Novel triheterocyclic compounds

Abstract

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

Description

NOVEL TRIHETEROCYCLIC COMPOUNDS

[0001] The present disclosure relates to novel triheterocyclic compounds, and more specifically to novel triheterocyclic compounds useful as KRAS protein inhibitors, and a pharmaceutical composition including the same for treating cancers.

[0002] The RAS gene is responsible for signal transduction within the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) pathways, and is known as an oncogene due to frequent mutations. The RAS gene family is divided into KRAS, NRAS, and HRAS, in which these three genes encode four proteins, the splice variants K-Ras4A and K-Ras4B, N-Ras, and H-Ras. K-Ras is the most frequently mutated isoform in Ras-induced cancer (86%), followed by N-Ras (11%) and H-Ras (3%) (Non-patent Document 1). For example, oncogenic changes in KRAS are 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, mostly located at codons 12, 13, and 61, constitutively activate RAS proteins and are detected in various types of human cancer. 98% of tumor Ras mutations are found in active site amino acid residues G12, G13 and Q61, and these mutations impair intrinsic and GAP-mediated GTP hydrolysis 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 the mutations of codon 12. Additionally, mutations at codon 13 Gly→Asp (G13D) (7%) and codon 61 Gln→His (Q61H) (0.6%) are also (Non-patent Document 1).

[0004] The well-known role of KRAS in malignant tumors and reports of mutations in KRAS in various tumor types indicate that KRAS may be an efficient target for cancer therapy. The present inventors developed a new KRAS inhibitor, thereby completing the present invention.

[0005] [Prior art documents]

[0006] (Non-Patent Document 1)Scientific Reports6(1):21949

[0007] (Non-Patent Document 2)J Cancer Metastasis Treat2021;7:26

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

[0009] 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 thereof; and a pharmaceutical composition including the same for treating cancers.

[0010] According to an aspect of an embodiment, provided is a compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0011] According to an aspect of another embodiment, provided is a pharmaceutical composition including the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0012] The present disclosure relates to novel triheterocyclic compounds useful as KRAS protein inhibitors, and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof, and a pharmaceutical composition including the same for treating cancers.

[0013] Hereinafter, the present disclosure will be described in more detail.

[0014] All technical terms used in the present disclosure, unless defined otherwise, are used with the same meaning as commonly understood by those skilled in the art associated with the present disclosure. In addition, although preferred methods or samples are described in this specification, those similar or equivalent thereto are also included in the scope of the present disclosure.

[0015] Also, the numerical values set forth herein are considered to include the meaning of "about" unless explicitly stated. All publications disclosed as references herein are incorporated in their entirety by reference.

[0016]

[0017] Triheterocyclic compounds

[0018] According to an aspect of an embodiment, provided is a compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0019] [Formula 1]

[0020]

[0021] In Formula 1,

[0022] X is N or CR11;

[0023] R1is R1A-substituted or unsubstituted phenyl, R1A-substituted or unsubstituted naphthyl, R1A-substituted or unsubstituted benzothiophenyl;

[0024] each R1Ais independently selected from hydrogen, hydroxy, a halogen, C1-C3haloalkyl, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C3alkoxy, C3-C6cycloalkyl, NH2, NH(C1-C3alkyl), N(C1-C3alkyl)2, and CN;

[0025] R2is hydrogen or a halogen;

[0026] R3is hydrogen, -O-L-W, or ;

[0027] L is a bond or LA-substituted or unsubstituted C1-C3alkylene;

[0028] LAis hydrogen, a halogen, or C1-C3alkyl;

[0029] W is R6-substituted or unsubstituted C1-C3alkyl, R6-substituted or unsubstituted 3- to 10-membered monocyclic heterocycle, or R6-substituted or unsubstituted 6- to 14-membered bicyclic heterocycle;

[0030] each R6is independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C3alkoxy, C3-C6cycloalkyl, amino, CN, =CH2, oxo(=O), S(C1-C3alkyl), SO2NH2, SO2NH(C1-C3alkyl), SO2(C1-C3alkyl), and SO2(C1-C3haloalkyl), or halo C1-C3alkoxy;

[0031] R4is hydrogen, R4A-substituted or unsubstituted C1-C6haloalkyl, R4A-substituted or unsubstituted C1-C6alkyl, R4A-substituted or unsubstituted C3-C10cycloalkyl, R4A-substituted or unsubstituted C5-C8aryl, R4A-substituted or unsubstituted 3- to 10-membered heterocycle, or R4A-substituted or unsubstituted 5- to 10-membered heteroaryl;

[0032] each R4Ais independently selected from hydrogen, CN, NR9R10, =O, OR7, SR8, SO2R8, C(O)N(R7)2, C(O)R7, R4B-substituted or unsubstituted C1-C6haloalkyl, R4B-substituted or unsubstituted C1-C6alkyl, R4B-substituted or unsubstituted C3-C10cycloalkyl, R4B-substituted or unsubstituted C5-C8aryl, R4B-substituted or unsubstituted 3- to 6-membered heterocycle, and R4B-substituted or unsubstituted 5- to 9-membered heteroaryl;

[0033] wherein two of R4Atogether form R4B-substituted or unsubstituted C3-C10cycloalkyl, R4B-substituted or unsubstituted C5-C8aryl, R4B-substituted or unsubstituted 3- to 10-membered heterocycle, or R4B-substituted or unsubstituted 5- to 10-membered heteroaryl;

[0034] each R4Bis independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C3-C6cycloalkyl, CN, NR9R10, =O, C1-C3alkoxy, halo C1-C3alkoxy, hydroxy, SCH3, SO2NH2, SO2CH3, C(O)NH2, C(O)CH3, a 3- to 6-membered heterocycle, C5-C8aryl, and 5- or 6-membered heteroaryl;

[0035] each R5is independently selected from hydrogen, hydroxy, a halogen, C1-C3haloalkyl, and C1-C3alkyl,

[0036] each R7is independently selected from hydrogen, amino, C1-C3haloalkyl, C1-C3alkyl, C3-C6cycloalkyl, and a 3- or 4-membered heterocycle;

[0037] each R8is independently selected from hydrogen, amino, and C1-C3alkyl;

[0038] R9and R10are each independently selected from hydrogen, C1-C3alkyl, C3-C6cycloalkyl, C(O)NH2, C(O)CH3, and a 3- to 6-membered heterocycle;

[0039] each R11is independently selected from hydrogen, hydroxy, a halogen, C1-C3haloalkyl, and C1-C3alkyl,

[0040] n is an integer selected from 0 to 2; and

[0041] wherein the heterocycles or heteroaryls each comprise 1 to 3 heteroatoms independently selected from N, O, and S.

[0042]

[0043] In an embodiment, L is methylene;

[0044] W is R6-substituted or unsubstituted 3- to 10-membered monocyclic heterocycle or R6-substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; and

[0045] each R6is independently selected from a halogen, C1-C3haloalkyl, C1-C3alkyl, C1-C3alkoxy, CN, =CH2, =O, SCH3, SO2NH2, SO2NH(CH3), SO2CH3, andSO2CF3.

[0046]

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

[0048] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0049]

[0050] In an embodiment, wherein L is methylene;

[0051] each W is independently R6-substituted or unsubstituted

[0052] , , , , , , , , , , , , , , , , , or ; and

[0053] each R6is independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C1-C3alkoxy, CN, =CH2, =O, SCH3, SO2NH2, SO2NH(CH3), SO2CH3, andSO2CF3.

[0054]

[0055] In one embodiment, for example, W may be 1-methylpyrrolidinyl ( ), 1-(2,2-difluoroethyl)azetidine ( ), 2-fluorohexahydro-1H-pyrrolizinyl ( ), 2,6-dimethylidenehexahydro-1H-pyrrolizinyl ( ), 1-methyloctahydro-1H-cyclopenta[b]pyridine ( ), or 2-oxabicyclo[2.1.1]hexane ( ), but is not limited thereto.

[0056] In one embodiment, for example, W may be a substituted 4-membered to 10-membered heterocycle. For example, W may be morpholine ( ), but is not limited thereto.

[0057]

[0058] In an embodiment, wherein R4is R4A-substituted or unsubstituted C1-C3alkyl;

[0059] each R4Ais independently selected from hydrogen, a halogen, CN, NH2, NH(C1-C3alkyl), N(C1-C3alkyl)2, =O, R4C-substituted or unsubstituted C3-C6cycloalkyl, R4C-substituted or unsubstituted phenyl, R4C-substituted or unsubstituted pyridinyl, R4C-substituted or unsubstituted pyrimidinyl, and R4C-substituted or unsubstituted pyrazinyl;

[0060] or wherein two of R4Atogether form 5- to 10-membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; and

[0061] each R4Cis independently selected from hydrogen, a halogen, C1-C3alkyl, NH2, NH(C1-C3alkyl), and N(C1-C3alkyl)2.

[0062]

[0063] In one embodiment, R4may be substituted or unsubstituted C1-C6alkyl, C3-C10cycloalkyl, azetidinyl, pyrrolizinyl, or pyridinyl, but is not limited thereto.

[0064] In one embodiment, R4may be C3-C10cycloalkyl including spiro C3-C10cycloalkyl, each substituted or unsubstituted by R4A. For example, R4may be each substituted or unsubstituted spiro[3.3]alkanyl (e.g., ), but is not limited thereto.

[0065] In one embodiment, R4may be substituted with halogen, amino, (C1-C6alkyl)amino, di(C1-C6alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C3-C10cycloalkyl), di( C1-C6alkyl)amino(C3-C10cycloalkyl), or 1-morpholino(C3-C10cycloalkyl) (e.g., 1-morpholin-4-ylcyclobutyl( )), but is not limited thereto.

[0066] R4may be for example, C1-C6alkyl or C3-C10cycloalkyl substituted with halogen, amino, (C1-C6alkyl)amino, di(C1-C6alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino (C3-C10cycloalkyl), di(C1-C6alkyl)amino(C3-C10cycloalkyl), or 1-morpholin-4-ylcyclobutyl.

[0067] R4may be, for example, unsubstituted azetidinyl or unsubstituted pyrrolizinyl. R4may be, for example, amino substituted spiro[3.3]heptanyl, amino substituted pyridine, or amino substituted C3-C10cycloalkyl.

[0068]

[0069] In an embodiment, wherein X is CR11,

[0070] each R11is independently selected from hydrogen, a halogen, C1-C3haloalkyl, and C1-C3alkyl;

[0071] R1is R1A-substituted or unsubstituted benzothiophenyl;

[0072] each R1Ais independently selected from hydrogen, a halogen, NH2, NH(C1-C3alkyl), N(C1-C3alkyl)2, and CN.

[0073]

[0074] In an embodiment, wherein R1is , , or

[0075] each substituted or unsubstituted with one or more substituents independently selected hydrogen, hydroxy, a halogen, C1-C3alkyl, C3-C6cycloalkyl, amino, and CN;

[0076] R2is F;

[0077] R3is hydrogen, -O-L-W, or ;

[0078] L is methylene;

[0079] W is , , , , , , , , , , , , , , , , , or ,

[0080] each substituted or unsubstituted 1 to 3 times by R6;

[0081] each R6is independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C1-C3alkoxy, CN, =CH2, and =O;

[0082] R4is , , , , , , , , , , , , , , , , or ,

[0083] each substituted or unsubstituted with one or more substituents independently selected from hydrogen, a halogen, C1-C3alkyl, NH2, NH(C1-C3alkyl), and N(C1-C3alkyl)2; and

[0084] n is selected from 1 and 2.

[0085]

[0086] In an embodiment, wherein the compound is selected from the group consisting of the following compounds and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof:

[0087] , ,

[0088] , ,

[0089] , ,

[0090] , ,

[0091] , ,

[0092] , ,

[0093] , ,

[0094] , ,

[0095] , ,

[0096] , ,

[0097] , ,

[0098] , ,

[0099] , ,

[0100] , ,

[0101] , ,

[0102] , ,

[0103] , ,

[0104] , ,

[0105] , ,

[0106] , ,

[0107] , ,

[0108] , ,

[0109] , ,

[0110] , ,

[0111] and .

[0112]

[0113] According to an aspect of another embodiment, provided is a pharmaceutical composition including the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0114] In an embodiment, wherein the pharmaceutical composition exhibits KRAS protein inhibitory activity.

[0115]

[0116] Definitions

[0117] The term "halogen" used herein refers to fluorine, chlorine, bromine or iodine, unless stated otherwise.

[0118] The term "alkyl" used herein refers to a straight-chain or branched, saturated, monovalent hydrocarbon group, unless stated otherwise.

[0119] The term "alkylene" used herein refers to a divalent straight-chain or branched hydrocarbon group having (-CH2-)n, and includes, but is not limited to, methylene, ethylene, propylene, butylene, isobutylene, etc., unless stated otherwise.

[0120] The term "alkenyl" used herein refers to a monovalent hydrocarbon group including at least one carbon-carbon double bond, where each double bond has anE-orZ-type configuration, unless stated otherwise.

[0121] The term "alkynyl" used herein refers to refers to a monovalent hydrocarbon radical including at least one carbon-carbon triple bond, unless stated otherwise.

[0122] The term "alkoxy" used herein refers to a straight-chain or branched hydrocarbon residue linked by oxygen, unless stated otherwise.

[0123] The term "aryl" used herein refers to an aromatic group that may be substituted or unsubstituted, and includes monocyclic, bicyclic, or more than bicyclic aromatic groups that may be substituted or unsubstituted, and may include unsaturated or partially saturated aryl, unless stated otherwise. For examples, it includes, but is not limited to, C6-15aryl, and may include, but is not limited to, phenyl, biphenyl, naphthyl, toluyl etc.

[0124] The term "heteroaryl" used herein refers to an aromatic group including one or more heteroatoms selected from N, O, and S, that may be substituted or unsubstituted, and includes monocyclic, bicyclic, or more than bicyclic aromatic groups that may be substituted or unsubstituted, and may include unsaturated or partially saturated heteroaryl, unless stated otherwise. For examples, it includes, but is not limited to, C4-15heteroaryl, and may include, but is not limited to, morpholinyl, piperidinyl, pyrrolidinyl, or pyrrolizinyl etc.

[0125] The term "fused heteroaryl" used herein refers to an unsaturated or partially saturated, substituted or unsubstituted ring system in which the heteroaryl group is linked in a fused manner with another aryl, heteroaryl or heterocycloalkyl group, unless stated otherwise. For example, it may include a C8-20heteroaryl, and may include, but is not limited to, a 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered or 15-membered benzo-fused heteroaryl group. For example, it may include, but is not limited to, a 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system. For example, it may include, but is not limited to, pyrrolizine, benzothiazole, benzothiazolinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, benzothionyl, indolyl, isoindolinyl, indazolyl, indazolinyl, benzimidazolinyl, benzoxazolinyl, benzisoxazolinyl, benzothiadiazolinyl, benzoxadiazolinyl, benztriazolinyl, quinolinyl, isoquinolinyl, quinazolinyl, etc.

[0126] The term "partially saturated" used herein refers to including at least one saturated site, i.e., at least one single bond, within an aryl, heteroaryl, or fused heteroaryl ring as defined above. The term "unsaturated" used herein refers to an aryl, heteroaryl, or fused heteroaryl ring as defined above that does not include a saturated site, i.e., a single bond.

[0127] The term "cycloalkyl" used herein refers to a saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic hydrocarbon ring that may be substituted or unsubstituted, and it may include bridged cycloalkyl, fused cycloalkyl, and spirocycloalkyl, unless stated otherwise. For example, it includes, but is not limited to, C3-10cycloalkyl or C3-6cycloalkyl, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "cycloalkylene" used herein refers to a radical (divalent radical) derived from cycloalkene. The term "heterocycloalkyl" used herein refers to cycloalkyl including one or more heteroatoms selected from N, O, and S, that may be substituted or unsubstituted, and includes monocyclic, bicyclic, or more than bicyclic aromatic groups that may be substituted or unsubstituted, unless stated otherwise.

[0128] The term "heterocycle" used herein refers to a saturated, partially unsaturated, or aromatic ring, monocyclic, bicyclic, or polycyclic ring comprising one or more heteroatoms selected from N, O, and S, which may be substituted or unsubstituted, and it may include bridged heterocycles, fused heterocycles, and spiroheterocycles, unless otherwise specified. For example, it includes, but is not limited to, C4-15heterocycloalkyl and may include, but is not limited to, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, imidazolidinyl, pyrrolidin-2-one, pyrrolizinyl, or pyrrolyl, etc. The heterocycles may be carbon linkages or heteroatom linkages, for example, it may be connected to the base molecule through a cyclic atom (may be C or N). For example, the heterocycle connected to the base molecule through the nitrogen of the ring atoms of the heterocycle may include, but is not limited to, N-morpholinyl, N-piperidinyl, N-pyrrolidinyl, or N-pyrrolyl, etc.

[0129] The term "fused heterocycle" or "fused cycloalkyl" used herein refers to a substituted or unsubstituted ring system, and it can be classified into bicyclic, tricyclic, tetracyclic, or more polycyclic fused cycloalkyl, depending on the number of rings, unless stated otherwise. Fused cycloalkyls are polycyclic rings in which each ring shares an adjacent pair of carbon atoms with the other ring, and one or more rings may share one or more double bonds, but none of these rings has a fully conjugated ð-electron system. For example, it includes, but is not limited to, C3-20fused cycloalkyl and may include, but is not limited to, a 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system depending on the number of atoms forming each of the two rings being fused. A bicyclic fused cycloalkyl also referred to as "bicycloalkyl" or "bicyclic heterocycle" includes any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring.

[0130] The term "fused heterocycloalkyl" used herein refers to a substituted or unsubstituted fused cycloalkyl including one or more heteroatoms selected from N, O, and S, for example, it includes, but is not limited to, C8-20fused heterocycloalkyl. For example, bicyclic fused heterocycloalkyl is also referred to as "heterobicycloalkyl" and it includes, but is not limited to, a 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system depending on the number of atoms forming each of the two rings being fused. For example, it may be hexahydro-1H-pyrrolizine, but is not limited thereto.

[0131] The term "stereoisomers" used herein refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. It is a compound that has the same chemical or molecular formula but is optically or sterically different. The term "enantiomers" used herein refers to various stereoisomers and geometric isomers that may exist for the compound according to the present disclosure. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.

[0132] Compounds described herein may have asymmetric centers, geometric centers (e.g., double bonds), or both. Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of the structure are intended.

[0133] Compounds of Formula 1 according to one aspect of the present disclosure may have an asymmetric carbon center (asymmetric carbon) and therefore may exist as enantiomers (RorSisomers), racemates, diastereomers, or any mixtures thereof, and all these isomers and mixtures are included within the scope of the present disclosure.

[0134] The compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. In some embodiments, the compounds described herein have one or more chiral centers. It is understood that if an absolute stereochemistry is not expressly indicated, then each chiral center may independently be of the R-configuration or the S-configuration or a mixture thereof. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures of R-enantiomer and S-enantiomer, and enantio-enriched stereomeric mixtures comprising of R- and S-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0135] Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries.

[0136] The term "atropisomers" used herein refers to all stereoisomers that can be separated from each other. It is an isomer that occurs when the single bond formed between carbon and carbon among the bonds that make up the compound cannot rotate freely due to a bulky substituent. It refers to stereoisomers resulting from an asymmetric axis and includes complete isolation of stable non-interconverting diastereomeric or enantiomeric species. Additionally, it can result from limited rotation around a single bond, where rotational barriers are high enough to allow differentiation of isomeric species.

