC to obtain 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Intermediate 9) (0.03 g, yield: 11%) as an off-white solid.1 1H NMR (400 MHz, DMSO-d 6 ) δ 0.83 (q, J = 7.20 Hz, 3H), 1.58 (dd, J = 10.4, 7.20 Hz, 3H), 1.78 - 1.85 (m, 3H), 2.02 - 2.07 (m, 2H), 2.13 - 2.16 (m, 1H), 2.83 (q, J = 6.40 Hz, 1H), 3.08 - 3.10 (m, 2H), 3.42 (d, J = 3.20 Hz, 3H), 3.69 - 3.76 (m, 2H), 4.05 - 4.09 (m, 1H), 4.14 - 4.15 (m, 1H), 4.22 (dd, J = 10.4, 3.20 Hz, 1H), 4.28 - 4.36 (m, 4H), 5.22 - 5.35 (m, 3H), 5.69 - 5.77 (m, 1H), 6.07 (brs, 1H), 6.37 (q, J = 5.89 Hz, 1H), 6.67 (dd, J = 6.40, 5.20 Hz, 1H), 7.17 (d, J = 2.40 Hz, 1H), 7.40 - 7.45 (m, 1H), 7.63 - 7.65 (m, 2H), 7.88 (dd, J = 9.20, 6.00 Hz, 1H), 7.98 (t, J = 3.60 Hz, 1H). MS (LC-MS): 716.36 m / z [M+H].

[0391] Step 6: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy-)9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 14)

[0392] To a stirred solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14 - Intermediate 9) (0.03 g, 0.042 mmol) at 0 °C was added a 1,4-dioxane solution of 4 M HCl (0.2 mL), and the reaction mixture was stirred at 0 °C for 30 minutes. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude product was purified by preparative HPLC to give Example 14 as an off-white solid (0.007 g, yield: 25%). MS: m / z = 672.2 (M+H + , ESI+) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (brs, 1H), 7.97 (s, 1H), 7.81–7.54 (m, 2H), 7.42–7.21 (m, 2H), 7.00 (s, 1H), 6.75–6.59 (m, 1H), 6.44 - 6.30 (m, 1H), 5.72 (d, J = 26.4 Hz, 2H), 5.29 (d, J = 54.3 Hz, 1H), 4.44 - 4.04 (m, 4H), 3.80 - 3.66 (m, 2H), 3.12 - 2.96 (m, 3H), 2.88 - 2.76 (m, 1H), 2.42 - 2.24 (m, 2H), 2.18 - 1.98 (m, 3H), 1.88 - 1.70 (m, 3H), 1.64 - 1.52 (m, 3H), 0.88 - 0.72 (m, 3H).

[0393] The racemic Example 14 was purified by SFC (column: IE, n-hexane / EtOH (+0.1% MeOH solution of 7.0 M ammonia) = 50 / 60) to give Example 14a as a white solid and Example 14b as a white solid.

[0394] Example 14a: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0395] MS: m / z = 672.2 (M+H + , ESI+)

[0396] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (brs, 1.18H, FA), 8.03–7.92 (m, 1H), 7.80–7.64 (m, 2H), 7.44–7.31 (m, 2H), 7.02 (t, J = 2.5 Hz, 1H), 6.79–6.72 (m, 1H), 6.37 (q, J = 6.7 Hz, 1H), 5.39 (d, J = 53.9 Hz, 1H), 4.46–4.25 (m, 4H), 3.83 - 3.68 (m, 1H), 3.51–3.16 (m, 4H), 3.02 - 2.90 (m, 1H), 2.43–2.10 (m, 5H), 2.03–1.80 (m, 3H), 1.60 (t, J = 6.7 Hz, 3H), 0.88 - 0.72 (m, 3H).

[0397] Example 14b: 4-(10-((S)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0398] MS: m / z = 672.2 (M+H + , ESI+)

[0399] 1 H NMR (400 MHz, DMSO-d 6)δ8.20(s,0.53H,FA),7.99 - 7.95(m,1H),7.74(dd,J = 9.0,6.0Hz,1H),7.64(d,J = 7.5Hz,1H),7.40 - 7.26(m,2H),6.99(d,J = 2.5Hz,1H),6.68(dd,J = 6.8,5.3Hz,1H),6.43 - 6.32(m,1H),5.73(d,J = 27.4Hz,2H),5.30(d,J = 54.1Hz,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).

[0400] 15. Synthetic Scheme of Example 15

[0401]

[0402] Experimental Procedure of Example 15: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0403] 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 (Example 15-Intermediate 1)

[0404] A solution of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (144 mg, 0.95 mmol) in THF (1 mL) was added to a slurry of NaH (60%) (25 mg, 0.63 mmol) in THF (1 mL) at 0 °C. The reaction mixture was stirred 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-tetraazacyclotetradec[dec]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 6) (250 mg, 0.32 mmol) in THF (1 mL) was added to the above mixture. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na 2 SO 4 . The residue was then purified by silica gel chromatography eluting with DCM / MeOH = 20:1 to afford 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-tetraazacyclotetradec[dec]naphthalen-10-yl)ethyl)pyridin-2-amine (148 mg, 54%) as a yellow solid. MS: m / z = 860.2 (M+H + ,ESI+)

[0405] 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-tetraazacyclotetradec[dec]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 15 - Intermediate 2)

[0406] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (118 mg, 0.14 mmol), CsF (209 mg, 1.37) in DMF (2 mL) was stirred for 2 h. Then filtration was carried out and the filtrate was concentrated under reduced pressure. Then the residue was purified by preparative HPLC (column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL / min) to 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (84 mg, 87%) as a yellow solid. MS: m / z = 704.1 (M+H + ,ESI+)

[0407] 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-tetraazacyclotetradec[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 15)

[0408] HCl / dioxane (0.3 mL) was added 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (64 mg, 0.09 mmol) in DCM (1 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 3 (aqueous solution, 10 mL), then washed with brine (10 mL), and passed through Na 2 SO 4Drying was carried out. The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda column: Pursuit XRs 10 C18, 250 * 21.2 mm, 10 μm; mobile phase A: 0.05% trifluoroacetic acid (TFA) / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 20 - 25%; retention time: 7.8 - 9.8 minutes out of 16 minutes) and preparative HPLC (Waters 2767 / Qda, column: XBridge C18, 19 * 250 mm, 10 μm; mobile phase A: 0.05% NH 3 H 2 O / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 39% - 39%; retention time: 8 - 11.1 minutes out of 16 minutes) to obtain Example 15 as a pale yellow solid (2.42 mg, 4%). MS: m / z = 660.4 (M + H + , ESI+)

[0409] 1 H NMR (400 MHz, CDCl 3 ) δ8.02 (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).

[0410] 16. Synthetic Scheme of Example 16

[0411]

[0412] Experimental Procedure for Example 16: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol

[0413] Step 1: tert-Butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 16 - Intermediate 1)

[0414] Under argon at 0 °C, potassium peroxymonosulfate (2.42 g, 3.945 mmol) was added to a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 12 - Intermediate 4) (400 mg, 0.789 mmol) in ACN (6 mL) and H 2 O (2 mL). The resulting mixture was stirred at 0 °C for 1 hour. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with a NaHSO 3 solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H 2 O (50 mL). The mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give the desired product, tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[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+)

[0415] Step 2: tert-Butyl (3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 16 - Intermediate 2)

[0416] Under argon, at 0 °C, NaH (46 mg, 1.15 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (137 mg, 0.863 mmol) in THF (3 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon, at 0 °C, tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (310 mg, 0.575 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with NH 4 Cl (20 mL) solution. The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with (MeOH / DCM = 1:10) to give the desired product as a yellow solid, tert-butyl (3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (290 mg, 70% yield). MS: m / z = 618.2 (M+H+, ESI+)

[0417] Step 3: 3-(1-(5-(7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 16 - Intermediate 3)

[0418] To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (120 mg, 0.194 mmol) in dioxane (3 mL) and H 2To the solution in O (1 mL) was added 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-G 3 (48 mg, 0.058 mmol), and K 3 PO 4 (124 mg, 0.582 mmol). The mixture was stirred at 100 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H 2 O (40 mL). The resulting mixture was extracted with EA (20 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to 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-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, yield 53%). MS: m / z = 706.2 (M+H+, ESI+)

[0419] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolizin-7a-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol (Example 16)

[0420] To a solution of 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 0.113 mmol) in ACN (2 mL) was added HCl / dioxane (2 mL, 2.040 mmol). The mixture was stirred at 25 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a white solid (Example 16) (21.89 mg, 29% yield): Preparative HPLC (Waters 2767 / Qda) column: Sunfire C18, 19 * 250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 15 - 23%; retention time: 7.5 - 9.3 min out of 16 min). MS: m / z = 662.0 (M+H+, ESI+)

[0421] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 0.81H, FA), 7.98 (d, J = 4.3 Hz, 1H), 7.77–7.51 (m, 3H), 7.39 (s, 1H), 7.22 (d, J = 1.9 Hz, 1H), 6.72 (dd, J = 7.3, 5.0 Hz, 1H), 6.45 - 6.33 (m, 1H), 5.35 (d, J = 54.4 Hz, 1H), 4.58–3.99 (m, 4H), 3.50 - 3.35 (m, 1H), 3.26 - 3.10 (m, 3H), 2.96 - 2.85 (m, 1H), 2.28–1.78 (m, 6H), 1.59 (d, J = 4.6 Hz, 3H).

