Novel tricyclic compounds as KRAS G12D inhibitors and uses thereof

Abstract

The invention relates to a novel tricyclic derivative compound serving as a KRAS G12D inhibitor and application of the novel tricyclic derivative compound. The compound according to one embodiment of the present application inhibits the activity of a KRAS G12D mutant protein, and thus can be used for the prevention or treatment of diseases caused by KRAS G12D mutation.

Description

Technical Field

[0001] The present application relates to novel tricyclic compounds, pharmaceutical compositions containing the same and their use as drugs. Background Art

[0002] Kristen rat sarcoma virus (KRAS) is a protein belonging to the RAS family (NRAS, HRAS, KRAS), which plays an important role in transmitting signals related to cell proliferation and differentiation. KRAS receives signals from cell membrane receptors and relays them to downstream signaling proteins, including PI3K, Raf, MEK, and ERK.

[0003] The KRAS protein acts as a molecular switch. When GDP at the nucleotide binding site is exchanged for GTP via intrinsic nucleotide exchange, the KRAS protein becomes "activated (GTP-bound, on) state," thereby transmitting the signal to downstream signaling proteins. Conversely, when GTP bound to the KRAS protein is intrinsically hydrolyzed to GDP, it transitions to an "inactivated (GDP-bound, off) state," at which point downstream signaling no longer occurs. In actual cells, guanine exchange factors (GEFs) promote the exchange of GDP for GTP, while GTPase-activating proteins (GAPs) accelerate the hydrolysis of GTP to GDP.

[0004] Mutations in the KRAS gene have been identified as playing an important role in the proliferation of cancer cells in many malignancies, and approximately 89% of patients with KRAS mutant cancers carry a mutation in which the glycine at codon 12 of the KRAS gene (KRASG12) is replaced by another amino acid. KRAS G12 mutations are found in 86% of pancreatic ductal adenocarcinomas (PDAC), 41% of colorectal cancers (CRC), and 32% of non-small cell lung cancers (NSCLC). Among the KRAS G12 variants, the most commonly reported are G12D (36%), G12V (23%), and G12C (14%). The KRAS G12 mutant protein will inhibit GAP-mediated GTP hydrolysis, thereby maintaining an activated (GTP-bound) state, which will lead to continued downstream signal transduction and promote rapid proliferation and survival of cancer cells.

[0005] Previous KRAS inhibitors were developed as competitive inhibitors targeting GTP binding to suppress the activated state of KRAS; however, many of these inhibitors failed because the intracellular concentration of GTP is significantly higher than the concentration of the inhibitor. For this reason, the development of targeted therapies that directly inhibit KRAS has long been considered unfeasible. As alternative approaches to suppress KRAS mutant cancers, attempts have been made to inhibit downstream signaling proteins such as PI3K, MEK, AKT, and mTOR, or to inhibit KRAS farnesyltransferase by inhibiting post-translational modification of the KRAS protein, thereby indirectly suppressing the activity of KRAS mutant cancer cells. However, none of these approaches have achieved satisfactory clinical results.

[0006] Recently, with the identification of the switch-II pocket as the allosteric binding pocket for the KRAS G12C mutant protein, sotolacib (LUMAKRAS TM ), a selective KRAS G12C-targeting small molecule that inhibits KRAS activity by covalently binding to a cysteine ​​residue in the GDP-bound form of KRAS G12C, has been developed and approved by the FDA for the treatment of non-small cell lung cancer.

[0007] However, the development of targeted therapies targeting the most prevalent KRAS mutation, KRAS G12D, remains limited, representing a significant unmet medical need. Summary of the Invention

[0008] Technical issues

[0009] The present inventors have identified that a novel tricyclic compound according to one embodiment of the present application exhibits an inhibitory effect on KRAS G12D activity. Therefore, one object of the present application is to provide a novel tricyclic ring-based compound represented by Chemical Formula 1, which exhibits excellent inhibitory effect on KRAS G12D activity, as well as their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0010] Another object of the present application is to provide a pharmaceutical composition comprising the novel tricyclic ring-based compound or its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts as an active ingredient.

[0011] Technical Solutions

[0012] According to one embodiment of the present application, there is provided a compound represented by the following Chemical Formula 1 or an optical isomer, stereoisomer, isotope variant, hydrate, solvate or pharmaceutically acceptable salt thereof:

[0013] [Chemical Formula 1]

[0014]

[0015] in,

[0016] A is

[0017] X is C or N;

[0018] R1 is hydrogen, halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0019] L is a direct bond, O or NR6;

[0020] R2 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, R x ,-Z1-R x ,-Z1-R y -R x ,-Z1-R y -Z2-N(R 15 )2.-Z1-R y -Z2-R x 、-N(R 15 )2, -Z1-N(R 15 )2, -Z1-C(O)N(R 15 )2OR-Z1-OR 15 ;

[0021] R x and R y Each is independently 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 20-membered aryl or 6 to 20-membered heteroaryl, and may be optionally substituted with one or more R7;

[0022] R7 is independently H, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Alkoxy, C 1-4 Alkyl-N(R 16 )2、=C-(R 16 )2, cyano, C(O)R 16 、C(=O)OR 16、C(=O)N(R 16 )2, -NHC(O)-6 to 20-membered aryl, -N(R 16 )2、(C 1-4 Alkoxy) C 1-4 Alkyl-, oxo, -OR 16 、-SR 16 、-(C 1-4 alkyl)C(O)R 16 , 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl, 6 to 20-membered heteroaryl, -Z3-3 to 10-membered cycloalkyl, -Z3-3 to 10-membered heterocycloalkyl, -Z3-6 to 20-membered aryl, -Z3-6 to 20-membered heteroaryl, -Z3-OC(O)N(R 16 )2 or -Z3-OC(O)-3 to 10-membered heterocyclic group; and R7 may be 1 to 3 cyano, halogen, haloalkyl, amino, -OR 17 、-SR 17 or -N(R 17 )2;

[0023] Z1 to Z3 are each independently C 1-4 and optionally substituted by hydroxyl, C 1-4 substituted by hydroxyalkyl or 6- to 20-membered heteroaryl;

[0024] R6, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 and R 21 Each independently is H or C 1-3 alkyl;

[0025] R3 is 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl or 6 to 20-membered heteroaryl, and may be optionally substituted with one or more R8;

[0026] R8 is H, halogen, hydroxyl, -N(R 18 )2、OR 18 ,SH,S(C 1-3 alkyl), S(=O)(C 1-6 alkyl), S(=O)2(C 1-6 alkyl), C(=O)(C 1-6 alkyl), C(=O)OH, C(=O)N(R 18 )2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxyalkyl, C 1-4 Alkyl-N(R 18 )2、C 1-3 Alkoxy, C 1-3 haloalkoxy, cyanoalkyl, cyano, oxo, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl;

[0027] R4 is or -NH-R9-R 10 ;

[0028] R9 is a direct key or C 1-4 alkyl;

[0029] R 10 is a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocycloalkyl group, and may be optionally replaced by one or more R 11 replaced by;

[0030] R 11 C 1-3 Alkyl, hydroxyl, N(R 19 )2、C 1-3 Alkyl-N(R 19 )2、C 1-3 cyanoalkyl or 3- to 10-membered heterocyclic group;

[0031] R 12 H, C 1-3 Alkyl, OH, -N(R 20 )2、-CH2N(R 20 )2, cyano, cyanomethyl or a 3- to 10-membered heterocyclic group;

[0032] R 13 is H or -C(=O)R 14 ;

[0033] R 14 C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -N(R6)2, -OR6, -SR6, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl;

[0034] n is an integer from 1 to 4; and

[0035] R5 is H, halogen, C 1-6 Alkyl, C 1-3haloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, cyano, cyano C 1-3 Alkyl, hydroxyl, C 1-3 Hydroxyalkyl, C(O)(NR 21 )2, 6 to 20-membered aryl, C 1-3 Alkyl-3 to 6-membered cycloalkyl, C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, C 1-3 Alkyl-6 to 20-membered aryl or C 1-3 Alkyl-6 to 20-membered heteroaryl.

[0036] Specifically, A can be

[0037] Specifically, R1 can be hydrogen, halogen or C 1-3 alkyl.

[0038] Specifically, L may be a direct bond or O.

[0039] Specifically, R2 can be R x ,-Z1-R x ,-Z1-R y -R x ,-Z1-R y -Z2-N(R 15 )2 or -Z1-R y -Z2-R x .

[0040] Specifically, R x and R y Each is independently a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and may be optionally substituted by one or more R7.

[0041] More specifically, R x It can be a 3- to 10-membered heterocyclic group, R y is a 3- to 10-membered cycloalkyl group, R x and R y may be optionally substituted with one or more R7. More specifically, R x It may be a 3- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S, or a 3- to 10-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N and O.

[0042] In one example, R x and R yEach is independently 3- to 5-membered cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl], 6-azaspiro[2.5]octyl, quinolizidinyl, indolyl, benzimidazolyl, azaspirooctyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl or acridinyl, and may be optionally substituted with one or more R7.

[0043] In one embodiment, R x is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl] or 6-azaspiro[2.5]octyl, and may be optionally substituted with one or more R7.

[0044] In one embodiment, R y is 3- to 5-membered cycloalkyl (eg, cyclopropyl or cyclobutyl), and may be optionally substituted with one or more R7.

[0045] In one embodiment, in Chemical Formula 1, R2 is R x ,-Z1-R x ,-Z1-R y -R x ,-Z1-R y -Z2-N(R 15 )2 or -Z1-R y -Z2-R x ; R x is a 3- to 10-membered heterocyclic group; R y is a 3- to 10-membered cycloalkyl group; and R x and R y May be optionally substituted with one or more R7.

[0046] In one embodiment, in Chemical Formula 1, R2 is R x ,-Z1-R x ,-Z1-R y -R x ,-Z1-R y -Z2-N(R 15 )2 or -Z1-R y -Z2-R x ; R xis azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl] or 6-azaspiro[2.5]octyl; Ry is a 3- to 5-membered cycloalkyl group; and R x and R y May be optionally substituted with one or more R7.

[0047] In one embodiment, in Chemical Formula 1, R2 is azetidinyl, Z1-pyrrolizidinyl, Z1-tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl] or Z1-R y -Z2-R x ; R y is a 3- to 5-membered cycloalkyl group (eg, cyclopropyl or cyclobutyl); and R x is a 3- to 10-membered heterocyclic group (e.g., pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl or 6-azaspiro[2.5]octyl).

[0048] Specifically, R7 is independently H, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 1-4 Alkoxy, C 1-4 Alkyl-N(R 16 )2、=C-(R 16 )2、C(O)R 16 、C(=O)OR 16 、C(=O)N(R 16 )2, -NHC(O)aryl, -N(R 16 )2、(C 1-4 Alkoxy) C 1-4 Alkyl-, oxo, -OR 16 、-SR 16 、-(C 1-4 alkyl)C(O)R 16 , 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl, 6 to 20-membered heteroaryl, -Z3-3 to 10-membered cycloalkyl, -Z3-3 to 10-membered heterocycloalkyl, -Z3-6 to 20-membered aryl, -Z3-6 to 20-membered heteroaryl, -Z3-OC(O)N(R 16)2 or -Z3-OC(O)-3 to 10-membered heterocyclic group; and may be substituted by 1 to 3 cyano, halogen, haloalkyl (e.g., C 1-4 haloalkyl), amino, -OR 17 、-SR 17 or -N(R 17 )2.

[0049] In one embodiment, R7 is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Alkoxy, =C-(R 16 )2、-N(R 16 )2 or (C 1-4 Alkoxy) C 1-4 Alkyl-, and may be substituted by 1 to 3 halogens.

[0050] In one embodiment, R7 is independently H, halogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-3 Alkoxy, =C-(R 16 )2、-N(R 16 )2 or (C 1-3 Alkoxy) C 1-3 Alkyl-, and may be substituted by 1 to 3 halogens.

[0051] In one embodiment, R7 is H, halogen, C 1-4 Alkyl, =CH2, =CF2, =CFH, -N(R 16 )2、C 1-4 Alkoxy or (C 1-4 Alkoxy) C 1-4 alkyl-.

[0052] Specifically, R3 is 6 to 20-membered aryl or 6 to 20-membered heteroaryl, and may be optionally substituted with one or more R8.

[0053] Specifically, R3 is phenyl, biphenyl, naphthyl, toluoyl, naphthalenyl, pyridyl, anthracenyl, indenyl, indanyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzofuranyl or indazolyl, and may be optionally substituted by one or more R8.

[0054] More specifically, R3 is phenyl, naphthyl, naphthalenyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, benzothienyl, benzofuranyl or indazolyl, and may be optionally substituted with one or more R8.

[0055] Specifically, R8 can be H, halogen, hydroxyl, -N(R 18 )2、OR6、SH、S(C 1-3 alkyl), S(=O)(C 1-6 alkyl), S(=O)2(C 1-6 alkyl), C(=O)(C 1-6 alkyl), C(=O)OH, C(=O)N(R 18 )2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxyalkyl, C 1-4 Alkyl-N(R 18 )2, cyano, oxo or 3 to 10-membered cycloalkyl.

[0056] More specifically, R8 can be H, halogen, hydroxyl, -N(R 18 )2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 hydroxyalkyl or cyano.

[0057] Specifically, R 10 is a 3 to 10-membered cycloalkyl group, and may be optionally substituted by one or more R 11 replaced.

[0058] Specifically, R 11 C 1-3 Alkyl, hydroxyl, N(R 19 )2、C 1-3 Alkyl-N(R 19 )2 or cyano C 1-3 alkyl.

[0059] In one example, in Chemical Formula 1, R9 may be C 1-3 Alkyl, R 10 may be a 3- to 5-membered cycloalkyl group, and R 11 Can be N(R 19 )2.

[0060] Specifically, R 12 It can be H.

[0061] Specifically, R 14 It may be a 3- to 10-membered heterocyclic group, a 3- to 10-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O and S, or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O and S, for example, oxirane.

[0062] Specifically, R5 can be H or C 1-3 alkyl.

[0063] For example, in Chemical Formula 1, L-R2 can be selected from the following structures. When having such a structure, it not only exhibits inhibitory activity against KRAS G12D but is also suitable for achieving the various aforementioned purposes of the present application.

[0064]

[0065] For example, in Chemical Formula 1, R3 can be selected from the following structures. When having such a structure, it not only exhibits inhibitory activity against KRAS G12D but is also suitable for achieving the various aforementioned purposes of the present application.

[0066]

[0067] For example, in Chemical Formula 1, R4 can be selected from the following structures. When having such a structure, it not only exhibits inhibitory activity against KRAS G12D but is also suitable for achieving the various aforementioned purposes of the present application.

[0068]

[0069] The present application provides the aforementioned compound or its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts:

[0070] Examples of compounds of Formula 1 according to the present application are the compounds prepared in Examples 1 to 120 below. Each Example number corresponds to a compound number. For example, the final compound prepared in Example 90 is numbered Compound 90.

[0071] For example, representative examples of the compound of Chemical Formula 1 according to one embodiment of the present application include those listed in the following Table 1, but are not limited thereto.

[0072] Table 1

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] Unless otherwise defined, all technical terms used in this application should be understood to have the same meaning as those commonly understood by those skilled in the art to which this application belongs. In addition, although exemplary methods and samples may be described herein, equivalent or similar methods and materials are also considered to be within the scope of this application. In addition, even if not explicitly stated, the numerical values ​​described in this specification should be understood to include the meaning of "about". All publications cited in this specification are hereby incorporated by reference in their entirety.

[0090] In Chemical Formula 1, R1 to R 21 、R x and R y The listed residues are used with the same meaning as commonly understood by those skilled in the art.

[0091] As used herein, unless otherwise indicated, the term "halogen," used alone or in combination with another term (eg, haloalkyl), refers to fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, but not limited thereto.

[0092] As used herein, unless otherwise indicated, the term "alkoxy" refers to an alkyloxy group, for example an alkyloxy group having 1 to 7 carbon atoms.

[0093] Unless otherwise indicated, as used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by the same or different halogen atoms. Examples of haloalkyl groups include, but are not limited to, -CH2Cl, -CH2CF3, -CH2CCl3, -CF3, and the like.

[0094] As used herein, unless otherwise indicated, the term "hydroxyalkyl" includes an alkyl group in which one or more hydrogen atoms are replaced with one or more hydroxy (-OH) groups, such as divalent or trivalent hydroxy groups.

[0095] Unless otherwise indicated, as used herein, the term "aminoalkyl" includes an alkyl group in which one or more hydrogen atoms are replaced by one or more amino groups (-NH2), such as divalent or trivalent amino groups.

[0096] As used herein, unless otherwise indicated, the term "oxo" refers to a group of formula =0 (ie, an oxygen with a double bond).

[0097] Unless otherwise indicated, as used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group, unless otherwise indicated. For example, an alkyl group may be C 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl or C 1-3 alkyl.

[0098] As used herein, the term "alkenyl" refers to a monovalent hydrocarbon group containing at least one carbon-carbon double bond, unless otherwise specified, wherein each double bond may have an E- or Z-configuration. For example, an alkenyl group may be C 2-10 Alkenyl, C 2-8 Alkenyl, C 2-6 Alkenyl or C 2-4 Alkenyl.

[0099] As used herein, the term "alkynyl" refers to a monovalent group derived from an unsaturated straight or branched chain hydrocarbon moiety having at least one carbon-carbon triple bond, unless otherwise specified. For example, an alkynyl group may be C 2-10 Alkynyl, C 2-8 Alkynyl, C 2-6 Alkynyl or C2-4 Alkynyl.

[0100] These " alkyl ", " alkenyl " and " alkynyl ", when used alone or in combination with another term (for example, haloalkyl), can be straight or branched. According to their definition, they refer to a saturated aliphatic hydrocarbon group with 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4 or 1 to 3 carbon atoms in the alkyl group. Common examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and tert-pentyl, 1-methylpentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, n-hexyl, 3,3-dimethylbutyl and isohexyl, but are not limited thereto. Each of the double and triple bonds of the alkenyl and alkynyl groups can be substituted at any position. Examples of alkenyl and alkynyl groups include vinyl, prop-1-enyl, prop-2-enyl, but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl, but-2-ynyl, but-3-ynyl, hex-4-ynyl, or hex-5-ynyl, but are not limited thereto.

[0101] Unless otherwise indicated herein, as used herein, the term "cycloalkyl", "cycloalkenyl" or "cycloalkynyl" refers to a hydrocarbon group that may be substituted or unsubstituted cyclic alkyl and forms a single or fused cyclic ring with unsaturated or partially or fully saturated (e.g., 3 to 24) carbon atoms. Specifically, the cycloalkyl, cycloalkenyl or cycloalkynyl group may have 3 to 10, 3 to 8, 3 to 6, 3 to 5, 4 to 10, 4 to 8, 4 to 6, or 4 to 5 carbon atoms. The cycloalkyl group may include a carbocyclyl, a spirocarbocyclyl, a fused carbocyclyl, a bridged carbocyclyl, but is not limited thereto.

[0102] According to a specific example of the present disclosure, the cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, spiro[3.5]nonane, spiro[3.3]heptane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octyl, adamantane-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, benzene, naphthalene, and may include all possible isomers thereof, but is not limited thereto.

[0103] Unless otherwise indicated herein, the term "saturated or unsaturated heterocyclic group" refers to a substituted or unsubstituted 3 to 24-membered hydrocarbon group containing one or more heteroatoms (e.g., 1 to 8 heteroatoms) selected from nitrogen (N), oxygen (O) and sulfur (S), which forms an unsaturated or partially or fully saturated single or fused cyclic ring. Specifically, the heterocyclic group can be a 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 10-membered, 4 to 8-membered or 4 to 6-membered hydrocarbon having 1 to 3 heteroatoms. Heterocycles include heteroaryl, heterocyclic group, heterospirocarbocyclic group, fused heterocyclic group, bridged heterocyclic group, but are not limited thereto.

[0104] According to a specific embodiment of the present invention, the heterocyclic group can be pyrrolidinyl, morpholinyl, pyrrolizidinyl, quinolizidinyl, azaspirooctanyl, piperidinyl, pyrrolidinyl, imidazolinyl, piperazinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspirooctanyl, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-6-azaspiroheptyl, azetidine 1 ] octyl, 2-aza-5-azabicyclo[2.2.1]heptyl, pyridyl, tetrahydrofuranyl, 8-azabicyclo[3.2.1]octyl, 2-azaspiro[3.3]heptyl, 2-oxa-7-azaspiro[3.4]octyl, 2-azabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, pyrimidinyl, pyrazolyl, oxetane and the like, but are not limited thereto. For example, with respect to C 2-10 For heterocyclic groups, the carbon number is marked as C 2-10 It refers to the ring size of at least three-membered rings including one or more heteroatoms.

[0105] In this application, unless otherwise indicated, the term "aryl" refers to an aromatic group, which may be substituted or unsubstituted and, for example, may be 6 to 20-membered. For example, aryl may include, but is not limited to, phenyl, biphenyl, naphthyl, toluoyl, naphthalenyl, anthracenyl, indenyl, indanyl, or all possible isomers thereof.

[0106] In this application, unless otherwise indicated, the term "heteroaryl" refers to a monocyclic or bicyclic or higher-ring aromatic group containing one or more heteroatoms (e.g., 1 to 4, 1 to 3, or 1 to 2) selected from O, N, and S, and can be, for example, 6 to 20-membered. For example, examples of monocyclic heteroaryl groups include thiazolyl, oxazolyl, thienyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl, indazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, or the like, but are not limited thereto. For example, examples of bicyclic heteroaryl groups include, but are not limited to, pyrrolizidinyl, indolyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, quinolyl, isoquinolyl, azaspirooctanyl, purinyl, furopyridinyl, or the like. For example, examples of tricyclic heteroaryl groups include, but are not limited to, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, or the like.

[0107] In the present application, a numerical range indicated using the term "to" means a range including the numerical values ​​described before and after the term "to" as the lower limit and the upper limit, respectively.

[0108] The compounds of the present application may have asymmetric carbon centers, asymmetric axes, or asymmetric planes, and therefore may exist in all optical and stereoisomers, including substantially pure enantiomers such as R- and S-enantiomers, as well as mixture racemates. All such isomers and mixtures thereof are within the scope of the present application. In terms of pure enantiomers, the optical purity of such enantiomers represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof is preferably 60% ee or higher, more preferably 95% ee or higher, and most preferably 98% ee or higher.

[0109] The term "ee" refers to enantiomeric excess. For example, one enantiomeric form of a particular compound is present in a mixture of enantiomeric forms in an amount greater than the other enantiomeric forms of the compound. An enantiomerically enriched form may comprise a mixture of enantiomers of a particular compound, wherein the concentration of a single enantiomeric form relative to the other enantiomeric forms of the compound is at least 50%, more typically at least 60%, 70%, 80% or 90%, or even higher (e.g., >95%, >97%, >99%, >99.5%).