[0137] Compounds according to one embodiment may generate atropisomers with a high probability.

[0138] The term "tautomers" used herein refers to one of two or more structural isomers that readily convert from one isomeric form to another and that exist in equilibrium. Compounds according to one embodiment may also include "tautomers". The tautomers result from the exchange of a single bond with an adjacent double bond and the concomitant transfer of the proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. The tautomeric forms may be in equilibrium or sterically fixed in one form by appropriate substitution.

[0139] The term "solvates" used herein may include a molecular complex comprising a compound of Formula 1 and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. Complexes where the solvent molecule is water are also referred to as "hydrates."

[0140] The term "pharmaceutically acceptable salts" used herein includes any salt as long as it has low toxicity to the human body and does not adversely affect the biological activity and physicochemical properties of the parent compound.

[0141] Compounds according to one embodiment may include "isotopic variants." The present disclosure also encompasses isotopically-labeled compounds which are identical to those compounds as 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 usually found in nature ("isotopologues"). The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constituted such compounds. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H ("D"),3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound described herein can have one or more H atoms replaced with deuterium.

[0142] Generally, reference to or depiction of a certain 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, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium,14C,32P and35S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0143] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C- enriched carbon are within the scope of the present disclosure.

[0144] In some embodiments, certain isotopically-labeled compounds, such as those labeled with3H and14C, can be useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes can be particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. Isotopically-labeled compounds can generally be prepared by following procedures analogous to those disclosed herein, for example, in the Examples section, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0145] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0146] The term "treatment" used herein includes treatment, improvement, amelioration, or management of disease. The term "treating" or "treatment" used herein refers to inhibiting disease, for example, inhibiting a disease, condition or disorder, preventing further development of pathology and / or symptoms, improving disease, or reversing pathology and / or symptoms, for example, reducing the severity of the disease, in a subject who experiences or shows a pathology or symptom of a disease, condition or disorder.

[0147] The term "preventing" or "prevention" used herein refers to prevention of a disease, for example, prevention of a disease, condition, or disorder in a subject that may be predisposed to have the disease, condition, or disorder but have not yet experienced or exhibited pathology or a symptom of the disease.

[0148] The term "subject" or "patient" used herein refers to any animal, including mammals, for example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates and humans.

[0149] The terms "having," "may have," "including," or "may include" may refer to the presence of a feature (e.g., a component such as a number, component, etc.), and does not exclude the presence of additional features.

[0150]

[0151] KRAS protein inhibitor

[0152] Kirsten Rat Sarcoma Virus Oncogene Homolog (KRAS) is a GTPase that integrates signals from outside the cell into intracellular proliferation and survival signals and it is a member of the small GTPase family of Ras, Rho, Rab, Arf, and Ran. It receives signals from various receptor tyrosine kinases, especially EGFR at the upper level, and transmits signals mainly to Raf and PI3K at the lower level through the GTPase cycle of KRAS, thereby regulating various processes including cell proliferation.

[0153] KRAS plays a significant role in cancer, but inhibiting its activity has been challenging due to the structure of the protein. Attempts to block signaling have shown some promise but have also presented issues with toxicity and treatment resistance. However, the discovery of the switch II pocket and compounds that bind to mutant cysteine have led to the development of adagrasib and sotorasib, which have been approved by the FDA for non-small cell lung cancer.

[0154] Compounds of the present disclosure are novel KRAS inhibitor compounds that inhibit a mutation in any one of KRAS codons 12, 13, and 61, such as at least one of, but not limited to, KRAS G12D, KRAS G12V, KRAS G12C, KRAS G13D, and KRAS Q61H mutations.

[0155]

[0156] Pharmaceutical compositions

[0157] According to an aspect of another embodiment, provided is a pharmaceutical composition including the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof for the treatment of cancer.

[0158] In one embodiment, the composition may comprise the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts as a therapeutically effective amount.

[0159] In one embodiment, the composition may comprise other therapeutic drugs in addition to the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts.

[0160] In one embodiment, the composition may further include a pharmaceutically acceptable carrier or excipient.

[0161] In one embodiment, the composition may comprise the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts or other therapeutic drugs in the range of 0.005% to 100%, and a pharmaceutically acceptable carrier or excipient may be included in the remaining range.

[0162] In one embodiment, the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, or the pharmaceutical composition including the same can be used for cancer treatment.

[0163] In one embodiment, the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, or the pharmaceutical composition including the same can exhibit KRAS protein inhibitory activity.

[0164] According to an aspect of another embodiment, provided is a use for the treatment of cancer using the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, or the pharmaceutical composition including the same.

[0165]

[0166] Route and form of administration

[0167] The compounds and pharmaceutical compositions of the present disclosure may be provided in any suitable administration route and dosage form acceptable in the pharmaceutical arts.

[0168]

[0169] Manufacturing method

[0170] 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, are known in the literature, or can be prepared by a person skilled in the art by selecting an appropriate synthetic method among known organic synthesis techniques. Some compounds of the present disclosure can be synthesized using the schemes, examples, or intermediates described herein. Those skilled in the art will recognize that reaction times, number of equivalents of reagents, and / or temperature may be modified from the synthetic methods described herein, and different work-up and / or purification techniques may be utilized.

[0171] The structure of the synthesized compound can be verified by methods known to those skilled in the art, such as nuclear magnetic resonance (NMR) spectroscopy and / or mass spectroscopy.

[0172]

[0173] General information

[0174] Unless otherwise stated, reagents and solvents obtained from commercial suppliers were used without purification or drying.1H NMR was recorded using Bruker 400 MHz and 500 MHz and TMS was used as an internal standard. LCMS analysis was performed on a Waters UPLC with a SQD-2 mass detector (Single quadruple), and HPLC analysis was performed on an Acquity UPLC H CLASS (WATERS).

[0175]

[0176] The numerical values described in this specification are considered to include the meaning of "about" even if not specified. The term "about" means within 5% of a predetermined value or range, preferably within 1% to 2%.

[0177] In this specification, the numerical range expressed using the term "to" includes a range including the numerical values written before and after the term "to" as the lower limit and upper limit, respectively.

[0178] All references, publications, issued patents, and patent applications cited within the text of this specification are hereby incorporated by reference in their entirety for all purposes.

[0179]

[0180] Examples

[0181] Hereinafter, the present disclosure will be described in more detail with reference to the following Examples and Experimental Examples. However, Examples and Experimental Examples are intended to help understand the present disclosure, and the scope of the present disclosure is not limited thereto in any sense.

[0182]

[0183] 1. Synthetic scheme for Example 1

[0184]

[0185]

[0186] Experimental procedures for 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

[0187]

[0188] Step 1: 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1-Int-2)

[0189] To a stirred solution of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-oneExample 1-Int-1(5.00 g, 18.9 mmol) in MeOH (50 mL, 10 vol) was added 0.1M NaOH (25.0 mL, 5 vol) at room temperature and stirred for 30 min, followed by an addition of Ethyliodide (2.20 mL, 28.4 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and acidified with conc. HCl up to pH~4 to get solid, the solid was filtered, washed with water and dried under high vacuum to get crude compound 5,7-Dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-oneExample 1-Int-2(4.80 g, crude) as a light brown solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 294.12m / z[M+H].

[0190]

[0191] 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-Int-5)

[0192] To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-olExample 1-Int-4(1.17 g, 6.80 mmol) in THF (10 mL, 10 vol) was added NaH (0.67 g, 15.3 mmol) at 0℃ and stirred for 1 h at 0℃. To this was added 5,7-Dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-oneExample 1-Int-2(1.00 g, 3.40 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 4 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with 10% methanol in DCM (2 x 30 mL), combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-oneExample 1-Int-5(1.20 g, crude) as a yellow liquid. The crude compound was used as such in next step without further purification. MS (LC-MS): 430.33m / z[M+H].

[0193]

[0194] * Synthesis of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-ol (Example 1-Int-4)

[0195] Step 1a:To a stirred solution of 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amineExample 1-Int-3(1.00 g, 7.80 mmol) in THF (10 mL, 10 vol) was added 2-bromoethan-1-ol (0.97 g, 7.80 mmol) and TEA (3.26 mL, 23.4 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. 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 filtered to get filtrate, the filtrate was concentrated under reduced pressure to get crude compound 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-olExample 1-Int-4(1.40 g, crude) as a yellow liquid. The crude compound was used as such in next step without further purification. MS (LC-MS): 173.48m / z[M+H].

[0196]

[0197] 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-Int-6)

[0198] 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)-oneExample 1-Int-5(1.00 g, 2.32 mmol) in DCM (15 mL, 15 vol) was added BOP-Cl (2.07 g, 8.14 mmol) and DIPEA (6.07 mL, 34.9 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with water ice cold water (20 mL) and extracted with 10% methanol in DCM (2 x 50 mL), combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by reverse phase column chromatography using C18 column, eluted with 60% ACN in water to afford 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-amineExample 1-Int-6(0.45 g, Y: 47%) as a white solid. MS (LC-MS): 412.36m / z[M+H].

[0199]

[0200] Step 4: 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1-Int-8)

[0201] To a stirred solution of 1-((5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 1-Int-6(0.45 g, 1.09 mmol) in a mixture of solvents 1,4-dioxane and water (3:1, 20 mL) was added K3PO4(0.81 g, 3.82 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneExample 1-Int-7(0.39 g, 1.09 mmol) at room temperature and degassed under argon for 15 min. To this was added Ruphos PdG3(0.092 g, 0.11 mmol) at room temperature and the reaction mixture was heated to 90℃ and stirred for 1 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with 10% methanol in DCM (2 x 50 mL), combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 1-Int-8(0.61 g, crude) as a reddish solid. MS (LCMS): 610.48m / z[M+H].

[0202]

[0203] Step 5: 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1-Int-9)

[0204] To a stirred solution of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 1-Int-8(0.60 g, 0.98 mmol) in a mixture of solvents ACN and water (4:1, 20 mL) was added Oxone (3.02 g, 9.83 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 2 h. 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 10% methanol in DCM (2 x 30 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get residue. The residue was washed with 20% THF in Hexane solution to get solid, the solid was filtered and dried under high vacuum to get crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 1-Int-9(0.30 g, crude) as a brown color solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 642.44m / z[M+H].

[0205]

[0206] 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-Int-10)

[0207] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanolExample 1-Int-9(0.099 g, 0.62 mmol) in toluene (10 mL, 30 vol) was added NaOtBu (0.06 g, 0.62 mmol) at 0℃ and stirred for 15 min, followed by an addition of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine(0.33 g, 0.51 mmol) at 0℃. The reaction mixture was allowed to warm up to room temperature and stirred for 4 h. 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 (2 x 15 mL), combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get 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-amineExample 1-Int-10(0.32 g, crude) as a yellow solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 707.58m / z[M+H].

[0208]

[0209] 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)

[0210] To a stirred solution of 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 1-Int-10(0.32 g, 0.45 mmol) was added 4M HCl in 1,4-dioxane (5.0 mL) at 0℃ and the reaction mixture was stirred at 0℃ for 1 h. Progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude was purified by Prep-HPLC to affordExample 1(0.037 g, Y: 12%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 0.80 (t,J= 7.38 Hz, 3H), 1.65-1.85 (m, 7H), 1.96 (brs, 1H), 2.03-2.13 (m, 4H), 2.23 (s, 6H), 2.26-2.30 (m, 1H), 2.36-2.42 (m, 1H), 2.79-2.85 (m, 1H), 3.01 (brs, 1H), 3.08 (d,J= 6.50 Hz, 2H), 3.97-4.25 (m, 6H), 4.57 (t,J= 4.88 Hz, 2H), 5.21-5.34 (m, 1H), 7.01 (d,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): 663.47m / z[M+H].

[0211]

[0212] 2. Synthetic scheme for Example 2

[0213]

[0214]

[0215] Experimental procedures 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[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0216]

[0217] Step 1: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2-Int-2)

[0218] To a stirred solution of 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4(3H)-oneExample 2-Int-1(7.60 g, 28.69 mmol) in MeOH (477 mL, 63 vol) was added 0.1M NaOH (477 mL, 240.99 mmol) and MeI (3.30 mL, 40.17 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 h. 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 conc. HCl up to pH~6 to get solid, the solid was filtered, washed with water and dried under high vacuum to get crude compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-oneExample 2-Int-2(4.0 g, crude) as an off-white solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 279.97m / z[M+H].

[0219]

[0220] 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-Int-3)

[0221] To a stirred solution of 2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethan-1-olExample 1-Int-4(0.37 g, 2.16 mmol) in THF (10 mL, 20 vol) was added NaH (0.35 g, 8.09 mmol) at 0℃ and stirred for 1 h at 0℃. To this was added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-oneExample 2-Int-2(0.50 g, 1.80 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (2 x 30 mL), combined organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-oneExample 2-Int-3(0.40 g, crude) as a yellow liquid. The crude compound was used as such in next step without further purification. MS (LC-MS): 416.29m / z[M+H].

[0222]

[0223] 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-Int-4)

[0224] 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)-oneExample 2-Int-3(0.40 g, 0.96 mmol) in DCM (10 mL, 25 vol) was added BOP-Cl (0.86 g, 3.36 mmol) and DIPEA (2.51 mL, 14.42 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 2 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by reverse phase column chromatography using C18 column, eluted with 60% ACN in water to afford 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-amineExample 2-Int-4(0.30 g, Y: 78%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 1.65-1.69 (m, 2H), 1.80 (brs, 2H), 2.08 (brs, 2H), 2.27 (brs, 3H), 2.54 (s, 6H), 3.17 (d,J= 5.00 Hz, 2H), 4.00-4.11 (m, 2H), 4.20 (brs, 2H). MS (LC-MS): 398.32m / z[M+H].

[0225]

[0226] Step 4: 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-6)

[0227] To a stirred solution of 1-((5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-4(0.28 g, 0.71 mmol) in a mixture of solvents 1,4-dioxane and water (4:1, 5.0 mL) was added K3PO4(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)triisopropylsilaneExample 2-Int-5(0.36 g, 0.71 mmol) at room temperature and degassed under argon for 15 min. To this was added Ruphos PdG3(0.06 g, 0.07 mmol) at room temperature and the reaction mixture was heated to 100℃ and stirred for 1 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude compound. The crude compound was purified by reverse phase column chromatography using C18 column, eluent with 80% ACN and H2O to afford 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-6(0.30 g, Y: 56%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 0.86 (dd,J= 7.38, 3.63 Hz, 18H), 1.13-1.18 (m, 3H), 1.67-1.87 (m, 4H), 2.06-2.15 (m, 2H), 2.24 (s, 6H), 2.53 (s, 3H), 3.42-3.44 (m, 3H), 3.91-4.02 (m, 3H), 4.40-4.48 (m, 2H), 4.59-4.63 (m, 1H), 5.34 (d,J= 10.81 Hz, 2H), 7.31 (d,J= 2.75 Hz, 1H), 7.54-7.59 (m, 1H), 7.72 (d,J= 2.50 Hz, 1H), 8.07-8.12 (m, 1H). MS (LCMS): 748.62m / z[M+H].

[0228]

[0229] Step 5: 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-7)

[0230] To a stirred solution of 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-6(0.29 g, 0.39 mmol) in a mixture of solvents ACN and water (4:1, 10 mL) was added Oxone (1.19 g, 3.88 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with 10% methanol in DCM (2 x 20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude compound 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-7(0.35 g, crude) as a yellow solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 780.63m / z[M+H].

[0231]

[0232] 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[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-8)

[0233] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.32 g, 0.41 mmol) in THF (5 mL, 16 vol) was added NaH (0.02 g, 0.49 mmol) at 0℃ and stirred for 30 min, followed by an addition of 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-7(0.32 g, 0.41 mmol) at 0℃. The reaction mixture was allowed to warm up to room temperature and stirred for 1.5 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by reverse phase column chromatography using C18 column, eluted with 70% ACN and H2O to afford 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)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-8(0.30 g, crude) as a yellow solid. MS (LC-MS): 859.89m / z[M+H].

[0234]

[0235] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-9)

[0236] 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-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-8(0.29 g, 0.34 mmol) in THF (3.0 mL, 10 vol) was added 1M TBAF in THF (0.35 mL, 0.34 mmol) at 0℃ and the reaction mixture was stirred at 0℃ for 1 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by reverse phase column chromatography using C18 column, eluted with 70% ACN in H2O to afford 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)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-9(0.23 g, Y: 96%) as a yellow solid. MS (LC-MS): 703.64m / z[M+H].

[0237]

[0238] Step 8: 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 2)

[0239] 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[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amineExample 2-Int-9(0.22 g, 0.31 mmol) was added 4M HCl in 1,4-dioxane (2.0 mL) at 0℃ and the reaction mixture was stirred at 0℃ for 1 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with NaHCO3solution (20 mL) and extracted with ethyl acetate (20 mL), separated organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude was purified by Prep-HPLC to affordExample 2(0.053 g, Y: 26%) as a pale brown solid.1H NMR (400 MHz, DMSO-d6) δ 1.67-1.91 (m, 8H), 2.05-2.10 (m, 4H), 2.26 (brs, 6H), 2.85 (d,J= 6.01 Hz, 1H), 3.03-3.11 (m, 4H), 3.93-4.17 (m, 6H), 4.45 (dd,J= 14.13, 4.88 Hz, 1H), 4.56 (brs, 2H), 5.22-5.35 (m, 1H), 7.15 (d,J= 2.25 Hz, 1H), 7.37 (d,J= 2.50 Hz, 1H), 7.46 (t,J= 9.01 Hz, 1H), 7.96 (dd,J= 9.13, 5.88 Hz, 1H), 10.14 (brs, 1H). MS (LC-MS): 659.39m / z[M+H].

[0240]

[0241] 3. Synthetic scheme for Example 3

[0242]

[0243]

[0244] Experimental procedures for 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

[0245]

[0246] Step 1:tert-butyl (3-acetylpyridin-2-yl)carbamate (Example 3-Int-2)

[0247] To a mixture of 1-(2-aminopyridin-3-yl)ethan-1-oneExample 3-Int-1(25.0 g, 183 mmol) in t-BuOH (200 mL) was added Boc2O (59.8 g, 274 mmol) and the mixture was stirred at 90℃ for 16 h. LCMS showed the starting material was consumed and the desired mass was formed. The mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EA = 2 / 1) to givetert-butyl (3-acetylpyridin-2-yl)carbamate (30 g, 69.4% yield) as a white solid. MS:m / z=237.2 (M+H+, ESI+)

[0248]

[0249] Step 2: tert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (Example 3-Int-3)

[0250] To a solution oftert-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℃ for 3 h. LCMS showed 39% starting material was remained and 51% desired mass was formed. The reaction mixture was diluted with water and extracted with EA (100 mL Х 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EA = 1 / 1) to givetert-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+)

[0251]

[0252] Step 3:tert-butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (Example 3-Int-4)

[0253] To a solution oftert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (25 g, 85.3 mmol) in MeOH (100 mL) was added NaBH4(4.19 g, 110 mmol) at 0℃ and the mixture was stirred at 25℃ for 1 h. TLC (EA / MeOH = 10 / 1) showed SM1(Rf = 0.4) was consumed and a new spot (Rf = 0.2) was formed. The reaction mixture was diluted with water and extracted with EA (100 mL Х 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to givetert-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+).