[0422] 17. Synthetic Scheme of Example 17

[0423]

[0424] Experimental procedure for Example 17: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[3,4-b]pyridin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloundeca[5,4,3-cde]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0425] Step 1: 3-(1-(4-Fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[3,4-b]pyridin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[5,4,3-cde]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 17 - Intermediate 1)

[0426] To a solution of ((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[3,4-b]pyridin-7a(5H)-yl)methanol (250 mg, 0.32 mmol) in THF (1 mL) was added NaH (25 mg, 0.63 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes under N 2 2 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-tetraazacycloundeca[5,4,3-cde]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 6) SM1 (250 mg, 0.32 mmol) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 2 hours under N 2 2. The reaction mixture was quenched with concentrated NH 4 4Cl (aqueous solution, 5 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL) and dried over Na 2 2SO 4Drying was carried out. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography with elution using DCM / MeOH = 10:1 to obtain the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (156 mg, 56%). MS: m / z = 880.3 (M+H+, ESI+)

[0427] Step 2: 3-(1-(5-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 17 - Intermediate 2)

[0428] 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-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]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 2 for 2 h. The reaction mixture was quenched with water (10 mL), and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)pyridin-2-amine as a yellow solid (136 mg, 121%). MS: m / z = 724.2 (M+H+, ESI+)

[0429] Step 3: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradec[4,5]naphthalen-5-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradeca[4,5]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 17 - Intermediate 3)

[0430] To a solution of 3-(1-(5-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradec[4,5]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 2 for 1 h. The reaction mixture was concentrated under reduced pressure to afford the desired product 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradec[4,5]naphthalen-5-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradeca[4,5]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (136 mg, 106%) as a yellow solid. MS: m / z = 680.2 (M+H+, ESI+)

[0431] Step 4: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradec[4,5]naphthalen-5-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradeca[4,5]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 17)

[0432] To a solution of 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradec[4,5]naphthalen-5-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradeca[4,5]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (136 mg, 0.20 mmol) in MeOH (2 mL) was added Pd / C (60 mg). In H 2The reaction mixture was stirred at below 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: Sunfire C18, 19 * 250 mm, 10 µm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 16 - 26%; retention time: 8.7 - 10.2 minutes out of 16 minutes) to obtain Example 17 as a pale yellow solid (26.31 mg, 19%). MS: m / z = 684.0 (M+H+, ESI+)

[0433] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 1.8H, FA), 7.98 (s, 1H), 7.81–7.73 (m, 1H), 7.70 - 7.62 (m, 1H), 7.43–7.29 (m, 2H), 7.07 - 6.97 (m, 1H), 6.78–6.68 (m, 1H), 6.42–6.31 (m, 1H), 4.55–4.29 (m, 4H), 4.23 - 4.12 (m, 1H), 3.58 - 3.40 (m, 3H), 3.35 - 3.24 (m, 4H), 3.20 - 3.10 (m, 1H), 2.46–2.25 (m, 3H), 2.21–1.86 (m, 5H), 1.68 - 1.52 (m, 3H), 0.90 - 0.75 (m, 3H).

[0434] 18. Synthetic Scheme of Example 18

[0435]

[0436] 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

[0437] 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 (Example 18-Intermediate 1)

[0438] A solution of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (101 mg, 0.76 mmol) in THF (1 mL) was added to a slurry of NaH (60%) (20 mg, 0.51 mmol) in THF (1 mL) at 0 °C. The reaction mixture was stirred 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12 - Intermediate 6) (200 mg, 0.25 mmol) in THF (1 mL) was added to the above mixture. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 5 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na 2 SO 4 . Then, the residue was 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (87 mg, 40%) as a yellow solid. MS: m / z = 842.3 (M+H+, ESI+)

[0439] 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 18 - Intermediate 2)

[0440] CsF (121 mg, 0.79 mmol) was added 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (67 mg, 0.08 mmol) in DMF (1 mL). Under N2 The reaction mixture was stirred at below room temperature for 2 hours. The reaction mixture was quenched with water (10 mL), and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL × 3) and dried over Na 2 SO 4 The organic phase was concentrated under reduced pressure to afford 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (52 mg, 95%) as a yellow solid. MS: m / z = 686.2 (M+H+, ESI+)

[0441] 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-tetraazacyclotetradec[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 18)

[0442] To a solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (42 mg, 0.06 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N 2 for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: Sunfire C18, 19*250 mm, 10 µm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 13 - 23%; retention time: 7.3 - 9.3 min out of 16 min) to afford the desired product as a white solid to give Example 18 (7.28 mg, 18%). MS: m / z = 642.1 (M+H + , ESI+)

[0443] 11H 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).

[0444] 19. Synthetic Scheme of Example 19

[0445]

[0446] Experimental Procedure of Example 19: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0447] 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)

[0448] 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 of Example 12) (1.0 g, 1.972 mmol) in dioxane (12 mL) and H 2 O (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 3 (495 mg, 0.592 mmol) and K 3 PO 4(1.25 g, 5.916 mmol). The mixture was stirred at 100 °C under argon for 2 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction mixture was diluted with H 2 O (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 Na 2 SO 4 . 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 afford 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (590 mg, 49% yield). MS: m / z = 605.1 (M+H + , ESI+)

[0449] 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19 - Intermediate 2)

[0450] 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (300 mg, 0.496 mmol) in ACN (3 mL) and H 2 O (1 mL) at 0 °C under argon was added Oxone® (1.52 g, 5.481 mmol). The resulting mixture was stirred at 0 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched with an aqueous NaHSO 3 solution at 0 °C. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H 2 O (50 mL). The mixture was extracted with EA (3×30 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (210 mg, crude). MS: m / z = 637.1 (M+H + ,ESI+)

[0451] Step 3: 3-(1-(2-((2,6-Dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19 - Intermediate 3)

[0452] Under argon at 0 °C, NaH (21 mg, 0.534 mmol) was added to a solution of (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (66 mg, 0.401 mmol) in THF (2 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (170 mg, 0.267 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with NH 4 Cl solution (60 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel using precipitation with (MeOH / DCM = 1:20) to obtain the desired product 3-(1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolo[3,4-c]pyrazin-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-tetraazacycloundeca[1,3,6,10]tetradeca-10-yl)ethyl)pyridin-2-amine (90 mg, yield 46%). MS: m / z = 722.2 (M+H + ,ESI+)

[0453] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolo[3,4-c]pyrazin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacycloundeca[1,3,6,10]tetradeca-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 19)

[0454] To a solution of 3-(1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolo[3,4-c]pyrazin-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-tetraazacycloundeca[1,3,6,10]tetradeca-10-yl)ethyl)pyridin-2-amine (70 mg, 0.097 mmol) in ACN (2 mL) was added HCl / dioxane (1.8 mL, 1.745 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC under the following conditions to obtain the desired product as a yellow solid (Example 19) (17.98 mg, yield 27%): Preparative HPLC (Waters 2767 column: XBridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol of NH 4 HCO 3 / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 55 - 55%; retention time: 9.2 - 10.8 min out of 16 min). MS: m / z = 678.0 (M+H + ,ESI+)

[0455] 1 H 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).

[0456] 20. Synthetic Scheme of Example 20

[0457]

[0458] Experimental Procedure of Example 20: 4-(10-(1-(2-Aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0459] Step 1: tert-Butyl (Z)-(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (Example 20 - Intermediate 2)

[0460] To a solution of tert-butyl (2-acetylphenyl)carbamate (Example 20 - Intermediate 1) (11 g, 46.81 mmol) in EtOH (110 mL) was added 2-aminoethan-1-ol (8.5 g, 140.42 mmol). The mixture was stirred at 90 °C for 4 h. After completion, water (100 mL) was added to the reaction mixture and extraction was carried out with EA (100 mL). The organic layer was filtered and concentrated, and dried over Na 2 SO 4 was used. 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+)

[0461] Step 2: tert-Butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (Example 20 - Intermediate 3)

[0462] To a solution of (Z)-tert-butyl (2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (5.3 g, 19.06 mmol) in MeOH (50 mL) was added NaBH 4 (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 purified by silica gel chromatography eluting with PE / EA = 2:1 to afford the desired product, tert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (2.1 g, 39%) as a colorless oil. MS: m / z = 281.0 (M+H + ,ESI+)

[0463] 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 (Example 20 - Intermediate 4)

[0464] To a solution of tert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (1.6 g, 5.70 mmol) in THF (5 mL) at 0 °C was added NaH (685 mg, 17.14 mmol). The reaction mixture was stirred at 0 °C under N 2 for 20 min, and 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 above mixture. The reaction mixture was stirred at room temperature under N 2 for 2 h. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 10 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 3:1 to afford 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+)

[0465] Step 4: tert-Butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20 - Intermediate 5)

[0466] To a solution of tert-Butyl (2-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)phenyl)carbamate (2.2 g, 4.20 mmol) in DCM (20 mL) was added BOPCl (3.2 g, 12.59 mmol), DIEA (4.9 g, 37.79 mmol). The reaction mixture was stirred at 25 °C under N 2 for 16 h. The reaction mixture was diluted with DCM (40 mL). The organic phase was washed with brine (40 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 4:1 to afford tert-Butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (1.4 g, 65%) as a white solid. MS: m / z = 506.0 (M+H + , ESI+)