[0110] As used herein, unless otherwise specified for convenience, the compound of Chemical Formula 1 is intended to include all of the compound of Chemical Formula 1, optical isomers, stereoisomers, isotopic variations, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0111] As used herein, the term "isotopic variant" refers to a compound that contains an unusual ratio of isotopes at one or more atoms comprising the compound. For example, an isotopic variant of a compound may be radiolabeled, e.g., the hydrogen atom may be selected from hydrogen, deuterium, and tritium, and may contain carbon-13 ( 13 C), nitrogen-15 ( 15 N) etc.

[0112] The compound of Chemical Formula 1 of the present application or its optical isomers, stereoisomers or isotopic variants may form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include both acid addition salts and base addition salts and stereochemical isomeric forms thereof. The salt includes any salt that maintains the activity of the parent compound and does not cause adverse effects in the subject to which the salt is administered, and is not particularly limited thereto. Such salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esylic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium edetate, camphorsulfonic acid, carbonic acid, chlorobenzoic acid, citric acid, edetic acid, toluenesulfonic acid, edisilic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, pamoic acid, gluconic acid, glycolylarsanilic acid, methyl nitric acid, polygalacturonic acid, hexylisorcynic acid, malonic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, Acid, mucic acid, naphsylic acid, muconic acid, p-nitromethanesulfonic acid, cyclohexanesulfonic acid, pantothenic acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylic acid, sulfamic acid, p-aminobenzenesulfonic acid, methanesulfonic acid and theoclic acid. In addition, the form of basic salts includes, for example, alkali metal salts and alkaline earth metal salts, such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, salts with organic bases such as benzathine, N-methyl-D-glucamine, hydrazine salts, and salts with amino acids such as arginine and lysine. In addition, the salt form can be converted into a free form by treatment with a suitable base or acid. The term "other salt" includes solvate compounds that can be formed by the compound of Chemical Formula 1 and its salt. Such solvate compounds include, for example, hydrates and alcoholates.

[0113] Unless otherwise defined, the terms and abbreviations used herein have their original meanings.

[0114] The present application also provides a method for preparing a compound of Chemical Formula 1. Hereinafter, a method for preparing a compound of Chemical Formula 1 will be described based on an exemplary reaction scheme to help understand the present application. However, a person of ordinary skill in the art can prepare the compound of Chemical Formula 1 by various methods based on the structure of Chemical Formula 1 using known compounds or compounds that can be easily prepared therefrom, and all such methods should be understood to be included within the scope of the present application. That is, the compound of Chemical Formula 1 can be prepared by any combination of various synthesis methods described in this specification or disclosed in the prior art, and therefore, the following description of the method for preparing the compound of Chemical Formula 1 only presents an exemplary method, and if necessary, the order of the unit operations, etc. can be selectively changed, and the scope of the preparation method of the present application is not limited thereto.

[0115] [Reaction Scheme 1]

[0116]

[0117] Step A: Phosphorus oxychloride and N-ethyl-N-isopropylpropan-2-amine are added to compound 1 of reaction scheme 1, and heat is applied to obtain compound 2.

[0118] Step B: Compound 2 of Reaction Scheme 1 is reacted with a nucleophile having the chemical formula H-Y1-X-R1 in the presence of a solvent such as dichloromethane and a base such as N-ethyl-N-isopropylpropan-2-amine via a SNAR reaction to synthesize compound 3.

[0119] Step C: In Reaction Scheme 1, the substituent -Y2-R2 is introduced via the 2-chloro substituent of the nucleophilic compound having the chemical formula H-Y2-R2 using a strong base such as sodium hydride in a non-polar solvent such as tetrahydrofuran.

[0120] Step D: To synthesize compound 5 in Reaction Scheme 1, compound 4 and boronic acid or aryl stannan are used in Step D through Suzuki reaction or Stille reaction.

[0121] According to another aspect of the present application, a pharmaceutical composition for preventing or treating a disease associated with the KRAS G12D mutant protein comprises a therapeutically effective amount of a compound represented by Chemical Formula 1 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the pharmaceutical composition can prevent or treat a disease associated with the KRAS G12D mutant protein by inhibiting the activity of the KRAS G12D mutant protein.

[0122] The compound represented by Chemical Formula 1 according to one embodiment of the present application, or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, exhibits high binding affinity to GDP- / GppNHp-KRASG12D mutant protein and can act as a KRAS G12D mutation-specific inhibitor by inhibiting the phosphorylation of extracellular signal-regulated kinase (phospho-ERK, pERK) induced by KRAS G12D mutation. Therefore, one embodiment of the present application relates to a composition for binding to a KRAS G12D mutant protein, comprising a compound according to one embodiment of the present application, or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt. In addition, the compound of Chemical Formula 1 according to one embodiment of the present application and its related forms can be used to prevent, alleviate or treat diseases or conditions associated with KRAS G12D mutant protein, more specifically, diseases or conditions caused by KRAS G12D mutant protein. For example, the compound of Chemical Formula 1 and its related forms according to the present application, as an inhibitor of KRAS G12D mutant protein, can effectively suppress the growth signal transduction of cancer cells caused by KRAS G12D mutation and can be effectively used as a pharmaceutical composition for preventing or treating cancer.

[0123] According to another aspect of the present application, a pharmaceutical composition for preventing or treating cancer is provided, comprising a therapeutically effective amount of a compound represented by Chemical Formula 1 or its optical isomers, stereoisomers, racemates, isotopic variants, solvates, hydrates or pharmaceutically acceptable salts as an active ingredient.

[0124] In addition, various forms of prodrugs (which are converted into the compound of Formula 1 as expected in vivo) are also included in the scope of the present application. The pharmaceutical composition may further comprise one or more additives selected from pharmaceutically acceptable carriers, diluents and adjuvants.

[0125] As used herein, the term "treat" refers to the act of stopping, slowing, or alleviating the progression of a disease when administered to a subject exhibiting symptoms of the disease.

[0126] As used herein, the term "prevent" or "prevent" refers to the act of reducing or eliminating the likelihood of developing a disease.

[0127] As used herein, the term "pharmaceutical composition" may include, in addition to the active compound of the present application, other chemical components such as carriers, diluents, and excipients. Therefore, the pharmaceutical composition may optionally include one or more pharmaceutically acceptable carriers, diluents, excipients, or a combination thereof. Such pharmaceutical compositions facilitate administration of the active compound to a subject. Various techniques for administering pharmaceutical compositions comprising compounds are known in the art, including but not limited to oral, injection, aerosol, parenteral, and topical administration. In addition, the pharmaceutical composition may be sterile and may also include adjuvants such as preservatives, stabilizers, hydrating agents, emulsifiers, salts for controlling osmotic pressure, and / or buffers, or other therapeutically useful substances. It may also be formulated by conventional methods such as mixing, granulation, or coating.

[0128] As used herein, the term "carrier" refers to a compound that facilitates the delivery of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the delivery of various organic compounds into cells or tissues of living organisms.

[0129] As used herein, the term "diluent" is defined as a compound that not only stabilizes the biologically active form of the subject compound but also dilutes it in water to dissolve the compound. In the art, salts dissolved in buffers are used as diluents. One commonly used buffer is phosphate-buffered saline, a salt form that simulates human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely alter the biological activity of a compound.

[0130] As used herein, the term "pharmaceutically acceptable" refers to properties that do not impair the biological activity and physical properties of the compound.

[0131] In addition, the pharmaceutical composition can be a composition for preventing and / or treating a disease associated with the KRAS G12D mutant protein. As used herein, a disease associated with the KRAS G12D mutant protein can be, for example, cancer, and can include any disease known to be associated with the KRAS G12D mutation.

[0132] Cancers include angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated multicellular carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchiolar adenoma, sarcoma, lymphoma, enchondromatosis, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, biliary tract cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma, benign enchondroma, chondromyxoid fibroma tumor, chondroostoma, giant cell tumor, skull tumor, skull hemangioma, skull granuloma, skull xanthomas, skull deforming osteitis, meningioma, meningioma sarcoma, glioblastoma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma, endometrial cancer, cervical cancer, ovarian cancer, blood cancer, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, malignant melanoma, basal cell carcinoma, adenocarcinoma, neuroblastoma, but are not limited to these.

[0133] The pharmaceutical composition can be formulated into various oral or parenteral dosage forms. For example, it can be in the form of any oral dosage form such as tablets, pills, hard or soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc. These oral dosage forms may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier, including diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, or lubricants such as silicon dioxide, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol, depending on the typical composition of each dosage form.

[0134] In addition, if the oral administration formulation is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally a disintegrant such as starch, agar, alginic acid or its sodium salt, an effervescent mixture and / or an absorbent, a colorant, a flavoring agent or a sweetener.

[0135] The pharmaceutical composition can also be formulated into a parenteral administration form. In this case, it can be administered by a parenteral administration method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. In such a case, in order to formulate the pharmaceutical composition into a parenteral dosage form, the active ingredient, i.e., the compound of Chemical Formula 1 or its optical isomers, stereoisomers, isotopic variants or pharmaceutically acceptable salts, is mixed with a stabilizer or buffer in water to prepare a solution or suspension, and the solution or suspension can be prepared into a unit dosage form of an ampoule or a vial.

[0136] In addition, the pharmaceutical composition may be sterilized, or may further contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsifiers, salts for controlling osmotic pressure and / or buffers or other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating or coating.

[0137] For mammals including humans, the active ingredient, i.e., the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, can be contained in the pharmaceutical composition in an effective amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight) per day, and the pharmaceutical composition can be administered orally or parenterally once a day or in two or more divided doses.

[0138] In addition, a pharmaceutical composition can be used to treat cancer by comprising a compound according to one embodiment of the present application and at least one additional therapeutic agent. The compound according to one embodiment of the present application can exhibit a synergistic effect when used in combination with different therapeutic agents. The term "synergistic" refers to a combination that is more therapeutically effective than the additive effect of two or more individual agents. Combination therapy provides a "synergistic" effect and is proven to be "synergistic", that is, the therapeutic effect obtained when the active ingredients are used together is greater than the sum of the effects obtained when the compounds are used alone. A synergistic effect can be obtained when the active ingredients: (1) are co-formulated in a combined unit dosage form and administered or delivered simultaneously; or (2) are administered as separate formulations in an alternative manner. A synergistic effect can be obtained when delivered by an alternative therapy regimen, for example, when the compounds are administered sequentially from separate syringes via different injections. Typically, during alternative therapy, the therapeutically effective dose of each active ingredient is administered sequentially, i.e., in a time-staggered manner. In certain embodiments, the synergistic effect is manifested as a lower toxicity of the combination compared to the same total dose of any single component of equal amount. For example, when the compound of Chemical Formula 1 is administered in combination with a different therapeutic agent, the toxicity of a 50:50 (w / w) combination of the compound of Chemical Formula 1 and the different therapeutic agent may be lower than the toxicity of 100% (w / w) of the compound of Chemical Formula 1 and / or 100% (w / w) of the different therapeutic agent, while the combination exhibits approximately the same or even higher efficacy. In other words, the toxicity of the combination of the compound of Chemical Formula 1 and the different therapeutic agent is lower than the toxicity of either agent alone, while the efficacy of the combination is higher than that of a single agent. In addition, the reason for combining the compound of Chemical Formula 1 with different therapeutic agents is not only to reduce toxicity and improve safety, but also to obtain a higher efficacy than that obtained by using a single agent alone. Improved efficacy is one of the advantages of combination therapy.

[0139] The one or more therapeutic agents may include, but are not limited to, RTK / Ras-MAPK pathway-related protein inhibitors (EGFR inhibitors, FGFR inhibitors, ALK inhibitors, ROS inhibitors, MET inhibitors, RAF inhibitors, ERK inhibitors, MEK inhibitors, SHP-2 inhibitors, PI3K inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, SOS1 inhibitors), DNA damaging agents, EGFR antibodies or immuno-oncology therapeutics.

[0140] For example, RTK / Ras-MAPK pathway inhibitors are EGFR inhibitors (erlotinib, gefitinib, afatinib or osimertinib); FGFR inhibitors (pemitinib or infigratinib (BGJ398)); ALK / ROS / MET inhibitors (crizotinib, cabozantinib or foretinib); RAF inhibitors (vemurafenib, dabrafenib or bevafenib); ERK / MEK inhibition (trametinib or cobimetinib); SHP-2 inhibitors (TNO155 and RMC-4630); PI3K inhibitors (AMG 511 and bupanib); KRAS inhibitors and KRAS G12C inhibitors (soutolaciib, adagraciib and divarasib), and include one or more of these inhibitors, but are not limited thereto.

[0141] For example, chemotherapeutic agents of DNA damaging agents include alkylating agents (platinum chemotherapy: cisplatin, carboplatin, oxaliplatin / nitrogen mustard drugs: mechlorethamine (nitrogen mustard), cyclophosphamide, ifosfamide, melphalan, chlorambucil / nitrosourea drugs: carmustine (BCNU), lomustine (CCNU), nimustine / others: altretamine, busulfan, dacarbazine, procarbazine, temozolomide, thiotepa, rubitidine, etc.), antimetabolites (fluorouracil (5-FU), capecitabine, cytarabine, gemcitabine, Methotrexate, mercaptopurine (6-MP), folinic acid, pemetrexed, etc.), topoisomerase inhibitors (epipodophyllotoxins: etoposide, teniposide / camptothecins: topotecan, irinotecan, SN-38 / antitumor antibiotics: dactinomycin, doxorubicin, daunorubicin, mitomycin, bleomycin, etc.), microtubule inhibitors (vinca alkaloids: vinblastine, vincristine, vinorelbine / taxanes: paclitaxel, docetaxel, etc.), hormone antagonists (tamoxifen, flutamide, leuprorelin, etc.), but not limited to these.

[0142] In one example, the EGFR antibody includes, but is not limited to, cetuximab.

[0143] In one example, the immuno-oncology therapeutic includes, but is not limited to, AMG-404, pembrolizumab, or nivolumab.

[0144] Beneficial effects

[0145] According to the present application, a tricyclic derivative compound or its optical isomer, stereoisomer, isotopic variant, or pharmaceutically acceptable salt that exhibits excellent KRASG12D inhibitory activity can be provided. Therefore, such a compound or its optical isomer, stereoisomer, isotopic variant, or pharmaceutically acceptable salt can be effectively used to prevent or treat diseases associated with KRASG12D mutant proteins, such as cancer.

[0146] In addition, the compounds according to the present application or optical isomers, stereoisomers or isotopic variants thereof, or pharmaceutically acceptable salts thereof may exhibit excellent therapeutic effects or improved pharmacokinetic properties. DETAILED DESCRIPTION

[0147] Hereinafter, the present invention will be described in more detail by way of examples. However, the examples are only intended to illustrate the present invention and the scope of the present invention is not limited thereto.

[0148] Intermediate 1: Synthesis of 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.

[0149]

[0150] Step 1: Dissolve 6-chloro-3-nitropicolinecarbonitrile (10 g, 54.48 mmol) in HSO (276 g, 2.53 mol) and heat at 70°C for 3.5 hours. After completion of the reaction, cool the reaction mixture to 20°C and add ice water (1200 mL) dropwise. The precipitate is filtered, washed with water, and dried, then concentrated under reduced pressure to afford 6-chloro-3-nitropicolinecarbonitrile (9.85 g, crude compound) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ 8.54 (d, J = 8.8 Hz, 1H), 8.29 (brs, 1H), 8.03 (brs, 1H) 7.95 (d, J = 8.8 Hz, 1H).

[0151] Step 2: A solution of 6-chloro-3-nitropicolinamide (7.35 g, 36.46 mmol) was dissolved in ethanol (30 mL) and a saturated 28% aqueous ammonia solution (27.30 g, 218.09 mmol) was added dropwise. The reaction was carried out at 100 ° C for 48 hours in a 100 mL sealed tube. After the reaction was completed, the mixture was cooled and concentrated under reduced pressure to obtain a residue. The residue was diluted with a Na2CO3 aqueous solution (100 mL), the mixture was stirred at 20 ° C for 1 hour, filtered, and the filter cake was washed with water (50 mL). The residue was concentrated under reduced pressure to obtain a residue. 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, crude compound) was obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.11 (d, J = 9.2 Hz, 1H), 7.83 (brs, 1H), 7.57 (brs, 2H), 7.52 (brs, 1H), 6.50 (d, J = 9.2Hz, 1H).

[0152] Step 3: 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, 26.63 mmol) was dissolved in DMF (49 mL), and NBS (5.69 g, 31.95 mmol) was added, and the reaction mixture was stirred at 25 ° C for 4 hours. After the reaction was completed, most of the solvent was removed under reduced pressure, and the residue was suspended in purified water (100 mL). The solid was filtered and dried under reduced pressure. The product was stirred with petroleum ether (45 mL) and ethyl acetate (40 mL) at 20 ° C for 30 minutes, the solid was filtered and dried under reduced pressure. 6-amino-3-nitropicolinamide (5.6 g, 21.13 mmol, yield 79.37%) was obtained as a yellow solid. LCMS (ES-API, m / z): [M + H] + =263.0; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.48(s,1H),7.90(brs,2H),7.65(brs,2H).

[0153] Step 4: 6-amino-3-nitropicolinamide (5.9 g, 22.60 mmol) was dissolved in ethanol (59 mL) and distilled water (59 mL), and 2-bromo-1,1-diethoxyethane (6.68 g, 33.90 mmol) and HBr (9.14 g, 45.21 mmol) were added dropwise at 20 ° C. The reaction mixture was heated at 100 ° C for 16 hours. The reaction mixture was concentrated in vacuo to remove ethanol, and the pH of the residue was adjusted to 8 with aqueous NaHCO3 solution to precipitate a solid, which was then filtered. The filter cake was concentrated in vacuo to give gray 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (5.28 g, 18.14 mmol, yield 80.26%). The results were confirmed by LCMS and HNMR. LCMS (ES-API, m / z): [M + H] + =287.0; 1 H NMR (400MHz, DMSO-d6, ppm): δ 8.55 (d, J = 10.0 Hz, 2H), 8.34 (d, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H).

[0154] Step 5: 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (4.5 g, 15.79 mmol), Fe (3.53 g, 63.15 mmol) and NH4Cl (6.76 g, 126.29 mmol) were added to ethanol (90 mL) and distilled water (18 mL), and the mixture was stirred at 85 ° C for 16 hours. The reaction mixture was filtered and the filter cake was washed with 800 mL EA / MeOH (10: 1). The organic phases were combined to obtain a residue. The residue was then washed with saturated sodium bicarbonate, filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. 6-amino-8-bromoimidazo[1,2-a]pyridine-5-carboxamide (3.1 g, crude compound) was obtained as a green solid. LCMS (ES-API, m / z): [M+H] + =254.9; 1 HNMR (400MHz, DMSO-d6, ppm): δ8.21-7.61(m,3H),7.57-7.20(m,2H),6.02-5.40(m,2H).

[0155] Step 6: 6-amino-8-bromoimidazo[1,2-a]pyridine-5-carboxamide (10.47 g, 35.28 mmol) was dissolved in 1,4-dioxane (100 mL). The resulting suspension was refluxed at 110 ° C for 16 hours under nitrogen. After the starting material was consumed, the reaction solution was cooled to 20 ° C, distilled water (20 mL) was added, and the reaction was terminated by stirring for 10 minutes. The mixture was filtered, the solid was washed with ethyl acetate (200 mL), and then dried. 6-bromoimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine-1,3(2H,4H)-dione (10.7 g, crude compound) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =283.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ 12.00-11.95 (m, 1H), 11.91-11.83 (m, 1H), 9.11 (d, J = 0.8Hz, 1H), 8.02-7.94 (m, 1H), 7.84-7.74 (m, 1H).

[0156] Step 7: In a 250 mL three-necked round-bottom flask, POCl3 (117.84 g, 768.50 mmol) was added dropwise to 6-bromoimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine-1,3(2H,4H)-dione (5.4 g, 19.21 mmol) obtained in Step 6. DIPEA (6.21 g, 48.03 mmol) was then slowly added dropwise. The reaction mixture was filled with nitrogen and stirred at 110°C for 20 hours. After the starting material was completely consumed, the solvent and most of the POCl3 were removed in vacuo at 40°C, ethyl acetate (100 mL) was added, and the reaction mixture was basified to pH 7-8 with saturated Na2CO3 solution at 0°C. The reaction mixture was extracted with ethyl acetate (200 mL*3), and the organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography. 6-Bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2.44 g, 7.24 mmol, 37.68% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =275.0; 1 HNMR (400MHz, DMSO-d6, ppm): δ9.28 (d, J = 1.2Hz, 1H), 9.17-9.12 (m, 2H), 8.12-8.07 (m, 1H), 7.95-7.93 (m, 1H), 7.92-7.90 (m, 2H), 7.87-7.84 (m, 1H).

[0157] Intermediate 2: Synthesis of 6-bromo-1,3-dichloro-8-methylfuro[3,2-f]quinazoline.

[0158]

[0159] Step 1: Dissolve 4-bromo-5-fluoro-2-nitrobenzoic acid (50.0 g, 189 mmol) in distilled water (600 mL), add 12 M KOH (63.8 g, 1.14 mol), and stir the reaction solution at 80°C for one day. Adjust the pH to 3 with 1N aqueous HCl. Ethyl acetate is added to extract the organic layer, which is then washed with saturated aqueous NaCl and dried over anhydrous MgSO₄. The solvent is concentrated to yield 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol, crude compound). 1 HNMR (400MHz, DMSO-d6, ppm): δ13.7(s,1H),12.1(s,1H),8.27(s,1H),7.14(s,1H).

[0160] Step 2: Dissolve 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol) obtained in Step 1 in methanol (599 mL). Add sulfuric acid (51.6 mL) at 0°C, and stir the reaction solution at 70°C for one day. Distilled water was added to the reaction mixture to terminate the reaction. Ethyl acetate was added to extract the organic layer, which was washed with saturated aqueous NaCl and dried over anhydrous MgSO4. The solvent was concentrated to yield methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol, crude compound).

[0161] Step 3: Methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol) obtained from Step 2 and TEA (79.0 mL, 567 mmol) were dissolved in DCM (798 mL). Acetyl chloride (20.2 mL, 283 mmol) was added at 0°C, and the reaction solution was stirred at the same temperature for 2 hours. Purified water was added to the reaction mixture to quench the reaction. The organic layer was extracted with DCM and dried over anhydrous MgSO4. The solvent was concentrated to synthesize methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.1 g, 189 mmol, crude compound). 1 H NMR (400MHz, DMSO-d6, ppm): δ8.55(s,1H),7.94(s,1H),3.87(s,3H),2.39(s,3H).