[0254]

[0255] 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-Int-5)

[0256] To a mixture oftert-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% suspension in mineral oil) and the mixture was stirred at 0℃ for 0.5 h. After addition 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (8.5 g, 30.5 mmol) was added to the mixture and the mixture was stirred at 25℃ for another 1 h. TLC (EA / MeOH = 15 / 1) showed SM2(Rf = 0.2) was consumed and a new spot (Rf = 0.4) was formed. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (100 mL Х 3). The combined organic layers were washed with brine 60 mL, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EA = 0 / 1) to givetert-butyl (3-(1-(((S)-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (12 g, 73.1% yield) as a yellow solid. MS:m / z=539.1 (M+H+, ESI+)

[0257]

[0258] 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-Int-6)

[0259] To a solution oftert-butyl (3-(1-(((S)-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (7 g, 13.0 mmol) in DCM (70 mL) was added BoPCl (9.95 g, 39.0 mmol) and DIEA (15.1 g, 117 mmol). Then the mixture was stirred at 25℃ 12 h. TLC (PE / EA = 0 / 1) showed SM2(Rf = 0.2) was consumed and a new spot (Rf = 0.5) was formed. The reaction mixture was diluted with water (100 ml) and extracted with DCM (60 mL Х 2). The combined organic layers were washed with brine 60 mL, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EA = 1 / 1) to givetert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (4.00 g, 59.2% yield) as a yellow solid. The structural confirmation was determined through two-dimensional NMR. MS:m / z=521.2 (M+H+, ESI+)

[0260]

[0261] Step 6:3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3-Int-7)

[0262] A mixture oftert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1 g, 1.92 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.69 g, 1.92 mmo), RuPhos-Pd-G3(0.40 g, 0.47 mmol) and K3PO4(1.22 g, 5.75 mmol) in dioxane / H2O (30 mL / 10 mL) was stirred at 100℃ for 4 h under N2atmosphere. TLC (PE / EA = 0 / 1) showed about 10% SM1 (Rf = 0.5) was remained 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 Х 2). The combined organic layers were washed with brine 60 mL, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EA = 0 / 1) to give 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (460 mg, 38.8% yield) as a yellow solid. MS:m / z=619.2 (M+H+, ESI+)

[0263]

[0264] Step 7:3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3-Int-8)

[0265] To a solution of 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (460 mg, 0.74 mmol) in CAN / H2O (10 mL / 10 mL) was added Oxone (2.28 g, 3.72 mmol) and the mixture was stirred at 25℃ for 1 hr. LCMS showed the starting material was consumed and the desired mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL Х 2). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under vacuum to give 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, crude) as a yellow oil. MS:m / z=651.1(M+H+, ESI+)

[0266]

[0267] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3-Int-9)

[0268] To a solution of 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (500 mg, 0.77 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-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℃ for 1 h. LCMS showed the starting material was consumed and the desired mass was detected. The reaction mixture was diluted with water (40 mL) and extracted with DCM (30 mL Х 2). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by MPLC (FA condition) to give 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-10-yl)ethyl)pyridin-2-amine (250 mg, 44.5% yield) as a white solid. MS:m / z=730.3 (M+H+, ESI+)

[0269]

[0270] 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[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 3)

[0271] To a solution of 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.27 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (2 mL) and the mixture was stirred at 0℃ for 1 h, LCMS showed the starting material was consumed and the desired mass was formed. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by pre-HPLC (NH3·H2O condition) to affordExample 3(100 mg, 53%) as a white solid. MS:m / z=686.2 (M+H+, ESI+)

[0272]

[0273] Step 10:Example 3a and Example 3b

[0274]

[0275] Compound Example 3(100 mg) was purified by SFC (column: REGIS (S,S)WHELK-O1, MeOH (+0.1% 7.0mol / l Ammonia in MeOH) / CO2=50 / 50) to affordExample 3a(30.43 mg, 30.43%) andExample 3b(20.87 mg, 20.87%).

[0276]

[0277] 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

[0278] LC-MS: (ES,m / z): [M+H]+=686.2

[0279] 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).

[0280] 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

[0281] LC-MS: (ES,m / z): [M+H]+=686.3

[0282] 1H NMR (400 MHz, MeOD) δ 7.96 (s, 1H), 7.78 (d,J= 6.9 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.31 - 7.17 (m, 2H), 7.03 (d,J= 23.2 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.72 - 6.62 (m, 1H), 5.31 (d,J= 54.4 Hz, 1H), 4.69 - 4.53 (m, 2H), 4.34 (dd,J= 23.5, 10.5 Hz, 2H), 3.75 - 3.64 (m, 1H), 3.27 - 3.17 (m, 2H), 3.06 - 2.97 (m, 1H), 2.57 - 2.12 (m, 5H), 2.05 - 1.85 (m, 3H), 1.76 - 1.64 (m, 3H), 1.36 - 1.22 (m, 3H), 0.96 - 0.79 (m, 3H).

[0283]

[0284] 4. Synthetic scheme for Example 4

[0285]

[0286]

[0287] Experimental procedures for 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

[0288]

[0289] Step 1: ethyl (E)-2-((4-bromobenzylidene)amino)acetate (Example 4-Int-2)

[0290] To the solution of 4-bromobenzaldehydeExample 4-Int-1(5 g, 27.024 mmol) in DCM (75 mL) was added ethyl glycinate hydrochloride (3.77 g, 27.024 mmol), Mg2SO4(3.74 g, 31.078mmol) and TEA (5.47 g, 54.048mmol). The mixture was stirred at 25℃ for 14 h under Argon. The reaction was detected by LCMS. The resulting mixture was filtered, the filter cake was washed with DCM (25 mL). The filtrate was concentrated under reduced pressure to get residue. The residue was diluted with H2O (50 mL), extracted with MTBE (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4. Filtered and concentrated under reduced pressure to give 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+)

[0291]

[0292] Step 2: ethyl (E)-2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (Example 4-Int-3)

[0293] To the solution of ethyl (E)-2-((4-bromobenzylidene)amino)acetate (5.0 g, 18.510 mmol) in THF (125 mL) were added NaH (1.63 g, 8.144 mmol) at 25℃ under N2. The mixture was stirred at 25℃ for 5 min. To the above mixture was added 3-chloro-2-(chloromethyl)prop-1-ene (6.95 g, 55.530 mmol) dropwise at 25℃ under N2. The resulting mixture was stirred for additional 5 h at 65℃ under N2. The reaction was detected by LCMS. The reaction mixture was diluted with H2O (250 mL), extracted with EA (150 mL). The organic phase was washed with brine (250 mL), dried over Na2SO4. Filtered and concentrated under reduced pressure to give 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+)

[0294]

[0295] Step 3:ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Example 4-Int-4)

[0296] To the 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 1M HCl (10 mL, 10.063 mmol). The mixture was stirred at 25℃ for 0.5h. The mixture was diluted with H2O (60 mL). The aqueous layer was extracted with EA (40 mL) to get 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+)

[0297]

[0298] Step 4:ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Example 4-Int-5)

[0299] 1M NaOH (12 mL, 11.572 mmol) was added dropwise into the above aqueous layer to adjust PH=9~10. The resulting mixture was stirred at 25℃ for 0.5h. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was extracted with EA (2Х40 mL). The combined organic layers were washed with brine (90 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (DCM / MeOH=10:1) to give the desired product ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (140 mg, 2 steps 20% yield) as a brown liquid.MS:m / z=208.0 (M+H+, ESI+)

[0300]

[0301] Step 5:(2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Example 4-Int-6)

[0302] To the solution of ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (680 mg, 3.278 mmol) in THF (7 mL) were added LiAlH4(6.6 ml, 6.562 mmol) at 0℃ under N2. The mixture was stirred at 25℃ for 14 h. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched by the addition of H2O (0.3 mL), 15% solution of NaOH (0.3 mL) and H2O (0.6 mL) at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (80 mL). The aqueous layer was extracted with DCM (60 mL). The organic layer was concentrated under reduced pressure afford (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+)

[0303]

[0304] Step 6:3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-7)

[0305] To the solution oftert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (2.8 g, 5.373 mmol) in dioxane (42 mL) and H2O (14 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.765 g, 5.373 mmol), Ruphos-Pd-G3 (1.343 g, 1.607 mmol) and K3PO4(3.416 g, 16.094 mmol). The mixture was stirred at 100℃ for 4 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (140 mL). The resulting mixture was extracted with EA (100 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified with by silica gel column chromatography, eluted with EA / PE (78%) to give the desired product 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (2.4 g, 57% yield) as a yellow solid. MS:m / z=771.1 (M+H+, ESI+)

[0306]

[0307] Step 7:3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-8)

[0308] To the solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, 1.297 mmol) in THF (10 mL) and H2O (10 mL) was added Oxone (4 g, 6.483 mmol) at 0℃ under Argon. The resulting mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NaHSO3at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (100 mL). The mixture was extracted with EA (3Х40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (1 g, 96% yield) as a yellow solid. MS:m / z=803.2 (M+H+, ESI+)

[0309]

[0310] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-9)

[0311] To the solution of (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (61 mg, 0.372 mmol) in THF (3 mL) was added NaH (20 mg, 0.500 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.248 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （60 mL） at 0℃. The resulting mixture was extracted with EA (3Х40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, 65% yield) as a yellow solid. MS:m / z=888.3(M+H+, ESI+)

[0312]

[0313] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-10)

[0314] To the 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (160 mg, 0.180 mmol) in DMF (3 mL) was added CsF (274 mg, 1.800 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to give 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 53% yield) as a yellow solid. MS:m / z=732.3 (M+H+, ESI+)

[0315]

[0316] 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[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 4)

[0317] To the 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, 0.082 mmol) in ACN (1 mL) was added HCl / dioxane (1.5 ml 1.476 mmol). The mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 um; Mobile Phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 50%~50%; Retention Time: 6.4-11 min of 16 min to give the desired productExample 4(13.40 mg, 23% yield) as a yellow solid.

[0318] MS:m / z=688.2 (M+H+, ESI+)

[0319] 1H NMR (400 MHz, MeOD) δ 8.03 - 7.90 (m, 1H), 7.86 - 7.74 (m, 2H), 7.36 - 7.25 (m, 2H), 7.23 - 7.11 (m, 1H), 6.85 - 6.75 (m, 1H), 6.68 - 6.54 (m, 1H), 5.12 - 4.91 (m, 4H), 4.68 - 4.19 (m, 3H), 3.83 - 3.34 (m, 6H), 2.88 - 2.76 (m, 2H), 2.66 - 2.54 (m, 2H), 1.74 - 1.59 (m, 3H), 1.37 - 1.14 (m, 3H).

[0320]

[0321] 5. Synthetic scheme for Example 5

[0322]

[0323]

[0324] Experimental procedures 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

[0325]

[0326] 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-Int-2)

[0327] To the solution of (1-(morpholinomethyl)cyclopropyl)methanol (64 mg, 0.372 mmol) in THF (3 mL) was added NaH (20 mg, 0.500 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 4-Int-8(200 mg, 0.248 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl (60 mL) at 0℃. The resulting mixture was extracted with EA (3Х40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:20) to afford the desired product 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 71% yield) as a yellow solid. MS:m / z=894.4 (M+1, ESI+).

[0328]

[0329] Step 2: 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 5-Int-3)

[0330] To the solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, 0.198 mmol) in DMF (3 mL) was added CsF (306 mg, 1.98 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to give the desired product 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl) methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (100 mg, 60% yield) as a yellow solid. MS:m / z=738.2 (M+1, ESI+).

[0331]

[0332] Step 3: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 5)

[0333] To the solution of 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 0.108 mmol) in ACN (1 mL) was added HCl / dioxane (2 ml 1.944 mmol). The mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions:Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 um; Mobile Phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 46%~46%; Retention Time: 9.8-12.3 min of 18 min to give the desired productExample 5(14.13 mg, 18% yield) as a yellow solid.MS:m / z=694.0 (M+1, ESI+).

[0334] MS:m / z=694.0 (M+1, ESI+).

[0335] 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).

[0336]

[0337] 6. Synthetic scheme for Example 6

[0338]

[0339]

[0340] Experimental procedures 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

[0341]

[0342] 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-Int-2)

[0343] To the 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-amineExample 4-Int-8(300 mg, 0.374 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanolExample 6-Int-1(89 mg, 0.560 mmol) in THF (3 mL) was added t-BuONa (72 mg, 0.748 mmol) at -78℃ under Argon. The mixture was stirred at -78℃ for 1 h. The reaction was quenched with the solution of NH4Cl (60 mL) at -78℃. The resulting mixture was extracted with EA (3Х40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:10) to afford 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (240 mg, 72% yield) as a yellow solid. MS:m / z=882.3 (M+1, ESI+).

[0344]

[0345] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 6-Int-3)

[0346] To the solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (220 mg, 0.249 mmol) in DMF (3 mL) was added CsF (379 mg, 2.490 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1% FA), 30% to 70% gradient in 15 min; detector, UV 254 nm to give the desired product 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 75% yield) as a yellow solid. MS:m / z=726.2 (M+1, ESI+).

[0347]

[0348] 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)

[0349] To the solution of 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 0.21 mmol) in ACN (2 mL) was added HCl / dioxane (3.3 ml 3.224 mmol). The mixture was stirred at 25℃ for 2 h under Argon. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1% NH3H2O), 40% to 80% gradient in 10 min; detector, UV 254 nm 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) as a yellow solid. MS:m / z=682.2 (M+1, ESI+)

[0350] MS:m / z=682.2 (M+H, ESI+)

[0351] 1H NMR (400 MHz, MeOD) δ 8.04 - 7.93 (m, 1H), 7.87 - 7.75 (m, 2H), 7.35 - 7.25 (m, 2H), 7.24 - 7.10 (m, 1H), 6.86 - 6.76 (m, 1H), 6.72 - 6.55 (m, 1H), 5.32 (d,J= 53.0 Hz, 1H), 4.70 - 4.19 (m, 3H), 3.77 - 3.35 (m, 3H), 3.28 - 3.18 (m, 2H), 3.08 - 2.96 (m, 1H), 2.46 - 2.11 (m, 3H), 2.07 - 1.86 (m, 3H), 1.74 - 1.59 (m, 3H), 1.38 - 1.14 (m, 3H).

[0352]

[0353] Step 4: Example 6a and Example 6b

[0354]

[0355] Compound Example 6(100 mg) was purified by SFC (column: REGIS (S,S)WHELK-O1, MeOH (+0.1% 7.0mol / l Ammonia in MeOH) / CO2=55 / 45) to affordExample 6a(40.46 mg, 40%) andExample 6b(31.19 mg, 31%).

[0356]

[0357] Example 6a: 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0358] LC-MS: (ES,m / z): [M+H]+= 682.0

[0359] 1H 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).

[0360] 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

[0361] LC-MS: (ES,m / z): [M+H]+= 682.0

[0362] 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).

[0363]

[0364] 7. Synthetic scheme for Example 7

[0365]

[0366]

[0367] Experimental procedures 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

[0368]

[0369] 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-Int-2)

[0370] To the slurry of NaH (60%) (20 mg, 0.05 mmol) in THF (1 mL) was added (R)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanolExample 7-Int-1(113 mg, 0.75 mmol) in THF (1 mL) at 0℃. The solution was stirred at 0℃ for 30min. 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) was added to the above mixture. The mixture was stirred at 0℃ for 1 h. The reaction mixture was quenched with NH4Cl (aq, 10 mL) and the solution was extracted with EA (2 x 20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. Then the residue was purified with by silica gel chromatography eluted 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+).

[0371]

[0372] Step 2: 3-(1-((S)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 7-Int-3)

[0373] The mixture of 3-(1-((S)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, 0.22 mmol), CsF (330 mg, 2.18 mmol) in DMF (2 mL) was stirred at room temperature for 2 h. Then filtered and the filtrate was concentrated under reduced pressure. Then the residue was purified with by Prep-HPLC (column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL / min) to give the desired product 3-(1-((S)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (104 mg, 60%) as a yellow solid. MS:m / z=718.1 (M+1, ESI+).

[0374]

[0375] Step 3:4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 7)

[0376] To the solution of 3-(1-((S)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (94 mg, 0.13 mmol) in ACN (0.5 mL) was dropwised HCl / dioxane (4 M, 0.5 mL) slowly at 25℃. The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda, Column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 18-28%; Retention Time: 7.9-10.8 min of 16 min) to give the desired product to giveExample 7(20.08 mg, 22%) as a yellow solid. MS:m / z=673.9 (M+1, ESI+)

[0377] 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).

[0378]

[0379] 8. Synthetic scheme for Example 8

[0380]

[0381]

[0382] Experimental procedures for Example 8: 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0383]

[0384] Step 1: (S)-azetidin-2-ylmethanol (Example 8-Int-2)

[0385] To the solution oftert-butyl (S)-2-(hydroxymethyl)azetidine-1-carboxylateExample 8-Int-1(1 g, 5.35 mmol) in DCM (5 mL) were added HCl / dioxane (4M, 6 mL). The reaction mixture was stirred at 25℃ for 16 h. The solvent was removed under reduced pressure to give (S)-azetidin-2-ylmethanol(700 mg, 98%) as a colorless oil. MS:m / z=88.2 (M+1, ESI+).

[0386]

[0387] Step 2: (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (Example 8-Int-3)

[0388] To an ice-cooled solution of K2CO3(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 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. Then the residue was purified with by silica gel chromatography eluted PE / EA=1:1 to give (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (274 mg, 22%) as a colorless oil. MS:m / z=152.1 (M+1, ESI+).

[0389]

[0390] 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-Int-4)

[0391] To the slurry of NaH (60% in oil, 37 mg, 0.56 mmol) in THF (1 mL) was added the solution of (S)-(1-(2,2-difluoroethyl) azetidin-2-yl)methanol (125 mg, 0.82 mmol) in THF (1 mL) at 0℃. The reaction mixture was stirred at 0℃ for 30 min and the solution of 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (225 mg, 0.28 mmol) in THF (1 mL) was added to the above mixture. The reaction mixture was stirred at 0℃ for 1 h. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (2 x 20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. Then the residue was purified with by silica gel chromatography eluted DCM / MeOH=20:1 to give 3-(1-((S)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (261 mg, 36%) as a yellow oil. MS:m / z=874.2 (M+1, ESI+)

[0392]

[0393] Step 4:3-(1-((S)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 8-Int-5)

[0394] The 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 at 25℃ for 2 h. Then the residue was purified with by Prep-HPLC (column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL / min) to give the desired product 3-(1-((S)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (107 mg, 50%) as a yellow solid. MS:m / z=718.2 (M+1, ESI+)

[0395]

[0396] 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]naphthalene-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol(Example 8)

[0397] To the 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) were added HCl / dioxane (4M, 0.3 mL). The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was diluted with DCM / MeOH(10 / 1 mL). The mixture was washed with con. NaHCO3(aq, 10 mL), then washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda Column: Pursuit XRs 10 C18 250*21.2mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 18-23%; Retention Time: 7-9.2 min of 16 min) to giveExample 8(4.49 mg, 5%) as a light yellow solid. MS:m / z=674.0 (M+1, ESI+)

[0398] 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).

[0399]

[0400] 9. Synthetic scheme for Example 9

[0401]

[0402]

[0403] Experimental procedures 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

[0404]

[0405] 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-Int-2)

[0406] To the solution of (2-oxabicyclo[2.1.1]hexan-4-yl)methanol (44 mg, 0.372 mmol) in THF (3 mL) was added NaH (60% in oil, 20 mg, 0.500 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 4-Int-8(200 mg, 0.248 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was quenched with the solution of NH4Cl (40 mL) at 0℃. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:10) to afford the desired product 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 54% yield) as a yellow solid. MS:m / z=837.2 (M+H, ESI+).