[0467] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20 - Intermediate 6)

[0468] To a solution of tert-Butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (700 mg, 1.39 mmol) in dioxane (7 mL) / H 2 O (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), K 3 PO 4(890 mg, 4.16 mmol) and Ruphos-Pd-G 3 (116 mg, 0.14 mmol). The reaction mixture was stirred at 100 °C for 2 h under N 2 . The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 3:1 to afford the desired product as a yellow solid, 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (750 mg, 63%). MS: m / z = 856.1 (M+H + , ESI+)

[0469] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20 - Intermediate 7)

[0470] To a solution of 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (650 mg, 0.76 mmol) in THF (6 mL) / H 2 O (3 mL) at 0 °C was added Oxone (2.33 g, 3.79 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with concentrated NaHSO 3 (aqueous solution, 20 mL) and extracted with EA (10 mL). Through Na 2 SO 4Drying was carried out. The organic phase was concentrated under reduced pressure to obtain 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-tetraazacyclotetradeca[dec]naphthalen-10-yl)ethyl)phenyl)carbamate (670 mg, crude). MS: m / z = 872.3 (M+H + ,ESI+)

[0471] 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-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[dec]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20 - Intermediate 8)

[0472] Under argon at 0 °C, NaH (56 mg, 1.396 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (167 mg, 1.047 mmol) in THF (7 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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-tetraazacyclotetradeca[dec]naphthalen-10-yl)ethyl)phenyl)carbamate (620 mg, 0.698 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with NH 4 Cl solution (60 mL). The resulting mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as a yellow solid, tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (600 mg, crude). MS: m / z = 967.6 (M+H + , ESI+)

[0473] Step 8: tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20 - Intermediate 9)

[0474] 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-pyrrolizin-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) in DMF (1 mL) was added CsF (948 mg, 6.240 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was diluted with H 2 O (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 Na 2 SO 4 Drying was carried out. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as a yellow solid, tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (150 mg, yield 29%). MS: m / z = 811.5 (M+H+ ,ESI+)

[0475] Step 9: 4-(10-(1-(2-Aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]diazepin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradeca[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 20)

[0476] To a solution of tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolo[2,1-c][1,4]diazepin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)phenyl)carbamate (50 mg, 0.062 mmol) in ACN (2 mL) was added HCl / dioxane (1.2 mL, 1.110 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a white solid (Example 20) (8.15 mg, 19% yield): Preparative HPLC (Waters 2767) Column: XBridge C18, 19*250 mm, 10 μm; Mobile phase A: 10 mmol NH 4 HCO 3 / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 55 - 55%; Retention time: 9.2 - 10.8 min out of 16 min. MS: m / z = 667.2 (M+H + ,ESI+)

[0477] 1 H NMR (400 MHz, DMSO-d 6)δ10.22(s,1H),7.95(dd,J=9.0,5.9Hz,1H),7.46(t,J=9.0Hz,1H),7.37(s,1H),7.32(d,J=7.7Hz,1H),7.15(dd,J=7.7,2.4Hz,1H),7.09(t,J=7.2Hz,1H),6.78-6.65(m,2H),6.47-6.30(m,1H),5.30(d,J=54.6Hz,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).

[0478] 21.Synthesis Scheme of Example 21

[0479]

[0480] Experimental Procedure of Example 21: 4-(10-(1-(2-Aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0481] Step 1: 4-(10-(1-(2-Aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 21)

[0482] Under H 2 at 25 °C, Pd / C (15 mg) was added to a solution of 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (70 mg, 0.105 mmol) in MeOH (2 mL). Under H 2The mixture was stirred at below 25 °C for 16 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was filtered and the 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 under the following conditions to give the desired product as a white solid (Example 21) (21.45 mg, yield 28%): Preparative HPLC (Waters 2767 / Qda) Column: SunFire C18, 19 * 250 mm, 10 μm; Mobile phase A: 0.1% FA / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 13 - 21%; Retention time: 9.8 - 12.2 min out of 17 min. MS: m / z = 671.2 (M + H + , ESI+)

[0483] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.14 (s, 0.23H, FA), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.40 - 7.27 (m, 3H), 7.10 (t, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.79–6.66 (m, 2H), 6.50 - 6.35 (m, 1H), 5.47 (d, J = 54.4 Hz, 1H), 4.54–4.38 (m, 3H), 4.33 - 4.20 (m, 1H), 3.80 - 3.65 (m, 4H), 3.20 - 3.00 (m, 2H), 2.45 - 2.15 (m, 5H), 2.10 - 1.85 (m, 3H), 1.67–1.50 (m, 3H), 0.90 - 0.75 (m, 3H).

[0484] 22. Synthetic scheme of Example 22

[0485]

[0486] 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-tetraazacyclotetra[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0487] Step 1: 4-(10-((R)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 22)

[0488] Under H 2 At 25 °C under H, Pd / C (5 mg) was added to a solution of 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (40 mg, 0.062 mmol) in MeOH (2 mL). The mixture was stirred at 25 °C under H 2 for 16 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was filtered and the 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 under the following conditions to give the desired product as a white solid (Example 22) (16.37 mg, 40% yield): Preparative HPLC (Waters 2767 / Qda) Column: Sunfire C18, 19*250 mm, 10 μm; Mobile phase A: 0.1% FA / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 13 - 21%; Retention time: 9.8 - 12.2 min out of 17 min. MS: m / z = 646.0 (M+H + ,ESI+)

[0489] 1 H NMR (400 MHz, DMSO-d 6)δ 8.17 (s, 0.61H, FA), 7.98 (brs, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.02 (s, 1H), 6.77–6.65 (m, 1H), 6.45–6.32 (m, 1H), 5.21 (d, J = 55.9 Hz, 1H), 4.60–4.24 (m, 4H), 3.82 - 3.74 (m, 1H), 3.57–3.32 (m, 3H), 3.07 - 2.95 (m, 1H), 2.47–2.27 (m, 5H), 2.24–2.10 (m, 1H), 2.04–1.85 (m, 1H), 1.66–1.52 (m, 3H), 0.90 - 0.75 (m, 3H).

[0490] 23. Synthetic Scheme of Example 23

[0491]

[0492] Experimental Procedure of Example 23: 4-(10-(1-(2-Amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0493] Step 1: 3-(1-Ethoxyvinyl)-5-methylpyridin-2-amine (Example 23-Intermediate 2)

[0494] To a solution of 3-bromo-5-methylpyridin-2-amine (10 g, 53.46 mmol) and ethoxyvinyltributyltin (18 mL, 53.44 mmol) in 100 mL of dioxane was added Pd(PPh 3 )Cl 2 (1.87 g, 2.66 mmol). The solution was purged three times with N 2 and the solution was stirred at 100 °C for 4 hours under N 2 . The reaction mixture was concentrated to dryness in vacuo to give a yellow oil, which was purified by silica gel chromatography eluting with DCM / MeOH = 10:1. The desired fraction was collected and concentrated to dryness in vacuo to give the desired product 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine as a yellow oil (7.1 g, crude). MS: m / z = 179.0 (M + H + , ESI+)

[0495] Step 2: 1-(2-Amino-5-methylpyridin-3-yl)ethan-1-one (Example 23 - Intermediate 3)

[0496] To a mixture of 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (8.8 g, 49.44 mmol) in DCM (45 mL) at 25 °C was slowly added 4 M HCl / dioxane (45 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in H 2 O (40 mL), and the pH was adjusted to 8 using Na 2 CO 3 solution, and then the mixture was extracted with DCM (150 mL × 3). The combined organic layers were concentrated to dryness in vacuo to afford a black oil. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate = 5:1 to give the desired product 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one as a yellow solid (4.08 g, 55% yield). MS: m / z = 151.0 (M+H + ,ESI+)

[0497] Step 3: tert-Butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (Example 23 - Intermediate 4)

[0498] To a mixture of 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (4.08 g, 27.17 mmol) in t-BuOH (40 mL) was added (Boc) 2 O (12.4 mL, 54.07 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate = 10:1 to give the desired product tert-Butyl (3-acetyl-5-methylpyridin-2-yl)carbamate as a yellow solid (4.06 g, 60% yield). MS: m / z = 251.1 (M+H + ,ESI+)

[0499] Step 4: (Z)-(3-(1-((2-Hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamic acid tert-butyl ester (Example 23 - Intermediate 5)

[0500] 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-aminoethanol (2.9 g, 47.94 mmol). The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 1:3 to afford 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+)

[0501] Step 5: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23 - Intermediate 6)

[0502] 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) at 0 °C was added NaBH 4 (890 mg, 23.54 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography eluting with DCM / MeOH = 20:1 to afford 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+)

[0503] 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 (Example 23 - Intermediate 7)

[0504] To a solution of tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1 g, 3.39 mmol) in THF (10 mL) at 0 °C was added NaH (406 mg, 10.17 mmol). The reaction mixture was stirred at 0 °C under N 2 for 30 min and a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (949 mg, 3.39 mmol) in THF (10 mL) was added dropwise to the above mixture. Under N 2The reaction mixture was stirred at below room temperature for 2 hours. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 20 mL), and the solution was extracted with EA (30 mL). The organic phase was washed with brine (20 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 1:9 to afford the desired crude product as a yellow solid, 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%). MS: m / z = 539.2 (M+H + , ESI+)