[0162] Step 4: 5-acetoxy-4-bromo-2-nitrobenzoic acid methyl ester (60.0 g, 189 mmol) obtained from Step 3 was dissolved in ethanol (700 mL), purified water (300 mL) and acetic acid (75.5 mL, 1.32 mol), and Fe (26.3 g, 472 mmol) was slowly added. The reaction solution was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding 6N KOH aqueous solution, the solvent was removed, and the mixture was filtered. Ethyl acetate was added to the filtrate, the organic layer was extracted, washed with saturated NaCl aqueous solution and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize 5-acetoxy-2-amino-4-bromobenzoic acid methyl ester (24.5 g, 85.0 mmol, 45% yield) as a solid compound. 1 H NMR (400MHz, DMSO-d6, ppm): δ7.50(s,1H),7.13(s,1H),6.76(s,2H),3.79(s,3H),2.26(s,3H).

[0163] Step 5: Methyl 5-acetoxy-2-amino-4-bromobenzoate (2.28 g, 7.91 mmol) obtained in Step 4 was dissolved in MeOH (120 mL) and KCO (2.19 g, 15.8 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction mixture was acidified by adding 1N aqueous HCl, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. The solvent was concentrated to yield methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.91 mmol, crude compound). 1 H NMR (400MHz, CD3OD, ppm): δ8.36(d,J=1.2Hz,1H),8.23(d,J=1.2Hz,1H),7.57(d,J=2.0Hz,1H),7.44(d,J=2.0Hz,1H),5 .49(s,2H),5.42–5.37(m,1H),3.44–3.40(m,2H),3.31–3.27(m,2H),2.76(s,3H),2.30–2.27(m,2H),2.26–2.24(m,2H).

[0164] Step 6: Methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.92 mmol) obtained from Step 5 was dissolved in DMF (50 mL). 9.2 M 3-bromopropane (1.21 mL, 11.1 mmol) and KCO (2.19 g, 15.8 mmol) dissolved in toluene were added sequentially, and the reaction solution was stirred at room temperature for one day. Purified water was added to the reaction mixture to quench the reaction. Ethyl acetate was added to extract the organic layer, which was washed with saturated aqueous NaCl and dried over anhydrous MgSO. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol, 74% yield) as a solid compound. 1 H NMR (400MHz, DMSO-d6, ppm): δ7.43 (s, 1H), 7.11 (s, 1H), 6.48 (s, 2H), 4.74 (d, J = 2.4Hz, 2H), 3.80 (s, 3H), 3.58 (t, J = 2.3Hz, 1H).

[0165] Step 7: Methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol) obtained from Step 6 was dissolved in N,N-diethylaniline (10 mL), CsF (1.33 g, 8.76 mmol) was added, and the reaction solution was heated to reflux and stirred for 1 hour. It was diluted with ethyl acetate, washed twice with 1N aqueous hydrochloric acid, and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize solid methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol, 85% yield).

[0166] Step 8: Methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol) obtained in Step 7 was dissolved in THF (50 mL). Trichloroacetyl isocyanate (0.651 mL, 5.46 mmol) was added at 0°C, and the reaction solution was stirred at the same temperature for 30 minutes. The solvent was concentrated, and a 7N ammonia solution in methanol (1.69 g, 99.0 mmol) was added to the resulting mixture, which was stirred at room temperature for 1 day. Filtration with methanol yielded 6-bromo-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (1.23 g, 4.17 mmol, 84% yield) as a solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ10.01 (s, 2H), 7.24 (d, J = 1.3Hz, 1H), 7.22 (s, 1H), 2.54 (s, 3H).

[0167] Step 9: 6-bromo-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (1.22 g, 4.13 mmol) obtained from Step 8 was added with POCl3 (15.4 mL, 165 mmol) and DIPEA (1.80 mL, 10.3 mmol), and the reaction solution was stirred at 110°C for 1.5 hours. The solvent was concentrated, and the reaction mixture was quenched by the addition of saturated NaHCO3 solution. The organic layer was extracted by the addition of ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was filtered with DCM to remove the solid. The filtrate was concentrated, and the product was purified by silica gel chromatography to synthesize solid 6-bromo-1,3-dichloro-8-methylfuro[3,2-f]quinazoline (40.0 mg, 0.120 mmol, 3% yield). LCMS (ES-API, m / z): [M+H] + =329.9; 1H NMR (400MHz, DMSO-d6, ppm): δ8.23(s,1H),7.70(s,1H),2.68(s,3H).

[0168] Intermediate 3: Synthesis of 6-bromo-1,3-dichloro-5-fluoro-8-methyl-6a,9a-dihydrofuro[3,2-f]quinazoline.

[0169]

[0170] Step 1: Methyl 5-acetoxy-2-amino-4-bromobenzoate (20.0 g, 69.4 mmol) was dissolved in acetonitrile (1 L), selectfluor (27.1 g, 76.4 mmol) was added, and the reaction solution was stirred at 80°C for one day. Saturated aqueous NaHCO₃ was added to the reaction mixture to adjust the pH to 8, and ethyl acetate was added to extract the organic layer, which was washed with saturated aqueous NaCl and dried over anhydrous MgSO₄. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize solid methyl 5-acetoxy-2-amino-4-bromo-3-fluorobenzoate (5.5 g, 18.0 mmol, 26% yield). 1 H NMR (400MHz, DMSO-d6, ppm): δ7.45 (d, J = 2.0Hz, 1H), 6.74 (s, 2H), 3.83 (s, 3H), 2.29 (s, 3H).

[0171] Step 2: Methyl 5-acetoxy-2-amino-4-bromo-3-fluorobenzoate (5.50 g, 18.0 mmol) obtained in Step 1 was dissolved in methanol (275 mL), KCO (4.97 g, 35.9 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was acidified by adding 1N aqueous HCl, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. The solvent was concentrated to yield methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (4.74 g, 18.0 mmol, crude compound). 1 H NMR (400MHz, DMSO-d6, ppm): δ9.86 (s, 1H), 7.19 (d, J = 2.1Hz, 1H), 6.07 (s, 2H), 3.81 (s, 3H).

[0172] Step 3: Methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (2.00 g, 7.57 mmol) obtained in Step 2 was dissolved in DMF (47.8 mL). 9.2 M propargyl bromide (1.15 mL, 10.6 mmol) and KCO (2.09 g, 15.1 mmol) dissolved in toluene were added sequentially, and the reaction solution was stirred at room temperature for one day. Purified water was added to the reaction mixture to quench the reaction. Ethyl acetate was added to extract the organic layer, which was washed with saturated aqueous NaCl and dried over anhydrous MgSO. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to yield solid methyl 2-amino-4-bromo-3-fluoro-5-(prop-2-yn-1-yloxy)benzoate (1.03 g, 3.41 mmol, 45% yield). 1 H NMR (400MHz, DMSO-d6, ppm): δ7.34 (d, J = 2.0 Hz, 1H), 6.42 (s, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.61 (t, J = 2.3Hz, 1H).

[0173] Step 4: Methyl 2-amino-4-bromo-3-fluoro-5-(prop-2-yn-1-yloxy)benzoate (1.02 g, 3.38 mmol) obtained from Step 3 was dissolved in N,N-diethylaniline (10 mL), CsF (769 mg, 5.06 mmol) was added, and the reaction solution was heated to reflux and stirred for 1 hour. The solution was diluted with ethyl acetate, washed twice with 1N aqueous HCl, and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize solid methyl 5-amino-7-bromo-6-fluoro-2-methylbenzofuran-4-carboxylate (910 mg, 3.01 mmol, 89% yield). 1 H NMR (400MHz, DMSO-d6, ppm): δ6.91(s,1H),6.67(s,2H),3.89(s,3H),2.45(s,3H).

[0174] Step 5: Methyl 5-amino-7-bromo-6-fluoro-2-methylbenzofuran-4-carboxylate (910 mg, 3.01 mmol) obtained in Step 4 was dissolved in THF (30.3 mL). Trichloroacetyl isocyanate (0.395 mL, 3.31 mmol) was added at 0°C, and the reaction solution was stirred at the same temperature for 30 minutes. The solvent was concentrated, and 7N NH₄ in methanol (8.62 mL, 60.3 mmol) was added to the resulting mixture, and the mixture was stirred at room temperature for 1 day. 6-Bromo-5-fluoro-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (863 mg, 2.76 mmol, 91% yield) was synthesized as a white solid by filtration with methanol. 1 H NMR (400MHz, DMSO-d6, ppm): δ9.90 (s, 2H), 7.21 (s, 1H), 2.53 (s, 3H).

[0175] Step 6: To the bromo-5-fluoro-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (750 mg, 2.40 mmol) obtained from step 5 was added POCl3 (8.93 mL, 95.80 mmol) and DIPEA (1.04 mL, 5.99 mmol), and the reaction solution was stirred at 110°C for 7 hours. Saturated NaHCO3 solution was added to the reaction mixture to quench the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was filtered with DCM to obtain a white solid. The filtrate was concentrated and purified by silica gel chromatography to obtain 6-bromo-1,3-dichloro-5-fluoro-8-methyl-6a,9a-dihydrofuro[3,2-f]quinazoline (707 mg, 2.02 mmol, 84% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ7.64 (s, 1H), 2.66 (s, 3H).

[0176] Intermediate 4: Synthesis of 4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline.

[0177]

[0178] Step 1: 7-bromo-5-nitro-1H-indazole (20 g, 82.6 mmol) was dissolved in THF (200 mL), NaH (8.3 g, 124 mmol) was added at 0°C, and the mixture was stirred at 20°C. After stirring at 20°C for 30 minutes, MeI (35.2 g, 248 mmol) was added. The reaction mixture was stirred at 20°C for 1 hour under nitrogen. After the reaction was completed, purified water (80 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (40 mL*3) and dried over Na2SO4. The filtered solution was concentrated under reduced pressure to obtain a residue. The residue was stirred with hexane at 20°C for 30 minutes, and the solid was filtered. 7-bromo-2-methyl-5-nitro-2H-indazole (20 g, 78.1 mmol, 94% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =257.1.

[0179] Step 2: To a solution of ethanol (120 mL), THF (120 mL) and purified water (40 mL) were added 7-bromo-2-methyl-5-nitro-2H-indazole (20 g, 78.1 mmol), Fe (21.8 g, 391 mmol) and NH4Cl (5.01 g, 93.7 mmol), and the mixture was stirred at 90 ° C for 1 hour. The reaction mixture was filtered through celite to obtain a residue. The residue was purified by silica gel chromatography. 7-bromo-2-methyl-2H-indazole-5-amine (7 g, 31 mmol, yield 40%) was obtained as a yellow solid. LCMS (ES-API, m / z): [M + H] + =227.1; 1 H NMR (400MHz, CDCl3, ppm): δ7.73(s,1H),6.85(s,1H),6.72(s,1H),4.18(s,3H),3.52(br,2H).

[0180] Step 3: Dissolve 7-bromo-2-methyl-2H-indazol-5-amine (6.67 g, 29.5 mmol), chloral hydrate (9.76 g, 29.5 mmol), and Na2SO4 (33.5 g, 236 mmol) in purified water (70 mL), and slowly add HCl (4 mL) dropwise. The mixture is stirred at 90°C for 30 minutes. Then, N-chlorohydroxylamine (11.9 g, 177 mmol) is added and stirred at 90°C for 1 hour. After the reaction mixture is cooled to room temperature, purified water (70 mL) is added and stirred for 10 minutes. A solid precipitates and is then filtered. The filter cake is concentrated in vacuo to afford N-(7-bromo-2-methyl-2H-indazol-5-yl)-2-(N-hydroxyamino)acetamide (8.77 g, 29.5 mmol, 100% yield, crude compound) as a black solid. LCMS (ES-API, m / z): [M+H] + =298.1.

[0181] Step 4: To N-(7-bromo-2-methyl-2H-indazol-5-yl-2-(N-hydroxyamino)acetamide (9 g, 30.3 mmol) was slowly added concentrated sulfuric acid (60 mL) dropwise, and the reaction mixture was stirred at 90° C. for 30 minutes. After the reaction mixture was cooled to room temperature, ice was added, and the mixture was stirred for 30 minutes. A solid precipitated and then filtered. The solid was dried to give black 4-bromo-2-methyl-2H,6H,7H,8H-pyrrolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol, yield 60%). LCMS (ES-API, m / z): [M+H] + =281.1; 1 H NMR (400MHz, CD3OD, ppm): δ8.30(s,1H),8.14(s,1H),7.74(s,1H),7.61(s,1H),4.24(s,3H).

[0182] Step 5: Dissolve 4-bromo-2-methyl-2H,6H,7H,8H-pyrrolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol) in 2N aqueous NaOH (7.28 g, 182 mmol), slowly add H2O2 (3.1 g, 91 mmol) dropwise, and stir for 1 hour. Acetic acid was added to the reaction mixture at 0°C to adjust the pH to 3, and the precipitated solid was filtered. The solid was dried to give black 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid (3.08 g, 11.4 mmol, 63% yield). LCMS (ES-API, m / z): [M+H] + =271.1; 1H NMR (400MHz, DMSO-d6, ppm): δ10.81(s,1H),8.58(s,1H),7.25(s,1H),4.19(s,3H).

[0183] Step 6: Dissolve 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid (962 mg, 3.56 mmol) in methanol (14 mL) and toluene (42 mL), and slowly add 2M (diazomethyl)trimethylsilane (488 mg, 4.27 mmol) dropwise at 0°C. Warm the mixture to room temperature and stir for 5 minutes. Extract the compound with ethyl acetate (200 mL*3), dry the organic layer over Na2SO4, filter, and concentrate. Purify the residue by silica gel chromatography. 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid methyl ester (283 mg, 0.996 mmol, 28% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =285.1; 1 H NMR (400MHz, CD3OD, ppm): δ8.16(s,1H),7.17(s,1H),4.14(s,3H),3.93(s,3H).

[0184] Step 7: 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid methyl ester (276 mg, 0.971 mmol) was dissolved in THF (13 mL), trichloroacetyl isocyanate (220 mg, 1.17 mmol) was added dropwise at 0 ° C and reacted for 5 minutes. Most of the solvent was removed under reduced pressure, and the residue was suspended in ether (10 mL). The solid was filtered and dried under reduced pressure. 7-bromo-2-methyl-5 [[(2,2,2-trichloroacetyl)carbamoyl] amino] -2H-indazole-4-carboxylic acid methyl ester (459 mg, 0.971 mmol, yield 100%) was obtained as a white solid. LCMS (ES-API, m / z): [M + H] + =473.5.

[0185] Step 8: 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylic acid methyl ester (459 mg, 0.971 mmol) obtained in step 7 was dissolved in 7N NH4 in methanol (100 mL). The resulting suspension was refluxed at 110 ° C for 36 hours under nitrogen. After the reaction was completed, it was cooled to 20 ° C, the solvent was removed with nitrogen, and the mixture was filtered. The filtered solid was washed with ether (200 mL) and dried to give white 4-bromo-2-methyl-2H,6H,7H,8H,9H-pyrazolo[4,3-f]quinazoline-7,9-dione (287 mg, yield 100%, crude compound). LCMS (ES-API, m / z): [M + H] + =296.1; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.75 (s, 1H), 7.42 (s, 1H).

[0186] Step 9: POCl3 (5.9 g, 38.9 mmol) was added dropwise to 4-bromo-2-methyl-2H,6H,7H,8H,9H-pyrazolo[4,3-f]quinazoline-7,9-dione (287 mg, 0.973 mmol) obtained in Step 8. DIPEA (377 mg, 2.92 mmol) was then slowly added dropwise. The mixture was filled with nitrogen and stirred at 110°C for 20 hours. After the reaction was complete, the solvent and most of the POCl3 were removed in vacuo at 40°C, ethyl acetate (100 mL) was added, and the mixture was basified to pH 7-8 with saturated Na2CO3 solution at 0°C. The compound was extracted with ethyl acetate (200 mL*3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give 4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (124 mg, 0.374 mmol, 38% yield). LCMS (ES-API, m / z): [M+H] + =333.0.

[0187] Intermediate 5: Synthesis of 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline.

[0188]

[0189] Step 1: 7-bromo-6-fluoro-2H-indazole (40.0 g, 186 mmol) was dissolved in ethyl acetate (500 mL) and Me3OBF4 (41.3 g, 279 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction was quenched with purified water (500 mL) and extracted with ethyl acetate (500 mL*2). The extracted organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography to give 7-bromo-6-fluoro-2-methyl-2H-indazole (37.3 g, 163 mmol, 88% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.54 (s, 1H), 7.78 (dd, J = 5.2, 8.8Hz, 1H), 7.05 (t, J = 9.2Hz, 1H), 4.19 (s, 3H).

[0190] Step 2: After cooling H2SO4 (370 mL) to 0°C, 7-bromo-6-fluoro-2-methyl-2H-indazole (37.0 g, 162 mmol) was added dropwise. KNO3 (19.8 g, 1956 mmol) was added dropwise to the reaction mixture at 0°C and stirred at room temperature for 12 hours. After confirming the reaction, the reaction was quenched with cold purified water and slowly neutralized with aqueous NaHCO3 at 0°C. The organic layer was extracted with ethyl acetate (500 mL*3) and washed with saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4 and concentrated to give 7-bromo-6-fluoro-2-methyl-5-nitro-2H-indazole (38.0 g, 139 mmol, 86% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.91 (s, 1H), 8.85 (d, J = 7.2Hz, 1H), 4.26 (s, 3H).

[0191] Step 3: 7-bromo-6-fluoro-2-methyl-5-nitro-2H-indazole (38.0 g, 139 mmol) and NH4Cl (59.3 g, 1.11 mol) were dissolved in EtOH (400 mL) and H2O (200 mL), Fe (62.0 g, 1.11 mol) was added dropwise, and stirred at 80 ° C for 2 hours. After confirming the reaction, the resulting solid was filtered, washed with EtOH, and dried. The mixture was purified by silica gel chromatography to give 7-bromo-6-fluoro-2-methyl-2H-indazole-5-amine (30.0 g, 123 mmol, 89% yield) as a yellow solid.

[0192] Step 4: 2-((Benzyloxy)imino)acetic acid (34.5 g, 193 mmol) was dissolved in DMF (245 mL), and HATU (54.9 g, 144 mmol), DIPEA (99.6 g, 770 mmol), and 7-bromo-6-fluoro-2-methyl-2H-indazol-5-amine (23.5 g, 96.3 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 2 hours and quenched with cold purified water. The organic layer was extracted with ethyl acetate (400 mL*2), washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated. The product was solidified with petroleum ether / EtOAc = 5:1 to give (E)-2-((Benzyloxy)imino)-N-(7-bromo-6-fluoro-2-methyl-2H-indazol-5-yl)acetamide (35.5 g, 87.6 mmol, 91% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =407.0; 1 HNMR (400MHz, DMSO-d6, ppm): δ10.10 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 7.2Hz, 1H), 7.94 (s, 1H), 7.54-7.27 (m, 5H), 5.27 (s, 2H), 4.18 (s, 3H).

[0193] Step 5: (E)-2-((Benzyloxy)imino)-N-(7-bromo-6-fluoro-2-methyl-2H-indazol-5-yl)acetamide (34.0 g, 83.9 mmol) was dissolved in H2SO4 (680 mL) and stirred at 90 ° C for 2 hours. After the reaction was confirmed, it was cooled and quenched with cold purified water. The organic layer was extracted with ethyl acetate (1.00 L*5) and freeze-dried. It was then solidified with MeOH to give 4-bromo-5-fluoro-2-methyl-2,6-dihydropyrrolo[3,2-e]indazole-7,8-dione (11.0 g, 36.9 mmol, yield 44%) as a red solid. LCMS (ES-API, m / z): [M+H] + =320.1; 1 H NMR (400MHz, DMSO-d6, ppm): δ11.42(s,1H),8.63(s,1H),4.18(s,3H).

[0194] Step 6: 4-bromo-5-fluoro-2-methyl-2,6-dihydropyrrolo[3,2-e]indazole-7,8-dione (10.5 g, 35.2 mmol) and NaOH (14.1 g, 352 mmol) were dissolved in 1,4-dioxane (200 mL). H2O2 (20.5 g, 180 mmol) was added dropwise to the reaction mixture at 0°C and stirred at room temperature for 1 hour. After the reaction was confirmed, the reaction was quenched with Na2SO3 aqueous solution (500 mL) and concentrated under reduced pressure. The pH was adjusted to 4 with 6N HCl aqueous solution, and the resulting yellow solid was filtered and dried. 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylic acid (8.80 g, 30.6 mmol, yield 86.7%) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =287.9; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.26 (s, 1H), 4.09 (s, 3H).

[0195] Step 7: 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylic acid (9.00 g, 31.2 mmol) and K2CO3 (8.64 g, 62.5 mmol) were dissolved in DMF (90.0 mL), and CH3I (5.10 g, 35.9 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours. After confirming the reaction, the solution was quenched with NH4Cl aqueous solution (500 mL) and the organic layer was extracted with ethyl acetate (300 mL*3). It was dried over anhydrous Na2SO4 and concentrated to give 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylic acid methyl ester (10.0 g, crude mixture) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =303.9; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.31(s,1H),7.15(s,2H),4.11(s,3H),3.89(s,3H).

[0196] Step 8: Dissolve methyl 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylate (9.70 g, 32.1 mmol) in THF (100 mL) and slowly add 2,2,2-trichloroacetyl isocyanate (12.1 g, 64.2 mmol) dropwise at 0°C. The reaction mixture is stirred at room temperature for 2 hours and concentrated after reaction is confirmed. The resulting white solid is dissolved in NH3·H2O (91.0 g, 727 mmol) and MeOH (100 mL) and stirred at 40°C for 2 hours. The reaction solution is concentrated and solidified with MeOH (100 mL) to afford 4-bromo-5-fluoro-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-f]quinazoline-7,9(8H)-dione (9.10 g, 29.1 mmol, 90% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =314.8; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.72 (s, 1H), 4.19 (s, 3H).

[0197] Step 9: 4-Bromo-5-fluoro-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-f]quinazoline-7,9(8H)-dione (8.10 g, 25.9 mmol) was dissolved in toluene (80.0 mL), and POCl3 (39.7 g, 259 mmol) and DIPEA (7.36 g, 56.9 mmol) were slowly added dropwise. The reaction mixture was stirred at 115°C for 40 hours. After the reaction was confirmed, it was cooled with purified water, and the organic layer was extracted with ethyl acetate (500 mL*2). The extracted organic layer was dried over anhydrous Na2SO4 and concentrated to obtain 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (9.00 g, 25.12 mmol, 97% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =350.8; 1 H NMR (400 MHz, CDCl 3, ppm): δ8.80(s,1H),4.37(s,3H).