[0407]

[0408] Step 2: 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 9-Int-3)

[0409] To the solution of 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (180 mg, 0.216 mmol) in DMF (3 mL) was added CsF (324 mg, 2.160 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The resulting mixture was filtered, the filter cake was washed with EA (20 mL). The filtrate was concentrated under reduced pressure to get residue. The residue was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1%FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to afford the desired product 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 79% yield) as a yellow solid. MS:m / z=681.2 (M+H, ESI+).

[0410]

[0411] Step 3:4-((8S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 9)

[0412] To the solution of 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (110 mg, 0.160 mmol) in ACN (2 mL) was added HCl / dioxane (4M, 3.3 ml 2.910 mmol). The mixture was stirred at 25℃ for 2 h under Argon. The reaction mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC (Waters 2767 Column: Xbridge C18, 19*250 mm, 10μ, Mobile Phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient:42-42%; Retention Time: 7.1-10 min of 16 min) to give the desired productExample 9(17.69 mg, 17% yield) as a yellow solid. MS:m / z=636.9 (M+H, ESI+)

[0413] 1H 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).

[0414]

[0415] 10. Synthetic scheme for Example 10a and 10b

[0416]

[0417]

[0418] Experimental procedures for Examples 10a and 10b

[0419]

[0420] Step 1: tert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 10-Int-1)

[0421] To the solution oftert-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)carbamateExample 3-Int-6(1 g, 1.920 mmol) in ACN (12 mL) and H2O (4 mL) was added Oxone (5.9 g, 9.595 mmol) at 0℃ under Argon. The resulting mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NaHSO3at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (80 mL). The mixture was extracted with EA (3Х50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired producttert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1 g, 94% yield) as a yellow solid. MS:m / z=553.1 (M+H, ESI+).

[0422]

[0423] Step 2: 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[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 10-Int-3)

[0424] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanolExample 10-Int-2(440 mg, 2.72 mmol) in THF (10 mL) was added NaH (160 mg, 3.60 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was addedtert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.0 g, 1.80 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl (100 mL) at 0℃. The resulting mixture was extracted with EA (3Х60 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:10) to afford the desired producttert-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[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (800 mg, 69% yield) as a yellow solid. MS:m / z=632.2 (M+H, ESI+).

[0425]

[0426] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 10-Int-5)

[0427] To the solution oftert-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[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (150 mg, 0.237 mmol) in dioxane (3 mL) and H2O (1 mL) were added 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneExample 10-Int-4(84 mg, 0.237 mmol), Ruphos-Pd-G3 (60 mg, 0.071 mmol) and K3PO4(153 mg, 0.711 mmol). The mixture was stirred at 100℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (40 mL). The resulting mixture was extracted with EA (20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified with by silica gel column chromatography, eluted with MeOH / DCM (9%) to give the desired product 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, 83% yield) as a yellow solid. MS:m / z=720.2 (M+H, ESI+).

[0428]

[0429] Step 4:Example 10a and 10b

[0430]

[0431] To the solution of 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (170 mg, 0.236 mmol) in ACN (2 mL) was added HCl / dioxane (4.3 ml 4.252 mmol). The mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC(Waters 2767 Column:Xbridge C18,19*250 mm, 10 μm；Mobile Phase A: 0.05% NH3H2O / H2O, B: ACN; flow rate: 20 mL / min; gradient: 39-39%; Retention Time:8.8-12.8 min of 16 min to give the desired products.

[0432]

[0433] Example 10a: 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol(7.90 mg, 4% yield) as a white solid.

[0434] MS:m / z=676.0 (M+H, ESI+)

[0435] 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.01 (dd,J= 4.9, 1.5 Hz, 1H), 7.79 - 7.66 (m, 2H), 7.63 - 7.51 (m, 1H), 7.37 (s, 1H), 7.28 - 7.12 (m, 1H), 6.75 - 6.66 (m, 1H), 6.45 - 6.32 (m, 1H), 5.73 (s, 2H), 5.41 - 5.20 (m, 1H), 4.23 - 4.10 (m, 3H), 3.53 - 3.46 (m, 2H), 3.13 - 2.99 (m, 3H), 2.88 - 2.78 (m, 1H), 2.18 - 1.94 (m, 4H), 1.90 - 1.75 (m, 3H), 1.60 - 1.48 (m, 3H), 1.10 (d,J= 6.5 Hz, 3H).

[0436] Example 10b:4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol(5.90 mg, 3%) as a white solid.

[0437] MS:m / z=676.0 (M+H, ESI+)

[0438] 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d,J= 4.1 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.58 - 7.44 (m, 1H), 7.30 (s, 1H), 7.18 (d,J= 34.6 Hz, 1H), 6.72 - 6.60 (m, 1H), 6.46 - 6.34 (m, 1H), 5.72 (s, 2H), 5.43 - 5.19 (m, 1H), 4.72 - 4.56 (m, 1H), 4.24 - 4.07 (m, 2H), 3.66 - 3.55 (m, 2H), 3.11 - 3.01 (m, 3H), 2.88 - 2.78 (m, 1H), 2.14 - 1.98 (m, 4H), 1.90 - 1.75 (m, 3H), 1.60 (d,J= 6.7 Hz, 3H), 1.23 - 1.20 (m, 3H).

[0439]

[0440] 11. Synthetic scheme for Example 11

[0441]

[0442]

[0443] Experimental procedures for 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

[0444]

[0445] 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-Int-2)

[0446] To the solution of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneExample 11-Int-1(100 mg, 0.29 mmol) in dioxane (2 mL) / H2O (0.2 mL) were addedtert-butyl (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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamateExample 10-Int-3(186 mg, 0.29 mmol), Cs2CO3(192 mg, 0.59 mmol) and Pd(dppf)Cl2(21 mg, 0.03 mmol). The reaction mixture was stirred at 100℃ for 4 h under N2. Upon completion, the reaction mixture was added water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was filtered and concentrated, dried over Na2SO4. The residue was purified by silica gel chromatography eluted DCM / MeOH = 20:1 and Prep-HPLC (Waters 2767 / Qda Column: Pursuit XRs 10 C18 250*21.2 mm, 10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 18-23%; Retention Time: 7-9.2 min of 16 min) to give 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(80 mg, 38%) as a yellow solid.

[0447] MS:m / z=708.2 (M+H+, ESI+)

[0448]

[0449] Step 2: 3-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-chloro-4-cyclopropylphenol(Example 11)

[0450] To the solution of 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 11-Int-2(60 mg, 0.08 mmol) in DCM (1 mL) were added HCl / dioxane (0.3 mL). The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was diluted with DCM / MeOH(10 / 1 mLХ2). The mixture was washed with con. NaHCO3(aq, 10 mL), then washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda Column: Pursuit XRs 10 C18 250*21.2mm, 10 um；Mobile Phase A: 0.05% TFA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 18-23%; Retention Time: 7.3-9.8 min of 16 min) to giveExample 11(4.62 mg, 8%) as a light yellow solid. MS:m / z= 664.2 (M+H+, ESI+)

[0451] 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.97 (d,J= 4.7 Hz, 1H), 7.53 (d,J= 7.8 Hz, 1H), 6.89 (d,J= 2.2 Hz, 1H), 6.75 - 6.67 (m, 2H), 6.66 - 6.56 (m, 1H), 5.92 (brs, 2H), 5.41 (d,J= 52.4 Hz, 1H), 4.61 - 4.43 (m, 3H), 3.46 - 3.08 (m, 6H), 2.60 - 2.23 (m, 3H), 2.18 - 2.04 (m, 3H), 1.893 - 1.80 (m, 1H), 1.59 (d,J= 6.7 Hz, 3H), 1.33 (d,J= 6.5 Hz, 3H), 0.72 - 0.55 (m, 2H), 0.18 - 0.06 (m, 2H).

[0452]

[0453] 12. Synthetic scheme for Example 12

[0454]

[0455]

[0456] Experimental procedures 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

[0457]

[0458] Step 1: tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (Example 12-Int-1)

[0459] To the solution oftert-butyl (3-acetylpyridin-2-yl)carbamateExample 3-Int-2(20 g, 84.65 mmol) in EtOH (200 mL) were added 2-aminoethan-1-ol (15.5 g, 253.95 mmol) at 25℃ under N2. The mixture was stirred at 90℃ for 2h. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (200 mL), extracted with EA (120 mL). dried over Na2SO4. Filtered and concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (EA / PE= 85%) to afford the desired producttert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (7.6 g, crude) as a colorless oil. MS:m / z= 280.0 (M+H, ESI+).

[0460]

[0461] Step 2: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 12-Int-2)

[0462] To the solution oftert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (7.6 g, 27.207 mmol) in MeOH (80 mL) were added NaBH4(3.087 g, 81.621 mmol) at 0℃ under N2. The mixture was stirred at 25℃ for 1h. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (150 mL), extracted with EA (100 mL). dried over Na2SO4. Filtered and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography on silica gel eluted with (MeOH / DCM= 10%) to afford the desired producttert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (3.0 g, 39% yield) as a colorless oil. MS:m / z= 282.1 (M+H, ESI+).

[0463]

[0464] 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-Int-3)

[0465] To the solution oftert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (4.4 g, 15.709 mmol) in THF (50 mL) was added NaH (1.89 g, 47.126 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (4.4 g, 15.709 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched by the addition of H2O (30 mL) at 0℃. The reaction mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (150 mL), extracted with EA (100 mL). dried over Na2SO4. Filtered and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography on silica gel eluted with (MeOH / DCM= 9%) to afford the desired producttert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl) amino)ethyl)pyridin-2-yl)carbamate (3.4 g, 41% yield) as a yellow solid. MS:m / z= 525.1 (M+H, ESI+).

[0466]

[0467] Step 4: tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 12-Int-4)

[0468] To the solution oftert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (3.1 g, 5.905 mmol) in THF (30 mL) was added DIEA (6.87 g, 53.145 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added BopCl (4.51 g, 17.714 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 16 h at 25℃ under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (150 mL), extracted with EA (100 mL). dried over Na2SO4. Filtered and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography on silica gel eluted with (EA / PE= 82%) to afford the desired producttert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.6 g, 53% yield) as a yellow solid. The structural confirmation was determined through two-dimensional NMR. MS:m / z= 507.1 (M+H, ESI+).

[0469]

[0470] Step 5: 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-5)

[0471] To the solution oftert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (1.6 g, 3.156 mmol) in dioxane (21 mL) and H2O (7 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.624 g, 3.156 mmol), Ruphos-Pd-G3 (792 mg, 0.947 mmol) and K3PO4(2 g, 9.468 mmol). The mixture was stirred at 100℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (100 mL). The resulting mixture was extracted with EA (60 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified with by silica gel column chromatography, eluted with EA / PE (70%) to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (1.3 g, 54% yield) as a yellow solid. MS:m / z= 757.2 (M+H, ESI+).

[0472]

[0473] Step 6: 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-6)

[0474] To the solution of SM (1.3 g, 1.717 mmol) in ACN (15 mL) and H2O (5 mL) was added Oxone (5.28 g, 8.587 mmol) at 0℃ under Argon. The resulting mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NaHSO3at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (80 mL). The mixture was extracted with EA (3 Х 60 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (1.20 g, crude) as a yellow solid. MS:m / z= 789.1 (M+H, ESI+).

[0475]

[0476] Step 7: 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-7)

[0477] To the solution of (1-(morpholinomethyl)cyclopropyl)methanol (65 mg, 0.380 mmol) in THF (2 mL) was added NaH (20 mg, 0.506 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (200 mg, 0.253 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. The reaction was quenched by the addition of H2O (4 mL) at 0℃. The reaction mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (30 mL), extracted with EA (20 mL). dried over Na2SO4. Filtered and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography on silica gel eluted with (MeOH / DCM= 10%) to afford the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 48% yield) as a yellow solid. MS:m / z= 880.3 (M+H, ESI+).

[0478]

[0479] 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-tetraaza cyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-8)

[0480] To the solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 0.148 mmol) in DMF (3 mL) was added CsF (225 mg, 1.48 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to give the desired product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 56% yield) as a yellow solid. MS:m / z= 723.9 (M+H, ESI+).

[0481]

[0482] Step 9: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 12)

[0483] To the solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (20 mg, 0.028 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; Retention Time: 8.9-9.8 min of 16 min to give the desired productExample 12(2.21 mg, 11% yield) as a white solid. MS:m / z= 680.0 (M+1, ESI+)

[0484] 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.99 (d,J= 4.6 Hz, 1H), 7.70 - 7.54 (m, 2H), 7.22 - 7.10 (m, 3H), 6.78 - 6.59 (m, 2H), 5.95 (brs, 2H), 4.51 - 4.18 (m, 4H), 3.78 - 3.54 (m, 5H), 3.52 - 3.38 (m, 1H), 2.99 (d,J= 33.9 Hz, 1H), 2.64 - 2.46 (m, 6H), 1.60 (dd,J= 18.7, 6.8 Hz, 3H), 0.78 - 0.66 (m, 2H), 0.56 - 0.44 (m, 2H).

[0485]

[0486] 13. Synthetic scheme for Example 13

[0487]

[0488]

[0489] Experimental procedures 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-ol formate

[0490]

[0491] 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-Int-1)

[0492] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (302 mg, 1.901 mmol) in THF (10 mL) was added NaH (60% in oil, 101 mg, 2.534 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 12-Int-6(1 g, 1.267 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was quenched with the solution of NH4Cl (60 mL) at 0℃. The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:10) to afford 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (920 mg, 83% yield) as a yellow solid. MS:m / z= 868.3 (M+H)+, ESI+

[0493]

[0494] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 13-Int-2)

[0495] To the 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (820 mg, 0.945 mmol) in DMF (10 mL) was added CsF (1.43 g, 9.447 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The resulting mixture was diluted with H2O (60mL). The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. to give the desired product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (450 mg, crude) as a yellow solid. MS:m / z= 712.2 (M+H)+, ESI+

[0496]

[0497] Step 3: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorohexahydro-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)

[0498] To the 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℃ for 1 h under Argon. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H2O (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to give the desired productExample 13(23.93 mg, 5% yield) as a yellow solid. MS:m / z= 667.9 (M+H+, ESI+)

[0499] 1H NMR (400 MHz, DMSO-d6) δ 10.16 (brs, 1H), 8.15 (s, 0.76H, FA), 8.01 - 7.91 (m, 2H), 7.66 (d,J= 7.4 Hz, 1H), 7.46 (t,J= 9.0 Hz, 1H), 7.37 (d,J= 1.3 Hz, 1H), 7.15 (s, 1H), 6.74 - 6.63 (m, 1H), 6.39 - 6.26 (m, 1H), 5.82 (s, 1H), 5.74 (s, 1H), 5.36 (d,J= 54.6 Hz, 1H), 4.53 - 4.14 (m, 4H), 4.04 (d,J= 54.6 Hz, 1H), 3.83 - 3.67 (m, 1H), 3.50 - 3.37 (m, 3H), 2.97 - 2.87 (m, 1H), 2.31 - 1.77 (m, 6H), 1.66 - 1.52 (m, 3H).

[0500]

[0501] Step 4: Example 13a and Example 13b

[0502]

[0503]

[0504] Compound Example 13(120 mg) was purified by SFC (column: DAICELCHIRALPAK®W, EtOH(+0.1% 7.0mol / l Ammonia in EtOH) / CO2=63:37) to affordExample 13a(20.55 mg, 17.1%),Example 13b(21.20 mg, 17.6%).

[0505]

[0506] 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

[0507] MS:m / z= 668.2 (M+H+, ESI+)

[0508] 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.07 - 7.87 (m, 2H), 7.65 (d,J= 7.5 Hz, 1H), 7.46 (t,J= 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (t,J= 2.2 Hz, 1H), 6.72 - 6.64 (m, 1H), 6.40 - 6.25 (m, 1H), 5.76 (d,J= 28.3 Hz, 2H), 5.30 (d,J= 54.2 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.26 - 4.08 (m, 3H), 3.80 - 3.64 (m, 1H), 3.51 - 3.44 (m, 1H), 3.15 - 3.00 (m, 3H), 2.90 - 2.78 (m, 1H), 2.19 - 1.78 (m, 6H), 1.67 - 1.54 (m, 3H).

[0509] 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

[0510] MS:m / z= 668.2 (M+H+, ESI+)

[0511] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (brs, 1H), 8.16 - 7.94 (m, 2H), 7.65 (d,J= 7.4 Hz, 1H), 7.46 (t,J= 9.0 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 6.72 - 6.64 (m, 1H), 6.45 - 6.24 (m, 1H), 5.76 (d,J= 30.0 Hz, 2H), 5.31 (d,J= 55.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.27 - 4.06 (m, 3H), 3.82 - 3.74 (m, 1H), 3.72 - 3.67 (m, 1H), 3.16 - 2.99 (m, 3H), 2.90 - 2.80 (m, 1H), 2.15 - 1.78 (m, 6H), 1.69 - 1.51 (m, 3H).

[0512]

[0513] 14. Synthetic scheme for Example 14

[0514]

[0515]

[0516]

[0517]

[0518] Experimental procedures for 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

[0519]

[0520] * Synthesis of (Example 14-Int-2)

[0521] Step 1a: tert-butyl (3-acetylpyridin-2-yl)carbamate (Example 14-Int-2b)

[0522] To a stirred solution of 1-(2-aminopyridin-3-yl)ethan-1-oneExample 14-Int-2a(4.00 g, 29.4 mmol) int-BuOH (20 mL, 5 vol.) was added (Boc)2O (10.0 mL, 44.1 mmol) at room temperature and the reaction mixture was heated to 80℃ and stirred for 5 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get solid, the solid was filtered and dried under high vacuum to get crude compoundtert-butyl (3-acetylpyridin-2-yl)carbamateExample 14-Int-2b(5.0 g, crude) as a pale yellow solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 237.28m / z[M+H].

[0523]

[0524] Step 2a: tert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate (Example 14-Int-2d)

[0525] To a stirred solution oftert-butyl (3-acetylpyridin-2-yl)carbamateExample 14-Int-2b(5.00 g, 21.2 mmol) and 2-aminoethan-1-olExample 14-Int-2c(2.50 g, 31.8 mmol) in THF (50 mL, 10 vol) was added titanium ethoxide (14.5 g, 63.6 mmol) at room temperature and the reaction mixture was stirred at room temperature for 12 h. 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), combined organic layer was washed with brine solution, dried overanhydrousNa2SO4, filtered and evaporated under reduced pressure to get crude compoundtert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamateExample 14-Int-2d(5.50 g, crude) as a white solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 280.33m / z[M+H].

[0526]

[0527] Step 3a: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14-Int-2)

[0528] To a stirred solution oftert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamateExample 14-Int-2d(5.00 g, 17.9 mmol) in MeOH (50 mL, 10 vol) was added NaBH4(1.35 g, 35.8 mmol) at 0℃ and the reaction mixture was allowed to warm up to room temperature and stirred for 12 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude compoundtert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamateExample 14-Int-2(1.80 g, crude) as a white solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 282.30m / z[M+H].

[0529]

[0530] 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-Int-3)

[0531] To a stirred solution of 5,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-oneExample 1-Int-2(1.80 g, 6.14 mmol) in THF (31 mL, 17 vol) was added NaH(1.00 g, 27.6 mmol) at 0℃ and stirred for 30 min, followed by an addition oftert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamateExample 14-Int-2(2.00 g, 7.37 mmol) at 0℃ and the reaction mixture was stirred at 0℃ for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 mL), combined organic layer was washed with brine solution, dried overanhydrousNa2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 5% methanol in DCM as an eluent to affordtert-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)carbamateExample 14-Int-3(1.50 g, Y: 45%) as an off-white solid. MS (LC-MS): 539.37m / z[M+H].