[0505] Step 7: tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23 - Intermediate 8)

[0506] To a solution of tert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1.3 g, 2.41 mmol) in DCM (15 mL) 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 2 for 16 hours. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 1:1 to afford tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate as a yellow solid (580 mg, 46%). MS: m / z = 521.3 (M+H + , ESI+)

[0507] 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23 - Intermediate 9)

[0508] To a solution of tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate (500 mg, 0.96 mmol) in dioxane (5 mL) / H 2 O (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), K 3 PO 4 (610 mg, 2.88 mmol) and Ruphos-Pd-G 3 (241 mg, 0.29 mmol). The reaction mixture was stirred at 100 °C under N 2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM / MeOH = 50:1 to afford 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (175 mg, 29%) as a yellow solid. MS: m / z = 619.4 (M+H + ,ESI+)

[0509] 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23 - Intermediate 10)

[0510] To 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-tetraazacyclotetradeca[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, 0.20 mmol) in ACN (3 mL) / H 2The solution in O (1 mL) was added with potassium monopersulfate (621 mg, 1.01 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with concentrated NaHSO 3 (aqueous solution, 5 mL), and extracted with EA (5 mL). Dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure to obtain 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-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, crude) as a yellow solid. MS: m / z = 651.3 (M+H + , ESI+)

[0511] Step 10: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23 - Intermediate 11)

[0512] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (92 mg, 0.58 mmol) in THF (1 mL) at 0 °C was added NaH (15 mg, 0.38 mmol). The reaction mixture was stirred at 0 °C under N 2 for 30 minutes, and a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacycloundeca[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, 0.19 mmol) in THF (1 mL) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature under N 2 for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 5 mL), and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL), and dried over Na 2 SO 4It was dried to obtain 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (55 mg, crude). MS: m / z = 730.4 (M+H + ,ESI+)

[0513] Step 11: 4-(10-(1-(2-amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 23)

[0514] To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (55 mg, 0.07 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N 2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: XBridge C18, 19*250 mm, 10 µm; mobile phase A: 0.05% NH 3 H 2 O / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 47% - 47%; retention time: 9.2 - 11.2 min out of 16 min) to obtain the desired product as a white solid to give Example 23 (3.82 mg, 7%). MS: m / z = 686.5 (M+H + ,ESI+)

[0515] 1 H NMR (400 MHz, MeOD-d 4)δ 7.81 (s, 1H), 7.69–7.59 (m, 2H), 7.30–7.18 (m, 2H), 7.06 - 7.01 (m, 1H), 6.67 - 6.56 (m, 1H), 5.41 - 5.23 (m, 1H), 4.57–4.30 (m, 4H), 3.84–3.68 (m, 1H), 3.64 - 3.46 (m, 1H), 3.28 - 2.96 (m, 4H), 2.61 - 2.33 (m, 3H), 2.27 (s, 3H), 2.23 - 2.10 (m, 2H), 2.03 - 1.86 (m, 3H), 1.71 - 1.61 (m, 3H), 0.92–0.81 (m, 3H).

[0516] 24. Synthetic Scheme of Example 24

[0517]

[0518] Experimental Procedure of Example 24: 4 - ((((10 - (1 - (2 - aminopyridin - 3 - yl)ethyl)-5-(8 - ethyl - 7 - fluoro - 3 - hydroxynaphthalen - 1 - yl)-4 - fluoro - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 2 - yl)oxy)methyl)tetrahydro - 2H - pyran - 4 - carbonitrile

[0519] 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 (Example 24 - Intermediate 1)

[0520] Under argon at 0 °C, NaH (17 mg, 0.408 mmol) was added to a solution of 4 - (hydroxymethyl)tetrahydro - 2H - pyran - 4 - carbonitrile (44 mg, 0.306 mmol) in THF (2 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. At 0 °C, using NH 4The reaction was quenched with Cl solution (50 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 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-tetraazacyclotetradec[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+)

[0521] 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-tetraazacyclotetradec[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (Example 24)

[0522] 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-tetraazacyclotetradec[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (70 mg, 0.100 mmol) in ACN (2 mL) was added HCl / dioxane (1.8 mL, 1.806 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to afford the desired product (Example 24) (17.05 mg, 25% yield) as a white solid: preparative HPLC (Waters 2767 / Qda) column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 26 - 36%; retention time: 8.9 - 9.9 min out of 16 min). MS: m / z = 654.2 (M+H + , ESI+)

[0523] 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).

[0524] 25. Synthetic Scheme of Example 25

[0525]

[0526] Experimental Procedure of 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

[0527] 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 (Example 25-Intermediate 1)

[0528] Under argon at 0 °C, NaH (18 mg, 0.372 mmol) was added to a solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (48 mg, 0.282 mmol) in THF (1 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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-tetraazacyclotetradecino[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19 - Intermediate 2) (120 mg, 0.186 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with NH 4 Cl solution (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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 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-tetraazacyclotetradecino[de]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, yield 38%) as a yellow solid. MS: m / z = 714.5 (M+H + ,ESI+)

[0529] 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-tetraazacyclotetradecino[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 25)

[0530] 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-tetraazacyclotetradeca[de]naphthalen-10-yl)ethyl)pyridin-2-amine (50 mg, 0.070 mmol) in ACN (2 mL) was added to HCl / dioxane (1.3 mL, 1.261 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a white solid (Example 25) (10.38 mg, 22% yield, FA salt): Preparative HPLC (Waters 2767 / Qda) Column: Sunfire C18, 19*250 mm, 10 μm; Mobile phase A: 0.1% FA / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 15 - 23%; Retention time: 7.7 - 9.1 min out of 16 min). MS: m / z = 670.2 (M+H + , ESI+).

[0531] Step 3: Example 25 - Free form

[0532] The 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-tetraazacyclotetradeca[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (20 mg, 0.030 mmol, FA salt) in DCM (10 mL) was washed with concentrated NaHCO 3 (aqueous solution) (5 mL × 3). The organic phase was concentrated to give the desired product as a white solid (Example 25 - free) (10.16 mg, 51% yield). MS: m / z = 670.2 (M+H + , ESI+)

[0533] 1 H NMR (400 MHz, DMSO-d 6)δ9.93(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).

[0534] 26. Synthetic Scheme of Example 26

[0535]

[0536] Experimental Procedure of Example 26: 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0537] Step 1: Methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (Example 26-Intermediate 1)

[0538] Under argon at 0 °C, (COCl) was added to a solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (1.5 g, 10.353 mmol) in DCM (20 mL). 2(1.72 g, 13.551 mmol) and DMF (12 mg, 0.080 mmol). The resulting mixture was stirred at 25 °C under argon for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. To a stirred solution of (R)-3-fluoropyrrolidine hydrochloride (1.5 g, 10.353 mmol) and DIEA (1.5 g, 10.353 mmol) in DCM (20 mL) at 25 °C under an argon atmosphere was added the residue. The resulting mixture was stirred at 25 °C under an argon atmosphere for 16 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give the desired product (R)-methyl 1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (1.5 g, crude) as a yellow solid. MS: m / z = 216.1 (M+H + ,ESI+)

[0539] Step 2: (R)-(1-((3-Fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (Example 26 - Intermediate 2)

[0540] To a solution of (R)-methyl 1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (1.5 g, 6.970 mmol) in THF (20 mL) at 0 °C under N 2 was added lithium aluminum hydride (LAH) (14 mL, 13.939 mmol). The mixture was stirred at 25 °C for 3 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched by adding H 2 O (0.14 mL), 15% NaOH solution (0.14 mL) and H 2 O (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+)

[0541] 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 (Example 26 - Intermediate 3)

[0542] Under argon at 0 °C, NaH (28 mg, 0.706 mmol) was added to a solution of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (61 mg, 0.353 mmol) in THF (4 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 0.236 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The reaction was quenched at 0 °C with NH 4 Cl solution (50 mL). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford 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[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, crude) as a yellow solid. MS: m / z = 730.4 (M+H + , ESI+)

[0543] 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[deca]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 26)

[0544] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (140 mg, 0.192 mmol) in ACN (2 mL) was added HCl / dioxane (3.5 mL, 3.453 mmol). The mixture was stirred at 25 °C under argon for 1 h. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC under the following conditions to give the desired product as a white solid (Example 26) (3.10 mg, yield 2%): Preparative HPLC (Waters 2767 / Qda) Column: Sunfire C18, 19 * 250 mm, 10 μm; Mobile phase A: 0.1% FA / H 2 O, B: ACN; Flow rate: 20 mL / min; Gradient: 13 - 23%; Retention time: 8.9 - 9.8 min out of 16 min). MS: m / z = 686.2 (M + H + , ESI+)

[0545] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (s, 1.52H, 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).