[0198] Intermediate 6: Synthesis of (1-(morpholinomethyl)cyclopropyl)methanol

[0199]

[0200] Step 1: Dissolve 1-(Methoxycarbonyl)cyclopropane-1-carboxylic acid (1 g, 6.94 mmol) in DCM (10 mL), and slowly add oxalyl chloride (1.76 g, 13.88 mmol) and DMF (50.72 mg, 694.00 μmol) dropwise at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. Without purification, methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate (1.1 g, crude mixture) was obtained as a yellow oil.

[0201] Step 2: 1-(chlorocarbonyl)cyclopropane-1-carboxylic acid methyl ester (1.1 g, 6.77 mmol) obtained in step 1 was dissolved in THF (22 mL) and TEA (1.37 g, 13.53 mmol) was added dropwise at 0 ° C. Then, morpholine (884.22 mg, 10.15 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, purified water was added, and the mixture was extracted with ethyl acetate. The residue was purified by silica gel chromatography to give 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylic acid methyl ester (650 mg, 3.05 mmol, 45% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6, ppm): δ3.74(s,3H),3.71-3.63(m,6H),3.53-3.49(m,2H),1.53-1.48(m,2H),1.36-1.32(m,2H).

[0202] Step 3: 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylic acid methyl ester (650 mg, 3.05 mmol) was dissolved in THF (13 mL) and LAH (289.25 mg, 7.62 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Purified water was slowly added to quench the reaction, and a saturated aqueous NaOH solution was added. The reaction mixture was filtered and the filtrate was concentrated. (1-(morpholinomethyl)cyclopropyl)methanol (520 mg, crude mixture) was obtained as a yellow oil. 1 H NMR (400MHz, DMSO-d6, ppm): δ3.75-3.69(m,4H), 3.58-3.52(m,2H), 2.75-2.53(m,4H), 2.51-2.43(m,2H), 0.55-0.49(m,2H), 0.40-0.34(m,2H).

[0203] Intermediate 7: (R)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol.

[0204]

[0205] Synthesis was performed in the same manner as Intermediate 6 using (R)-3-methylmorpholine to give (R)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol (843 mg, 70% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6, ppm): δ0.18-0.25(m,1H),0.26-0.34(m,1H),0.47-0.54(m,1H),0.73(dt,J=9. 2,4.8Hz,1H),1.06(d,J=6.0Hz,3H),1.76-1.85(m,1H),2.25-2.32(m,1H),2.41-2.51(m,1H),3.12(br d,J=11.2Hz,1H),3.19-3.40(m,3H),3.59-3.74(m,3H),3.80(dt,J=11.6,3.2Hz,1H),3.96(brd,J=11.2Hz,1H).

[0206] Intermediate 8: Synthesis of (1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol.

[0207]

[0208] The synthesis was carried out in the same manner as Intermediate 6 using 1,1-difluoro-6-azaspiro[2.5]octane to give (1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol (820 mg, crude mixture) as a yellow oil. 1 H NMR (400MHz, DMSO-d6, ppm): δ3.64-3.62(m,2H),3.57-3.54(m,2H),2.82-2.68(m ,2H),2.54-2.40(m,4H),1.09-1.03(m,2H),0.54-0.52(m,4H),0.39-0.35(m,2H).

[0209] Intermediate 9: Synthesis of (1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methanol.

[0210]

[0211] The synthesis was carried out in the same manner as Intermediate 6 using (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane to give (1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methanol (470 mg, crude mixture) as a yellow oil.1 H NMR (400MHz, CDCl3, ppm): δ4.41 (s, 1H), 3.95 (d, J = 8.0Hz, 1H), 3.69-3.80 (m, 2H), 3.64 (dd, J = 8.0, 1.6Hz, 1H), 3.39 (d, J = 11.2Hz, 1H), 3.06 (d d,J=10.4,1.6Hz,1H),2.90(d,J=12.6Hz,1H),2.55-2.64(m,2H),1.73 -1.82(m,2H),0.51-0.60(m,1H),0.41-0.49(m,2H),0.25-0.35(m,1H).

[0212] Intermediate 10: Synthesis of (R)-(1-((2-methylmorpholino)methyl)cyclopropyl)methanol.

[0213]

[0214] The synthesis was carried out in the same manner as Intermediate 6 using (R)-2-methylmorpholine to give (R)-(1-((2-methylmorpholino)methyl)cyclopropyl)methanol (760 mg, crude mixture) as a yellow oil. 1 H NMR (400MHz, CDCl3, ppm): δ5.97-4.68(m,1H),3.92-3.83(m,1H),3.69-3.59(m,2H),3.57-3.52(m,2H),3.09-2.95(m, 2H),2.51-2.43(m,2H),2.16-2.04(m,1H),1.82-1.73(m,1H),1.20-1.13(m,3H),0.55-0.50(m,2H),0.40-0.34(m,2H).

[0215] Intermediate 11: (1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methanol.

[0216]

[0217] Synthesis was performed in the same manner as Intermediate 6 using (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane to obtain (1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methanol (542 mg, crude mixture) as a yellow oil. LCMS (ES-API, m / z): [M+H] + =200.2.

[0218] Intermediate 12: (S)-(1-((3-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol.

[0219]

[0220] Synthesis was performed in the same manner as Intermediate 6 using (S)-3-fluoropiperidine to give (S)-(1-((3-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol (352 mg, crude mixture) as a colorless oil. LCMS (ES-API, m / z): [M+H] + =174.2; 1 H NMR (400MHz, CDCl3, ppm): δ5.52-4.95(m,1H),4.77-4.56(m,1H),3.63(d,J=11.2Hz,1H),3.46(d,J=11.2Hz,1H),2.90-2.64(m,2H),2.58(br d,J=12.4Hz,2H),2.51-2.36(m,2H),1.94-1.75(m,2H),1.73-1.66(m,1H),1.55(br dd,J=3.6,8.4Hz,1H),0.60-0.48(m,2H),0.40-0.31(m,2H).

[0221] Intermediate 13: Synthesis of (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol.

[0222]

[0223] Synthesis was performed using pyrrolidine in the same manner as Intermediate 6 to obtain (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (328 mg, 2.11 mmol, 67% yield) as a yellow oil. LCMS (ES-API, m / z): [M+H] + =174.2; 1 HNMR (400MHz, CDCl3, ppm): δ6.25-5.82(m,1H),3.56(s,2H),2.65-2.58(m,6H),1.77(td,J=3.2,6.8Hz,4H),0.52-0.47(m,2H),0.40-0.34(m,2H).

[0224] Intermediate 14: Synthesis of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol.

[0225]

[0226] Synthesis was performed using (R)-3-fluoropyrrolidine in the same manner as Intermediate 6 to give (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (837 mg, crude mixture) as a colorless oil. LCMS (ES-API, m / z): [M+H] + =174.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ0.19-0.26(m,2H),0.33-0.43(m,2H),1.74-1.92(m,1H),1.99-2. 19(m,1H),2.21-2.36(m,2H),2.39-2.45(m,1H),2.51-2.63(m,1H),2.73-2.90(m,2H),3.28(br s,1H),3.32-3.50(m,1H),4.47(br s,1H),5.01-5.29(m,1H).

[0227] Intermediate 15: Synthesis of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methanol.

[0228]

[0229] Synthesis was performed in the same manner as Intermediate 6 using (R)-3-fluoropyrrolidine to give (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methanol (1.8 g, crude mixture) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ5.82-4.99(m,2H),3.80(s,2H),3.03-2.66(m,5H),2.59-2.47(m,1H),2.18-1.92(m,3H),1.90-1.77(m,5H).

[0230] Intermediate 16: Synthesis of ((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol.

[0231]

[0232] Step 1: 1-tert-Butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.5 g, 10.19 mmol) was dissolved in DCM (25 mL), imidazole (1.73 g, 25.48 mmol) was added, and the mixture was stirred at 0 ° C for 10 minutes. Then, TBSCl (1.84 g, 12.23 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the product was purified by silica gel chromatography to obtain 1-tert-Butyl 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.68 g, 7.31 mmol, 72% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6, ppm): δ4.38 (br dd,J=3.6,8.4Hz,1H),4.32-4.22(m,1H),3.66-3.56(m,3H),3.55-3.46(m,1H),3.15-3.05(m,1H ),2.42-2.25(m,1H),1.92-1.82(m,1H),1.43-1.31(m,9H),0.84-0.79(m,9H),0.08–0.04(m,6H).

[0233] Step 2: 1-tert-Butyl 2-methyl (2R, 4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.18 g, 6.06 mmol) was dissolved in THF (21 mL) and LiHMDS (1 M, 12.13 mL) was added at -78 ° C under nitrogen. The reaction mixture was stirred at -78 ° C for 15 minutes. Then, 3-chloro-2-(chloromethyl)prop-1-ene (1.89 g, 15.16 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. After completion of the reaction, the product was purified by silica gel chromatography to obtain 1-tert-Butyl 2-methyl (2R, 4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (2.62 g, 5.55 mmol, 91% yield) as a yellow oil. 1H NMR (400MHz, CDCl3, ppm): δ5.41 (d, J = 1.2Hz, 1H), 5.16-5.06 (m, 1H), 4.49-4.20 (m, 1H), 4.14-4.00 (m, 2H), 3.78-3.69 (m, 3H), 3.69-3.53 (m ,1H),3.37-3.01(m,2H),2.83-2.60(m,1H),2.36-2.17(m,1H),2.16- 2.06(m,1H),1.50-1.39(m,9H),0.91-0.83(m,9H),0.09-0.00(m,6H).

[0234] Step 3: 1-tert-Butyl 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (4 g, 8.93 mmol) was dissolved in THF (40 mL), TBAF·3H2O (1 M, 10.71 mL) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was purified by silica gel chromatography to obtain 1-tert-butyl 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 7.82 mmol, 88% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3, ppm): δ5.42(s,1H),5.06(s,1H),4.17-4.27(m,1H),4.04-3.93(m,2H),3.92-3.73(m,4H),3.5 7(d,J=10.8Hz,1H),3.44-3.24(m,2H),2.60(t,J=13.6Hz,1H),2.53-2.37(m,1H),2.15-2.03(m,2H),1.47(s,9H).

[0235] Step 4: Dissolve 1-tert-butyl 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 8.69 mmol) in DCM (30 mL) and slowly add BAST (2.88 g, 13.03 mmol, 2.85 mL) dropwise at -78°C. The reaction mixture is stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture is purified by silica gel chromatography to afford 1-tert-butyl 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.82 g, 4.88 mmol, 56% yield) as a light yellow oil. 1H NMR (400MHz, CDCl3, ppm): δ5.45-5.32(m,1H),5.30-5.05(m,2H),4.18-4.11(m,2H),4.07-3.74(m, 2H),3.74-3.64(m,3H),3.38-3.15(m,1H),2.85(d,J=14.4Hz,1H),2.67-2.23(m,2H),1.46(s,9H).

[0236] Step 5: 1-tert-Butyl 2-methyl (2R, 4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.8 g, 5.36 mmol) was dissolved in DCM (15 mL) and TFA (7.68 g, 67.31 mmol, 5 mL) was slowly added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the starting material, 7M NH4 in MeOH was added. The reaction was quenched by adding water and extracted with DCM. The compound was purified by silica gel chromatography to give (2S, 7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (950 mg, 4.29 mmol, 80% yield) as a light yellow oil. LCMS (ES-API, m / z): [M + H] + =236.0; 1 H NMR (400MHz, CDCl3, ppm): δ5.38-5.13(m,1H),4.94(dt,J=14.8,2.0Hz,2H),3.89(br d,J=13.6Hz,1H),3.73(s,3H),3.56(br d,J=14.0Hz,1H),3.46-3.27(m,1H),3.22-3.00(m,2H),2.76(br d,J=16.0Hz,1H),2.64-2.54(m,1H),2.38-2.21(m,1H).

[0237] Step 6: Methyl (2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (940 mg, 4.72 mmol) was dissolved in THF (10 mL). LAH (2.5 M, 1.89 mL) was added at 0°C under nitrogen, and the mixture was stirred at room temperature for 2 hours. When the starting material was consumed, the reaction was quenched with water and 15% aqueous NaOH. ((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (720 mg, 3.78 mmol, 80% yield) was obtained as a white oil. 1H NMR (400MHz, CDCl3, ppm): δ5.33-5.10(m,1H),4.97-4.85(m,2H),3.72(br d,J=14.0Hz,1H),3.53(br d,J=14.0Hz,1H),3.34-3.02(m,4H),2.68(br d,J=15.6Hz,1H),2.36(dt,J=15.6,1.60Hz,1H),2.25-2.18(m,1H),2.17-2.02(m,2H).

[0238] Intermediate 17: Synthesis of ((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol.

[0239]

[0240] Steps 1, 2: (S)-2-methyl 1-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate (40 g, 164.44 mmol) was dissolved in DCM (600 mL). DIBAL-H (1 M, 500 mL) was slowly added dropwise at -68°C and stirred for 30 minutes. The mixture was then allowed to react at room temperature for 2 hours. MeOH (200 mL) and HCl solution (2 M, 180 mL) were added at 0°C under nitrogen and stirred at 20°C for 2 hours. After completion of the reaction, 10% potassium sodium tartrate (500 mL) was added to the reaction mixture to terminate the reaction. Ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO₄. The reaction residue was separated by silica gel chromatography to obtain tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-1-carboxylate (19 g, 82.15 mmol, 50% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3, ppm): δ5.17(brs,1H),4.03–4.06(m,1H),3.75–3.77(m,1H ),3.52–3.56(m,1H),3.48(s,1H),3.33(s,3H),1.77–2.05(m,5H),1.49(s,9H).

[0241] Step 3: To tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-1-carboxylate (19 g, 82.15 mmol) was added a solution of NaH (6.58 g, 164.44 mmol) in DMF (190 mL) at 0°C and stirred for 15 minutes. Then, MeI (23.32 g, 164.30 mmol, 10.23 mL) was added at 0°C and stirred at 20°C for 2 hours. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer and dried over anhydrous MgSO4. The product was purified by silica gel chromatography to obtain tert-butyl (5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylate (10.7 g, 43.62 mmol, 53% yield) as a yellow oil. 1 HNMR (400MHz, CDCl3, ppm): δ5.21(brs,1H),3.97(brs,1H),3.75(brs,1H),3 .38(s,3H),3.30(s,3H),2.07–2.18(m,1H),1.71–2.01(m,3H),1.49(s,9H).

[0242] Step 4: (5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (10.7 g, 43.62 mmol) was dissolved in DCM (100 mL), TMSOTf (969.44 mg, 4.36 mmol) was added dropwise at 0 ° C and stirred for 15 minutes. TMSCN (6.49 g, 65.43 mmol, 8.19 mL) was slowly added dropwise and reacted at 0 ° C for 2 hours. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The product was purified by silica gel chromatography to obtain (5S)-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.3 g, 26.22 mmol, 60% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3, ppm): δ4.39–4.59(m,1H),3.89–4.10(m,1H),3.55–3.63(m,0.5H) ,3.41–3.52(m,1.3H),3.39(s,1.4H),3.33(s,1.5H),2.04–2.17(m,4H),1.51(s,9H).

[0243] Step 5: To HCl / MeOH (2M, 30.00 mL) was added tert-butyl (5S)-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylate (3 g, 12.48 mmol) and allowed to react at 20°C for 12 hours. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. After removal of the solvent, methyl (5S)-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol, 69% yield) was obtained as a yellow oil. 1 HNMR (400MHz, CDCl3, ppm): δ3.72–3.85(m,1H),3.72(s,3H),3.37–3.38(m,1H),3.35 (s,3H),3.29–3.33(m,1H),2.01–2.19(m,2H),1.86–1.91(m,2H),1.47–1.53(m,1H).

[0244] Step 6: Methyl (5S)-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol) and Boc2O (1.89 g, 8.66 mmol) were dissolved in MeOH (30 mL) and reacted at 20°C for 12 hours. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The product was purified to obtain 1-tert-butyl 2-methyl (5S)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2 g, 7.32 mmol, 84% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3, ppm): δ4.30–4.33(m,0.7H),4.25–4.27(s,1H),3.71–3.73(m,3H),3.38– 3.43(m,1H),3.35(d,J=12Hz,3H),3.29–3.34(m,0.5H),1.88–2.02(m,4H),1.40–1.47(m,9H).

[0245] Step 7: 1-tert-Butyl 2-methyl (5S)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.4 g, 8.78 mmol) was dissolved in THF (24 mL) and LiHMDS (1 M, 17.56 mL) was stirred at -68°C for 0.5 hours. (2.2 g, 17.56 mmol, 2.04 mL) was added to the reaction, and the reaction was allowed to proceed at room temperature for 12 hours. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The product was purified to obtain 1-tert-Butyl 2-methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (1.2 g, 2.95 mmol, 34% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3, ppm): δ5.34–5.43(m,1H),5.05–5.12(m,1H),4.01–4.11(m,3.4H),3.73(s,3H),3.3 7(s,3H),3.27–3.35(m,2H),3.11–3.25(m,1H),2.62–2.77(m,1H),1.81–2.28(m,4H),1.40–1.52(m,9H).

[0246] Step 8: 1-tert-Butyl 2-methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (600 mg, 1.66 mmol) was dissolved in DCM (6 mL), TFA (2.4 mL) was added at 0°C, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to give methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-2-carboxylate (434 mg, crude mixture) as a brown oil. LCMS (ES-API, m / z): [M+H] + =490.2.

[0247] Step 9: Methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-2-carboxylate (434 mg, 1.66 mmol) and K2CO3 (458.32 mg, 3.32 mmol) were dissolved in MeOH (6 mL) and stirred at room temperature for 3 hours. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The product was purified to give methyl (5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (180 mg, 798.99 μmol, 48% yield) as a yellow oil. LCMS (ES-API, m / z): [M+H] + =226.0; 1 H NMR (400MHz, DMSO-d6, ppm): δ4.88 (br d, J=10.4Hz, 2H), 3.58 (s, 3H), 3.53 (br d,J=14.8Hz,1H),3.31-3.28(m,1H),3.27-3.24(m,1H),3.23(s,3H),3.21-3.16(m,1H),2.78(s,2H),2.39(br dd,J=1.2,16.0Hz,1H),2.32-2.24(m,1H),1.99-1.88(m,1H),1.76-1.66(m,1H),1.44(br d,J=9.2Hz,1H).

[0248] Step 10: Methyl (5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (234 mg, 1.04 mmol) was dissolved in THF (2.5 mL). LiAlH (2.5 M, 415.48 μL) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction. Ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO. After removal of the solvent, ((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (190 mg, 963.13 μmol, 93% yield) was obtained as a yellow oil.

[0249] Intermediate 18: Synthesis of 6-fluoro-4-methyl-5-((triisopropylsilyl)ethynyl)naphthalene-2-amine.

[0250]

[0251] Step 1: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (2.5 g, 6.97 mmol) was dissolved in DCM (17.5 mL) and then diethylamine (3.60 g, 27.89 mmol) and Tf2O (4.13 g, 14.64 mmol) were added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C for 3 hours under nitrogen. The reaction was quenched by adding purified water and the reaction mixture was extracted with DCM. Purification was performed by silica gel chromatography to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate) (3.95 g, 6.34 mmol, 91% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.55 (d, J = 2.4Hz, 1H), 8.42-8.33 (m, 1H), 8.16-8.08 (m, 1H), 7.91-7.82 (m, 1H), 1.20-1.16 (m, 3H), 1.15-1.07 (m, 18H).

[0252] Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate (4.6 g, 7.39 mmol) and diphenylmethaneimine (1.34 g, 7.39 mmol, 1.24 mL) obtained in step 1 were dissolved in toluene (46 mL) and purged with nitrogen three times. Then, the mixture was stirred at 100 ° C. under nitrogen for 12 hours. After completion of the reaction, purified water was added and extracted several times with ethyl acetate. Silica gel chromatography was performed to obtain 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (3.5 g, 5.35 mmol, yield 72%) as a brown solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ7.96-7.90(m,1H),7.75-7.67(m,3H),7.54(brs,4H),7.41-7.39(m,1H),7.32-7.28(m,3H),7.23-7.19(m,2H),1.13(br s,21H).

[0253] Step 3: 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3 g, 4.59 mmol) obtained in Step 2 was dissolved in THF (30 mL), and HCl (1 M, 30.00 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the product was purified by silica gel chromatography to give 3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.78 g, 3.35 mmol, 73% yield). LCMS (ES-API, m / z): [M+H] + =490.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ7.81-7.72(m,1H),7.45-7.34(m,1H),7.23-7.15(m,1H),7.05-6.96(m,1H),6.01-5.90(m,2H),1.18-1.08(m,21H).

[0254] Step 4: 3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl trifluoromethanesulfonate (800 mg, 1.63 mmol) obtained in step 3 was dissolved in toluene together with BPD (829.87 mg, 3.27 mmol), potassium acetate (320.72 mg, 3.27 mmol) and Pd(dppf)Cl2 (119.56 mg, 163.40 μmol). Then, three nitrogen purges were performed. The reaction mixture was stirred at 110 ° C under nitrogen for 12 hours. After purification by silica gel chromatography, 6-fluoro-4-methyl-5-((triisopropylsilyl)ethynyl)naphthalene-2-amine (360 mg, 671.26 μmol, 41% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M + H] + =468.5; 1 H NMR (400MHz, DMSO-d6, ppm): δ7.63 (dd, J=6.0, 9.0Hz, 1H), 7.33-7.24 (m, 1H), 7.23-7.1 9(m,1H),6.91-6.85(m,1H),5.54-5.44(m,2H),1.36-1.29(m,12H),1.13-1.07(m,21H).

[0255] Intermediate 19: Synthesis of (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic acid.

[0256]

[0257] Step 1: 4-bromo-7-fluorobenzo[d]thiazol-2-amine (450 mg, 1.82 mmol) was dissolved in THF (9 mL), followed by the addition of Boc2O (476.97 mg, 2.19 mmol), diethylamine (353.07 mg, 2.73 mmol) and DMAP (4.45 mg, 36.42 μmol), and the mixture was purged with nitrogen three times. The reaction mixture was stirred for 2 hours, concentrated, and purified by silica gel chromatography to afford tert-butyl (4-bromo-7-fluorobenzo[d]thiazol-2-yl)carbamate (500 mg, 1.40 mmol, 77% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =313.2; 1 H NMR (400MHz, CDCl3, ppm): δ8.99-8.52(m,1H),7.55(dd,J=4.8,8.6Hz,1H),6.91(t,J=8.6Hz,1H),1.56(s,8H),1.50-1.47(m,1H).