[0532]

[0533] Step 2: tert-butyl (3-(1-(5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 14-Int-4)

[0534] To a stirred solution oftert-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)carbamateExample 14-Int-3(0.25 g, 0.46 mmol) in DCM (2.5 mL, 10 vol) was added BOP-Cl (0.13 g, 1.62 mmol) and DIPEA (1.20 mL, 6.72 mmol) at room temperature and the reaction mixture was heated to 60℃ and stirred for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2 X 20 mL), combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 50% ethyl acetate in pet ether as an eluent to affordtert-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)carbamateExample 14-Int-4(0.90 g, overall 6 batches (6 x 250 mg) of yield, crude) as a brown solid. MS (LCMS): 521.35m / z[M+H].

[0535]

[0536] 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-Int-6)

[0537] To a stirred solution oftert-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)carbamateExample 14-Int-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-dioxaborolaneExample 14-Int-5(0.25 g, 0.69 mmol) in a mixture of solvents 1,4-dioxane and water (2:1, 9 mL) was added KOtBu (0.19 g, 1.73 mmol) at room temperature and degassed under N2gas for 10 min. To this was added tetrakis (0.067 g, 0.06 mmol) at room temperature and the reaction mixture was heated to 90℃ and stirred for 4 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 25 mL)), combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 5% methanol in DCM as an eluent to afford 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 14-Int-6(0.30 g, overall 3 batches (3 x 250 mg) of yield, Y: 28%) as a light yellow solid. MS (LC-MS): 619.40m / z[M+H].

[0538]

[0539] Step 4: 3-(1-(5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Int-7)

[0540] To a stirred solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 14-Int-6(0.30 g, 0.48 mmol) in a mixture of solvents ACN and water (2:1, 36 mL) was added Oxone (1.49 g, 4.85 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get residue. The residue was diluted with water and ethyl acetate (2 x 25 mL), combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure and washed with n-pentane to get crude compound 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 14-Int-7(0.25 g, crude) as a light yellow solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 651.36m / z[M+H].

[0541]

[0542] Step 5: 3-(1-(5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Int-9)

[0543] To a stirred solution of ((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanolExample 14-Int-8(0.073 g, 0.46 mmol) in THF (5.0 mL, 20 vol) was added NaOtBu (0.074 g, 0.77 mmol) at 0℃ and stirred for 15 min, followed by an addition of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 14-Int-7(0.25 g, 0.38 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 15 min. 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), combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by Prep-HPLC to afford 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 14-Int-9(0.03 g, Y: 11%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 0.83 (q,J= 7.20 Hz, 3H), 1.58 (dd,J= 10.4, 7.20 Hz, 3H), 1.78-1.85 (m, 3H), 2.02-2.07 (m, 2H), 2.13-2.16 (m, 1H), 2.83 (q,J= 6.40 Hz, 1H), 3.08-3.10 (m, 2H), 3.42 (d,J= 3.20 Hz, 3H), 3.69-3.76 (m, 2H), 4.05-4.09 (m, 1H), 4.14-4.15 (m, 1H), 4.22 (dd,J= 10.4, 3.20 Hz, 1H), 4.28-4.36 (m, 4H), 5.22-5.35 (m, 3H), 5.69-5.77 (m, 1H), 6.07 (brs, 1H), 6.37 (q,J= 5.89 Hz, 1H), 6.67 (dd,J= 6.40, 5.20 Hz, 1H), 7.17 (d,J= 2.40 Hz, 1H), 7.40-7.45 (m, 1H), 7.63-7.65 (m, 2H), 7.88 (dd,J= 9.20, 6.00 Hz, 1H), 7.98 (t,J= 3.60 Hz, 1H). MS (LC-MS): 716.36m / z[M+H].

[0544]

[0545] 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)

[0546] To a stirred solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 14-Int-9(0.03 g, 0.042 mmol) was added 4M HCl in 1,4-dioxane (0.2 mL) at 0℃ and the reaction mixture was stirred at 0℃ for 30 min. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude was purified by prep- HPLC to affordExample 14(0.007 g, Y: 25%) as an off-white solid. MS:m / z= 672.2 (M+H+, ESI+)1H NMR (400 MHz, DMSO-d6) δ 10.01 (brs, 1H), 7.97 (s, 1H), 7.81 - 7.54 (m, 2H), 7.42 - 7.21 (m, 2H), 7.00 (s, 1H), 6.75 - 6.59 (m, 1H), 6.44 -6.30 (m, 1H), 5.72 (d, J = 26.4 Hz, 2H), 5.29 (d, J = 54.3 Hz, 1H), 4.44 - 4.04 (m, 4H), 3.80 - 3.66 (m, 2H), 3.12 - 2.96 (m, 3H), 2.88 - 2.76 (m, 1H), 2.42 - 2.24 (m, 2H), 2.18 - 1.98 (m, 3H), 1.88 - 1.70 (m, 3H), 1.64 - 1.52 (m, 3H), 0.88 - 0.72 (m, 3H).

[0547]

[0548] The racemicExample 14was purified by SFC (column: DAICELCHIRALPAK®IE, n-Hexane / EtOH (+0.1% 7.0mol / l Ammonia in MeOH) =50 / 60) to giveExample 14aas a white solid andExample 14bas a white solid.

[0549] Example 14a: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0550] MS:m / z= 672.2 (M+H+, ESI+)

[0551] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (brs, 1.18H, FA), 8.03 - 7.92 (m, 1H), 7.80 - 7.64 (m, 2H), 7.44 - 7.31 (m, 2H), 7.02 (t,J= 2.5 Hz, 1H), 6.79 - 6.72 (m, 1H), 6.37 (q,J= 6.7 Hz, 1H), 5.39 (d,J= 53.9 Hz, 1H), 4.46 - 4.25 (m, 4H), 3.83 - 3.68 (m, 1H), 3.51 - 3.16 (m, 4H), 3.02 - 2.90 (m, 1H), 2.43 - 2.10 (m, 5H), 2.03 - 1.80 (m, 3H), 1.60 (t,J= 6.7 Hz, 3H), 0.88 - 0.72 (m, 3H).

[0552] 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

[0553] MS:m / z= 672.2 (M+H+, ESI+)

[0554] 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 0.53H, FA), 7.99 - 7.95 (m, 1H), 7.74 (dd,J= 9.0, 6.0 Hz, 1H), 7.64 (d,J= 7.5 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (d,J= 2.5 Hz, 1H), 6.68 (dd,J= 6.8, 5.3 Hz, 1H), 6.43 - 6.32 (m, 1H), 5.73 (d,J= 27.4 Hz, 2H), 5.30 (d,J= 54.1 Hz, 1H), 4.45 - 4.07 (m, 4H), 3.78 - 3.73 (m, 1H), 3.19 - 3.00 (m, 4H), 2.88 - 2.78 (m, 1H), 2.43 - 2.28 (m, 2H), 2.19 - 1.97 (m, 3H), 1.91 - 1.71 (m, 3H), 1.65 - 1.51 (m, 3H), 0.88 - 0.76 (m, 3H).

[0555]

[0556] 15. Synthetic scheme for Example 15

[0557]

[0558]

[0559] Experimental procedures for Example 15: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0560]

[0561] 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-Int-1)

[0562] To the slurry of NaH (60%) (25 mg, 0.63 mmol) in THF (1 mL) was added the solution of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (144 mg, 0.95 mmol) in THF (1 mL) at 0℃. The reaction mixture was stirred at 0℃ for 30 min and the solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 12-Int-6(250 mg, 0.32 mmol) in THF (1 mL) was added to the above mixture. The reaction mixture was stirred at 0℃ for 1 h. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). Then the residue was purified with by silica gel chromatography eluted DCM / MeOH=20:1 to give 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (148 mg, 54%) as a yellow solid. MS:m / z= 860.2 (M+H+, ESI+)

[0563]

[0564] Step 2: 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 15-Int-2)

[0565] The mixture of 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (118 mg, 0.14 mmol), CsF (209 mg, 1.37) in DMF (2 mL) was stirred at 25℃ for 2 h. Then filtered and the filtrate was concentrated under reduced pressure. Then the residue was purified with by Prep-HPLC (column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL / min) to give the desired product 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (84 mg, 87%) as a yellow solid. MS:m / z= 704.1 (M+H+, ESI+)

[0566]

[0567] Step 3: 44-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 15)

[0568] To the solution of 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (64 mg, 0.09 mmol) in DCM (1 mL) were added HCl / dioxane (0.3 mL). The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was diluted with DCM / MeOH(10 / 1 mLХ2). The mixture was washed with con. NaHCO3(aq, 10 mL), then washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda Column: Pursuit XRs 10 C18 250*21.2mm, 10 um；Mobile Phase A: 0.05% TFA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 20-25%; Retention Time: 7.8-9.8 min of 16 min) and Prep-HPLC (Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 um; Mobile Phase A: 0.05% NH3H2O / H2O, B: ACN; flow rate: 20 mL / min; gradient: 39%~39%; Retention Time: 8-11.1 min of 16 min) to giveExample 15(2.42 mg, 4%) as a light yellow solid. MS:m / z= 660.4 (M+H+, ESI+)

[0569] 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.67 - 7.47 (m, 2H), 7.23 - 7.06 (m, 3H), 6.80 - 6.53 (m, 2H), 5.89 - 5.36 (m, 2H), 4.68 - 4.11 (m, 4H), 3.67 - 3.30 (m, 3H), 3.10 - 2.87 (m, 2H), 2.82 - 2.63 (m, 1H), 2.55 - 2.30 (m, 5H), 1.65 - 1.45 (m, 3H).

[0570]

[0571] 16. Synthetic scheme for Example 16

[0572]

[0573]

[0574] Experimental procedures 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

[0575]

[0576] Step 1: tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 16-Int-1)

[0577] To the solution oftert-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)carbamateExample 12-Int-4(400 mg, 0.789 mmol) in ACN (6 mL) and H2O (2 mL) was added Oxone (2.42 g, 3.945 mmol) at 0℃ under Argon. The resulting mixture was stirred at 0℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NaHSO3at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (50 mL). The mixture was extracted with EA (3Х30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired producttert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (360 mg, 84% yield) as a yellow solid. MS:m / z= 538.9 (M+H+, ESI+)

[0578]

[0579] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 16-Int-2)

[0580] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (137 mg, 0.863 mmol) in THF (3 mL) was added NaH (46 mg,1.15 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was addedtert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (310 mg, 0.575 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （20 mL） at 0℃. The resulting mixture was extracted with EA (3Х10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:10) to afford the desired producttert-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[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (290 mg, 70% yield) as a yellow solid. MS:m / z= 618.2 (M+H+, ESI+)

[0581]

[0582] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 16-Int-3)

[0583] To the solution oftert-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[de] naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (120 mg, 0.194 mmol) in dioxane (3 mL) and H2O (1 mL) were 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-G3 (48 mg, 0.058 mmol) and K3PO4(124 mg, 0.582 mmol). The mixture was stirred at 100℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (40 mL). The resulting mixture was extracted with EA (20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified with by silica gel column chromatography, eluted 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 53% yield) as a yellow solid. MS:m / z= 706.2(M+H+, ESI+)

[0584]

[0585] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol (Example 16)

[0586] To the solution of 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 0.113 mmol) in ACN (2 mL) was added HCl / dioxane (2 ml 2.040 mmol). The mixture was stirred at 25℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 15-23%; Retention Time: 7.5-9.3 min of 16 min to give the desired productExample 16(21.89 mg, 29% yield) as a white solid. MS:m / z= 662.0 (M+H+, ESI+)

[0587] 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 0.81H, FA), 7.98 (d,J= 4.3 Hz, 1H), 7.77 - 7.51 (m, 3H), 7.39 (s, 1H), 7.22 (d,J= 1.9 Hz, 1H), 6.72 (dd,J= 7.3, 5.0 Hz, 1H), 6.45 - 6.33 (m, 1H), 5.35 (d,J= 54.4 Hz, 1H), 4.58 - 3.99 (m, 4H), 3.50 - 3.35 (m, 1H), 3.26 - 3.10 (m, 3H), 2.96 - 2.85 (m, 1H), 2.28 - 1.78 (m, 6H), 1.59 (d,J= 4.6 Hz, 3H).

[0588]

[0589] 17. Synthetic scheme for Example 17

[0590]

[0591]

[0592] Experimental procedures for Example 17: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0593]

[0594] Step 1: 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 17-Int-1)

[0595] To the solution of ((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (250 mg, 0.32 mmol) in THF (1 mL) was added NaH (25 mg, 0.63 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2and the solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 12-Int-6SM1 (250 mg, 0.32 mmol) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 2 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted DCM / MeOH = 10:1 to give the desired product 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (156 mg, 56%) as a yellow solid. MS:m / z= 880.3 (M+H+, ESI+)

[0596]

[0597] 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 17-Int-2)

[0598] To the 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[de]naphthalen-10-yl)ethyl)pyridin-2-amine (136 mg, 0.15 mmol) in DMF (2 mL) was added CsF (235 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for 2 h under N2. 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 Na2SO4(s). The organic phase was concentrated under reduced pressure to give 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (136 mg, 121%) as a yellow solid. MS:m / z= 724.2 (M+H+, ESI+)

[0599]

[0600] Step 3: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 17-Int-3)

[0601] To the solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (136 mg, 0.19 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was concentrated under reduced pressure to give the desired product to give 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (136 mg, 106%) as a yellow solid. MS:m / z= 680.2 (M+H+, ESI+)

[0602]

[0603] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 17)

[0604] To the solution of 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (136 mg, 0.20 mmol) in MeOH (2 mL) was added Pd / C (60 mg). The reaction mixture was stirred at 25℃ for 2 h under H2. The reaction mixture was concentrated under reduced pressure. The residue was concentrated was purified by Prep-HPLC (Waters 2767 / Qda)Column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 16-26%; Retention Time: 8.7-10.2 min of 16 min to giveExample 17(26.31 mg, 19%) as a slight yellow solid. MS:m / z= 684.0 (M+H+, ESI+)

[0605] 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1.8H, FA), 7.98 (s, 1H), 7.81 - 7.73 (m, 1H), 7.70 - 7.62 (m, 1H), 7.43 - 7.29 (m, 2H), 7.07 - 6.97 (m, 1H), 6.78 - 6.68 (m, 1H), 6.42 - 6.31 (m, 1H), 4.55 - 4.29 (m, 4H), 4.23 - 4.12 (m, 1H), 3.58 - 3.40 (m, 3H), 3.35 - 3.24 (m, 4H), 3.20 - 3.10 (m, 1H), 2.46 - 2.25 (m, 3H), 2.21 - 1.86 (m, 5H), 1.68 - 1.52 (m, 3H), 0.90 - 0.75 (m, 3H).

[0606]

[0607] 18. Synthetic scheme for Example 18

[0608]

[0609]

[0610] Experimental procedures 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

[0611]

[0612] 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-Int-1)

[0613] To the slurry of NaH (60%) (20 mg, 0.51 mmol) in THF (1 mL) was added the solution of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (101 mg, 0.76 mmol) in THF (1 mL) at 0℃. The reaction mixture was stirred at 0℃ for 30 min and the solution of 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 12-Int-6(200 mg, 0.25 mmol) in THF (1 mL) was added to the above mixture. The reaction mixture was stirred at 0℃ for 1 h. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). Then the residue was purified with by silica gel chromatography eluted DCM / MeOH=20:1 to give 3-(1-(4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (87 mg, 40%) as a yellow solid. MS:m / z= 842.3 (M+H+, ESI+)

[0614]

[0615] Step 2: 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 18-Int-2)

[0616] To the solution of 3-(1-(4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (67 mg, 0.08 mmol) in DMF (1 mL) was added CsF (121 mg, 0.79 mmol). The reaction mixture was stirred at room temperature for 2 h under N2. The reaction mixture was quenched with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL x 3), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure to give the desired crude product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (52 mg, 95%) as a yellow solid. MS:m / z= 686.2 (M+H+, ESI+)

[0617]

[0618] Step 3: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 18)

[0619] To the solution of 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (42 mg, 0.06 mmol) in ACN (1 mL) was added 4 M HCl / dioxane(1 mL). The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; Retention Time: 7.3-9.3 min of 16 min to give the desired product to giveExample 18(7.28 mg, 18%) as a white solid. MS:m / z= 642.1 (M+H+, ESI+)

[0620] 1H 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).

[0621]

[0622] 19. Synthetic scheme for Example 19

[0623]

[0624]

[0625] Experimental procedures for 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

[0626]

[0627] 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 (Example 19-Int-1)

[0628] To the solution oftert-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)carbamateExample 12-Int-4(1.0 g, 1.972 mmol) in dioxane (12 mL) and H2O (4 mL) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (715 mg, 1.972 mmol), Ruphos-Pd-G3 (495 mg, 0.592 mmol) and K3PO4(1.25 g, 5.916 mmol). The mixture was stirred at 100℃ for 2 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was diluted with H2O (80 mL). The resulting mixture was extracted with EA (40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified with by silica gel column chromatography, eluted with EA / PE (75%) to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (590 mg, 49% yield) as a yellow solid. MS:m / z= 605.1 (M+H+, ESI+)

[0629]

[0630] Step 2: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19-Int-2)

[0631] To the solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl) pyridin-2-amine (300 mg, 0.496 mmol) in ACN (3 mL) and H2O (1 mL) was added Oxone (1.52 g, 5.481 mmol) at 0℃ under Argon. The resulting mixture was stirred at 0℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NaHSO3at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (50 mL). The mixture was extracted with EA (3Х30 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (210 mg, crude) as a yellow solid. MS:m / z= 637.1 (M+H+, ESI+)

[0632]

[0633] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19-Int-3)

[0634] To the solution of (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (66 mg, 0.401 mmol) in THF (2 mL) was added NaH (21 mg, 0.534 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (170 mg, 0.267 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （60 mL） at 0℃. The resulting mixture was extracted with EA (3Х30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified by column chromatography on silica gel eluted with (MeOH / DCM=1:20) to afford the desired product 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 46% yield) as a yellow solid. MS:m / z= 722.2(M+H+, ESI+)

[0635]

[0636] Step 4: 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 (Example 19)

[0637] To the solution of 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 0.097 mmol) in ACN (2 mL) was added HCl / dioxane (1.8 ml 1.745 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 Column:Xbridge C18,19*250 mm,10μm；Mobile Phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 55-55%; Retention Time: 9.2-10.8 min of 16 min to give the desired productExample 19(17.98 mg, 27% yield) as a yellow solid. MS:m / z= 678.0 (M+H+, ESI+)

[0638] 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.09 - 7.94 (m, 1H), 7.75 (dd,J= 9.0, 6.0 Hz, 1H), 7.65 (d,J= 7.5 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (t,J= 2.5 Hz, 1H), 6.68 (dd,J= 7.3, 5.0 Hz, 1H), 6.40 - 6.28 (m, 1H), 5.70 (d,J= 28.4 Hz, 2H), 4.95 (d,J= 12.0 Hz, 4H), 4.50 - 4.09 (m, 4H), 3.82 - 3.58 (m, 3H), 3.26 -3.14 (m, 3H), 2.75 - 2.62 (m, 2H), 2.49 - 2.15 (m, 4H), 1.67 - 1.50 (m, 3H), 0.90 - 0.75 (m, 3H).