[0546] 27. Synthetic Scheme for Example 27

[0547]

[0548] 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

[0549] Step 1: (S)-Pyrrolidin-2-ylmethanol hydrochloride (Example 27 - Intermediate 2)

[0550] To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.84 mmol) at 25 °C was slowly added 4 M HCl / dioxane (62 mL). 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+)

[0551] Step 2: (S)-(1-(2,2-Difluoroethyl)pyrrolidin-2-yl)methanol (Example 27 - Intermediate 3)

[0552] To a cold solution of K 2 CO 3 (7.1 g, 51.16 mmol) in ACN (30 mL) and (S)-pyrrolidin-2-ylmethanol hydrochloride (3.2 mg, 23.25 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (4.97 g, 23.25 mmol). The reaction mixture was warmed to room temperature. The mixture was stirred at 25 °C for 16 h. The reaction was diluted with water (30 mL), the resulting mixture was extracted with EA (40 mL), and the solution was washed with brine (30 mL). The organic phase was concentrated under reduced pressure. The residue was then purified by silica gel chromatography eluting with PE / EA = 2:1 to give (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (1.2 g, 31%) as a colorless oil. MS: m / z = 166.1 (M+H + ,ESI+)

[0553] 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 (Example 27 - Intermediate 4)

[0554] To a solution of (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (174 mg, 1.05 mmol) in THF (2 mL) was added NaH (28 mg, 0.70 mmol) at 0 °C. Under N 2 , the reaction mixture was stirred at 0 °C for 30 minutes, and a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (224 mg, 0.35 mmol) in THF (2 mL) was added dropwise to the above mixture. Under N 2 , the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 5 mL), and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL), dried over Na 2 SO 4 to afford 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 12%) as a yellow solid. MS: m / z = 722.4 (M+H + ,ESI+)

[0555] 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-tetraazacyclotetradec[deca]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 27)

[0556] 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-tetraazacyclotetradec[deca]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 0.12 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). Under N 2The reaction mixture was stirred at below room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: Sunfire C18, 19 * 250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 18 - 28%; retention time: 7.9 - 10.8 minutes out of 16 minutes) and preparative HPLC (Waters 2767 / Qda, column: XBridge C18, 19 * 250 mm, 10 μm; mobile phase A: 0.05% NH 3 H 2 O / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 53% - 53%; retention time: 9.4 - 11.4 minutes out of 16 minutes) to obtain the desired product as a white solid to give Example 27 (14.55 mg, 17%). MS: m / z = 678.4 (M + H + , ESI+)

[0557] 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.93 (s, 1H), 7.98 (s, 1H), 7.75 (dd, J = 8.8, 6.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.41–7.24 (m, 2H), 6.99 (s, 1H), 6.74–6.63 (m, 1H), 6.42 - 6.30 (m, 1H), 6.08 (t, J = 56.4 Hz, 1H), 5.76 - 5.60 (m, 2H), 4.48 - 4.16 (m, 4H), 3.80 - 3.66 (m, 1H), 3.48 - 3.38 (m, 2H), 3.16 - 2.98 (m, 2H), 2.93–2.75 (m, 1H), 2.44 - 2.26 (m, 3H), 2.02–1.89 (m, 1H), 1.81–1.50 (m, 6H), 0.90 - 0.78 (m, 3H).

[0558] 28. Synthetic Scheme of Example 28

[0559]

[0560] Experimental Procedure for Example 28: 5 - Ethyl - 6 - fluoro - 4-(4 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolo[2,1 - c][1,4]diazepin - 7a(5H)-yl)methoxy)-10 - methyl - 9,10 - dihydro - 8H - 7 - oxa - 1,3,6,10 - tetraazacyclotetra[de]naphthalen - 5 - yl)naphthalen - 2 - ol

[0561] Step 1: 7-Chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Example 28 - Intermediate 2)

[0562] To a solution of 2-(methylamino)ethan-1-ol (3 g, 10.71 mmol) in THF (30 mL) at 0 °C was added NaH (1.28 g, 32.13 mmol). The reaction mixture was stirred at 0 °C under N 2 for 30 minutes, and a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (804 mg, 10.71 mmol) in THF (30 mL) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature under N 2 for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution, 30 mL), and the solution was extracted with EA (30 mL). Filtration was carried out, and then the filter cake was washed with EA. The filter cake was collected to obtain the desired crude product 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol as a yellow solid (2.1 g, 61%). MS: m / z = 319.0 (M+H + , ESI+)

[0563] Step 2: 5-Chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28 - Intermediate 3)

[0564] 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) were added BOPCl (4.6 g, 17.88 mmol), DIEA (6.9 g, 53.65 mmol). The reaction mixture was stirred at 25 °C under N 2 for 16 hours. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 1:4 to obtain 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene as a yellow solid (220 mg, 12%). MS: m / z = 301.0 (M+H+ , ESI+)

[0565] 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-tetraazacyclotetradeca[de]naphthalene (Example 28 - Intermediate 4)

[0566] To a solution of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclotetradeca[de]naphthalene (220 mg, 0.73 mmol) in dioxane (3 mL) / H 2 O (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), K 3 PO 4 (465 mg, 2.19 mmol) and Ruphos-Pd-G 3 (61 mg, 0.07 mmol). The reaction mixture was stirred at 100 °C under N 2 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 afford 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-tetraazacyclotetradeca[de]naphthalene (80 mg, 22%) as a white solid. MS: m / z = 499.2 (M + H + , ESI+)

[0567] 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-tetraazacyclotetradeca[de]naphthalene (Example 28 - Intermediate 5)

[0568] 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-tetraazacyclotetradeca[de]naphthalene SM1 (80 mg, 0.16 mmol) in THF (3 mL) / H 2 O (1 mL) at 0 °C was added potassium peroxymonosulfate (493 mg, 0.80 mmol). The mixture was stirred at 25 °C for 1 h. Using concentrated NaHSO 3(An aqueous solution, 5 mL) quenched the reaction mixture, and extraction was carried out using EA (5 mL). Drying was performed over Na 2 SO 4 . The organic phase was concentrated under reduced pressure to obtain 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+)

[0569] Step 5: 5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28 - Intermediate 6)

[0570] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (50 mg, 0.32 mmol) in THF (1 mL) at 0 °C was added NaH (8 mg, 0.21 mmol). The reaction mixture was stirred at 0 °C under N 2 for 30 minutes, and a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (56 mg, 0.11 mmol) in THF (1 mL) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature under N 2 for 1 hour. The reaction mixture was quenched with concentrated NH 4 Cl (an aqueous solution, 5 mL), and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL) and dried over Na 2 SO 4 to obtain 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (63 mg, 97%) as a yellow solid. MS: m / z = 610.5 (M+H + , ESI+)

[0571] Step 6: 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Example 28)

[0572] To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (63 mg, 0.10 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature under N 2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda), column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 23 - 31%; retention time: 7.9 - 9.6 min out of 16 min) to afford the desired product as a white solid to give Example 28 (5.78 mg, 9%). MS: m / z = 566.3 (M+H + ,ESI+)

[0573] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 0.48H, 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).

[0574] 29. Synthetic Scheme for Example 29 (Example 29a and Example 29b)

[0575]

[0576] Experimental procedure for Example 29 (Example 29a and Example 29b)

[0577] 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 (Example 29 - Intermediate 1)

[0578] Under argon at 0 °C, NaH (60%, oil, 351 mg, 8.793 mmol) was added to a solution of tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (824 mg, 2.928 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, 7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-ol (1.0 g, 2.928 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched at 0 °C by adding NH 4 Cl (30 mL), and the solution was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel 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+)

[0579] Step 2: tert-Butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (Example 29 - Intermediate 2)

[0580] Under argon at 0 °C, DIEA (2.43 g, 18.810 mmol) was added to a solution of tert-butyl (3-(1-((2-((7-bromo-6-chloro-8-fluoro-4-hydroxy-2-(methylthio)quinazolin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (1.26 g, 2.090 mmol) in THF (20 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, BopCl (1.60 g, 6.270 mmol) was added to the above mixture. The resulting mixture was stirred at 25 °C under argon for an additional 16 h. The reaction mixture was diluted with H 2 O (80 mL), and the solution was extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (ethyl acetate in petroleum ether = 82%) to afford the desired product, tert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazino[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+)

[0581] Step 3: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 29 - Intermediate 3)

[0582] Under argon at 105 °C, tert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazino[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-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (332 mg, 0.821 mmol), Pd(DPEPhos)Cl 2 (30 mg, 0.041 mmol), KF (48 mg, 0.821 mmol), and K 3 PO 4(261 mg, 1.230 mmol) in dioxane (3 mL) was stirred for 3 h. The reaction mixture was diluted with H 2 O (40 mL), and the solution was extracted with EA (20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with a solution of ethyl acetate in petroleum ether (75%) to give the desired product as a yellow solid, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (154 mg, 53% yield). MS: m / z = 696.2 (M+H + , ESI+)

[0583] Step 4: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 29 - Intermediate 4)

[0584] 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]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (130 mg, 0.187 mmol) in THF (3 mL) and H 2 O (1 mL) at 0 °C under argon was added Oxone (575 mg, 0.934 mmol). The resulting mixture was stirred at 0 °C under argon for 1 h. The reaction was quenched with a NaHSO 3 solution at 0 °C. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4Drying was carried out, filtration and concentration under reduced pressure were carried out to obtain the desired product as a yellow solid (tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (90 mg, crude). MS: m / z = 712.3 (M+H + , ESI+). The crude product was directly used in the next step.