[0258] Step 2: Dissolve the compound obtained in Step 1, tert-butyl (4-bromo-7-fluorobenzo[d]thiazol-2-yl)carbamate (250 mg, 720.04 μmol) in THF (2 mL). Add n-BuLi (2.5 M in THF, 351.38 μL) dropwise at -15°C and stir for 30 minutes. Add triisopropyl borate (338.55 mg, 1.80 mmol) at -65°C and stir for 30 minutes. Then, add MeLi (1.6 M, 540.03 μL) at -65°C and purge with nitrogen three times. The reaction mixture is allowed to react at 0°C under nitrogen for 1 hour. After completion of the reaction, add NH4Cl solution and ethyl acetate to extract the compound. Na2SO4 was added for drying, and water and solvent were removed under reduced pressure to give (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic acid (220 mg, crude mixture) as a white solid. LCMS (ES-API, m / z): [M+H] + =256.9; 1 H NMR (400MHz, CDCl3, ppm): δ7.94 (dd, J=6.0, 8.1Hz, 1H), 7.06 (dd, J=8.1, 9.5Hz, 1H), 1.68 (s, 9H).

[0259] Intermediate 20: Synthesis of tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate.

[0260]

[0261] Step 1: 4-Bromobenzo[d]thiazol-2-amine (1 g, 4.36 mmol) was dissolved in THF (4 mL) and DCM (6 mL) and the temperature was lowered to 0°C. Di-tert-butyl dicarbonate (1.1 mL, 4.8 mmol), TEA (1.16 mL, 8.73 mmol) and DMAP (53.3 mg, 436 μmol) were added at 0°C and stirred for 2 hours. After the starting material was completely consumed, the reaction was quenched by the addition of water and the organic layer was extracted with ethyl acetate. After drying over anhydrous Na2SO4, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate / hexane) to give tert-butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (1.2 g, 3.65 mmol, 84% yield). LCMS (ES-API, m / z): [M+H] + =330.2.

[0262] Step 2: Dissolve tert-butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (1.2 g, 3.65 mmol) obtained in Step 1 in 1,4-dioxane (10 mL). Then add potassium acetate (1.07 g, 10.9 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.85 g, 7.29 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM complex (267 mg, 365 μmol). The temperature was raised to 100°C and stirred for 24 hours. After completion of the reaction, the reaction temperature was lowered to room temperature. After removing the palladium catalyst through a Celite filter, the organic layer was extracted with ethyl acetate. After drying over anhydrous NaSO, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate / hexane) to give tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (1.2 g, 3.19 mmol, 88% yield). LCMS (ES-API, m / z): [M+H] + =376.7.

[0263] Intermediate 21: Synthesis of (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid.

[0264]

[0265] Step 1: Dissolve 1-bromo-5-fluoro-2-iodo-3-methylbenzene (3 g, 9.53 mmol) in DMF (60 mL), and add CuI (10.89 g, 57.16 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (10.98 g, 57.16 mmol, 7.27 mL). The reaction mixture was stirred at 60°C for 12 hours. After completion of the reaction, purified water (60 mL) was added dropwise to the reaction mixture, and ethyl acetate (60 mL*3) was added to extract the organic layer, which was washed with saturated aqueous NaCl (150 mL*2) and then dried over anhydrous MgSO4. The resulting reaction residue was purified by silica gel chromatography to yield 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.1 g, 4.28 mmol, 45% yield). 1 H NMR (400MHz, CDCl3, ppm): δ7.33 (dd, J=2.4, 7.6Hz, 1H), 6.95 (dd, J=2.4, 8.8Hz, 1H), 2.54 (q, J=3.6Hz, 3H).

[0266] Step 2: 1-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.7 g, 6.61 mmol) was dissolved in THF (34 mL), and LDA (2 M, 6.61 mL) was slowly added dropwise at -60 ° C under nitrogen and stirred for 30 minutes. DMF (1.45 g, 19.84 mmol, 1.53 mL) was added dropwise to the reaction mixture and stirred at -60 ° C for 1.5 hours. After the reaction was completed, saturated NH4Cl aqueous solution (40 mL) was added dropwise to the reaction mixture, and ethyl acetate (40 mL * 3) was added to extract the organic layer, washed with saturated NaCl aqueous solution (100 mL * 2), and dried over anhydrous MgSO4. The resulting reaction residue was purified by silica gel chromatography to obtain 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (860 mg, 3.02 mmol, 46% yield) as a yellow oil. 1 HNMR (400MHz, CDCl3, ppm): δ10.35 (s, 1H), 7.08 (d, J = 10.5Hz, 1H), 2.61 (q, J = 4.0Hz, 3H).

[0267] Step 3: 2-Bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (860 mg, 3.02 mmol) and NH2NH2·H2O (4.43 g, 86.72 mmol, 4.29 mL) were dissolved in DMSO (9 mL), and then purged with nitrogen three times. The reaction mixture was allowed to react at 60 ° C for 2 hours. After the reaction was completed, purified water (20 mL) was added dropwise to the reaction mixture, and ethyl acetate (20 mL * 3) was added to extract the organic layer, which was washed with saturated NaCl aqueous solution (30 mL * 2) and dried over anhydrous MgSO4. The resulting reaction residue was purified by silica gel chromatography to obtain 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (618 mg, 2.21 mmol, yield 73%) as a yellow oil. LCMS (ES-API, m / z): [M + H] + =278.9; 1 H NMR (400MHz, CDCl3, ppm): δ8.20 (s, 1H), 7.34 (s, 1H), 2.66 (q, J = 3.2Hz, 3H).

[0268] Step 4: 4-Bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (618 mg, 2.21 mmol) was dissolved in DCM (12 mL), followed by the addition of TsOH·H₂O (42.13 mg, 221.46 μmol) and a solution of DHP (745.14 mg, 8.86 mmol) in acetonitrile (3 mL). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, purified water (60 mL) was added dropwise to the reaction mixture, and ethyl acetate (20 mL*3) was added to extract the organic layer, which was washed with saturated aqueous NaCl (30 mL*2) and then dried over anhydrous MgSO₄. The resulting reaction residue was purified by silica gel chromatography to afford 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (800 mg, 2.20 mmol, 99% yield) as a light yellow oil. 1 H NMR (400MHz, CDCl3, ppm): δ8.11 (s, 1H), 7.43 (s, 1H), 5.69 (dd, J = 2.8, 8.8Hz, 1H), 4.05-3.96 (m, 1H), 3.81-3. 70(m,1H),2.67(q,J=3.2Hz,3H),2.57-2.46(m,1H),2.23-2.12(m,1H),1.78-1.67(m,3H),1.59-1.54(m,1H).

[0269] Step 5: Dissolve diboric acid (185.14 mg, 2.07 mmol), 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (250 mg, 688.38 μmol), and cataCXium Pd G4 (50.20 mg, 68.84 μmol) in MeOH (3 mL), and slowly add DIEA (266.90 mg, 2.07 mmol) dropwise under nitrogen. After degassing with nitrogen for 10 minutes, it was stirred at 60 ° C for 40 minutes. After the reaction was completed, the solvent was removed under reduced pressure to give (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (210 mg, crude mixture) as a black solid. LCMS (ES-API, m / z): [M + H] + =245.1.

[0270] Intermediate 22: Synthesis of (5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid.

[0271]

[0272] Step 1: 4-bromo-5-chloro-6-methyl-1H-indazole (2 g, 8.15 mmol) was dissolved in MeOH (25 mL), and then NaOH (4 M, 13.24 mL) and I2 (2.48 g, 9.78 mmol, 1.97 mL) were added dropwise at 0 ° C. It was stirred at room temperature for 2 hours under nitrogen. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. Purification by silica gel chromatography gave 4-bromo-5-chloro-3-iodo-6-methyl-1H-indazole (2.9 g, 7.73 mmol, yield 95%) as a white solid. LCMS (ES-API, m / z): [M + H] + =372.8; 1 HNMR (400MHz, DMSO-d6, ppm): δ14.24-13.32(m,1H),7.60(s,1H),2.50(s,3H).

[0273] Step 2: 4-bromo-5-chloro-3-iodo-6-methyl-1H-indazole (200 mg, 538.50 μmol), p-TsOH (4.64 mg, 26.93 μmol), DHP (90.59 mg, 1.08 mmol) were dissolved in DCM (2.5 mL), degassed and purged with nitrogen three times, and stirred at room temperature under nitrogen for 2 hours. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO4. Trituration with ethyl acetate gave 4-bromo-5-chloro-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (120 mg, 252.90 μmol, yield 47%) as a white solid. LCMS (ES-API, m / z): [M+H] + =454.9; 1 H NMR (400MHz, DMSO-d6, ppm): δ7.88(d,J=0.6Hz,1H),5.83(dd,J=2.5,9.8Hz,1H),3.93-3.82(m,1H),3.74(td, J=6.9,11.5Hz,1H),2.54(s,3H),2.41-2.21(m,1H),2.10-1.90(m,2H),1.81-1.64(m,1H),1.64-1.49(m,2H).

[0274] Step 3: 4-bromo-5-chloro-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 2.20 mmol) and Pd(dppf)Cl2·CH2Cl2 (89.64 mg, 109.77 μmol) were dissolved in DMF (10 mL), dimethylzinc (1 M, 5.49 mL) was added under nitrogen, and stirred at 80 ° C for 12 hours. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO4. The reaction residue was purified by silica gel chromatography to obtain 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 931.19 μmol, yield 42%) as a white solid. LCMS (ES-API, m / z): [M+H] + =260.8; 1H NMR (400MHz, CDCl3, ppm): δ7.34(s,1H),5.55(dd,J=2.4,9.6Hz,1H),4.10-3.99(m,1H),3.73(dt,J=2.4,11.2Hz,1H),2.74(s, 3H),2.55(s,3H),2.54-2.46(m,1H),2.20-2.10(m,1H),2.01(brdd,J=3.2,12.8Hz,1H),1.82-1.70(m,2H),1.69-1.62(m,1H).

[0275] Step 4: 4-Bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 651.83 μmol), diboric acid (175.31 mg, 1.96 mmol), DIEA (252.73 mg, 1.96 mmol), and cataCXium PdG4 (47.54 mg, 65.18 μmol) were dissolved in MeOH (4 mL), degassed and purged with nitrogen three times, and then stirred at 60° C. for 40 minutes. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The reaction residue was purified by silica gel chromatography to obtain (5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (200 mg, 582.04 μmol, 89% yield) as a black solid. LCMS (ES-API, m / z): [M+H] + =309.0; 1 H NMR (400MHz, CDCl3, ppm): δ7.36 (s, 1H), 5.55 (dd, J = 2.4, 9.7Hz, 1H), 5.33-5.12 (m, 1H), 4.09-4.02 (m,1H),3.77-3.72(m,1H),3.70(s,1H),2.53(s,3H),2.50-2.49(m,3H),2.18-2.10(m,1H),2.01(br d,J=13.2Hz,2H),1.81-1.71(m,3H).

[0276] Intermediate 23: Synthesis of N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine.

[0277]

[0278] Step 1: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (110.67 mg, 190.78 μmol) and Su2Bu6 (110.67 mg, 190.78 μmol) were dissolved in 1,4-dioxane (1 mL), and Pd2(dba)3 (5.55 mg, 6.06 μmol), tricyclohexylphosphane (3.40 mg, 12.11 μmol), and LiCl (12.84 mg, 302.83 μmol) were added. The reaction mixture was stirred at 110°C for 16 hours. After the reaction was complete, silica gel chromatography was performed to purify the product to give N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (25 mg, 32.25 μmol, 53.24% yield) as a colorless oil. LCMS (ES-API, m / z): [M+H] + =705.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ0.76 (t, J=7.2Hz, 9H), 0.87 (br t,J=7.2Hz,2H),0.96-1.03(m,5H),1.14-1.22(m,6H),1.39-1.47(m,5H),2.24(s,3H),3.71(s,6H),4.72(br s, 4H), 6.48 (s, 1H), 6.86 (d, J = 8.4Hz, 4H), 7.12 (d, J = 8.4Hz, 4H).

[0279] Intermediate 24: Synthesis of N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine.

[0280]

[0281] Step 1: Dissolve 6-bromo-5-(trifluoromethyl)pyridin-2-amine (700 mg, 2.9 mmol) in DMF (10 mL) and cool to 0°C. Add sodium hydride (290 mg, 7.26 mmol) and stir at 0°C for 30 minutes. After 30 minutes, add 4-methoxybenzyl chloride (1.07 mL, 7.26 mmol) to the reaction mixture and stir at room temperature for 4 hours. After the reaction is complete, the temperature is lowered to 0°C, water is slowly added to quench the reaction, and the organic layer is extracted with ethyl acetate. After drying over anhydrous MgSO4, the mixture is concentrated under reduced pressure. The residue is purified by silica gel chromatography to give 6-bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (1.1 g, 2.29 mmol, 79% yield). LCMS (ES-API, m / z): [M+H]+ =481.3.

[0282] Step 2: 6-Bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (1.1 g, 2.29 mmol) obtained in Step 1 was dissolved in 1,4-dioxane (10 mL), followed by the addition of tricyclohexylphosphane (128 mg, 457 μmol), bis(tributylstannane) (3.48 mL, 6.86 mmol), tris(dibenzylideneacetone)dipalladium(0) (209 mg, 229 μmol), and lithium chloride (484 mg, 11.4 mmol). The mixture was heated to 110°C and stirred for 5 hours. After the reaction was complete, the temperature was lowered to room temperature. After removing the palladium catalyst using a celite filter, the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (160 mg, 231 mmol, 10% yield). LCMS (ES-API, m / z): [M+H] + =692.5.

[0283] Intermediate 25: Synthesis of N,N-bis(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine.

[0284]

[0285] Step 1: Dissolve 3-bromo-4-(trifluoromethyl)aniline (500 mg, 2.08 mmol) in DMF (10 mL) and cool to 0°C. Add NaH (416 mg, 10.41 mmol) at 0°C and stir the mixture for 30 minutes. After 30 minutes, add 4-methoxybenzyl chloride (1.4 mL, 10.41 mmol) to the reaction mixture, and stir at room temperature for 24 hours. After completion of the reaction, lower the reaction temperature to 0°C, slowly add water to quench the reaction, and extract the organic layer with ethyl acetate. After drying over anhydrous NaSO, concentrate under reduced pressure. The residue is purified by silica gel chromatography (5% ethyl acetate / hexane) to yield 3-bromo-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline (816 mg, 1.7 mmol, 85% yield). LCMS (ES-API, m / z): [M+H] + =481.3.

[0286] Step 2: 3-Bromo-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline (160 mg, 333 μmol) obtained in Step 1 was dissolved in 1,4-dioxane (2 mL). Potassium acetate (98.1 mg, 999 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (102 mg, 400 μmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complexed with dichloromethane (24.4 mg, 33.3 μmol)) were added. The temperature was raised to 90°C and stirred for 24 hours. After complete consumption of the starting material, the reaction temperature was lowered to room temperature. After removing the palladium catalyst through a Celite filter, the organic layer was extracted with ethyl acetate. After drying over anhydrous MgSO4, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N,N-bis(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (175 mg, 333 mmol, 100% yield). LCMS (ES-API, m / z): [M+H] + =528.4.

[0287] Intermediate 26: Synthesis of 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0288]

[0289] Step 1: Dissolve 2,3,4,5-tetrafluoroaniline (5 g, 30.3 mmol) in acetonitrile (20 mL). Add NBS (5.93 mg, 33.3 mmol) at room temperature and stir the mixture at 60°C for 2 hours. Cool the reaction temperature to room temperature and quench with saturated aqueous sodium thiosulfate, followed by extraction with ethyl acetate. Purify by silica gel chromatography to obtain 2-bromo-3,4,5,6-tetrafluoroaniline (5.5 g, 22.5 mmol, 74% yield) as a brown solid. 1 H NMR (400MHz, CDCl3, ppm): δ4.27-4.15 (m, 2H).

[0290] Step 2: 2-bromo-3,4,5,6-tetrafluoroaniline (0.5 g, 2.05 mmol), B2pin2 (1.30 g, 5.12 mmol), Pd(dppf)Cl2 (149.95 mg, 204.93 μmol), potassium acetate (402.25 mg, 4.10 mmol) obtained in step 1 were added to 1,4-dioxane (5 mL) and purged with nitrogen three times. The mixture was then allowed to react at 100 ° C for 2 hours under nitrogen. After purification by silica gel chromatography, 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 628.59 μmol, yield 31%) was obtained as a white solid. LCMS (ES-API, m / z): [M + H] + =210.0; 1 H NMR (400MHz, DMSO-d6, ppm): δ1.19-1.15 (m, 12H).

[0291] Example 1: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0292]

[0293] Step 1: Dissolve 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2.4 g, 7.55 mmol) in DCM (48 mL), then add N,N-diisopropylamine (1.46 g, 11.32 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.92 g, 9.06 mmol), and stir the reaction mixture at 25°C for 1 hour. Dilute the reaction mixture with purified water (80 mL) and extract with DCM (50 mL*3). Wash the organic material with aqueous NaCl (50 mL*2), dry over Na2SO4, filter, and concentrate to obtain a residue. Stir the product with petroleum ether (50 mL) and EA (20 mL) at 25°C for 30 minutes, then filter the solid and dry. Tert-butyl (1R,5S)-3-(6-bromo-3-chloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.44 g, 0.63 mmol, 88% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H]+ =494.1; 1 HNMR (400MHz, DMSO-d6, ppm): δ8.28(s,1H),7.82-7.69(m,2H),4.17-4.09(m,2H),3.84- 3.70(m,2H),3.65-3.51(m,2H),1.71-1.60(m,2H),1.58-1.49(m,2H),1.48-1.43(m,9H).

[0294] Step 2: tert-Butyl (1R,5S)-3-(6-bromo-3-chloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.44 g, 4.94 mmol) obtained in Step 1 was dissolved in THF (45 mL), and then NaH (395.28 mg, 9.88 mmol) was added at 0°C. The reaction mixture was heated at room temperature for 30 minutes, and then a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (865.35 mg, 5.44 mmol) dissolved in THF (5 mL) was added. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Purified water was added to the reaction mixture, and extraction was performed with ethyl acetate (50 mL*3). The combined organic layers were washed with a NaCl aqueous solution (40 mL * 2) and dried over Na2SO4. The filtered solution was concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (0.1% FA conditions). (1R, 5S) -3- (4- bromo -7- (((2R, 7aS) -2-fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) imidazo [1, 2-a] [1, 5] naphthyridin-9-yl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (920 mg, 1.58 mmol, 32% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M + H] + =572.5; 1H NMR (400MHz, DMSO-d6, ppm): δppm 8.19(s,1H),7.69-7.65(m,1H),7.62-7.55(m,1H),5.39-5.16(m,1H),4.17-4.08(m,3H),3.83-3.69(m,2H),3.62-3.49(m,2H),3. 12-2.98(m,4H),2.79-2.87(m,1H),2.10-2.15(m,1H),2.03-2.06(m,1H),1.73-1.88(m,4H),1.54-1.69(m,4H),1.42-1.48(m,9H).

[0295] Step 3: (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,2-a][1,5]naphthyridin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (470 mg, 821.57 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (355.14 mg, 985.89 μmol), cataCXium A Pd G3 (29.92 mg, 41.08 μmol) and Cs2CO3 (535.37 mg, 1.64 mmol) were added to ethanol (9.4 mL) and purified water (0.9 mL), and degassing and nitrogen purging were repeated three times. Then, the reaction mixture was stirred at 80 ° C for 16 hours under nitrogen. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), and the compound was extracted with ethyl acetate (5 mL * 2). The organic layer was washed with saturated NaCl aqueous solution (5 mL * 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative-TLC. Tert-butyl (1R,5S)-3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 128.84 μmol, 16% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =770.4; 1H NMR (400MHz, DMSO-d6, ppm): δ8.23-8.11(m,1H),7.93-7.84(m,1H),7.68-7.61(m,1H), 7.60-7.34(m,3H),7.27-7.14(m,1H),5.34(s,3H),4.23-4.11(m,2H),4.09-3.95(m,2H) ,3.95-3.90(m,1H),3.76-3.51(m,2H),3.43(s,3H),3.06-3.14(m,2H),2.98-3.05(m,1 H),2.80-2.90(m,1H),1.95-2.23(m,6H),1.66-1.93(m,7H),1.41-1.50(m,9H),0.54(br t,J=6.4Hz,3H).

[0296] Step 4: Tert-butyl (1R,5S)-3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65 mg, 84.43 μmol) was dissolved in DCM (1.3 mL) and 4N HCl in ethyl acetate (650 μL) was added. The reaction mixture was stirred at 25 ° C for 1 hour. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated NaHCO3 solution (10 mL), and the compound was extracted with ethyl acetate (5 mL*2). The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC. 4-(1-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalene-2-ol (25.72 mg, 41.10 μmol, 49% yield) was obtained as an off-white solid. LCMS (ES-API, m / z): [M+H] + =626.3; 1HNMR (400MHz, DMSO-d6, ppm): δ9.86 (s, 1H), 8.11-7.99 (m, 1H), 7.75 (d, J = 2.4Hz, 1H), 7.68-7.52 (m, 1H), 7.51-7.42(m,1H),7.42-7.24(m,3H),7.08-7.02(m,1H),5.42-5.17(m,1H),4.12(s,3H),3.78-3.59(m,1 H),3.57-3.38(m,3H),3.15-3.07(m,2H),3.02(s,1H),2.88-2.79(m,1H),2.44–2.37(m,1H),2.24-2.08( m,2H),2.09–1.96(m,3H),1.92-1.67(m,5H),1.59-1.45(m,1H),1.42-1.15(m,1H),0.50(t,J=6.8Hz,3H).

[0297] Example 2: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0298]

[0299] Step 1: (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbamic acid tert-butyl ester (150 mg, 243.30 μmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (149.64 mg, 291.96 μmol), cataCXium A Pd G3 (8.86 mg, 12.16 μmol) and Cs2CO3 (158.54 mg, 486.60 μmol) were added to ethanol (3 mL) and water (0.3 mL), and degassing and nitrogen purging were repeated three times. Then, the mixture was stirred at 80 ° C for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove ethanol, the crude residue was diluted with purified water (15 mL) and extracted with ethyl acetate (10 mL * 2). The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative-TLC. Tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 126.59 μmol, 52% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =922.5; 1H NMR (400MHz, DMSO-d6, ppm): δ8.22-7.97(m,2H),7.77-7.63(m,1H),7.59-7.47(m,2H),7.46- 7.30(m,2H),5.36(s,3H),4.41(brs,1H),4.32-4.21(m,1H),4.18-3.99(m,2H),3.97-3.78(m, 1H),3.43(s,3H),3.14-3.07(m,2H),3.07-3.00(m,1H),2.93-2.79(m,2H),2.31-2.23(m,1H) ,2.22–1.95(m,5H),1.95-1.62(m,6H),1.46(brs,9H),0.83-0.62(m,18H),0.46-0.26(m,3H).