[0639]

[0640] 20. Synthetic scheme for Example 20

[0641]

[0642]

[0643] Experimental procedures for 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[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0644]

[0645] Step 1: tert-butyl (Z)-(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (Example 20-Int-2)

[0646] To a solution oftert-butyl (2-acetylphenyl)carbamateExample 20-Int-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℃ for 4 h. Upon completion, the reaction mixture was added water (100 mL) and extracted with EA (100 mL). The organic layer was filtered and concentrated, dried over Na2SO4. The residue was purified by silica gel chromatography eluted PE / EA = 2:1 to givetert-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+)

[0647]

[0648] Step 2: tert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (Example 20-Int-3)

[0649] To the solution oftert-butyl (Z)-(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (5.3 g, 19.06 mmol) in MeOH (50 mL) was added NaBH4 (2.2 g, 57.19 mmol). The reaction mixture was stirred at 25℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 2:1 to give the desired producttert-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+)

[0650]

[0651] 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-Int-4)

[0652] To the solution oftert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (1.6 g, 5.70 mmol) in THF (5 mL) was added NaH (685 mg, 17.14 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 20 min under N2and the 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 for 2 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 10 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 3:1 to give to givetert-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+)

[0653]

[0654] Step 4: tert-butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-5)

[0655] To the solution oftert-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 (2.2g, 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℃ for 16 h under N2. The reaction mixture was diluted with DCM (40 mL). The organic phase was washed with brine (40 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 4:1 to givetert-butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (1.4 g, 65%) as a white solid. MS:m / z= 506.0 (M+H+, ESI+)

[0656]

[0657] Step 5: tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-6)

[0658] To the solution oftert-butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (700 mg, 1.39 mmol) in dioxane (7 mL) / H2O (0.7 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (709 mg, 1.39 mmol), K3PO4(890 mg, 4.16 mmol) and Ruphos-Pd-G3 (116 mg, 0.14 mmol). The reaction mixture was stirred at 100℃ for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 3:1 to give the desired producttert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (750 mg, 63%) as a yellow solid. MS:m / z= 856.1 (M+H+, ESI+)

[0659]

[0660] Step 6: tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-7)

[0661] To a solution oftert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamatetert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (650 mg, 0.76 mmol) in THF (6 mL) / H2O (3 mL) was added Oxone (2.33 g, 3.79 mmol) at 0℃. The mixture was stirred at 25℃ for 2 h. The reaction mixture was quenched with con. NaHSO3(aq, 20 mL) and extracted with EA (10 mL), dried over Na2SO4. The organic phase was concentrated under reduced pressure to givetert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (670 mg, crude) as a yellow solid. MS:m / z= 872.3 (M+H+, ESI+)

[0662]

[0663] 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-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-8)

[0664] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (167 mg, 1.047 mmol) in THF (7 mL) was added NaH (56 mg, 1.396 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was addedtert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (620 mg, 0.698 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （60 mL） at 0℃. The resulting mixture was extracted with EA (3Х40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get the desired producttert-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) as a yellow solid. MS:m / z= 967.6 (M+H+, ESI+)

[0665]

[0666] 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-Int-9)

[0667] To the solution oftert-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℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was diluted with H2O (80 mL). The resulting mixture was extracted with EA (3Х50 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired producttert-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, 29% yield) as a yellow solid. MS:m / z= 811.5 (M+H+, ESI+)

[0668]

[0669] Step 9: 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 (Example 20)

[0670] To the solution oftert-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 (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℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 Column:Xbridge C18,19*250 mm,10μm；Mobile Phase A: 10 mmol NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 55-55%; Retention Time: 9.2-10.8 min of 16 min to give the desired productExample 20(8.15 mg, 19% yield) as a white solid. MS:m / z= 667.2 (M+H+, ESI+)

[0671] 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.95 (dd,J= 9.0, 5.9 Hz, 1H), 7.46 (t,J= 9.0 Hz, 1H), 7.37 (s, 1H), 7.32 (d,J= 7.7 Hz, 1H), 7.15 (dd,J= 7.7, 2.4 Hz, 1H), 7.09 (t,J= 7.2 Hz, 1H), 6.78 - 6.65 (m, 2H), 6.47 - 6.30 (m, 1H), 5.30 (d,J= 54.6 Hz, 1H), 5.00 - 4.80 (m, 2H), 4.45 - 4.30 (m, 1H), 4.25 - 4.07 (m, 3H), 3.78 - 3.65 (m, 1H), 3.27 - 3.22 (m, 1H), 3.15 - 3.00 (m, 3H), 2.89 - 2.81 (m, 1H), 2.18 - 1.79 (m, 6H), 1.68 - 1.55 (m, 3H).

[0672]

[0673] 21. Synthetic scheme for Example 21

[0674]

[0675]

[0676] Experimental procedures for 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

[0677]

[0678] 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)

[0679] To the 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) was added Pd / C (15 mg) at 25℃ under H2. The mixture was stirred at 25℃ for 16 h under H2. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was filtered, the filter cake was washed with MeOH (3Х5 mL). The filtrate was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 13-21%; Retention Time: 9.8-12.2 min of 17 min to afford the desired productExample 21(21.45 mg, 28% yield) as a white solid. MS:m / z= 671.2 (M+H+, ESI+)

[0680] 1H NMR (400 MHz, DMSO-d6) 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).

[0681]

[0682] 22. Synthetic scheme for Example 22

[0683]

[0684]

[0685] Experimental procedures for Example 22: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0686]

[0687] 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)

[0688] To the 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) was added Pd / C (5 mg) at 25℃ under H2. The mixture was stirred at 25℃ for 16 h under H2. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was filtered, the filter cake was washed with MeOH (3Х5 mL). The filtrate was concentrated under reduced pressure to get residue. The residue was purified by prep-HPLC with the following conditions:prep-HPLC(Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 13-21%; Retention Time: 9.8-12.2min of 17min to afford the desired productExample 22(16.37 mg, 40% yield) as a white solid. MS:m / z= 646.0 (M+H+, ESI+)

[0689] 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 0.61H, FA), 7.98 (brs, 1H), 7.75 (dd,J= 9.0, 6.0 Hz, 1H), 7.66 (d,J= 7.5 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.02 (s, 1H), 6.77 - 6.65 (m, 1H), 6.45 - 6.32 (m, 1H), 5.21 (d,J= 55.9 Hz, 1H), 4.60 - 4.24 (m, 4H), 3.82 - 3.74 (m, 1H), 3.57 - 3.32 (m, 3H), 3.07 - 2.95 (m, 1H), 2.47 - 2.27 (m, 5H), 2.24 - 2.10 (m, 1H), 2.04 - 1.85 (m, 1H), 1.66 - 1.52 (m, 3H), 0.90 - 0.75 (m, 3H).

[0690]

[0691] 23. Synthetic scheme for Example 23

[0692]

[0693]

[0694] Experimental procedures for 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

[0695]

[0696] Step 1: 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (Example 23-Int-2)

[0697] To a solution of 3-bromo-5-methylpyridin-2-amine (10 g, 53.46 mol) and Ethoxyvinyltri-n-butyltin (18 mL, 53.44mmol) in 100 mL of dioxane was added Pd(PPh3)Cl2(1.87 g, 2.66 mmol). The solution was purged with N2three times, and it was stirred for 4 h at 100℃ under N2. The reaction was concentrated to dryness in vacuo to give a yellow oil, which was purified by silica gel chromatography eluted DCM / MeOH= 10:1. The desired fractions were collected and concentrated to dryness in vacuo to give the desired product 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (7.1 g, crude) as a yellow oil. MS:m / z= 179.0 (M+H+, ESI+)

[0698]

[0699] Step 2: 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (Example 23-Int-3)

[0700] To a mixture of 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (8.8 g, 49.44 mmol) in DCM (45 mL) was dropwised 4 M HCl / dioxane (45 mL) slowly at 25℃. The reaction mixture was stirred at 25℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in H2O (40 mL), and adjust to pH to 8 with a solution of Na2CO3, then the mixture was extracted with DCM (150 mL x 3). The combined organic layers were concentrated to dryness in vacuo to give a black oil. The residue was purified by silica gel chromatography eluted petroleum ether / ethyl acetate= 5:1 to give the desired product 1-(2-amino-5-methylpyridin-3-yl)ethan-1-one (4.08 g, 55% yield) as a yellow solid. MS:m / z= 151.0 (M+H+, ESI+)

[0701]

[0702] Step 3:tert-butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (Example 23-Int-4)

[0703] To the 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)2O (12.4 mL, 54.07 mmol). The reaction mixture was stirred at 90℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted petroleum ether / ethyl acetate = 10:1 to give the desired producttert-butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (4.06 g, 60% yield) as a yellow solid. MS:m / z= 251.1 (M+H+, ESI+)

[0704]

[0705] Step 4: tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-5)

[0706] To a solution oftert-butyl (3-acetyl-5-methylpyridin-2-yl)carbamate (4 g, 15.98 mmol) in EtOH (40 mL) was added 2-aminoethan-1-ol (2.9 g, 47.94 mmol). The mixture was stirred at 90℃ for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 1:3 to givetert-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+)

[0707]

[0708] Step 5: tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-6)

[0709] To the solution oftert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamate (2.3 g, 7.84 mmol) in MeOH (20 mL) was added NaBH4 (890 mg, 23.54 mmol) at 0℃. The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography eluted DCM / MeOH= 20:1 to give the desired producttert-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+)

[0710]

[0711] 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-Int-7)

[0712] To the solution oftert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1 g, 3.39 mmol) in THF (10 mL) was added NaH (406 mg, 10.17 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2and the solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (949 mg, 3.39mmol) in THF (10 mL)was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 2 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 20 mL) and the solution was extracted with EA (30 mL). The organic phase was washed with brine (20 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 1:9 to give the desired crude producttert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (1.3 g, 71%) as a yellow solid. MS:m / z= 539.2 (M+H+, ESI+)

[0713]

[0714] Step 7: tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-8)

[0715] To the solution oftert-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), DIEA (2.8 g, 21.71 mmol). The reaction mixture was stirred at 25℃ for 16 h under N2. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 1:1 to givetert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate (580 mg, 46%) as a yellow solid. MS:m / z= 521.3 (M+H+, ESI+)

[0716]

[0717] Step 8: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23-Int-9)

[0718] To the solution oftert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate (500 mg, 0.96 mmol) in dioxane (5 mL) / H2O (0.5 mL) were added 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (345 mg, 0.96 mmol), K3PO4(610 mg,2.88 mmol) and Ruphos-Pd-G3 (241 mg, 0.29 mmol). The reaction mixture was stirred at 100℃ for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted DCM / MeOH = 50:1 to give the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (175 mg, 29%) as a yellow solid. MS:m / z= 619.4 (M+H+, ESI+)

[0719]

[0720] Step 9: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23-Int-10)

[0721] To a solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, 0.20 mmol) in ACN (3 mL) / H2O (1 mL) was added Oxone (621 mg, 1.01 mmol) at 0℃. The mixture was stirred at 25℃ for 1 h. The reaction mixture was quenched with con. NaHSO3 (aq, 5 mL) and extracted with EA (5 mL), dried over Na2SO4. The organic phase was concentrated under reduced pressure to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, crude) as a yellow solid. MS:m / z= 651.3 (M+H+, ESI+)

[0722]

[0723] Step 10: 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23-Int-11)

[0724] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (92 mg, 0.58 mmol) in THF (1 mL) was added NaH (15 mg, 0.38 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2and the solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (125 mg, 0.19 mmol) in THF (1 mL)was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL), dried over Na2SO4(s) to give 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (55 mg, crude) as a yellow solid. MS:m / z= 730.4 (M+H+, ESI+)

[0725]

[0726] Step 11: 4-(10-(1-(2-amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 23)

[0727] To the solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (55 mg, 0.07 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 um; Mobile Phase A: 0.05% NH3H2O / H2O, B: ACN; flow rate: 20 mL / min; gradient: 47%~47%; Retention Time: 9.2-11.2 min of 16 min) to give the desired product to giveExample 23(3.82 mg, 7%) as a white solid. MS:m / z= 686.5 (M+H+, ESI+)

[0728] 1H NMR (400 MHz, MeOD-d4) δ 7.81 (s, 1H), 7.69 - 7.59 (m, 2H), 7.30 - 7.18 (m, 2H), 7.06 - 7.01 (m, 1H), 6.67 - 6.56 (m, 1H), 5.41 - 5.23 (m, 1H), 4.57 - 4.30 (m, 4H), 3.84 - 3.68 (m, 1H), 3.64 - 3.46 (m, 1H), 3.28 - 2.96 (m, 4H), 2.61 - 2.33 (m, 3H), 2.27 (s, 3H), 2.23 - 2.10 (m, 2H), 2.03 - 1.86 (m, 3H), 1.71 - 1.61 (m, 3H), 0.92 - 0.81 (m, 3H).

[0729]

[0730] 24. Synthetic scheme for Example 24

[0731]

[0732]

[0733] Experimental procedures for Example 24: 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile

[0734]

[0735] 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-Int-1)

[0736] To the solution of 4-(hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile (44 mg, 0.306 mmol) in THF (2 mL) was added NaH (17 mg, 0.408 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (130 mg, 0.204 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （50 mL） at 0℃. The resulting mixture was extracted with EA (3Х30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get the desired product 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (70 mg, 49% yield) as a yellow solid. MS:m / z= 698.4 (M+H+, ESI+)

[0737]

[0738] Step 2: 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (Example 24)

[0739] To the solution of 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (70 mg, 0.100 mmol) in ACN (2 mL) was added HCl / dioxane (1.8 ml 1.806 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 26-36%; Retention Time: 8.9-9.9 min of 16min to give the desired productExample 24(17.05 mg, 25% yield) as a white solid. MS:m / z= 654.2 (M+H+, ESI+)

[0740] 1H 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).

[0741]

[0742] 25. Synthetic scheme for Example 25

[0743]

[0744]

[0745] Experimental procedures for Example 25: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0746]

[0747] 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-Int-1)

[0748] To the solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (48 mg, 0.282 mmol) in THF (1 mL) was added NaH (18 mg, 0.372 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amineExample 19-Int-2(120 mg, 0.186 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （60 mL） at 0℃. The resulting mixture was extracted with EA (3Х40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (60 mg, 38% yield) as a yellow solid. MS:m / z= 714.5 (M+H+, ESI+)

[0749]

[0750] Step 2: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 25)

[0751] To the solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (50 mg, 0.070 mmol) in ACN (2 mL) was added HCl / dioxane (1.3 ml 1.261 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 15-23%; Retention Time: 7.7-9.1 min of 16 min to give the desired productExample 25(10.38 mg, 22% yield, FA salt) as a white solid. MS:m / z= 670.2 (M+H+, ESI+).

[0752]

[0753] Step 3: Example 25-Free form

[0754] To 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-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (20 mg, 0.030 mmol, FA salt) in DCM (10 mL) was washed with con. NaHCO3(aq) (5 mL x 3). The organic phase was concentrated to give the desired productExample 25-Free(10.16 mg, 51% yield) as a white solid. MS:m / z= 670.2 (M+H+, ESI+)

[0755] 1H NMR (400 MHz, DMSO-d6) δ 9.93 (d,J= 2.0 Hz, 1H), 8.01 -7.92 (m, 1H), 7.75 (dd,J= 9.0, 6.0 Hz, 1H), 7.64 (d,J= 7.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.99 (d,J= 2.1 Hz, 1H), 6.72 - 6.62 (m, 1H), 6.42 - 6.30 (m, 1H), 5.72 (dd,J= 27.4, 10.6 Hz, 2H), 4.55 - 4.14 (m, 4H), 3.80 - 3.68 (m, 1H), 3.65 - 3.43 (m, 6H), 3.20 - 3.10 (m, 1H), 3.03 - 2.84 (m, 3H), 2.44 - 2.26 (m, 2H), 2.14 - 2.02 (m, 1H), 1.85 - 1.71 (m, 1H), 1.69 - 1.53 (m, 4H), 1.36 - 1.26 (m, 1H), 0.88 - 0.76 (m, 3H).

[0756]

[0757] 26. Synthetic scheme for Example 26

[0758]

[0759]

[0760] Experimental procedures for Example 26: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0761]

[0762] Step 1: methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (Example 26-Int-1)

[0763] To the solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (1.5 g, 10.353 mmol) in DCM (20 mL) were added (COCl)2(1.72 g, 13.551 mmol) and DMF (12 mg, 0.080 mmol) at 0℃ under Argon. The resulting mixture was stirred at 25℃ for 0.5 h under Argon. The mixture was concentrated under reduced pressure to get 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) was added the residue at 25℃ under Argon atmosphere. The resulting mixture was stirred for 16 h at 25℃ under Argon atmosphere. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to give the desired product methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (1.5 g, crude) as a yellow solid. MS:m / z= 216.1 (M+H+, ESI+)

[0764]

[0765] Step 2: (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (Example 26-Int-2)

[0766] To the solution of methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (1.5 g, 6.970 mmol) in THF (20 mL) were added LAH (14 ml, 13.939 mmol) at 0℃ under N2. The mixture was stirred at 25℃ for 3 h. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched by the addition of H2O (0.14 mL), 15% solution of NaOH (0.14 mL) and H2O (0.3 mL) at 0℃. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by silica gel column chromatography, eluted with MeOH:DCM (6%) to afford (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+)

[0767]

[0768] 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-Int-3)

[0769] To the solution of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (61 mg, 0.353 mmol) in THF (4 mL) was added NaH (28 mg, 0.706 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (150 mg, 0.236 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was detected by LCMS. LCMS detected the desired product. The reaction was quenched with the solution of NH4Cl （50 mL） at 0℃. The resulting mixture was extracted with EA (3Х30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get the desired product 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (190 mg, crude) as a yellow solid. MS:m / z= 730.4(M+H+, ESI+)

[0770]

[0771] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 26)

[0772] To the solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (140 mg, 0.192 mmol) in ACN (2 mL) was added HCl / dioxane (3.5 ml 3.453 mmol). The mixture was stirred at 25℃ for 1 h under Argon. The reaction was detected by LCMS. LCMS detected the desired product. The resulting mixture was concentrated under reduced pressure to get residue. The residue was purified by Prep-HPLC with the following conditions: Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; Retention Time: 8.9-9.8 min of 16 min to give the desired productExample 26(3.10 mg, 2% yield) as a white solid. MS:m / z= 686.2 (M+H+, ESI+)

[0773] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1.52 H, FA), 7.97 (s, 1H), 7.79 - 7.60 (m, 2H), 7.43 - 7.26 (m, 2H), 6.99 (s, 1H), 6.77 - 6.61 (m, 1H), 6.40 - 6.30 (m, 1H), 5.70 (dd,J= 27.6, 5.6 Hz, 2H), 5.17 (d,J= 56.5 Hz, 1H), 4.48 - 4.20 (m, 4H), 3.80 - 3.68 (m, 4H), 2.90 - 2.75 (m, 2H), 2.44 - 2.26 (m, 4H), 2.20 - 1.96 (m, 1H), 1.95 - 1.75 (m, 1H), 1.65 - 1.50 (m, 3H), 0.88 - 0.75 (m, 3H), 0.70 - 0.60 (m, 2H), 0.50 - 0.40 (m, 2H).