[0585] Step 5: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 29 - Intermediate 5)

[0586] Under argon at 0 °C, NaH (60%, oily, 10 mg, 0.252 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (30 mg, 0.190 mmol) in THF (2 mL). The mixture was stirred at 0 °C for 0.5 h. Under argon at 0 °C, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (90 mg, 0.126 mmol) was added to the above mixture. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched at 0 °C by adding NH 4 Cl solution (4 mL). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H 2 O (30 mL), and the solution was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 mL), and passed through Na 2 SO 4Drying was carried out, followed by filtration and concentration under reduced pressure. The residue was purified by column chromatography on silica gel using a solution of methanol in dichloromethane (9%) for elution to obtain the desired product as a yellow solid, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (30 mg, yield 29%). MS: m / z = 807.4 (M+H + ,ESI+)

[0587] Step 6: Example 29a and Example 29b

[0588]

[0589] Under a N 2 atmosphere at 25 °C, a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (70 mg, 0.097 mmol) in HCl / dioxane (3 mL) was stirred for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda, column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 2O, B: ACN; flow rate: 20 mL / min; gradient: 13 - 23%; retention time: 4.6 - 6 min out of 16 min) to obtain Example 29a as a white solid (2.62 mg, 9%) and Example 29b as a white solid (3.31 mg, 12%).

[0590] Example 29a: (4R)-2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0591] MS: m / z = 707.1 (M+H + ,ESI+)

[0592] 1 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).

[0593] Example 29b: (4S)-2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0594] MS: m / z = 707.1 (M+H + , ESI+)

[0595] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (s, 0.84H, 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).

[0596] Synthesis Scheme of Example 30

[0597]

[0598] Experimental Procedure of Example 30: 4-(10-(1-Amino-5,6,7,8-tetrahydroisoquinolin-8-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0599] Step 1: 8-Sideoxy-5,6,7,8-tetrahydroisoquinoline-2-oxide (Example 30-Intermediate 2)

[0600] m-CPBA (13.4 g, 77.48 mmol) was added to a solution of 6,7-dihydroisoquinolin-8(5H)-one (Example 30-Intermediate 1) (6.7 g, 45.58 mmol) in DCM (100 mL). The reaction mixture was stirred at 25 °C under N 2 for 16 h. The reaction mixture was quenched with concentrated NaHSO 3 (aqueous solution, 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 afford the desired product 8-sideoxy-5,6,7,8-tetrahydroisoquinoline-2-oxide as a slightly yellow solid (8 g, 89%). MS: m / z = 164.1 (M+H + , ESI+).

[0601] Step 2: 1-(Benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (Example 30-Intermediate 3)

[0602] BnNH 2 (11.5 g, 107.36 mmol), TEA (13 g, 128.83 mmol), and PyBrOP (26 g, 55.83 mmol) were added to a solution of 8-sideoxy-5,6,7,8-tetrahydroisoquinoline-2-oxide (7 g, 42.94 mmol) in dichloroethane (DCE) (70 mL). Under N 2The reaction mixture was stirred at below 25 °C for 4 h. The reaction mixture was quenched with DCM (70 mL), and the solution was washed with brine (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 10:1 to afford 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one as a yellow solid (3.8 g, 35%). MS: m / z = 252.9 (M+H + ,ESI+).

[0603] Step 3: (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-yl)amino)ethan-1-ol (Example 30 - Intermediate 4)

[0604] To a solution of 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (1.0 g, 3.968 mmol) in MeOH (10 mL) / DMF (10 mL) was added 2-aminoethan-1-ol (720 mg, 11.905 mmol), TEA (1.2 g, 11.905 mmol), AcOH (240 mg, 3.968 mmol). The reaction mixture was stirred at 60 °C for 2 h, and NaBH 3 CN (740 mg, 11.905 mmol) was added to the above solution. Then the reaction mixture was stirred at 60 °C for 48 h. The reaction mixture was diluted with DCM (100 mL), and the solution was washed with water (150 mL×3). The organic phase was washed with brine (100 mL), dried over Na 2 SO 4 and concentrated to afford the crude product (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-yl)amino)ethan-1-ol as a slightly yellow oil (1.0 g, 100%). MS: m / z = 296.0 (M+H + ,ESI+).

[0605] Step 4: 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (Example 30 - Intermediate 5)

[0606] To a solution of (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-yl)amino)ethan-1-ol (1.5 g, 5.078 mmol) in MeOH (10 mL) was added NaBH 4(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 purified by silica gel chromatography eluting with PE / EA = 1:1 to afford the desired product 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (440 mg, 29% yield) as a colorless oil. MS: m / z = 298.0 (M+H + ,ESI+)

[0607] 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 (Examples 30 - Example 6)

[0608] To a solution of 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (400 mg, 1.342 mmol) in THF (2 mL) at 0 °C was added NaH (60%, oil, 215 mg, 5.346 mmol). The reaction mixture was stirred at 0 °C under N 2 for 30 min and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (374 mg, 1.342 mmol) was added to the above solution. The reaction mixture was stirred at 25 °C under N 2 for 16 h. The reaction mixture was quenched with concentrated NH 4 Cl (aqueous solution) (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 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 3:1 to afford the desired product 5-(2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (185 mg, 25% yield) as a colorless oil. MS: m / z = 541.1 (M+H + ,ESI+).

[0609] 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 (Examples 30 - Intermediate 7)

[0610] 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), DIEA (398 mg, 3.087 mmol). The reaction mixture was stirred at 25 °C under N 2 for 16 h. The reaction mixture was diluted with DCM (10 mL). The organic phase was washed with brine (20 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EA = 3:1 to afford 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) as a colorless oil. MS: m / z = 523.1 (M+H + , ESI+).

[0611] 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 (Example 30 - Intermediate 8)

[0612] To a solution of N-benzyl-8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (90 mg, 0.172 mmol) in TFA (2.5 mL) was added CF 3 SO 3 H (0.5 mL). The reaction mixture was stirred at 25 °C under N 2 for 5 h. The reaction mixture was quenched with concentrated Na 2 CO 3 (50 mL) and the solution was extracted with DCM (50 mL × 3). The organic phase was washed with brine (50 mL) and dried over Na 2 SO 4Drying was carried out. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography with elution using PE / EA = 3:1 to obtain the desired product 8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (50 mg, yield 67%). MS: m / z = 433.0 (M+H + ,ESI+).

[0613] 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[deca]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (Example 30 - Intermediate 9)

[0614] To a solution of 8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[deca]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (40 mg, 0.092 mmol) in dioxane (3 mL) / H 2 O (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), K 3 PO 4 (60 mg, 0.276 mmol) and Ruphos-Pd-G 3 (16 mg, 0.0184 mmol). The reaction mixture was stirred at 100 °C under N 2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography with elution using PE / EA = 3:1 to obtain 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[deca]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (20 mg, yield 27%). MS: m / z = 783.3 (M+H + ,ESI+).

[0615] 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 (Example 30 - Intermediate 10)

[0616] To a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (20 mg, 0.025 mmol) in ACN (1 mL) / H 2 O (1 mL) was added Oxone (78 mg, 0.128 mmol) at 0 °C. The reaction mixture was stirred at room temperature under N 2 for 2 h. The reaction mixture was quenched with concentrated NaHSO 3 (aqueous solution, 5 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure to afford 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+).

[0617] Step 10: 8-(4-Fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (Example 30 - Intermediate 1)

[0618] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (14 mg, 0.090 mmol) in THF (1 mL) at 0 °C was added NaH (60%, oil, 2 mg, 0.128 mmol). Under N 2 2, the reaction mixture was stirred at 0 °C for 20 minutes, and a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (15 mg, 0.018 mmol) was added dropwise to the above mixture. Under N 2 2, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with concentrated NH 4 4Cl (aqueous solution, 5 mL), and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL) and dried over Na 2 2SO 4 4. The organic phase was concentrated under reduced pressure to give the desired crude product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, yield 60%). MS: m / z = 849.3 (M+H + , ESI+).

[0619] Step 11: 8-(5-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (Example 30 - Intermediate 12)

[0620] To a solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-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). Under N 2 The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL), and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL × 3) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure to afford the desired crude product 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, yield 100%) as a colorless oil. MS: m / z = 738.2 (M+H + , ESI+).

[0621] Step 12: 4-(10-(1-Amino-5,6,7,8-tetrahydroisoquinolin-8-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 30)

[0622] To a solution of 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (10 mg, 0.013 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). Under N 2The reaction mixture was stirred at below room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire C18, 19 * 250 mm, 10 μm; mobile phase A: 0.1% NH 4 HCO 3 / H 2 O, B: ACN; gradient: 5% - 95% B; flow rate: 50 mL / min) to obtain the desired product as a white solid (Example 30) (1.07 mg, yield 11%). MS: m / z = 694.4 (M + H + , ESI+).

[0623] 31. Synthetic Scheme of Example 36

[0624]

[0625] Experimental Procedure for Example 36: 2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0626] Step 1: tert-Butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 36-Intermediate 1)

[0627] Under argon at 0 °C, NaH (60%, oily, 10 mg, 0.41 mmol) was added to a solution of (S)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (13 mg, 0.082 mmol) in THF (1 mL). 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]oxazino[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 above mixture. The reaction mixture was stirred from 0 °C to room temperature under argon for 1 hour. Using H 2O (10 mL) quenched the resulting mixture. 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 Na 2 SO 4 . 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 afford the desired product as a yellow solid, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, yield 75%). MS: m / z = 801.4 (M+H + , ESI+)

[0628] Step 2: 2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 36)

[0629] To a solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, 0.062 mmol) in DCM (0.5 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. By preparative HPLC (Waters 2767 / Qda, column: XBridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mM NH 4 HCO 3, B: ACN; Flow rate: 20 mL / min; Gradient: 57% - 57%) was used to purify the residue. Retention time: 5.6 - 7.1 minutes out of 16 minutes to obtain the desired product as a white solid (Example 36a) (1.34 mg, 3%); Retention time: 9.5 - 11 minutes out of 16 minutes to obtain the desired product as a white solid (Example 36b) (6.06 mg, 14%).