[0300] Step 2: Tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 130.13 μmol) was dissolved in DCM (1.2 mL) and CsF (296.50 mg, 1.95 mmol, 71.97 μL) was added. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL*3). The organic material was washed with a saturated aqueous NaCl solution (10 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative-TLC. (1R, 5S) -3- (6- (8-ethynyl -7- fluoro-3- (methoxymethoxy) naphthalen-1-yl) -3- (( (2R, 7aS) -2-fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) imidazo [1 ', 2': 1, 6] pyrido [3, 2-d] pyrimidin-1-yl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (70 mg, 91.17 μmol, yield 70%) was obtained as a yellow solid. LCMS (ES-API, m / z): [M + H] + =766.5; 1 H NMR (400 MHz, CDCl 3,ppm): δ8.75-8.36(m,1H),7.85(dd,J=9.05,5.75Hz,1H),7.78-7.61(m,1H),7.56(s,1H),7.51(br d,J=13.2Hz,1H),7.40(d,J=2.0Hz,1H),7.32-7.26(m,2H),5.51-5.13(m,3H),4.60-4.11(m,4H),3.66-3.58(m,1H),3.55(s,3H),3 .52-3.46(m,2H),3.38-3.19(m,3H),2.12-3.99(m,1H),2.63-2.51(m,1H),2.40-2.09(m,5H),2.06-1.81(m,5H),1.57-1.48(m,9H).

[0301] Step 3: Tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 91.40 μmol) was dissolved in ACN (0.7 mL) and 4N HCl in dioxane (700 μL) was added at 0°C under nitrogen and stirred for 1 hour. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure and the residue was diluted with saturated sodium bicarbonate solution (10 mL) and the compound was extracted with ethyl acetate (5 mL*4). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was collected and purified by preparative HPLC. 4-(1-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (27.37 mg, 43.79 umol, 48% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =622.4; 1H NMR (400MHz, DMSO-d6, ppm): δ10.33-9.92(m,1H),8.55-8.36(m,1H),7.99-7 .93(m,1H),7.61-7.47(m,1H),7.47-7.34(m,3H),7.33-7.26(m,1H),7.20(br s,1H),5.40-5.17(m,1H),4.17-4.08(m,1H),4.06-3.84(m,2H),3.70-3.54(m,2H), 3.54-3.41(m,3H),3.15-3.05(m,2H),3.04-3.00(m,1H),2.99-2.88(m,1H),2.84(br d,J=7.2Hz,1H),2.20-1.98(m,4H),1.93-1.68(m,5H),1.57-1.42(m,1H).

[0302] Example 3: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalene-2-ol.

[0303]

[0304] Step 1: (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 262.20 μmol), 2-(7,8-difluoro-3-(methoxymethoxy)-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 262.20 μmol), 1,4-dioxane (2.4 mL) and water (0.6 mL) were added to 1,4-dioxane (2.4 mL) and water (0.6 mL), and degassing and nitrogen purging were repeated three times. The mixture was then stirred at 80°C under nitrogen for 1 hour. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), and the compound was extracted with ethyl acetate (5 mL*2). The organic layer was washed with a saturated aqueous NaCl solution (5 mL*2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give tert-butyl (1R,5S)-3-(6-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 195.70 μmol, 75% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =760.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ7.68(s,1H),7.57-7.34(m,4H),7.27-7.16(m,2H),5.33-5.12(m,3H),4.69(br d,J=2.4Hz,2H),4.46-4.10(m,4H),3.62(s,1H),3.46-3.42(m,3H),3.39(s,3H),3.37-3.28(m,1H),3.26-3 .15(m,2H),3.13-3.06(m,1H),2.97-2.86(m,1H),2.27-2.04(m,4H),1.94-1.83(m,3H),1.47-1.37(m,9H).

[0305] Step 2: Tert-butyl (1R,5S)-3-(6-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 171.09 μmol) was dissolved in ACN (1.3 mL), and HCl in dioxane (4 M, 1.30 mL) was added at 0°C and stirred at 0°C for 1 hour. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 solution (15 mL), and the compound was extracted with ethyl acetate (10 mL*3). The organic layer was washed with a NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was collected and purified by RP-HPLC to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol (14.11 mg, 22.48 μmol, 13% yield) as a yellow-green solid. LCMS (ES-API, m / z): [M+H] + =616.3; 1 HNMR (400MHz, DMSO-d6, ppm): δ10.21(s,1H),8.07-7.96(m,1H),7.74-7.59(m,1H) ),7.58-7.42(m,2H),7.42-7.32(m,2H),7.21(s,1H),5.39-5.18(m,1H),4.12(br d,J=9.2Hz,1H),4.03(br s,1H),3.97-3.83(m,1H),3.72-3.60(m,1H),3.59-3.42(m,3H),3.18-2.91(m,4 H),2.88-2.78(m,1H),2.20-1.95(m,4H),1.92-1.60(m,5H),1.58-1.36(m,2H).

[0306] Example 4: Synthesis of 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0307]

[0308] Step 1: Dissolve 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2 g, 6.29 mmol) in DCM (40 mL), and add DIPEA (1.22 g, 9.44 mmol) and 1-(aminoethyl)-N,N-dimethylcyclobutan-1-amine (967.79 mg, 7.55 mmol) sequentially. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted with DCM (50 mL*2). The organic material was washed with saturated aqueous NaCl (50 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The product was stirred with petroleum ether (15 mL) and ethyl acetate (45 mL) at 25°C for 30 minutes, filtered, and dried. 6-Bromo-3-chloro-N-((1-(dimethylamino)cyclobutyl)methyl)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-1-amine (2.2 g, 5.33 mmol, 85% yield) was obtained as an off-white solid. LCMS (ES-API, m / z): [M+H] + =365.0; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.57-8.48(m,1H),7.90(s,1H),7.77-7.75(m,1H),7 .74-7.64(m,1H),3.79(s,2H),2.27(s,6H),2.21-2.10(m,2H),1.91-1.65(m,4H).

[0309] Step 2: 6-Bromo-3-chloro-N-((1-(dimethylamino)cyclobutyl)methyl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (1.3 g, 3.56 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (2.27 g, 14.24 mmol) were dissolved in THF (26 mL), and then NaH (1.42 g, 35.59 mmol) was added at 0°C. The reaction mixture was warmed to 25°C and stirred for 10 minutes, and then the reaction mixture was stirred at 70°C under nitrogen for 16 hours. The mixture was poured into saturated aqueous NH4Cl solution (100 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL*3), dried, and concentrated under reduced pressure to give the product. The residue was purified by silica gel chromatography and then purified using preparative HPLC. 6-Bromo-N-((1-(dimethylamino)cyclobutyl)methyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (720 mg, 1.39 mmol, 39% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =488.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.42(s,1H),7.83(s,1H),7.66-7.54(m,1H), 7.40-7.20(m,1H),5.38-5.14(m,1H),4.15-3.95(m,2H),3.85-3.72(m,2H), 3.15-3.05(m,2H),3.04-2.98(m,1H),2.88-2.78(m,1H),2.29-2.22(m,6H), 2.19-2.11(m,3H),2.06-2.02(m,1H),2.01-1.94(m,1H),1.88-1.64(m,7H).

[0310] Step 3: 6-bromo-N-((1-(dimethylamino)cyclobutyl)methyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (150 mg, 307.38 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5- ,5-tetramethyl-1,3,2-dioxaborolane (132.87 mg, 368.85 μmol), PdCl2(dtbpf) (20.03 mg, 30.74 μmol), and K3PO4 (195.74 mg, 922.13 μmol) were dissolved in dioxane (2.4 mL) and water (0.6 mL), purged with nitrogen three times, and the mixture was stirred at 80°C under nitrogen for 1.5 hours. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and the compound was extracted with ethyl acetate (15 mL*3). The organic layer was washed with saturated aqueous NaCl solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (190 mg, 260.98 μmol, 85% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =488.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.15(s,1H),7.69-7.66(m,2H),7.52-7.51(m,2H),7.27-7.23(m ,1H),7.21-7.18(m,1H),6.98–6.94(m,1H),5.30-5.26(m,3H),4.31-4.30(m,1H),4.13-4.12( m,1H),3.85-3.84(m,2H),3.51(s,3H),3.29-3.21(m,3H),3.04-2.96(m,1H),2.46-2.42(m,2H ), 2.41 (s, 6H), 2.23-2.21 (m, 2H), 2.16–2.12 (m, 2H), 1.98-1.61 (m, 8H), 0.7 (t, J = 7.2Hz, 3H).

[0311] Step 4: N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (100 mg, 145.81 μmol) obtained in Step 3 was dissolved in ACN (1 mL), HCl in dioxane (4 M, 0.5 mL) was added at 0°C, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated NaHCO3 solution (20 mL), and the compound was extracted with ethyl acetate (10 mL*3). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was collected and purified by preparative HPLC. 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30.44 mg, 46.40 μmol, 32% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =488.2; 1 HNMR(400MHz,DMSO-d6,ppm): δ9.86(br s,1H),8.39(s,1H),7.75(dd,J=6.0,9.2Hz,1H),7.63(s,1H),7.41(s,1H),7.38-7. 26(m,3H),6.99(d,J=2.4Hz,1H),5.40-5.17(m,1H),4.16-4.01(m,2H),3.92(brs,1H ),3.75(brs,1H),3.16-2.97(m,3H),2.88-2.79(m,1H),2.47-2.40(m,1H),2.29(s, 6H), 2.24-2.11 (m, 3H), 2.10-1.96 (m, 3H), 1.93-1.67 (m, 7H), 0.60 (t, J = 7.2Hz, 3H).

[0312] Example 5: Synthesis of 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol.

[0313]

[0314] Synthesis was performed in the same manner as in Example 4 using 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol (46.13 mg, 72.23 μmol, 49% yield) was obtained as a gray solid. LCMS (ES-API, m / z): [M+H] + =632.5; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.34-10.07(m,1H),8.45-8.26(m,1H),7.75-7.67(m,1H) ,7.64-7.60(m,1H),7.57-7.48(m,1H),7.40-7.29(m,3H),7.23-7.10(m,1H),5.42-5.14( m,1H),4.15-4.01(m,2H),3.96-3.83(m,1H),3.81-3.71(m,1H),3.13-2.98(m,3H),2.89- 2.77(m,1H),2.32-2.26(m,6H),2.25-2.12(m,3H),2.10-1.97(m,2H),1.91-1.68(m,7H).

[0315] Example 6: Synthesis of 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0316]

[0317] Step 1: 6-bromo-N-((1-(dimethylamino)cyclobutyl)methyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (150 mg, 307.38 μmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189.05 mg, 368.85 μmol), PdCl2(dtbpf) (20.03 mg, 30.70 μmol), K3PO4 (195.74 mg, 922.13 μmol) were added to dioxane (2.4 mL) and water (0.6 mL), and the mixture was purged with nitrogen three times. The reaction mixture was stirred at 80 ° C under nitrogen for 1.5 hours. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and the compound was extracted with ethyl acetate (15 mL * 3). The organic layer was washed with saturated NaCl aqueous solution (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. N-((1-(dimethylamino)cyclobutyl)methyl)-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-1-amine (175 mg, 197.88 μmol, 64% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =838.6; 1 HNMR (400MHz, DMSO-d6, ppm): δ8.14-8.05(m,1H),7.83-7.74(m,1H),7.7 1-7.65(m,1H),7.54-7.48(m,2H),7.31-7.29(m,1H),7.27-7.23(m,1H),6 .98-6.86(m,1H),5.29(s,3H),4.38-4.26(m,1H),4.21-4.10(m,1H),3.94 -3.74(m,2H),3.52(s,3H),3.38-3.16(m,3H),3.09-2.93(m,1H),2.45(br d,J=10.8Hz,2H),2.37(s,6H),2.30-2.20(m,2H),2.01-1.79(m,8H),0.79-0.74(m,18H),0.51(quin,J=7.2Hz,3H).

[0318] Step 2: N-((1-(dimethylamino)cyclobutyl)methyl)-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (145 mg, 173.01 μmol) obtained in Step 1 was dissolved in DMF (1.5 mL), followed by the addition of CsF (394.20 mg, 2.60 mmol), and the mixture was stirred at 40° C. for 16 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (15 mL*3). The organic material was washed with a saturated aqueous NaCl solution (15 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative-TLC to give N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (90 mg, 128.62 μmol, 74% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =838.6; 1 HNMR (400 MHz, CDCl 3, ppm): δ8.20-8.09(m,1H),7.88-7.78(m,1H),7.71-7.66(m,1H),7.58- 7.52(m,1H),7.49-7.45(m,1H),7.39-7.34(m,1H),7.29-7.28(m,1H), 7.26-7.24(m,1H),7.07-6.92(m,1H),5.41-5.36(m,1H),5.31-5.29(m ,1H),5.28-5.22(m,1H),4.37-4.27(m,1H),4.25-4.10(m,1H),3.85(br d,J=2.4Hz,2H),3.54(s,3H),3.40-3.19(m,3H),3.02(br s,1H),2.62-2.56(m,1H),2.48-2.40(m,2H),2.36(s,6H),2.27(br d,J=12.0Hz,2H),2.04-1.78(m,8H).

[0319] Step 3: N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (80 mg, 117.34 μmol) obtained in step 2 was dissolved in acetonitrile (0.8 mL) and DCM (0.8 mL), and then HCl in dioxane (4M, 800 μL) was added at 0° C. and stirred for 1 hour. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated NaHCO 3 solution (15 mL), and the compound was extracted with ethyl acetate (10 mL*3). The organic layer was washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (56.98 mg, 88.14 μmol, 75% yield) as an off-white solid. LCMS (ES-API, m / z): [M+H] + =838.6; 1 HNMR (400MHz, DMSO-d6, ppm): δ10.34-9.88(m,1H),8.32(s,1H),7.95(dd,J=6.0,9.2H z,1H),7.58(s,1H),7.42(t,J=9.0Hz,1H),7.36(d,J=2.4Hz,1H),7.30(s,1H),7.26(br s,1H),7.17(d,J=2.0Hz,1H),5.44-5.16(m,1H),4.15-4.07(m,1H),4.05-3.91(m,2H),3.76-3.63(m,2H),3.16-2.98(m,3H),2.84(br d,J=6.0Hz,1H),2.29(s,6H),2.22(br d,J=9.6Hz,2H),2.14(br d,J=5.6Hz,1H),2.10-1.96(m,2H),1.92-1.67(m,7H).

[0320] Example 7: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0321]

[0322] The compound was synthesized using Intermediate 6 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (35 mg, 55.22 μmol, 43% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =634.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.27-10.03(m,1H),8.57-8.39(m,1H),8.02-7.92(m,1H),7.61-7.51(m ,1H),7.48-7.36(m,3H),7.32-7.14(m,2H),4.29(s,2H),3.71-3.63(m,1H),3.62-3.57(m,1H),3.54(br s,4H),3.51-3.48(m,1H),3.47-3.42(m,1H),3.25-3.13(m,1H),3.03-2.88(m,1H),2.45-2.29(m,6 H),2.26-2.05(m,1H),1.98-1.68(m,2H),1.64-1.35(m,2H),0.71-0.60(m,2H),0.47-0.39(m,2H).

[0323] Example 8: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0324]

[0325] The compound was synthesized using Intermediate 7 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (81.41 mg, 122.92 μmol, 51% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =648.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ0.31-0.39(m,1H),0.46-0.61(m,2H),0.62-0.73(m,1H),0.84(dd,J =6.0,3.2Hz,3H),1.36-1.66(m,3H),1.68-1.93(m,2H),2.03-2.19(m,2H),2.21-2.35(m,2H),2.83 -3.08(m,3H),3.39-3.55(m,6H),3.61-3.72(m,2H),3.79-4.11(m,2H),4.45-4.73(m,1H),7.15-7 .24(m,1H),7.26-7.43(m,3H),7.43-7.59(m,1H),7.96(dd,J=8.8,6.0Hz,2H),9.87-10.22(m,1H).

[0326] Example 9: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0327]

[0328] The compound was synthesized using Intermediate 8 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (66.62 mg, 94.29 μmol, 53% yield) was obtained as an off-white solid. LCMS (ES-API, m / z): [M+H]+ =694.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.25-10.00(m,1H),8.52-8.40(m,1H),8.05-7.90(m,1H),7.57- 7.51(m,1H),7.46-7.35(m,3H),7.32-7.26(m,1H),7.24-7.17(m,1H),4.35-4.24(m,2H),4.06-3 .92(m,1H),3.72-3.40(m,4H),3.01-2.87(m,1H),2.47-2.38(m,4H),2.38-2.33(m,2H),2.27-2 .04(m,1H),1.92-1.71(m,2H),1.64-1.41(m,6H),1.24-1.12(m,2H),0.71-0.60(m,2H),0.43(br s,2H).

[0329] Example 10: Synthesis of 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0330]

[0331] The compound was synthesized using Intermediate 9 in the same manner as in Example 2. 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (39 mg, 59.19 μmol, 31% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =646.2; 1H NMR (400MHz, DMSO-d6, ppm): δ10.21-10.02(m,1H),8.51-8.40(m,1H),8.02-7.90(m,2H),7.58-7.50(m,1H),7.47-7 .36(m,3H),7.30-7.25(m,1H),7.24-7.16(m,1H),4.38-4.28(m,2H),4.27-4.17(m,1H),3.84-3.74(m,1H),3.58(br s,1H),3.53-3.45(m,4H),3.44-3.39(m,2H),2.89(s,1H),2.88-2.82(m,1H),2.65-2.57(m,2H),2.44-2.36(m,1H),2.24-2. 05(m,1H),1.94-1.70(m,2H),1.70-1.63(m,1H),1.57-1.46(m,2H),0.62-0.55(m,2H),0.53-0.45(m,1H),0.44-0.38(m,1H).

[0332] Example 11: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(((R)-2-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0333]

[0334] The compound was synthesized using Intermediate 10 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-2-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (15 mg, 22.93 μmol, 20% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =648.5; 1H NMR (400MHz, DMSO-d6, ppm): δ10.23-9.97(m,1H),8.54-8.37(m,1H),8.03-7.89(m,1H),7.58-7.1 5(m,5H),4.36-4.21(m,2H),4.05-3.93(m,1H),3.84-3.61(m,2H),3.60-3.52(m,1H),3.51-3.35(m ,5H),2.99-2.72(m,2H),2.43-2.23(m,4H),2.16-2.06(m,1H),2.03-1.89(m,1H),1.88-1.75(m,1 H),1.73-1.59(m,1H),1.58-1.39(m,2H),1.05-0.95(m,3H),0.71-0.59(m,2H),0.46-0.38(m,2H).

[0335] Example 12: Synthesis of 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0336]

[0337] The compound was synthesized using Intermediate 11 in the same manner as in Example 2. 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (62 mg, 91.22 μmol, 40% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =646.5; 1H NMR (400MHz, DMSO-d6, ppm): δ10.16-10.03(m,1H),8.50-8.40(m,1H),8.02-7.90(m,1H),7.58-7.48(m,1H),7.46-7. 41(m,1H),7.41-7.35(m,2H),7.32-7.25(m,1H),7.24-7.16(m,1H),4.40-4.27(m,2H),4.26-4.19(m,1H),4.07-3.90( m,1H),3.82-3.74(m,1H),3.68-3.55(m,2H),3.53-3.38(m,5H),2.99-2.89(m,1H),2.88-2.79(m,1H),2.69-2.60(m,2 H),2.45-2.35(m,2H),2.27-2.04(m,1H),1.85-1.65(m,2H),1.57-1.43(m,2H),0.67-0.54(m,2H),0.53-0.36(m,2H).

[0338] Example 13: Synthesis of 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline.

[0339]

[0340] Step 1: In step 1 of Example 2, intermediate 26 was used instead of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to synthesize the compound in the same manner. Tert-butyl (1R,5S)-3-(6-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow solid (75 mg, 103.82 μmol, 27% yield). LCMS (ES-API, m / z): [M+H] + =701.4; 1H NMR (400MHz, CDCl3, ppm): δ8.68-8.53(m,1H),7.83-7.72(m,1H),7.69-7.6 3(m,1H),7.59-7.49(m,1H),5.39-5.21(m,2H),4.36-4.28(m,1H),4.23(br d,J=7.4Hz,3H),4.17-4.09(m,1H),3.88-3.54(m,2H),3.45-3.36(m,1H),3.26(br s,2H),3.19(br s,1H),3.05-2.95(m,1H),2.37-2.11(m,5H),2.02-1.80(m,7H),1.55-1.47(m,9H).

[0341] Step 2: Tert-butyl (1R,5S)-3-(6-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.00 mg, 107.04 μmol) obtained in step 1 was dissolved in acetonitrile and HCl in dioxane (4M, 0.8 mL) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. Saturated aqueous NaHCO3 was added, and then extracted with ethyl acetate. The crude compound was purified by preparative HPLC to give 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline (15 mg, 24.98 μmol, 23% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =601.3; 1H NMR (400MHz, CDCl3, ppm): δ8.64-8.47(m,1H),8.09-7.93(m,1H),7.75-7.51(m,1H) ),7.49-7.26(m,1H),5.61-5.42(m,2H),5.40-5.17(m,1H),4.16-4.08(m,1H),4.07 -3.97(m,1H),3.59-3.44(m,4H),3.13-3.05(m,2H),3.04-3.00(m,1H),2.88-2.79( m,1H),2.21-1.93(m,4H),1.91-1.70(m,4H),1.64-1.43(m,2H),1.42-1.09(m,2H).

[0342] Example 14: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0343]

[0344] The compound was synthesized in the same manner as in Example 2 using (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester and Intermediate 18. 4-(1-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (12.71 mg, 20.21 μmol, 15% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =621.5; 1H NMR (400MHz, CDCl3, ppm): δ8.78-8.59(m,1H),7.80-7.69(m,1H),7.48(s,1H),7. 35-7.26(m,2H),7.10-7.00(m,2H),5.67-5.53(m,2H),5.40-5.16(m,1H),4.22(br dd,J=4.4,6.4Hz,1H),4.14-4.07(m,1H),4.05-3.97(m,1H),3.91(br s,1H),3.56-3.38(m,1H),3.31-3.19(m,2H),3.18-3.04(m,3H),3.02(s,1H),2.88-2. 80(m,1H),2.80-2.70(m,1H),2.18-2.12(m,1H),2.11-1.93(m,4H),1.92-1.66(m,5H).

[0345] Example 15: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine.