[0774]

[0775] 27. Synthetic scheme for Example 27

[0776]

[0777]

[0778] Experimental procedures 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

[0779]

[0780] Step 1: (S)-pyrrolidin-2-ylmethanol hydrochloride (Example 27-Int-2)

[0781] To the solution oftert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.84 mmol) were dropwised 4 M HCl / dioxane (62 mL) slowly at 25℃. The reaction mixture was stirred at 25℃ 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+)

[0782]

[0783] Step 2: (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (Example 27-Int-3)

[0784] To an ice-cooled solution of K2CO3(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 warmed to room temperature. The mixture was stirred at 25℃ 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. Then the residue was purified with by silica gel chromatography eluted 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+)

[0785]

[0786] 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-Int-4)

[0787] To the 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℃. The reaction mixture was stirred at 0℃ for 30 min under N2and the solution of 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (224 mg, 0.35 mmol) in THF (2 mL)was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL), dried over Na2SO4(s) to give 3-(1-(2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 12%) as a yellow solid. MS:m / z= 722.4 (M+H+, ESI+)

[0788]

[0789] Step 4: 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 27)

[0790] To the solution of 3-(1-(2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (90 mg, 0.12 mmol) in ACN (1 mL) was added 4 M HCl / dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was concentrated under reduced pressure, The residue was purified by Prep-HPLC (Waters 2767 / Qda, Column: SunFire C18，19*250 mm，10 um；Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 18-28%; Retention Time: 7.9-10.8 min of 16 min) and Prep-HPLC (Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 um; Mobile Phase A: 0.05% NH3H2O / H2O, B: ACN; flow rate: 20 mL / min; gradient: 53%~53%; Retention Time: 9.4-11.4 min of 16 min) to give the desired product to giveExample 27(14.55 mg, 17%) as a white solid. MS:m / z= 678.4 (M+H+, ESI+)

[0791] 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.98 (s, 1H), 7.75 (dd,J= 8.8, 6.0 Hz, 1H), 7.65 (d,J= 7.5 Hz, 1H), 7.41 - 7.24 (m, 2H), 6.99 (s, 1H), 6.74 - 6.63 (m, 1H), 6.42 - 6.30 (m, 1H), 6.08 (t,J= 56.4 Hz, 1H), 5.76 - 5.60 (m, 2H), 4.48 - 4.16 (m, 4H), 3.80 - 3.66 (m, 1H), 3.48 - 3.38 (m, 2H), 3.16 - 2.98 (m, 2H), 2.93 - 2.75 (m, 1H), 2.44 - 2.26 (m, 3H), 2.02 - 1.89 (m, 1H), 1.81 - 1.50 (m, 6H), 0.90 - 0.78 (m, 3H).

[0792]

[0793] 28. Synthetic scheme for Example 28

[0794]

[0795]

[0796] Experimental procedures for Example 28: 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

[0797]

[0798] Step 1: 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Example 28-Int-2)

[0799] To the solution of 2-(methylamino)ethan-1-ol (3 g, 10.71 mmol) in THF (30 mL) was added NaH (1.28 g, 32.13 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2and the solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (804 mg, 10.71 mmol) in THF (30 mL)was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 30 mL) and the solution was extracted with EA (30 mL). Filtered and then washed with EA, collected the filter cake to give the desired crude product 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (2.1 g, 61%) as a yellow solid. MS:m / z= 319.0 (M+H+, ESI+)

[0800]

[0801] 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-Int-3)

[0802] To the solution of 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.9 g, 5.96 mmol) in DCM (20 mL) was added BOPCl (4.6 g, 17.88 mmol), DIEA (6.9 g, 53.65 mmol). The reaction mixture was stirred at 25℃ for 16 h under N2. The reaction mixture was diluted with DCM (20 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 1:4 to give 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (220 mg, 12%) as a yellow solid. MS:m / z= 301.0 (M+H+, ESI+)

[0803]

[0804] Step 3: 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28-Int-4)

[0805] To the solution of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (220 mg, 0.73 mmol) in dioxane (3 mL) / H2O (0.3 mL) were 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), K3PO4( 465 mg, 2.19 mmol) and Ruphos-Pd-G3 (61 mg, 0.07 mmol). The reaction mixture was stirred at 100℃ for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 1:1 to give the desired product 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (80 mg, 22%) as a white solid. MS:m / z= 499.2 (M+H+, ESI+)

[0806]

[0807] Step 4: 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28-Int-5)

[0808] To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene SM1 (80 mg, 0.16 mmol) in THF (3 mL) / H2O (1 mL) was added Oxone (493 mg, 0.80 mmol) at 0℃. The mixture was stirred at 25℃ for 1 h. The reaction mixture was quenched with con. NaHSO3 (aq, 5 mL) and extracted with EA (5 mL), dried over Na2SO4. The organic phase was concentrated under reduced pressure to give 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (56 mg, 65%) as a yellow solid. MS:m / z= 515.3 / 531.2 (M+H+, ESI+)

[0809]

[0810] 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-Int-6)

[0811] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (50 mg, 0.32 mmol) in THF (1 mL) was added NaH (8 mg, 0.21 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2and the 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 for 1 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (5 mL). The organic phase was washed with brine (5 mL), dried over Na2SO4(s) to give 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+)

[0812]

[0813] 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)

[0814] To the 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 for 1 h under N2. The reaction mixture was concentrated under reduced pressure, The residue was purified by Prep-HPLC (Waters 2767 / Qda) Column: SunFire C18，19*250 mm，10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 23-31%; Retention Time: 7.9-9.6 min of 16 min to give the desired product to giveExample 28(5.78 mg, 9%) as a white solid. MS:m / z= 566.3 (M+H+, ESI+)

[0815] 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.48 H, FA), 7.75 (dd,J= 8.6, 6.2 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.01 (s, 1H), 5.29 (d,J= 54.1 Hz, 1H), 4.63 - 4.48 (m, 2H), 4.11 (dd,J= 42.3, 10.3 Hz, 2H), 4.02 - 3.92 (m, 2H), 3.36 (s, 2H), 3.16 - 2.97 (m, 4H), 2.90 - 2.78 (m, 1H), 2.39 - 1.99 (m, 5H), 1.88 - 1.74 (m, 3H), 0.86 - 0.76 (m, 3H).

[0816]

[0817] 29. Synthetic scheme for Example 29 (Examples 29a and 29b)

[0818]

[0819]

[0820] Experimental procedures for Example 29 (Examples 29a and 29b)

[0821]

[0822] 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-Int-1)

[0823] To the solution oftert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (824 mg, 2.928 mmol) in THF (10 mL) was added NaH (60% in oil, 351 mg, 8.793 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added 7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-ol (1.0 g, 2.928 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was quenched by the addition of NH4Cl (30 mL) at 0℃. and the solution was extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with Ethyl acetate to afford the desired producttert-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+)

[0824]

[0825] Step 2: tert-butyl(3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (Example 29-Int-2)

[0826] To the solution oftert-butyl (3-(1-((2-((7-bromo-6-chloro-8-fluoro-4-hydroxy-2-(methylthio)quinazolin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (1.26 g, 2.090 mmol) in THF (20 mL) was added DIEA (2.43 g, 18.810 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was added BopCl (1.60 g, 6.270 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 16 h at 25℃ under Argon. The reaction mixture was diluted with H2O (80 mL), and the solution was extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (Ethyl acetate in Petroleum ether = 82%) to afford the desired producttert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (840 mg, 68% yield) as a yellow solid. MS:m / z= 586.1 (M+H+, ESI+)

[0827]

[0828] Step 3: tert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 29-Int-3)

[0829] The solution oftert-butyl (3-(1-(9-bromo-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-yl)carbamate (240 mg, 0.410 mmol),tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (332 mg, 0.821 mmol), Pd(DPEPhos)Cl2(30 mg, 0.041 mmol), KF (48 mg, 0.821 mmol) and K3PO4(261 mg, 1.230 mmol) in dioxane (3 mL) was stirred at 105℃ for 3h under Argon. The reaction mixture was diluted with H2O (40 mL) and the solution was extracted with EA (20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get residue. The residue was purified with by silica gel column chromatography, eluted with Ethyl acetate in Petroleum ether (75%) to give the desired producttert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (154 mg, 53% yield) as a yellow solid. MS:m / z= 696.2(M+H+, ESI+)

[0830]

[0831] Step 4: tert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfinyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 29-Int-4)

[0832] To the solution oftert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylthio)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (130 mg, 0.187 mmol) in THF (3 mL) and H2O (1 mL) was added Oxone (575 mg, 0.934 mmol) at 0℃ under Argon. The resulting mixture was stirred at 0℃ for 1h under Argon. The reaction was quenched with the solution of NaHSO3at 0℃. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired producttert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfinyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (90 mg, crude) as a yellow solid. MS:m / z= 712.3(M+H+, ESI+). The crude product was used for the next step directly.

[0833]

[0834] 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]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 29-Int-5)

[0835] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (30 mg, 0.190 mmol) in THF (2 mL) was added NaH (60% in oil, 10 mg, 0.252 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 0.5 h. To the above mixture was addedtert-butyl (4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(methylsulfinyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (90 mg, 0.126 mmol) at 0℃ under Argon. The resulting mixture was stirred for additional 1 h at 0℃. The reaction was quenched by the addition of NH4Cl (4 mL) at 0℃. The reaction mixture was concentrated under reduced pressure to get residue. The residue was diluted with H2O (30 mL), and the solution was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with Methanol in Dichloromethane (9%) to afford the desired producttert-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]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (30 mg, 29% yield) as a yellow solid. MS:m / z= 807.4(M+H+, ESI+)

[0836]

[0837] Step 6: Example 29a and 29b

[0838]

[0839]

[0840] A solution oftert-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]oxazepino[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 16h at 25℃ under N2atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Waters 2767 / Qda, Column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 13-23%; Retention Time: 4.6-6min of 16 min) to affordExample 29a(2.62 mg, 9%) as a white solid andExample 29b(3.31 mg, 12%) as a white solid.

[0841] 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0842] MS:m / z= 707.1 (M+H+, ESI+)

[0843] 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).

[0844] 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0845] MS:m / z= 707.1 (M+H+, ESI+)

[0846] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 0.84 H, FA), 8.08 (s, 2H), 8.00 - 7.95 (m, 1H), 7.64 (d,J= 7.3 Hz, 1H), 7.27 - 7.09 (m, 2H), 6.67 (dd,J= 7.5, 4.9 Hz, 1H), 6.37 - 6.23 (m, 1H), 5.84 (s, 2H), 5.29 (d,J= 54.5 Hz, 1H), 4.53 (dd,J= 11.3, 6.2 Hz, 1H), 4.25 - 3.99 (m, 3H), 3.72 (dd,J= 15.0, 6.3 Hz, 2H), 3.12 - 2.96 (m, 3H), 2.89 - 2.78 (m, 1H), 2.21 - 1.98 (m, 3H), 1.91 - 1.74 (m, 3H), 1.58 (d,J= 6.8 Hz, 3H).

[0847]

[0848] 30. Synthetic scheme for Example 30

[0849]

[0850]

[0851]

[0852] Experimental procedures for 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

[0853]

[0854] Step 1: 8-oxo-5,6,7,8-tetrahydroisoquinoline 2-oxide (Example 30-Int-2)

[0855] To the solution of 6,7-dihydroisoquinolin-8(5H)-oneExample 30-Int-1(6.7 g, 45.58 mmol) in DCM (100 mL) was added m-CPBA (13.4 g, 77.48 mmol). The reaction mixture was stirred at 25℃ for 16 h under N2. The reaction mixture was quenched with con. NaHSO3(aq, 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 purified with by silica gel chromatography eluted DCM / MeOH = 10:1 to give the desired product 8-oxo-5,6,7,8-tetrahydroisoquinoline 2-oxide (8 g, 89%) as a slightly yellow solid. MS:m / z= 164.1 (M+H+, ESI+).

[0856]

[0857] Step 2: 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (Example 30-Int-3)

[0858] To the solution of 8-oxo-5,6,7,8-tetrahydroisoquinoline 2-oxide (7 g, 42.94 mmol) in DCE (70 mL) was added BnNH2(11.5 g, 107.36 mmol), TEA (13 g, 128.83 mmol), PyBrOP (26 g, 55.83 mmol). The reaction mixture was stirred at 25℃ for 4 h under N2. The reaction mixture was diluted with DCM (70 mL) and the solution was washed with brine (100 mL). The organic phase was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 10:1 to give 1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-one (3.8 g, 35%) as a yellow solid. MS:m / z= 252.9 (M+H+, ESI+).

[0859]

[0860] Step 3:(E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-ylidene)amino)ethan-1-ol (Example 30-Int-4)

[0861] To the 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℃ for 2 h and NaBH3CN (740 mg, 11.905 mmol) was added to the above solution. Then the reaction mixture was stirred at 60℃ for 48 h. The reaction mixture was diluted with DCM (100 mL) and the solution was washed with water (150 mL x 3). The organic phase was washed with brine (100 mL), dried over Na2SO4(s) and concentrated to give the crude product (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-ylidene)amino)ethan-1-ol (1.0 g, 100%) as a slightly yellow oil. MS:m / z= 296.0 (M+H+, ESI+).

[0862]

[0863] Step 4:2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (Example 30-Int-5)

[0864] To the solution of (E)-2-((1-(benzylamino)-6,7-dihydroisoquinolin-8(5H)-ylidene)amino)ethan-1-ol (1.5 g, 5.078 mmol) in MeOH (10 mL) was added NaBH4(576 mg, 15.234 mmol). The reaction mixture was stirred at 25℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 1:1 to give the desired product 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (440 mg, 29% yield) as a colorless oil. MS:m / z= 298.0 (M+H+, ESI+)

[0865]

[0866] Step 5:5-(2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Example 30-Int-6)

[0867] To the solution of 2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethan-1-ol (400 mg, 1.342 mmol) in THF (2 mL) was added NaH (60% in oil, 215 mg, 5.346 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2and 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℃ for 16 h under N2. The reaction mixture was quenched with con. NH4Cl (aq) (5 mL) and the solution was extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 3:1 to give the desired product 5-(2-((1-(benzylamino)-5,6,7,8-tetrahydroisoquinolin-8-yl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (185 mg, 25% yield) as a colorless oil. MS:m / z= 541.1 (M+H+, ESI+).

[0868]

[0869] 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 (Example 30-Int-7)

[0870] To the 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℃ for 16 h under N2. The reaction mixture was diluted with DCM (10 mL). The organic phase was washed with brine (20 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was concentrated was purified by silica gel chromatography eluted PE / EA = 3:1 to give the desired product N-benzyl-8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (90 mg, 50% yield) as a colorless oil. MS:m / z= 523.1 (M+H+, ESI+).

[0871]

[0872] 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-Int-8)

[0873] To the solution of N-benzyl-8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (90 mg, 0.172 mmol) in TFA (2.5 mL) was added CF3SO3H (0.5 mL). The reaction mixture was stirred at 25℃ for 5 h under N2. The reaction mixture was quenched with con. Na2CO3(50 mL) and the solution was extracted with DCM (50 mL x 3). The organic phase was washed brine (50 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 3:1 to give the desired product 8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (50 mg, 67% yield) as a yellow solid. MS:m / z= 433.0 (M+H+, ESI+).

[0874]

[0875] Step 8:8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (Example 30-Int-9)

[0876] To the solution of 8-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (40 mg, 0.092 mmol) in dioxane (3 mL) / H2O (0.3 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (48 mg, 0.092 mmol), K3PO4(60 mg, 0.276 mmol) and Ruphos-Pd-G3 (16 mg, 0.0184 mmol). The reaction mixture was stirred at 100℃ for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted PE / EA = 3:1 to give the desired product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (20 mg, 27% yield) as a yellow solid. MS:m / z= 783.3 (M+H+, ESI+).

[0877]

[0878] 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-Int-10)

[0879] To the solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (20 mg, 0.025 mmol) in ACN (1 mL) / H2O (1 mL) was added Oxone (78 mg, 0.128 mmol) at 0℃. The reaction mixture was stirred at room temperature for 2 h under N2. The reaction mixture was quenched with conc. NaHSO3(aq, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure to give the desired crude product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(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+).

[0880]

[0881] 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-Int-11)

[0882] To the solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (14 mg, 0.090 mmol) in THF (1 mL) was added NaH (60% in oil, 2 mg, 0.128 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 20 min under N2and the solution of 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)-5,6,7,8-tetrahydroisoquinolin-1-amine (15 mg, 0.018 mmol) was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 2 h under N2. The reaction mixture was quenched with conc. NH4Cl (aq, 5 mL) and the solution was extracted with EA (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure to give the desired crude product 8-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-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, 60% yield) as a yellow solid. MS:m / z= 849.3 (M+H+, ESI+).

[0883]

[0884] 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-Int-12)

[0885] To the 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-tetrahydroiso quinolin-1-amine (10 mg, 0.011 mmol) in DMF (1 mL) was added CsF (17 mg, 0.110 mmol). The reaction mixture was stirred at room temperature for 2 h under N2. The reaction mixture was quenched with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL x 3), dried over Na2SO4(s). The organic phase was concentrated under reduced pressure to give the desired crude product 8-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-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, 100% yield) as a colorless oil. MS:m / z= 738.2 (M+H+, ESI+).

[0886]

[0887] 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)

[0888] To the 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). The reaction mixture was stirred at room temperature for 4 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: SunFire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% NH4HCO3 / H2O, B: ACN; gradient: 5%-95% B; flow rate: 50 mL / min) to give the desired product to give the desired productExample 30(1.07 mg, 11% yield) as a white solid. MS:m / z= 694.4 (M+H+, ESI+).

[0889]

[0890] 31. Synthetic scheme for Example 36

[0891]

[0892]

[0893] Experimental procedures 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0894]

[0895] Step 1: tert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methyl-enetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 36-Int-1)

[0896] To the solution of (S)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (13 mg, 0.082 mmol) in THF (1 mL) were added NaH (60% in oil, 10 mg, 0.41 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 10 min 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]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (60 mg, 0.082 mmol) was added into the above mixture. The reaction mixture was stirred at 0℃ to room temperature for 1h under Argon. The resulting mixture was quenched with H2O (10 mL). The resulting mixture was extracted with Ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get a residue, which was purified by silica gel column chromatography, eluted with Dichloromethane : Methanol (10 : 1) to get the desired producttert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methylene-tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, 75% yield) as a yellow solid. MS:m / z= 801.4 (M+H+, ESI+)

[0897]

[0898] 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 36)

[0899] To the solution oftert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((S)-2-methyl-enetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, 0.062 mmol) in DCM (0.5 mL) was added 4M 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 Prep-HPLC (Waters 2767 / Qda, Column: Xbridge C18 19*250 mm, 10 um; Mobile Phase A: 10mmol NH4HCO3, B: ACN; flow rate: 20 mL / min; gradient: 57%~57%). Retention Time: 5.6-7.1 min of 16 min to give the desired productExample 36a(1.34 mg, 3%) as a white solid; Retention Time: 9.5-11 min of 16 min to give the desired productExample 36b(6.06 mg, 14%) as a white solid.

[0900]

[0901] Example 36a:

[0902] MS:m / z= 701.3 (M+H+, ESI+).

[0903] 1H NMR (400 MHz, DMSO-d6) δ 8.08 (brs, 1.87 H, FA), 7.97 (d,J= 4.3 Hz, 1H), 7.64 (d,J= 7.0 Hz, 1H), 7.24 - 7.08 (m, 2H), 6.68 (dd,J= 7.4, 5.0 Hz, 1H), 6.30 - 6.20 (m, 1H), 5.67 (d,J= 15.6 Hz, 2H), 4.90 (d,J= 11.1 Hz, 2H), 4.45 - 4.25 (m, 2H), 4.10 - 3.98 (m, 2H), 3.60 - 3.50 (m, 2H), 3.25 - 3.13 (m, 2H), 3.05 - 2.95 (m, 1H), 2.70 - 2.56 (m, 1H), 2.40 - 2.30 (m, 2H), 2.03 - 1.70 (m, 4H), 1.66 - 1.55 (m, 3H).