[0630] Example 36a:

[0631] MS: m / z = 701.3 (M+H + , ESI+).

[0632] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (brs, 1.87H, 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).

[0633] Example 36b:

[0634] MS: m / z = 701.3 (M+H + , ESI+).

[0635] 1 H NMR (400 MHz, DMSO-d 6)δ8.09(brs,2H),7.97(d,J=5.0Hz,1H),7.65(d,J=7.4Hz,1H),7.25-7.09(m,2H),6.68(dd,J=7.4,4.9Hz,1H),6.35-6.25(m,1H),5.81(d,J=16.5Hz,2H),4.90(d,J=9.9Hz,2H),4.52(dd,J=11.8,6.1Hz,1H),4.21(dd,J=11.0,7.0Hz,1H),4.13–3.97(m,2H),3.70(dd,J=15.7,6.4Hz,1H),3.56(d,J=14.0Hz,1H),3.18(d,J=13.7Hz,2H),3.02–2.98(m,1H),2.67-2.59(m,1H),2.36(d,J=15.2Hz,2H),1.99–1.68(m,4H),1.58(d,J=6.6Hz,3H).

[0636] 32. Synthetic Scheme of Example 37

[0637]

[0638] Experimental Procedure of Example 37: 2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0639] Step 1: tert-Butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 37-Intermediate 1)

[0640] Under argon, at 0 °C, NaH (10 mg, 0.41 mmol) was added to a solution of ((7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (14 mg, 0.082 mmol) in THF (1 mL). The mixture was stirred at 0 °C for 10 minutes under argon. Then, tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfonyl)-5,6-dihydro-4H-[1,4]oxazino[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 above solution. The reaction mixture was stirred from 0 °C to room temperature for 1 hour under argon. The resulting mixture was quenched with H 2 O (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 Na 2 SO 4 . 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-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (40 mg, yield 60%). MS: m / z = 819.4 (M+H + , ESI+)

[0641] Step 2: 2-Amino-4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 37)

[0642] A solution of tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (40 mg, 0.048 mmol) in DCM (0.5 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: Waters 2767 / Qda, column: XBridge C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 19% - 28%; retention time: 7.9 - 9.7 min out of 16 min to afford the desired product as a white solid (Example 37a) (4.34 mg, 13%); retention time: 11.6 - 12.9 min out of 16 min to afford the desired product as a white solid (Example 37b) (4.88 mg, 14%).

[0643] Example 37a:

[0644] MS: m / z = 719.4 (M+H + ,ESI+)

[0645] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (brs, 3.59H, 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).

[0646] Example 37b:

[0647] MS: m / z = 719.4 (M+H + ,ESI+)

[0648] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (brs, 2.72H, 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).

[0649] In a similar manner, the compounds of Examples 1 to 37 in Table 1 below were prepared using samples suitable for preparing the compounds described in each example.

[0650] [Table 1]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663] Test Example

[0664] <Test Example 1: KRAS Nucleotide Exchange Assay>

[0665] Purpose

[0666] To evaluate the inhibitory effect of a compound on the SOS1-mediated nucleotide exchange activity of KRAS WT 、KRAS G12D 、KRAS G12V 、KRAS G12C and KRAS G13D mutants

[0667] Principle

[0668] The assay monitors the SOS1-mediated exchange of unlabeled GDP bound to KRAS for fluorescently labeled GTP. Detection is based on energy transfer between two fluorophores when they are in close proximity. The donor is an anti-GST antibody labeled with a Tb cryptate compound, and the acceptor is DY-647P1 GTP.

[0669] Test Conditions and Procedures

[0670] Materials

[0671] GST-tagged KRAS wild-type (WT) or mutant protein (amino acids 2 - 169),

[0672] SOS1 (amino acids 564 - 1049),

[0673] Labeled GTP (GTP-DY-647P1),

[0674] Assay buffer (20 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) pH 7.4, 150 mM NaCl, 5 mM MgCl 2 、1 mM dithiothreitol (DTT), 0.05% bovine serum albumin (BSA), 0.0025% NP40)

[0675] Test Procedure

[0676] 1. Dilute the KRAS protein with the assay buffer to a final concentration of 1.5-fold, then mix it with the Tb cryptate anti-GST antibody and add 10 μl aliquots to each assay well (KRAS WT 、KRASG12D and KRAS G12V The final concentrations of both were 20 nanomoles per liter (nM).

[0677] 2. The compound was dissolved in dimethyl sulfoxide (DMSO) and diluted to 100-fold of the final concentration.

[0678] 3. The compound was dispensed into the assay wells using an ECHO acoustic dispenser (Beckman), gently mixed with the KRAS / Ab mixture, and incubated for 60 minutes.

[0679] 4. SOS1 was mixed with labeled GTP, diluted to 3-fold of the final concentration using the assay buffer, and 5 μL of the solution was added to the assay wells to initiate the reaction (the final concentration of labeled GTP was 0.15 μL, the final concentration of SOS1 in WT was 7.5 nanomoles per liter, in G12D was 12.5 nanomoles per liter, and in G12V was 50 nanomoles per liter). Only the assay buffer and labeled GTP were added to the blank well.

[0680] 5. The reaction was monitored using a Pherastar Plate Reader (BMG) at Ex / Em = (337 / 665; 337 / 620).

[0681] 6. The homogenous time-resolved fluorescence (HTRF) signal was analyzed approximately 25 minutes after the start of the reaction (60 minutes for the G12V reaction).

[0682] 7. The nucleotide exchange activity was expressed as the percentage difference compared to the DMSO reaction value, and the IC 50 value was calculated based on the four-parameter logistic equation in GraphPad 4.0 software.

[0683] HTRF signal = ems 665 / ems 620 * 10000

[0684] The test results are shown in Table 2.

[0685] [Table 2]

[0686] Test results

[0687]

[0688] <Test Example 2: KRAS Nano Bioluminescence Resonance Energy Transfer (NanoBRET) Assay>

[0689] Purpose

[0690] To evaluate the test conditions and procedures for the binding of compounds to the NanoBRET target of KRAS (WT, G12D or G12V) HEK293 cells

[0691] Compound Preparation

[0692] The test compound was dissolved in 10 mM stock, and the reference compounds BI-2582 and MRTX1133 (MedChemExpress) were dissolved in DMSO at 10 mM and 1 mM stock solutions, respectively.

[0693] Cell Culture

[0694] The 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 the American Type Culture Collection (ATCC). HEK293 cells were cultured in Eagle’s Minimal Essential Medium (EMEM) medium supplemented with 10% FBS and 100 μg / mL penicillin-streptomycin in a humidified atmosphere of 5% CO 2 and 95% air at 37°C.

[0695] Test Procedure

[0696] 1. Transfect the NanoBRET KRAS (WT, G12D or G12V)-NanoLuc fusion vector into HEK293 cells.

[0697] 2. Adjust the density of the transfected cells to 2×10 5 cells / mL in phenol red-free Opti-MEM, and mix the 20x K-2 tracer with the cells.

[0698] 3. Distribute the cell and tracer mixture into 384 wells and incubate at 37°C in 5% CO 2Incubate for one hour in the incubator and then leave at room temperature for 15 minutes.

[0699] 4. Treat the substrate and test compound solutions into 384 wells seeded with cells and tracer, and react at room temperature for 15 minutes.

[0700] 5. Measurements were performed using an Envision 2104 plate reader at the donor emission wavelength (460 nm) and the acceptor emission wavelength (600 nm).

[0701] 6. Calculate the BRET ratio by dividing the acceptor emission value (600 nm) by the donor emission value (460 nm), and correct the background by eliminating the BRET ratio not including the tracer.

[0702] 6. Calculate the BRET reaction as the ratio of BRET ratio * 100 when treated with the compound compared to the BRET ratio when treated with DMSO.

[0703] 7. IC 50 values were calculated based on the sigmoidal dose-response equation in the GraphPad Prism 4 program.

[0704] <Test Example 3: Cell Proliferation Assay>

[0705] Purpose

[0706] Cell viability test of test compounds in AsPC-1 pancreatic cancer (KRAS G12D mutation) or SW480 colon cancer (KRAS G12V mutation) cells for 72 hours

[0707] Test Conditions and Procedures

[0708] Materials

[0709] The reference compound staurosporine was purchased from Sigma-Aldrich (St. Louis, MO), and 2.0( 2.0) The luminescent cell viability assay reagent (Catalog No. G9243) was purchased from Promega (Madison, Wisconsin). The AsPC-1 and SW480 cell lines were purchased from the American Type Culture Collection (Manassas, Virginia). The AsPC-1 cells were cultured using RPMI-1640 (ATCC, Catalog No. 30-2001), and the SW480 cells were cultured using Dulbecco’s minimum essential medium (DMEM) (ATCC Catalog No. 30-2002). The media supplemented with 10% FBS (Sigma-Aldrich, Catalog No. F2442) and 100 μg / mL penicillin-streptomycin (Sigma-Aldrich, Catalog No. P4333) were used. The cells were cultured in a humidified atmosphere of 5% CO 2 and 95% air at 37 °C.