[0346]

[0347] Step 1: (2-((tert-Butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic acid (220 mg, 563.88 μmol) and (1R,5S)-8-(6-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine-1 -yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (280 mg, 489.45 μmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), followed by the addition of K 3 PO 4 (311.68 mg, 1.47 mmol) and Pd(amphos)Cl 2 (31.90 mg, 48.94 μmol) and nitrogen purging three times. The reaction mixture was then stirred at 80° C. for 12 hours. After the reaction was completed, the product was purified by silica gel chromatography to obtain tert-butyl (1R,5S)-8-(6-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (280 mg, 318.67 μmol, yield 65%). LCMS (ES-API, m / z): [M+H] + =804.7; 1 H NMR (400MHz, DMSO-d6, ppm): δ12.23 (br s,1H),9.05-8.51(m,1H),8.17(dd,J=5.8,8.6Hz,1H),7.92(s,1H),7.67(s,1H),7.33(t,J=8.8Hz,1H),5.39-5.19(m,1H),4.28(br d,J=11.0Hz,2H),4.17-4.12(m,1H),4.06(d,J=9.8Hz,1H),3.19-2.99(m,4H),2. 88-2.78(m,1H),2.21-2.00(m,4H),1.93-1.66(m,7H),1.53-1.50(m,9H),1.43(br s,9H).

[0348] Step 2: Tert-butyl (1R,5S)-8-(6-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (227.62 mg, 323.42 μmol) obtained in step 1 was dissolved in ACN, HCl in dioxane (4 M, 0.5 mL) was added and stirred at 0°C for 2 h. After the reaction was complete, the compound was purified by preparative HPLC to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine (80 mg, 127.62 μmol, 39% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =604.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.93-8.61(m,1H),8.07-7.96(m,3H),7.92(s,1H),7.67(s,1H),7.08(t,J=8.9Hz,1H),5.42-5. 13(m,1H),4.29-4.05(m,3H),4.04-3.96(m,1H),3.31-2.94(m,6H),2.89-2.70(m,2H),2.26-1.95(m,5H),1.94-1.58(m,6H).

[0349] Example 16: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0350]

[0351] The compound was synthesized using Intermediate 14 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (70.42 mg, 108.56 μmol, 56% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =636.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ0.45(s,2H),0.56-0.67(m,2H),0.68-0.88(m,1H),1 .11-1.31(m,2H),1.74-1.93(m,3H),2.01-2.18(m,2H),2.28-2.34(m,1H),2.38(br dd,J=12.0,9.07Hz,1H),2.57(br d,J=4.4Hz,1H),2.60-2.68(m,1H),2.73-2.82(m,2H),2.87(br d,J=11.2Hz,1H),3.08-3.28(m,2H),3.52-3.64(m,1H),3.83-3.98(m,1H) ,4.07-4.26(m,2H),4.27-4.33(m,1H),5.03-5.30(m,1H),7.21(d,J=2.4H z,1H),7.35(s,1H),7.37(d,J=2.4Hz,1H),7.42(t,J=9.2Hz,1H),7.47(s, 1H), 7.96 (dd, J=9.2, 6.00Hz, 1H), 8.30-8.93 (m, 1H), 9.79-10.39 (m, 1H).

[0352] Example 17: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0353]

[0354] The compound was synthesized using Intermediate 13 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, 32.05 μmol, 19% yield) was obtained as a light yellow solid. LCMS (ES-API, m / z): [M+H] + =618.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.18-10.08(m,1H),8.78-8.60(m,1H),7.96(dd,J=6..0,9.2Hz,1H),7.46(br d,J=9.2Hz,1H),7.44-7.39(m,1H),7.37(d,J=2.4Hz,1H),7.35(s,1H),7.21 (d,J=2.4Hz,1H),4.25(s,3H),4.01-3.78(m,1H),3.67-3.48(m,1H),3.27(br d,J=12.4Hz,2H),2.81-2.70(m,1H),2.47-2.37(m,8H),1.91-1.78(m,2H),1.65(br s,5H),0.62-0.59(m,2H),0.45-0.41(m,2H).

[0355] Example 18: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.

[0356]

[0357] Step 1: Intermediate 21 (210 mg, 640.06 μmol) and tert-butyl (1R,5S)-8-(6-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (347.85 mg, 608.06 μmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), followed by the addition of CsCO (625.63 mg, 1.92 mmol) and cataCXium A Pd G (46.68 mg, 64.01 μmol). The reaction mixture was stirred at 90° C. under nitrogen for two hours. After the reaction was completed, purification was performed by preparative HPLC to give tert-butyl (1R,5S)-8-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (279 mg, 309.66 μmol, 48% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =820.5; 1 H NMR (400MHz, CDCD3, ppm): δ8.70(br s,1H),7.67(s,1H),7.63-7.59(m,1H),7.54(br s,1H),7.42(d,J=7.2Hz,1H),5.82-5.66(m,1H),5.42-5.16(m,1H),4.63-4.37(m,1H),4.34-4.17(m,2H),4.10-3. 99(m,2H),3.97-3.88(m,1H),3.85-3.68(m,2H),3.61-3.37(m,2H),3.32-3.11(m,3H),3.07-2.95(m,1H),2.73(br s,3H),2.61-2.42(m,1H),2.35-2.10(m,5H),2.02-1.93(m,3H),1.91-1.66(m,7H),1.53-1.45(m,9H).

[0358] Step 2: Tert-butyl (1R,5S)-8-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (100 mg, 121.97 μmol) obtained in Step 1 was dissolved in DCM (1 mL), and TFA (767.50 mg, 6.73 mmol) was added. The reaction mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction compound was purified by preparative HPLC. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (25.17 mg, 38.80 μmol, 32% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =636.3; 1 HNMR (400MHz, DMSO-d6, ppm): δ13.52-13.32(m,1H),9.05-8.48(m,1H),7.7 4-7.63(m,2H),7.59-7.51(m,1H),7.34(s,1H),5.37-5.18(m,1H),4.17(br s,1H),4.10(s,1H),4.07-4.01(m,1H),3.28(s,3H),3.09(br dd,J=2.0,8.0Hz,2H),3.05-3.00(m,1H),2.87-2.74(m,2H),2.66(br d,J=1.6Hz,3H),2.47-2.41(m,2H),2.21-2.08(m,2H),2.06(br s,3H),1.90-1.70(m,5H).

[0359] Example 19: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0360]

[0361] The compound was synthesized using Intermediate 12 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (23 mg, 35.05 μmol, 28% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.5; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.18-10.04(m,1H),8.82-8.58(m,1H),7.96(dd,J=6.0,9.2Hz,1H),7.48(s,1H),7.42(t,J=9.2Hz,1H),7.39-7.33(m, 2H),7.22(d,J=2.4Hz,1H),4.69-4.48(m,1H),4.46-4.04(m,4H),4.03-3.7 5(m,1H),3.72-3.38(m,2H),3.29-3.13(m,2H),2.96-2.69(m,3H),2.36(br s,3H),2.28-2.15(m,2H),2.13-1.94(m,1H),1.93-1.73(m,3H),1.71-1.62(m,1H),1.54-1.34(m,2H),0.65(s,2H),0.43(s,2H).

[0362] Example 20: Synthesis of 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.

[0363]

[0364] Step 1: Tert-butyl (1R,5S)-3-(6-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.28 mg, 108.86 μmol), Intermediate 23 (64 mg, 90.72 μmol), CuI (4.32 mg, 22.68 μmol), LiCl (9.61 mg, 226.80 μmol), and cataCXium Pd G4 (16.54 mg, 22.68 μmol) were dissolved in 1,4-dioxane (2 mL) and purged with nitrogen three times. The reaction mixture was then stirred at 110°C for 12 hours. After completion of the reaction, purification was performed by silica gel chromatography to obtain tert-butyl (1R,5S)-8-(6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (31 mg, 29.31 μmol, 32% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =952.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ1.41(br s,9H),1.56-1.62(m,6H),1.69(br s,4H),1.89-1.94(m,4H),2.39(br s,3H),2.77-2.88(m,2H),3.05-3.13(m,2H),3.73(s,6H),4.02-4.14(m,2H), 4.16-4.32(m,2H),4.59-4.75(m,4H),5.13-5.39(m,1H),6.79(s,1H),6.87(br d,J=8.0Hz,4H),7.19(d,J=8.4Hz,5H),7.26-7.29(m,1H),7.64-7.69(m,1H).

[0365] Step 3: Tert-butyl (1R,5S)-8-(6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octan-3-carboxylate (24 mg, 25.21 μmol) obtained in step 2 was dissolved in dichloroethane (0.24 mL), and TFA (368.40 mg, 3.23 mmol) was added. The reaction mixture was stirred at 60 ° C for 1 hour. The reaction was quenched by adding saturated NaHCO solution and extracted with ethyl acetate. The reaction mixture was purified by preparative HPLC to give 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (3.61 mg, 4.93 μmol, 20% yield). LCMS (ES-API, m / z): [M+H] + =612.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ1.19-1.28(m,2H),1.70-1.87(m,4H),1.96-2.08( m,3H),2.09-2.24(m,2H),2.37(s,3H),2.71-2.86(m,2H),3.01(s,1H),3.08(br d,J=6.4Hz,2H),3.13-3.23(m,2H),3.23-3.28(m,2H),3.92-4.27(m,4H) ,5.11-5.42(m,1H),6.50(s,1H),6.73(s,2H),7.18(s,1H),7.59(s,1H).

[0366] Example 21: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0367]

[0368] The compound was synthesized in the same manner as in Example 2 using (R)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (32.76 mg, 122.23 μmol, 36% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =616.3; 1 H NMR (400MHz, MeOD, ppm): δ8.87-8.62 (m, 1H), 7.82 (dd, J = 5.8, 9.1Hz, 1H), 7.51 (s, 1H), 7.4 1(s,1H),7.32(d,J=2.5Hz,1H),7.29-7.21(m,2H),5.00(s,2H),4.53-4.23(m,4H),3.78(br d,J=14.4Hz,1H),3.55-3.34(m,2H),3.25-3.15(m,1H),3.09-2.58(m,6H),2.51(br d,J=15.9Hz,1H),2.26-1.80(m,8H),1.36-1.21(m,2H).

[0369] Example 22: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.

[0370]

[0371] A compound was synthesized in the same manner as in Example 2 using ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane and (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (56.5 mg, 90.56 μmol, 50% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =618.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ1.67-1.73(m,1H),1.74-1.83(m,2H),1.83-1.92(m,2H),1.92-2.07(m,2H),2.08-2.27(m ,1H),2.28-2.39(m,1H),2.52-2.65(m,3H),2.66-2.90(m,2H),3.01(dt,J=9.6,4.91Hz,1H),3.08-3.32(m,3H),3.71(br d,J=14.8Hz,2H),3.93(br dd,J=2.8,1.38Hz,1H),3.99-4.11(m,2H),4.20(brd,J=2.4Hz,1H),6.63-6.90(m,1H),7.39(s,1H),7.47(br s,1H),7.57(t,J=9.2Hz,1H),7.64-7.72(m,2H),8.15-8.24(m,2H),8.59-8.79(m,1H).

[0372] Example 23: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0373]

[0374] The compound was synthesized in the same manner as in Example 2 using (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (8 mg, 12.27 μmol, 13% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =634.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.12 (br s,1H),8.86-8.56(m,1H),7.97(dd,J=6.0,9.2Hz,1H),7.49(s,1H),7.43(t,J=9.2Hz,1H),7.40-7.33( m,2H),7.22(d,J=2.0Hz,1H),7.01(t,J=7.6Hz,1H),6.90-6.63(m,1H),5.61(d,J=7.6Hz,1H),5.28(br s,2H),4.20(br s,1H),4.10-4.09(m,1H),4.11-4.01(m,2H),3.72(br d,J=15.2Hz,1H),3.27(br s,3H),3.11-2.90(m,2H),2.85-2.70(m,1H),2.63-2.53(m,3H),2.40-2.30(m,1H),2.12-1.94(m,2H),1.92-1.68(m,5H).

[0375] Example 24: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0376]

[0377] A compound was synthesized in the same manner as in Example 2 using Intermediate 18 instead of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (38 mg, 59.51 μmol, 47% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =621.3; 1 HNMR (400MHz, DMSO-d6, ppm): δ8.46(s,0.44H),7.96(s,0.45H),7.74–7.78(m ,1H),7.30(d,J=9.2Hz,2H),7.24–7.28(m,2H),7.04–7.07(m,2H),5.59(s,2H ),5.36(d,J=55.6Hz,1H),4.01–4.13(m,2H),3.33–3.59(m,4H),2.98–3.15(m ,4H),2.78–2.88(m,1H),1.95–2.23(m,5H),1.78–1.84(m,5H),1.53(brs,1H).

[0378] Example 25: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine.

[0379]

[0380] The compound was synthesized in the same manner as in Example 15 using tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine (71.61 mg, 118.61 μmol, 53% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =604.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.53 (br d,J=2.8Hz,1H),8.07-7.94(m,4H),7.93-7.55(m,2H),7.06(t,J=8.8Hz,1H),5.40-5.19(m,1H),4.15-3.97(m,2H),3.74-3.62(m,1H),3.54(br d,J=13.2Hz,2H),3.39(br s,1H),3.15-2.99(m,4H),2.89-2.80(m,1H),2.21-1.96(m,4H),1.91-1.72(m,4H),1.65-1.41(m,3H).

[0381] Example 26: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.

[0382]

[0383] The compound was synthesized in the same manner as in Example 18 using tert-butyl (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. 1-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidine (25.36 mg, 39.89 μmol, 23% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H]+ =636.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ13.44(br s,1H),8.58(brs,1H),8.02(br s,1H),7.74-7.63(m,2H),7.51-7.24(m,2H),5.41-5.15(m,1H),4.18-3.9 7(m,2H),3.81-3.37(m,5H),3.16-3.00(m,4H),2.89-2.78(m,1H),2.66(br d,J=1.6Hz,3H),2.23-1.95(m,4H),1.94-1.71(m,4H),1.63-1.47(m,2H),1.29-1.21(m,1H).

[0384] Example 27: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.

[0385]

[0386] A compound was synthesized using ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane and (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol in the same manner as in Example 2. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidine (28 mg, 44.88 μmol, 40% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =618.3; 1H NMR (400MHz, DMSO-d6, ppm): δ8.45(br d,J=1.5Hz,1H),8.26-8.12(m,2H),7.97(br s,1H),7.68(br s,2H),7.60-7.54(m,1H),7.41(br d,J=7.5Hz,2H),6.89-6.61(m,1H),4.12-3.99(m,2H),3.97-3.86(m,1H),3.77-3.63(m,2H),3.61-3.47(m,2H),3.43(br s,2H),3.09-2.91(m,2H),2.63-2.52(m,3H),2.34(br d,J=14.4Hz,1H),2.24-2.07(m,1H),2.02-1.94(m,1H),1.93-1.62(m,5H),1.55-1.42(m,1H).

[0387] Example 28: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.

[0388]

[0389] The compound was synthesized in the same manner as in Example 2 using ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidine (42.24 mg, 69.25 μmol, 49% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =606.4; 1H NMR (400MHz, DMSO-d6, ppm): δ8.4(br s,1H),8.25-8.13(m,2H),7.97(br s,1H),7.67(br d,J=4.8Hz,2H),7.60-7.51(m,1H),7.51-7.26(m,2H),5.38-5.20(m,1H),4.17-3.98(m,2H),3.98-3.70(m,1H),3 .70-3.37(m,4H),3.31-3.24(m,2H),3.20-2.90(m,4H),2.89-2.79(m,1H),2.25-1.96(m,4H),1.92-1.40(m,6H).

[0390] Example 29: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0391]

[0392] The compound was synthesized in the same manner as in Example 2 using (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50 mg, 78.11 μmol, 25% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =634.2; 1H NMR (400MHz, DMSO-d6, ppm): δ10.40-9.90(m,1H),8.45(br s,1H),7.96(dd,J=6.0,9.1Hz,1H),7.54(br s,1H),7.50-7.25(m,4H),7.21(br s,1H),6.94-6.56(m,1H),4.11-3.90(m,2H),3.74-3.41(m,5H),3.29-3.23(m,3H),3.05-2.91(m,2H),2.74-2.52(m,2H),2.34(br d,J=15.1Hz,2H),2.11(br d,J=1.1Hz,1H),2.02-1.66(m,6H),1.60-1.31(m,2H).

[0393] Example 30: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0394]

[0395] The compound was synthesized using Intermediate 14 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (22 mg, 33.92 μmol, 33% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =636.4; 1H NMR (400MHz, DMSO-d6, ppm): δ10.28-9.95(m,1H),8.46(br s,1H),7.97(br dd,J=6.1,8.9Hz,1H),7.54(br d,J=1.0Hz,1H),7.47-7.35(m,3H),7.33-7.26(m,1H),7.21(br s,1H),5.10(br s,1H),4.39-4.13(m,2H),4.04-3.92(m,1H),3.75-3.54(m,2H),3.51-3.43(m,2H),2.90-2.78(m,2H),2.68-2.6 0(m,1H),2.43-2.27(m,3H),2.26-1.96(m,3H),1.93-1.69(m,3H),1.55-1.41(m,1H),1.31-1.22(m,1H),0.64(br s,2H),0.46(br s,2H).

[0396] Example 31: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0397]

[0398] The compound was synthesized using Intermediate 12 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (22.27 mg, 33.86 μmol, 30% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.4; 1H NMR (400MHz, DMSO-d6, ppm): δ10.1(s,0.93H),8.44(s,0.45H),7.94–7.98(m,1H) ,7.53(s,0.48H),7.36–7.44(m,3H),7.20(d,J=30.8Hz,1.6H),4.52(d,J=47.6Hz, 2H),4.22–4.31(m,2H),3.97(brs,0.48H),3.47–3.65(m,4H),2.63–3.03(m,2H),2 .22–2.36(m,6H),1.60–1.88(m,4H),1.33–1.58(m,4H),0.65(s,2H),0.42(s,2H).

[0399] Example 32: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0400]

[0401] The compound was synthesized in the same manner as in Example 2 using Intermediate 16. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =634.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.83-9.19(m,1H),8.45(br s,1H),7.95(dd,J=6.0,9.2Hz,1H),7.59-7.25(m,4H),7.20(br s,1H),5.46-5.19(m,1H),4.92(br s,2H),4.15-3.79(m,2H),3.74-3.55(m,4H),3.30-3.11(m,5H),3.09-2.90(m,2H),2.62(br s,2H),2.27-2.05(m,3H),1.94-1.62(m,2H),1.60-1.20(m,2H).

[0402] Example 33: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0403]

[0404] The compound was synthesized in the same manner as in Example 2 using (R)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol instead of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (15 mg, 48.73 μmol, 37% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =616.3; 1 HNMR (400MHz, DMSO-d6, ppm): δ10.36-9.87(m,1H),8.45(br s,1H),7.96(dd,J=6.0,9.1Hz,1H),7.54(brs,1H),7.46-7.25(m,4H),7.20(br s,1H),4.90(br s,2H),4.07-3.93(m,2H),3.72-3.40(m,6H),3.20(br d,J=13.9Hz,2H),3.05-2.89(m,2H),2.69-2.53(m,2H),2.37(br d,J=15.6Hz,1H),2.25-2.05(m,1H),1.98(ddd,J=4.4,7.1,11.7Hz,1H),1.93-1.64(m,5H),1.60-1.22(m,2H).

[0405] Example 34: Synthesis of 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.

[0406]

[0407] The compound was synthesized in the same manner as in Example 20 using tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.11 mg, 11.44 μmol, 14.5% yield) was obtained as an off-white solid. LCMS (ES-API, m / z): [M+H] + =616.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.49(br d,J=1.2Hz,1H),7.98(br s,1H),7.75-7.46(m,1H),7.27-7.07(m,1H),6.70(br s,2H),6.50(s,1H),5.39-5.14(m,1H),4.16-3.93(m,2H),3.76-3.44(m ,4H),3.25-3.17(m,1H),3.14-2.94(m,4H),2.90-2.75(m,1H),2.37(br d,J=1.6Hz,3H),2.21-1.94(m,4H),1.90-1.69(m,4H),1.63-1.18(m,3H).

[0408] Example 35: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0409]

[0410] The compound was synthesized using Intermediate 13 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (95.78 mg, 148.54 μmol, 42% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =618.3; 1 H NMR(400MHz,DMSO-d6,ppm): δ9.81-10.39(m,1H),8.44(br s,1H),7.96(dd,J=9.2,6.00Hz,1H),7.26-7.57(m,4H),7.21(brs,1H),4.26(s,2H),3.89-4.08(m,1H),3.54-3.7 5(m,2H),3.38-3.53(m,4H),2.82-3.06(m,1H),2.38-2.47(m,6H),1.70-2.26(m,3H),1.21-1.57(m,2H),0.61(br s,2H),0.43(s,2H).

[0411] Example 36: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0412]

[0413] The compound was synthesized in the same manner as in Example 2 using Intermediate 18 and (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (36.17 mg, 56.71 μmol, 28% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =633.4; 1H NMR(400MHz,DMSO-d6,ppm): δ8.45(brs,1H),7.96(br s,1H),7.81-7.72(m,1H),7.59-7.39(m,1H),7.37-7.23(m,2H),7.12-7.01(m,2H),6.91-6.63(m,1H),5.59(br s,2H),4.14-3.95(m,2H),3.71(d,J=14.8Hz,1H),3.67-3.38(m,4H),3.28(br s,2H),3.08-2.88(m,2H),2.62-2.54(m,2H),2.34(br d,J=14.8Hz,1H),2.25-2.04(m,1H),2.02-1.93(m,1H),1.93-1.67(m,4H),1.62-1.34(m,2H).

[0414] Example 37: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0415]

[0416] The compound was synthesized in the same manner as in Example 2 using (7aR)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (79.66 mg, 122.23 μmol, 36% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =652.2; 1H NMR (400MHz, DMSO-d6, ppm): δ10.25-9.94(m,1H),8.45(br s,1H),7.96(dd,J=6.0,9.2Hz,1H),7.58-7.26(m,4H),7.20(br s,1H),4.19-4.06(m,2H),4.04-3.88(m,1H),3.71-3.42(m,5H),3.09-2.85(m,2H),2.70-2.5 2(m,3H),2.42(brd,J=16.0Hz,1H),2.27-2.06(m,1H),2.04-1.68(m,6H),1.59-1.35(m,2H).

[0417] Example 38: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0418]

[0419] The compound was synthesized in the same manner as in Example 2 using (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and Intermediate 18. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (8 mg, 12.39 μmol, 18% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =633.4; 1H NMR (400MHz, DMSO-d6, ppm): δ8.76-8.55 (m, 1H), 7.68 (dd, J = 5.6, 9.2Hz, 1H), 7.58 (s, 1H),7.46(s,1H),7.19(t,J=8.9Hz,1H),7.15-7.08(m,2H),6.66-6.38(m,1H),4.64-4 .43(m,1H),4.35-3.99(m,3H),3.98-3.83(m,3H),3.53-3.31(m,2H),3.28-3.14(m,1H ),2.99-2.84(m,2H),2.82-2.72(m,1H),2.71-2.58(m,2H),2.58-2.45(m,1H),2.37(br d,J=13.2Hz,2H),2.26-2.11(m,2H),1.95(br s,3H),1.83(ddd,J=4.8,8.2,12.4Hz,1H).