[0904] Example 36b:

[0905] MS:m / z= 701.3 (M+H+, ESI+).

[0906] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (brs, 2H), 7.97 (d,J= 5.0 Hz, 1H), 7.65 (d,J= 7.4 Hz, 1H), 7.25 - 7.09 (m, 2H), 6.68 (dd,J= 7.4, 4.9 Hz, 1H), 6.35 - 6.25 (m, 1H), 5.81 (d,J= 16.5 Hz, 2H), 4.90 (d,J= 9.9 Hz, 2H), 4.52 (dd,J= 11.8, 6.1 Hz, 1H), 4.21 (dd,J= 11.0, 7.0 Hz, 1H), 4.13 - 3.97 (m, 2H), 3.70 (dd,J= 15.7, 6.4 Hz, 1H), 3.56 (d,J= 14.0 Hz, 1H), 3.18 (d,J= 13.7 Hz, 2H), 3.02 - 2.98 (m, 1H), 2.67 - 2.59 (m, 1H), 2.36 (d,J= 15.2 Hz, 2H), 1.99 - 1.68 (m, 4H), 1.58 (d,J= 6.6 Hz, 3H).

[0907]

[0908]

[0909] 32. Synthetic scheme for Example 37

[0910]

[0911]

[0912] Experimental procedures for 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0913]

[0914] Step 1: tert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-meth-oxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Example 37-Int-1)

[0915] To the solution of ((7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (14 mg, 0.082 mmol) in THF (1 mL) were added NaH (10 mg, 0.41 mmol) at 0℃ under Argon. The mixture was stirred at 0℃ for 10 min 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]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (60 mg, 0.082 mmol) was added into the above solution. The reaction mixture was stirred at 0℃ to room temperature for 1h under Argon. The resulting mixture was quenched with H2O (10 mL). The resulting mixture was extracted with Ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get a residue, which was purified by silica gel column chromatography, eluted with Dichloromethane : Methanol (10 : 1) to get the desired producttert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-meth-oxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (40 mg, 60% yield) as a yellow solid. MS:m / z= 819.4 (M+H+, ESI+)

[0916]

[0917] 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 37)

[0918] To the solution oftert-butyl(4-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-10-fluoro-2-(((7aS)-2-meth-oxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (40 mg, 0.048 mmol) in DCM (0.5 mL) was added 4M 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 Prep-HPLC with the following conditions: Waters 2767 / Qda, Column: Xbridge C18 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 19%~28%; Retention Time: 7.9-9.7 min of 16 min to give the desired productExample 37a(4.34 mg, 13%) as a white solid; Retention Time: 11.6-12.9 min of 16 min to give the desired productExample 37b(4.88 mg, 14%) as a white solid..

[0919]

[0920] Example 37a:

[0921] MS:m / z= 719.4 (M+H+, ESI+)

[0922] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (brs, 3.59 H, FA), 8.09 (s, 2H), 8.00 - 7.92 (m, 1H), 7.64 (d,J= 6.7 Hz, 1H), 7.26 - 7.08 (m, 2H), 6.71 - 6.65 (m, 1H), 6.29 - 6.20 (m, 1H), 5.69 (s, 2H), 4.46 - 4.36 (m, 1H), 4.34 - 4.26 (m, 1H), 4.10 -4.02 (m, 3H), 4.00 - 3.94 (m, 2H), 3.20 (s, 3H), 3.08 - 2.96 (m, 2H), 2.76 - 2.66 (m, 2H), 2.18 - 2.08 (m, 1H), 1.94 - 1.70 (m, 5H), 1.66 - 1.54 (m, 3H).

[0923] Example 37b:

[0924] MS:m / z= 719.4 (M+H+, ESI+)

[0925] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (brs, 2.72 H, FA), 8.09 (s, 2H), 7.97 (d,J= 3.5 Hz, 1H), 7.64 (d,J= 7.4 Hz, 1H), 7.25 - 7.08 (m, 2H), 6.73 - 6.62 (m, 1H), 6.40 - 6.25 (m, 1H), 5.83 (s, 2H), 4.60 - 4.47 (m, 1H), 4.25 - 4.16 (m, 1H), 4.10 - 3.95 (m, 3H), 3.74 - 3.68 (m, 2H), 3.20 (s, 3H), 3.10 - 2.92 (m, 2H), 2.75 - 2.68 (m, 2H), 2.15 (dd,J= 12.8, 5.6 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.80 - 1.70 (m, 3H), 1.58 (d,J= 6.8 Hz, 3H).

[0926]

[0927] In a similar manner, the compounds of Examples 1 to 37 in Table 1 below were prepared using samples appropriate for the preparation of the compounds described in each example.

[0928] [Table 1]

[0929] [Rectified under Rule 91, 15.11.2023]

[0930] [Rectified under Rule 91, 15.11.2023]

[0931] [Rectified under Rule 91, 15.11.2023]

[0932] [Rectified under Rule 91, 15.11.2023]

[0933] [Rectified under Rule 91, 15.11.2023]

[0934] [Rectified under Rule 91, 15.11.2023]

[0935] [Rectified under Rule 91, 15.11.2023]

[0936] [Rectified under Rule 91, 15.11.2023]

[0937] [Rectified under Rule 91, 15.11.2023]

[0938] [Rectified under Rule 91, 15.11.2023]

[0939] [Rectified under Rule 91, 15.11.2023]

[0940] [Rectified under Rule 91, 15.11.2023]

[0941] [Rectified under Rule 91, 15.11.2023]

[0942] [Rectified under Rule 91, 15.11.2023]

[0943] [Rectified under Rule 91, 15.11.2023]

[0944]

[0945] Test Examples

[0946] <Test Example 1: KRAS Nucleotide Exchange Assay>

[0947]

[0948] Purpose

[0949] Evaluation of the inhibitory effect of compounds on SOS1-mediated nucleotide exchange activity of KRASWT, KRASG12D, KRASG12V, KRASG12Cand KRASG13Dmutants

[0950]

[0951] Principle

[0952] The assay monitors SOS1 mediated exchange of KRAS bound unlabeled GDP to fluorescently labeled GTP. The detection is based on the transfer of energy between two fluorophores when they are in close proximity. Donor is the Tb cryptate labeled anti-GST antibody and acceptor is a DY-647P1 GTP.

[0953]

[0954] Test conditions and procedures

[0955] Materials

[0956] GST-tagged KRAS WT or mutant protein (amino acids 2-169),

[0957] SOS1 (amino acids 564-1049),

[0958] Labeled GTP (GTP-DY-647P1),

[0959] Assay Buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40)

[0960]

[0961] Test procedure

[0962] 1. KRAS protein was diluted with assay buffer to reach 1.5 times of the final concentration, then mixed with Tb cryptate anti-GST antibody and added at 10 μL to each assay well (all of the final concentration was 20 nM for KRASWT, KRASG12D, and KRASG12V).

[0963] 2. The compound was dissolved in DMSO and diluted to prepare 100 times of the final concentration.

[0964] 3. Compounds were dispensed into assay wells using an ECHO acoustic dispenser (Beckman), mixed gently with the KRAS / Ab mixture, and incubated for 60 minutes.

[0965] 4. SOS1 and labeled GTP were mixed, diluted to 3 times of the final concentration with assay buffer, and 5 μL of the solution was added to the assay well to initiate the reaction (final concentration of labeled GTP was 0.15 μM, final concentration of SOS1 was 7.5 nM in WT, 12.5 nM in G12D and 50 nM in G12V). Only assay buffer and labeled GTP were added to the blank well.

[0966] 5. The reaction was monitored at Ex / Em=(337 / 665; 337 / 620) using a Pherastar Plate Reader (BMG).

[0967] 6. HTRF signals were analyzed approximately 25 minutes after the start of the reaction (60 minutes reaction for G12V).

[0968] 7. Nucleotide exchange activity is expressed as a percentage difference compared to the DMSO reaction value, and the IC50value was calculated based on the four-parameter logistic equation in GraphPad 4.0 software.

[0969]

[0970]

[0971] The test results are shown in Table 2.

[0972] [Table 2]

[0973] Test result

[0974]

[0975]

[0976] <Test Example 2: KRAS NanoBRET Assay>

[0977]

[0978] Purpose

[0979] Evaluation of NanoBRET target binding of compounds to KRAS (WT, G12D or G12V) HEK293 cells

[0980]

[0981] Test conditions and procedures

[0982] Compound manufacturing

[0983] The test compounds were dissolved in 10mM stock, and the reference compounds BI-2582 and MRTX1133 (MedChemExpress) were dissolved in DMSO at 10mM and 1mM stocks, respectively.

[0984]

[0985] Cell culture

[0986] NanoBRET KRAS (WT, G12D or G12V)-NanoLuc Fusion vector and tracer K-2 were purchased from Promega, and HEK293 cell line was purchased from ATCC. HEK293 cells were cultured at 37℃ in a humidified atmosphere of 5% CO2and 95% air using EMEM medium supplemented with 10% FBS and 100 μg / mL penicillin-streptomycin.

[0987]

[0988] Test procedure

[0989] 1. Transfect NanoBRET KRAS (WT, G12D or G12V)-NanoLuc Fusion Vector into HEK293 Cell.

[0990] 2. Adjust the density of transfected cells to 2 Х 105cells / mL in Opti-MEM without phenol red and mix 20x K-2 tracer with the cells.

[0991] 3. Dispense the cell and tracer mixture into 384 wells, place in a 37℃, 5% CO2incubator for one hour, and then leave at room temperature for 15 minutes.

[0992] 4. Substrate and test compound solutions are treated to 384 wells dispensed with cells and tracers and reacted at room temperature for 15 minutes.

[0993] 5. Measurements are made at the donor emission wavelength (460 nm) and the acceptor emission wavelength (600 nm) using the Envision 2104 plate reader.

[0994] 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 that does not include the tracer.

[0995] 6. The BRET reaction is calculated as the BRET ratio *100 when treated with a compound compared to the BRET ratio when treated with DMSO.

[0996] 7. The IC50value is calculated based on the sigmoidal dose-response equation in the GraphPad Prism 4 program.

[0997]

[0998] <Test Example 3: Cell proliferation assay>

[0999]

[1000] Purpose

[1001] Cell viability testing of test compounds in AsPC-1 pancreatic cancer (KRAS G12D mutation) or SW480 colon cancer (KRAS G12V mutation) cells for 72 hours

[1002]

[1003] Test conditions and procedures

[1004] Materials

[1005] The reference compound Staurosporine was purchased from Sigma-Aldrich (Saint Louis, MI), and CellTiter-Glo® 2.0 Luminescent cell viability assay reagent (cat# G9243) was purchased from Promega (Madison, WI). AsPC-1 and SW480 cell lines were purchased from American Type Culture Collection (Manassas, VA). AsPC-1 cells were cultured with RPMI-1640 (ATCC, cat#30-2001) and SW480 cells were cultured with DMEM (ATCC cat#30-2002). A medium supplemented with 10% FBS (Sigma-Aldrich, cat#F2442) and 100 μg / mL of penicillin-streptomycin (Sigma-Aldrich, cat#P4333) was used. Cells were cultured at 37℃ in a humidified atmosphere of 5% CO2and 95% air.

[1006]

[1007] Test procedure

[1008] 1. The test compound and reference compound, Staurosporine were dissolved in DMSO solution to prepare 20mM (test compound) and 10mM (control compound, Staurosporine) in the Source Plate and diluted with DMSO to 3-fold and 10 doses.

[1009] 2. From the Source Plate, 10 volumes of 125 nL test compound or 25 nL reference compound were dispensed into wells of a 384-well culture plate (VWR, cat#82050-076) using Echo 655.

[1010] 3. 25 μL of culture medium including 2000 AsPC-1 or SW480 cells was dispensed into each 384-well cell culture plate.

[1011] 4. Cells were cultured with the compound for 72 hours at 37℃ and 5% CO2conditions.

[1012] 5. 25 μL of CellTiter-Glo 2.0 reagent was added to each well of the plate.

[1013] 6. The contents were mixed for 2 minutes on an orbital shaker, and the luminescence signal was stabilized at room temperature for 15 minutes.

[1014] 7. Luminescence signals were measured with an Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA), and the number of surviving cells was determined through quantification of ATP present in each culture.

[1015] 8. IC50values were calculated based on the Sigmoidal dose-response equation in the GraphPad Prism 4 program.

[1016] The test results are shown in Table 3.

[1017] [Table 3]

[1018] Test result

[1019]

[1020]

[1021] (IC50< 1 μM = A; IC50≥ 1 μM, < 10 μM B; IC50> 10 μM = C)

[1022]

[1023] While this disclosure has been particularly shown and described with reference to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims. The example embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the disclosure is defined not by the detailed description of the disclosure but by the appended claims, and all differences within the scope will be construed as being included in the present disclosure.

Claims

1.A compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof:[Formula 1]In Formula 1,X is N or CR11;R1is R1A-substituted or unsubstituted phenyl, R1A-substituted or unsubstituted naphthyl, R1A-substituted or unsubstituted benzothiophenyl;each R1Ais independently selected from hydrogen, hydroxy, a halogen, C1-C3haloalkyl, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C3alkoxy, C3-C6cycloalkyl, NH2, NH(C1-C3alkyl), N(C1-C3alkyl)2, and CN;R2is hydrogen or a halogen;R3is hydrogen, -O-L-W, or;L is a bond or LA-substituted or unsubstituted C1-C3alkylene;LAis hydrogen, a halogen, or C1-C3alkyl;W is R6-substituted or unsubstituted C1-C3alkyl, R6-substituted or unsubstituted 3- to 10-membered monocyclic heterocycle, or R6-substituted or unsubstituted 6- to 14-membered bicyclic heterocycle;each R6is independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C3alkoxy, C3-C6cycloalkyl, amino, CN, =CH2, oxo(=O), S(C1-C3alkyl), SO2NH2, SO2NH(C1-C3alkyl), SO2(C1-C3alkyl), and SO2(C1-C3haloalkyl), or halo C1-C3alkoxy;R4is hydrogen, R4A-substituted or unsubstituted C1-C6haloalkyl, R4A-substituted or unsubstituted C1-C6alkyl, R4A-substituted or unsubstituted C3-C10cycloalkyl, R4A-substituted or unsubstituted C5-C8aryl, R4A-substituted or unsubstituted 3- to 10-membered heterocycle, or R4A-substituted or unsubstituted 5- to 10-membered heteroaryl;each R4Ais independently selected from hydrogen, CN, NR9R10, =O, OR7, SR8, SO2R8, C(O)N(R7)2, C(O)R7, R4B-substituted or unsubstituted C1-C6haloalkyl, R4B-substituted or unsubstituted C1-C6alkyl, R4B-substituted or unsubstituted C3-C10cycloalkyl, R4B-substituted or unsubstituted C5-C8aryl, R4B-substituted or unsubstituted 3- to 6-membered heterocycle, and R4B-substituted or unsubstituted 5- to 9-membered heteroaryl;wherein two of R4Atogether form R4B-substituted or unsubstituted C3-C10cycloalkyl, R4B-substituted or unsubstituted C5-C8aryl, R4B-substituted or unsubstituted 3- to 10-membered heterocycle, or R4B-substituted or unsubstituted 5- to 10-membered heteroaryl;each R4Bis independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C3-C6cycloalkyl, CN, NR9R10, =O, C1-C3alkoxy, halo C1-C3alkoxy, hydroxy, SCH3, SO2NH2, SO2CH3, C(O)NH2, C(O)CH3, a 3- to 6-membered heterocycle, C5-C8aryl, and 5- or 6-membered heteroaryl;each R5is independently selected from hydrogen, hydroxy, a halogen, C1-C3haloalkyl, and C1-C3alkyl,each R7is independently selected from hydrogen, amino, C1-C3haloalkyl, C1-C3alkyl, C3-C6cycloalkyl, and a 3- or 4-membered heterocycle;each R8is independently selected from hydrogen, amino, and C1-C3alkyl;R9and R10are each independently selected from hydrogen, C1-C3alkyl, C3-C6cycloalkyl, C(O)NH2, C(O)CH3, and a 3- to 6-membered heterocycle;each R11is independently selected from hydrogen, hydroxy, a halogen, C1-C3haloalkyl, and C1-C3alkyl,n is an integer selected from 0 to 2; andwherein the heterocycles or heteroaryls each comprise 1 to 3 heteroatoms independently selected from N, O, and S.2.The compound of claim 1, whereinL is methylene;W is R6-substituted or unsubstituted 3- to 10-membered monocyclic heterocycle or R6-substituted or unsubstituted 6- to 14-membered bicyclic heterocycle; andeach R6is independently selected from a halogen, C1-C3haloalkyl, C1-C3alkyl, C1-C3alkoxy, CN, =CH2, =O, SCH3, SO2NH2, SO2NH(CH3), SO2CH3, andSO2CF3.3.The compound of claim 1, whereinL is methylene;each W is independently R6-substituted or unsubstituted,,,,,,,,,,,,,,,,, or; andeach R6is independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C1-C3alkoxy, CN, =CH2, =O, SCH3, SO2NH2, SO2NH(CH3), SO2CH3, andSO2CF3.4.The compound of claim 1, whereinR4is R4A-substituted or unsubstituted C1-C3alkyl;each R4Ais independently selected from hydrogen, a halogen, CN, NH2, NH(C1-C3alkyl), N(C1-C3alkyl)2, =O, R4C-substituted or unsubstituted C3-C6cycloalkyl, R4C-substituted or unsubstituted phenyl, and R4C-substituted or unsubstituted pyridinyl, R4C-substituted or unsubstituted pyrimidinyl, and R4C-substituted or unsubstituted pyrazinyl;or wherein two of R4Atogether form 5- to 10-membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline; andeach R4Cis independently selected from hydrogen, a halogen, C1-C3alkyl, NH2, NH(C1-C3alkyl), and N(C1-C3alkyl)2.5.The compound of claim 1, whereinX is CR11,each R11is independently selected from hydrogen, a halogen, C1-C3haloalkyl, and C1-C3alkyl;R1is R1A-substituted or unsubstituted benzothiophenyl;each R1Ais independently selected from hydrogen, a halogen, NH2, NH(C1-C3alkyl), N(C1-C3alkyl)2, and CN.6.The compound of claim 1, whereinR1is,, oreach substituted or unsubstituted with one or more substituents independently selected hydrogen, hydroxy, a halogen, C1-C3alkyl, C3-C6cycloalkyl, amino, and CN;R2is F;R3is hydrogen, -O-L-W, or;L is methylene;W is,,,,,,,,,,,,,,,,, or,each substituted or unsubstituted 1 to 3 times by R6;each R6is independently selected from hydrogen, a halogen, C1-C3haloalkyl, C1-C3alkyl, C1-C3alkoxy, CN, =CH2, and =O;R4is,,,,,,,,,,,,,,,, or,each substituted or unsubstituted with one or more substituents independently selected from hydrogen, a halogen, C1-C3alkyl, NH2, NH(C1-C3alkyl), and N(C1-C3alkyl)2; andn is selected from 1 and 2.7.The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof:,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,and.8.A pharmaceutical composition for the treatment of cancer including, as an active ingredient, a compound selected from the compound of any one of claims 1-7 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.9.The pharmaceutical composition of claim 9, wherein the pharmaceutical composition exhibits KRAS protein inhibitory activity.

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