[0710] Test Procedure

[0711] 1. Dissolve the test compound and the reference compound staurosporine in DMSO solution to prepare 20 mmol / L (test compound) and 10 mmol / L (control compound, staurosporine) in the source plate, and dilute to 3-fold and 10 doses with DMSO.

[0712] 2. Use an Echo 655 to dispense 10 volumes of 125 nL of the test compound or 25 nL of the reference compound from the source plate into the wells of a 384-well culture plate (VWR, Catalog No. 82050-076).

[0713] 3. Dispense 25 μL of the medium containing 2000 AsPC-1 or SW480 cells into each 384-well cell culture plate.

[0714] 4. Incubate the cells with the compounds at 37 °C and 5% CO 2 for 72 hours.

[0715] 5. Add 25 μL of the CellTiter-Glo 2.0 reagent to each well of the plate.

[0716] 6. Mix the contents on an orbital shaker for 2 minutes and allow the luminescence signal to stabilize at room temperature for 15 minutes.

[0717] 7. Measure the luminescence signal using an EnVision 2104 multilabel reader (PerkinElmer, Santa Clara, California), and determine the number of viable cells by quantifying the ATP present in each culture.

[0718] 8. IC 50 The value is calculated based on the S-type dose response equation in the Graf-Ped prism 4 program.

[0719] The test results are shown in Table 3.

[0720] [Table 3]

[0721] Test results

[0722] Example AsPC-1 SW480 1 C - 2 B - 3 C - 3a C - 4 C - 5 C - 6 B - 6a B B 6b C - 7 C - 8 C - 9 B - 10a C - 10b C - 11 C - 12 B A 13 A A 13a A A 13b C - 14 A A 14a A A 14b B - 15 B - 16 A A 17 A A 18 B A 19 B - 20 - A 21 C - 22 B A 23 B A 24 C B 25 B A 26 B - 27 C - 28 C - 29a A A 29b B -

[0723] (IC 50 < 1 micromole per liter (μM) = A; IC 50 ≥ 1 micromole per liter, < 10 micromoles per liter = B; IC 50 > 10 micromoles per liter = C)

[0724] Although the present disclosure has been specifically shown and described with reference to the exemplary embodiments thereof, it should be understood that various changes in form and detail may be made thereto without departing from the spirit and scope of the present disclosure as defined by the scope of the claims. The exemplary embodiments should be considered as illustrative only and not for the purpose of limitation. Therefore, the scope of the present disclosure is not defined by the specific description of the present disclosure, but by the scope of the claims, and all differences within the scope should be understood to be included in the present disclosure.

Claims

1. A compound selected from the group consisting of compounds of Formula 1 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compounds of Formula 1: [Formula 1] In Formula 1, X is N or CR 11 ; R 1 is a phenyl group which is substituted or unsubstituted by R, 1A a naphthyl group which is substituted or unsubstituted by R, 1A a benzothienyl group which is substituted or unsubstituted by R; 1A ​ Each R 1A is independently selected from 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 a halogen; R 3 is hydrogen, -O-L-W or L is a key or via L A substituted or unsubstituted C 1 -C 3 alkylene; L A is hydrogen, a halogen or C 1 -C 3 alkyl; W is R 6 substituted or unsubstituted C 1 -C 3 alkyl, R 6 substituted or unsubstituted 3- to 10-membered monocyclic heterocycle, or R 6 substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; Each R 6 is independently selected from 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 , side oxygen group (=O), S(C 1 -C 3 alkyl), SO 2 NH 2 , SO 2 NH(C 1 -C 3 alkyl), SO 2 (C 1 -C 3 alkyl), and SO 2 (C 1 -C 3 haloalkyl), or halo C 1 -C 3 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 -substituted or unsubstituted 3- to 10-membered heterocycle, or R 4A -substituted or unsubstituted 5- to 10-membered heteroaryl; Each R 4A is independently selected from hydrogen, CN, NR 9 R 10 , =O, OR 7 , SR 8 , SO 2 R 8 , C(O)N(R 7 ) 2 , C(O)R 7 , an R 4B -substituted or unsubstituted C 1 -C 6 -haloalkyl, an R 4B -substituted or unsubstituted C 1 -C 6 -alkyl, an R 4B -substituted or unsubstituted C 3 -C 10 -cycloalkyl, an R 4B -substituted or unsubstituted C 5 -C 8 -aryl, an R 4B -substituted or unsubstituted 3- to 6-membered heterocycle, and an R 4B -substituted or unsubstituted 5- to 9-membered heteroaryl; Where R 4A The two together form the R 4B Substituted or unsubstituted C 3 -C 10 Cycloalkyl, R 4B Substituted or unsubstituted C 5 -C 8 Aryl, R 4B Substituted or unsubstituted 3- to 10-membered heterocyclic ring, or R 4B a substituted or unsubstituted 5- to 10-membered heteroaryl group; Each R 4B is independently selected from 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, halo C 1 -C 3 alkoxy, hydroxy, SCH 3 , SO 2 NH 2 , SO 2 CH 3 , C(O)NH 2 , C(O)CH 3 , a 3- to 6-membered heterocycle, C 5 -C 8 aryl, and a 5- or 6-membered heteroaryl; Each R 5 is independently selected from hydrogen, hydroxy, halogen, C 1 -C 3 -haloalkyl and C 1 -C 3 -alkyl, Each R 7 is independently selected from hydrogen, an amino group, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, and a 3- or 4-membered heterocycle; Each R 8 is independently selected from hydrogen, an amino group, and C 1 -C 3 alkyl; R 9 and R 10 each independently selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C(O)NH 2 -, C(O)CH 3 -, and 3- to 6-membered heterocycles; Each R 11 is independently selected from hydrogen, hydroxy, halogen, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl, n is an integer selected from 0 to 2; and wherein the heterocycle or heteroaryl each contains from 1 to 3 heteroatoms independently selected from N, O and S.

2. The compound according to claim 1, wherein L is methylene; W is a 3- to 10-membered monocyclic heterocycle which is substituted or unsubstituted by R 6 or a 6- to 14-membered bicyclic heterocycle which is substituted or unsubstituted by R; and 6 ​ Each R 6 is independently selected from halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, =CH 2 , =O, SCH 3 , SO 2 NH 2 , SO 2 NH(CH 3 ), SO 2 CH 3 and SO 2 CF 3 .

3. The compound according to claim 1, wherein L is methylene; Each W is independently R 6 substituted or unsubstituted and Each R 6 is independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, =CH 2 , =O, SCH 3 , SO 2 NH 2 , SO 2 NH(CH 3 ), SO 2 CH 3 and SO 2 CF 3 .

4. The compound according to claim 1, wherein R 4 is an R 4A substituted or unsubstituted C 1 -C 3 alkyl group; Each R 4A are independently selected from hydrogen, halogen, CN, NH 2 NH(C 1 -C 3 Alkyl), N(C 1 -C 3 alkyl) 2 , =O, through R 4C Substituted or unsubstituted C 3 -C 6 Cycloalkyl, R 4C Substituted or unsubstituted phenyl, R 4C Substituted or unsubstituted pyridyl, R 4C Substituted or unsubstituted pyrimidinyl, and R 4C a substituted or unsubstituted pyrazinyl group; or wherein R 4A together form a 5- to 10-membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; and Each R 4C is independently selected from hydrogen, halogen, C 1 -C 3 -alkyl, NH 2 , NH(C 1 -C 3 -alkyl), and N(C 1 -C 3 -alkyl) 2 .

5. The compound according to claim 1, wherein X is CR 11 , Each R 11 is independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl; R 1 is a benzo[b]thienyl group which is substituted or unsubstituted by R 1A ; a substituted or unsubstituted benzo[b]thienyl group Each R 1A is independently selected from hydrogen, halogen, NH 2 , NH(C 1 -C 3 -alkyl), N(C 1 -C 3 -alkyl) 2 and CN.

6. The compound according to claim 1, wherein R 1 is independently selected from one or more substituents of hydrogen, hydroxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, amino and CN, or is unsubstituted by said one or more substituents R 2 is F; R 3 is hydrogen, -O-L-W or L is methylene; W is each independently R 6 substituted one to three times or unsubstituted by R 6 substituted Each R 6 is independently selected from hydrogen, halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, =CH 2 and =O; R 4 is independently selected from one or more substituents of hydrogen, halogen, C 1 -C 3 alkyl, NH 2 , NH(C 1 -C 3 alkyl), and N(C 1 -C 3 alkyl) 2 and is unsubstituted or substituted by one or more of the foregoing substituents And n is selected from 1 and 2.

7. The compound according to claim 1, wherein the compound is selected from the group consisting of the following compounds and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the following compounds:

8. A pharmaceutical composition for treating cancer, comprising as an active ingredient a compound selected from the compounds as defined in any one of claims 1 to 7 and stereoisomers, diastereoisomers, enantiomers, configurational isomers, isotopic variants, tautomers, solvates and pharmaceutically acceptable salts of the compounds as defined in any one of claims 1 to 7.

9. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition exhibits inhibition activity against the Kirsten rat sarcoma viral oncogene homolog protein.

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