[0420] Example 39: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0421]

[0422] The compound was synthesized in the same manner as in Example 2 using (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester and intermediate 16. 4-(1-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2S, 7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (45.18 mg, 70.58 μmol, 69% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =634.4; 1H NMR (400MHz, DMSO-d6, ppm): δ10.20-10.06(m,1H),8.78-8.61(m,1H),7.96(dd,J=6.0,9.2Hz,1H),7.71(br s,1H),7.52-7.46(m,1H),7.43(t,J=9.2Hz,1H),7.39-7.30(m,2H),7.21(s,1H),5.44-5.21(m,1H),4.92(br s,2H),4.34-4.12(m,1H),4.09-4.00(m,2H),3.98-3.79(m,1H),3.68(br d,J=14.0Hz,1H),3.48(br d,J=13.6Hz,2H),3.29-3.12(m,3H),3.11-2.96(m,1H),2.89-2.66(m,2H),2.63(br s,2H),2.25-2.09(m,3H),2.01-1.62(m,3H).

[0423] Example 40: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0424]

[0425] The compound was synthesized using Intermediate 15 in the same manner as in Example 2. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (132.88 mg, 201.04 μmol, 65% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.4; 1H NMR (400MHz, DMSO-d6, ppm): δ10.36-9.95(m,1H),8.56-7.88(m,2H),7.43(s,2H),7.41-7.29(m,2H),7.21(br d,J=5.2Hz,1H),5.25-5.01(m,1H),4.44(br s,2H),4.05-3.90(m,1H),3.72-3.63(m,1H),3.59(br s,1H),3.55-3.39(m,3H),3.30-3.13(m,1H),3.04-2.90(m,1H),2.83-2.70(m,2H),2.70-2.57(m,3H),2.33(br d,J=2.0Hz,1H),2.27-1.97(m,3H),1.97-1.89(m,3H),1.89-1.79(m,4H),1.79-1.70(m,1H),1.58-1.43(m,1H).

[0426] Example 41: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol.

[0427]

[0428] Step 1: 6-Bromo-1,3-dichloro-8-methylfuro[3,2-f]quinazoline (40.0 mg, 0.120 mmol) was dissolved in DCM (3 mL). Tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.7 mg, 0.145 mmol) and DIPEA (0.064 mL, 0.361 mmol) were added sequentially at 0°C. The reaction solution was stirred at the same temperature for 30 minutes. Purified water was added to the reaction mixture to quench the reaction. The organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated and the resulting material was purified by silica gel chromatography to give a solid (1R,5S)-3-(6-bromo-3-chloro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.098 mmol, 81.7% yield). LCMS (ES-API, m / z): [M+H] + =510.1.

[0429] Step 2: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (33.0 mg, 0.207 mmol) was dissolved in THF (10 mL), NaH (78.8 mg, 0.207 mmol) was added, and the mixture was stirred for 30 minutes. Then, to the THF solution (1 mL), tert-butyl (1R,5S)-3-(6-bromo-3-chloro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.098 mmol) synthesized in Step 1 was slowly added, and the reaction solution was stirred at room temperature for 7 hours. Purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The solvent was concentrated and the resulting material was purified by silica gel chromatography to give a solid (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (51 mg, 0.081 mmol, 39% yield). LCMS (ES-API, m / z): [M+H] + =631.6.

[0430] Step 3: Tert-butyl (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28.0 mg, 0.044 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.9 mg, 0.089 mmol) and K3PO4 (28.3 mg, 0.133 mmol) obtained in Step 2 were dissolved in ethanol (1.50 mL), DMF (0.30 mL) and purified water (0.15 mL), and cataCXium A Pd G3 (4.84 mg, 0.007 mmol) was added and the reaction solution was stirred at 80 ° C for 5 minutes. Purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The solvent was concentrated and the resulting material was purified by silica gel chromatography to give a solid (1R, 5S)-3-(3-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (30.0 mg, 0.041 mmol, yield 93%). LCMS (ES-API, m / z): [M + H] + =738.9.

[0431] Step 4: Tert-butyl (1R,5S)-3-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 mg, 0.041 mmol) obtained in Step 3 was dissolved in DCM (1 mL), and a 4N hydrochloric acid solution in 1,4-dioxane (0.50 mL) was added at 0°C, and the reaction solution was stirred at room temperature for 30 minutes. The solvent was concentrated, purified using preparative HPLC, and then lyophilized to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol (17.0 mg, 0.029 mmol, 70% yield). LCMS (ES-API, m / z): [M+H] +=594.8; 1 H NMR (400MHz, DMSO-d6, ppm): δ7.84(d,J=8.3Hz,1H),7.50–7.43(m,2H),7.40(d ,J=8.5Hz,1H),7.32(d,J=2.4Hz,1H),7.24–7.17(m,2H),6.88(s,1H),5.66(s, 0.5H),5.53(s,0.5H),4.61(s,2H),4.37–4.23(m,3H),4.15(s,2H),3.95–3.88 (m,4H),3.37–3.27(m,2H),2.43(s,3H),2.25–2.13(m,4H),2.11–1.86(m,6H).

[0432] Example 42: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0433]

[0434] Step 1: (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (51.0 mg, 0.081 mmol), ((2-fluoro-6-(methoxymethoxy)-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1-Hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (62.2 mg, 0.121 mmol) and K PO (51.5 mg, 0.243 mmol) were dissolved in ethanol (1.50 mL), DMF (0.30 mL), and purified water (0.15 mL), cataCXium A PdG (8.82 mg, 0.012 mmol) was added, and the reaction solution was stirred at 80° C. for 1 hour. Purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO . The solvent was concentrated and the resulting substance was purified by silica gel chromatography to give tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.0 mg, 0.076 mmol, 81% yield) as a solid compound. LCMS (ES-API, m / z): [M+H] + =937.4.

[0435] Step 2: tert-Butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.0 mg, 0.066 mmol) obtained in Step 1 was dissolved in THF (0.5 mL). 1 M TBAF (0.13 mL, 0.132 mmol) dissolved in THF was added at 0° C., and the reaction solution was stirred at room temperature for 20 minutes. Purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO . The solvent was concentrated and the resulting substance was purified by silica gel chromatography to obtain tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.064 mmol, 97% yield) as a solid compound. LCMS (ES-API, m / z): [M+H] + =780.9.

[0436] Step 3: Tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.064 mmol) obtained in Step 2 was dissolved in DCM (1 mL), and a 4N HCl solution (0.30 mL) dissolved in 1,4-dioxane was added at 0°C, and the reaction solution was stirred at room temperature for 30 minutes. The solvent was concentrated, purified using preparative HPLC, and then lyophilized to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (38.0 mg, 0.051 mmol, 79% yield). LCMS (ES-API, m / z): [M+H] + =636.9; 1H NMR (400MHz, DMSO-d6, ppm): δ8.00 (dd, J=9.2, 6.0Hz, 1H), 7.52–7.35 (m, 3H), 7. 19(d,J=2.5Hz,1H),6.82(s,1H),5.66(s,0.5H),5.53(s,0.5H),4.64(s,2H),4.3 6–4.24(m,1H),4.22–4.10(m,3H),3.97–3.82(m,4H),3.35–3.26(m,2H),2.41(s, 3H),2.36–2.30(m,2H),2.27–2.13(m,3H),2.11–2.04(m,1H),2.04–1.86(m,5H).

[0437] Example 43: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol.

[0438]

[0439] Step 1: Tert-butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60.0 mg, 0.114 mmol), 2-[3-(methoxymethoxy)naphthalen-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane] (53.8 mg, 0.171 mmol), and Cs2CO3 (112 mg, 0.342 mmol) were dissolved in toluene (1.00 mL) and purified water (0.25 mL), cataCXium A Pd G3 (8.3 mg, 0.011 mmol) was added, and the reaction solution was stirred at 100°C for 2 hours. Purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize solid (1R,5S)-3-(3-chloro-5-fluoro-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20.0 mg, 0.032 mmol, 28% yield). LCMS (ES-API, m / z): [M+H] + =634.3.

[0440] Step 2: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (50.3 mg, 0.316 mmol) was dissolved in THF (3.00 mL), NaH (12.6 mg, 0.316 mmol) was added, and the mixture was stirred for 30 minutes. To this reaction solution was added tert-butyl (1R,5S)-3-(3-chloro-5-fluoro-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 0.032 mmol) obtained in Step 1, and the reaction solution was stirred at 70°C for one day. Purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to synthesize solid (1R,5S)-3-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (15.0 mg, 0.020 mmol, yield 63%). LCMS (ES-API, m / z): [M+H] + =756.6.

[0441] Step 3: Tert-butyl (1R,5S)-3-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (23.0 mg, 0.030 mmol) obtained in Step 2 was dissolved in DCM (3.00 mL), and a 4N hydrochloric acid solution (0.2 mL) dissolved in 1,4-dioxane was added at 0°C, and the reaction solution was stirred at room temperature for 3 hours. The solvent was concentrated, purified using preparative HPLC, and then lyophilized to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol (15.0 mg, 0.025 mmol, 65% yield). LCMS (ES-API, m / z): [M+H] + =612.8; 1H NMR (400MHz, MeOD) δ = 7.69 (d, J = 8.3Hz, 1H), 7.33 (ddd, J = 8.1, 6.7, 1.2Hz, 1H), 7.28– 7.17(m,2H),7.15–7.02(m,2H),6.77(d,J=1.2Hz,1H),5.54(t,J=3.7Hz,1,0.5H),5.4 1(s,0.5H),4.64(d,J=1.6Hz,2H),4.49(t,J=13.3Hz,2H),4.08(s,2H),4.02–3.71(m, 5H), 3.37 (td, J=10.7, 6.1Hz, 1H), 3.25 (s, 1H), 2.77–2.18 (m, 9H), 2.18–1.85 (m, 6H).

[0442] Example 44: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0443]

[0444] Step 1: Tert-butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.19 g, 2.26 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.74 g, 3.39 mmol) and Cs2CO3 (2.21 g, 6.79 mmol) were dissolved in toluene (34.0 mL) and purified water (8.5 mL), cataCXium A Pd G3 (165 mg, 0.226 mmol) was added and the reaction solution was stirred at 100°C for one day. Purified water was added to the reaction mixture to quench the reaction, ethyl acetate was added to extract the organic layer, and dried over anhydrous MgSO4. The solvent was concentrated and the resulting material was purified by silica gel chromatography. The resulting material was concentrated, dissolved in hexane, and the solid formed by ultrasonic treatment was filtered. The resulting solid was washed with hexane to give (1R, 5S) -3- (3- chloro-5- fluoro-6- (7- fluoro-3-methyl-8- ((triisopropylsilyl) ethynyl) naphthalene-1-yl) -8- methylfuro [3,2-f] quinazolin-1-yl) -3,8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (640 mg, 0.770 mmol, 34% yield) as a solid compound. LCMS (ES-API, m / z): [M + H] + =831.4; 1 H NMR (400MHz, CD3OD, ppm): δ8.04–7.98(m,1H),7.72(d,J=2.6Hz,1H),7.44(t,J=8.9Hz,1H), 7.33(d,J=2.6Hz,1H),6.88(s,1H),5.38(s,2H),4.66–4.62(m,1H),4.45–4.42(m,1H),4.29 –4.26(m,1H),4.04–3.99(m,1H),3.75–3.71(m,1H),3.54(s,3H),2.45(s,3H),1.91–1.82(m ,2H),1.56(s,9H),1.37–1.29(m,3H),0.80(dd,J=16.0,7.5Hz,18H),0.39(p,J=7.5Hz,3H).

[0445] Step 3: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.05 g, 6.61 mmol) was dissolved in THF (29 mL), and NaH (265 mg, 6.61 mmol) was added. The mixture was stirred for 30 minutes, and then a THF solution (22.0 mL) of tert-butyl (1R,5S)-3-(3-chloro-5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.661 mmol) obtained in Step 2 was slowly added, and the reaction solution was stirred at room temperature for 3 hours. Purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO₄. The solvent was concentrated and the resulting material was purified by silica gel chromatography to afford tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.524 mmol, 79% yield) as a solid compound. LCMS (ES-API, m / z): [M+H] + =954.5; 1 H NMR (400MHz, CD3OD, ppm): δ7.98 (dd, J=9.1, 5.7Hz, 1H), 7.68 (d, J=2.6Hz, 1H), 7.41 (t, J=8.9Hz, 1H), 7.30 (t, J=2.8Hz, 1H), 6 .82(s,1H),5.47–5.40(m,0.5H),5.36(s,2H),5.32–5.27(m,0.5H),4.84–4.70(m,1H),4.43–4.23(m,4H),3.99–3.87(m,1H), 3.82–3.71(m,1H),3.53(s,3H),3.50–3.41(m,1H),3.41–3.22(m,2H),3.14–3.04(m,1H),2.42(s,3H),2.38–2.16(m,4H),2.1 3–2.02(m,3H),1.99–1.83(m,3H),1.55(s,9H),1.47–1.37(m,1H),0.99–0.89(m,1H),0.86–0.72(m,18H),0.48–0.42(m,3H).

[0446] Step 4: Tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.524 mmol) obtained in Step 3 was dissolved in THF (17.5 mL). 1 M TBAF in THF (1.05 mL, 1.05 mmol) was added at 0° C., and the reaction solution was stirred at room temperature for 20 minutes. Purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO . The solvent was concentrated and the resulting substance was purified by silica gel chromatography to give tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-methylnaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.351 mmol, 67% yield) as a solid compound. LCMS (ES-API, m / z): [M+H] + =798.3; 1 H NMR (400MHz, CD3OD, ppm): δ7.99(dd,J=9.2,5.7Hz,1H),7.70(d,J=2.6Hz,1H),7.42–7.34(m,2H),6.81(d,J =1.2Hz,1H),5.45–5.40(m,1H),5.38(s,2H),5.32–5.26(m,1H),4.54–4.27(m,5H),4.27–4.09(m,1H),3.81 –3.69(m,1H),3.69–3.59(m,1H),3.55(s,3H),3.33(qd,J=3.3,2.2Hz,2H),3.14–3.04(m,1H),2.95–2.88(m ,1H),2.42(s,3H),2.38–2.16(m,3H),2.11–2.00(m,3H),2.00–1.82(m,4H),1.78–1.69(m,1H),1.55(s,9H).

[0447] Step 5: Tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-methylnaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.025 mmol) obtained in Step 4 was dissolved in DCM (3 mL), 4N HCl in 1,4-dioxane (0.06 mL) was added at 0°C, and the reaction solution was stirred at room temperature for 1 hour. The solvent was concentrated, purified using preparative HPLC, and then lyophilized to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (6.2 mg, 0.008 mmol, 32% yield). LCMS (ES-API, m / z): [M+H] + =654.3; 1 H NMR (400MHz, CD3OD, ppm): δ7.91 (dd, J=9.2, 5.7Hz, 1H), 7.41 (d, J=2.6Hz, 1H), 7.35 (t, J=8.9H z,1H),7.22(d,J=2.6Hz,1H),6.85(s,1H),5.66–5.61(m,1H),5.52–5.48(m,1H),4.82–4.66(m, 3H),4.44–4.35(m,1H),4.27–4.22(m,1H),4.18–4.14(m,1H),4.09–3.97(m,2H),3.97–3.84(m ,3H),3.54–3.44(m,1H),2.77–2.58(m,3H),2.47(s,3H),2.43–2.22(m,3H),2.20–1.95(m,4H).

[0448] Example 45: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0449]

[0450] A compound was synthesized in the same manner as in Example 43 using 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The product was purified by preparative HPLC and lyophilized to synthesize 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (10 mg, yield 61%). LCMS (ES-API, m / z): [M+H] + =657.29; 1 H NMR (400MHz, CD3OD, ppm): δ7.74 (dd, J=9.0, 5.9Hz, 1H), 7.36 (d, J=2.7Hz, 1H), 7.29 (t, J=9 .4Hz,1H),7.05(d,J=2.6Hz,1H),6.89(s,1H),5.66(s,0.5H),5.53(s,0.5H),4.80–4.68(m ,2H),4.63(s,1H),4.48(s,1H),4.21(d,J=23.7Hz,2H),4.05–3.87(m,4H),2.64(d,J=20.5 Hz, 1H), 2.46 (s, 3H), 2.38 (t, J = 8.7Hz, 2H), 2.14 (d, J = 48.8Hz, 5H), 0.59 (t, J = 7.3Hz, 2H).

[0451] Example 46: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5,6-difluoronaphthalene-2-ol.

[0452]

[0453] The compound was synthesized in the same manner as in Example 43 using 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The compound was purified by preparative HPLC and lyophilized to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol (14 mg, 57% yield). LCMS (ES-API, m / z): [M+H] + =647.25; 1 H NMR (400MHz, CD3OD, ppm): δ7.74 (dd, J=9.0, 5.9Hz, 1H), 7.36 (d, J=2.7Hz, 1H), 7.29 (t, J=9.4Hz ,1H),7.05(d,J=2.6Hz,1H),6.89(s,1H),5.66(s,0.5H),5.53(s,0.5H),4.79–4.69(m,2H),4.6 4(d,J=13.2Hz,1H),4.47(m,1H),4.21(d,J=23.4Hz,2H),3.96(m,4H),3.56–3.42(m,1H),2.87– 2.55(m,3H),2.46(s,3H),2.39(q,J=8.5Hz,3H),2.14(d,J=49.5Hz,6H),0.59(t,J=7.3Hz,3H).

[0454] Example 47: Synthesis of 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol.

[0455]

[0456] The compound was synthesized in the same manner as in Example 43 using 1-(aminomethyl)-N,N-dimethyl-cyclobutylamine. The product was purified by RP-HPLC and lyophilized to give 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol (14 mg, 75% yield). LCMS (ES-API, m / z): [M+H]+ =627.30; 1 H NMR (400MHz, CD3OD, ppm): δ7.81(d,J=8.3Hz,1H),7.46(t,J=7.5Hz,1H),7.39-7.32(m,2H),7.30-7.15(m,3H)5.61(s,0.5H),5.48(s,0.5H),4. 85–4.67(m,7H),4.53–4.31(m,2H),4.08–3.77(m,3H),3.46(t,J=8.6Hz ,1H),2.72–2.30(m,11H),2.13(p,J=9.0Hz,2H),2.02(d,J=6.5Hz,1H).

[0457] Example 48: Synthesis of 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0458]

[0459] The compound was synthesized in the same manner as in Example 44 using 1-(aminomethyl)-N,N-dimethyl-cyclobutylamine. The compound was purified by preparative HPLC and lyophilized to give 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (9 mg, 75% yield). LCMS (ES-API, m / z): [M+H] + =669.29; 1H NMR (400MHz, CD3OD, ppm): δ7.92 (dd, J=9.1, 5.8Hz, 1H), 7.42 (d, J=2.6Hz, 1H), 7.40–7.30 (m, 2H ),7.22(t,J=2.2Hz,1H),5.59(s,0.5H),5.46(s,0.5H),4.76(qd,J=13.3,6.8Hz,5H),4.41(dt, J=64.6,15.7Hz,3H),3.89(d,J=15.0Hz,3H),3.57–3.43(m,2H),3.02(s,5H),2.97(dd,J=15.2, 1.1Hz,1H),2.84(s,1H),2.68(s,1H),2.64(s,1H),2.51(s,7H),2.36(s,3H),2.19–1.97(m,4H).

[0460] Example 49: Synthesis of 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline.

[0461]

[0462] Step 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 285 μmol), N,N-bis(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (228 mg, 428 μmol), cataCXium A Pd G3 (20.8 mg, 28.5 μmol) and Cs2CO3 (279 mg, 856 μmol) were added to toluene (2 mL) and water (0.5 mL), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred at 110°C under nitrogen for 5 hours. After the starting material was completely consumed, the reaction temperature was lowered to room temperature, the palladium catalyst was removed through a celite filter, and the organic layer was extracted with ethyl acetate. After drying over anhydrous Na2SO4, it was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (1R,5S)-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg, 82.7 μmol, yield 29%). LCMS (ES-API, m / z): [M+H] + =946.3.

[0463] Step 2: The compound was synthesized in the same manner as in Example 43 to give tert-butyl (1R,5S)-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 51.6 μmol, yield 62%). LCMS (ES-API, m / z): [M+H] + =970.1.

[0464] Step 3: To tert-butyl (1R,5S)-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 41.3 μmol) obtained in step 3 was added TFA (4 mL) and stirred at room temperature for 9 hours. After complete consumption of the starting material, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline (19 mg, 25.9 μmol, 73% yield). LCMS (ES-API, m / z): [M+H] + =629.6; 1 H NMR(400MHz,MeOD)δ7.55(d,J=8.7Hz,1H),6.89–6.79(m,1H),6.77(d,J=1.2Hz,1H),6.65( d,J=2.3Hz,1H),5.45(s,0.5H),5.25(s,0.5H),4.32(d,J=10.3Hz,2H),4.24(dd,J=10.3,2. 6Hz,2H),3.64(q,J=12.7Hz,2H),3.54(s,2H),3.31–3.13(m,3H),3.03(td,J=9.6,5.5Hz,1 H), 2.46 (s, 4H), 2.35–2.13 (m, 3H), 2.01 (dq, J = 12.0, 6.5Hz, 2H), 1.77 (s, 2H), 1.31 (s, 1H).

[0465] Example 50: Synthesis of 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine.

[0466]

[0467] Step 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 152 μmol), N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (126 mg, 183 μmol), tetrakis(triphenylphosphine)palladium(0) (35.2 mg, 30.4 μmol), lithium chloride (19.3 mg, 456 μmol), and copper(I) iodide (5.8 mg, 30.4 μmol) were added to 1.4-dioxane (2 mL), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred at 130° C. under nitrogen for 8 hours. After the starting material was completely consumed, the reaction temperature was lowered to room temperature, the palladium catalyst was removed through a celite filter, and the organic layer was extracted with ethyl acetate. After drying over anhydrous Na2SO4, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (1R,5S)-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40 mg, 47.2 μmol, yield 31%). LCMS (ES-API, m / z): [M+H] + =848.3.

[0468] Step 2: The compound was synthesized in the same manner as in Example 43 to give tert-butyl (1R,5S)-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 30.9 μmol, 37% yield). LCMS (ES-API, m / z): [M+H] + =971.1.

[0469] Step 3: To tert-butyl (1R,5S)-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 41.3 μmol) obtained in step 2 was added TFA (2 mL) and stirred at 40° C. for 9 hours. After complete consumption of the starting material, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 30%) to give 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine (7.5 mg, 11.9 μmol, yield 58%). LCMS (ES-API, m / z): [M+H] + =630.6; 1 H NMR(400MHz,MeOD)δ7.94(d,J=8.9Hz,1H),6.87(d,J=1.5Hz,1H),5.67(s, 0.5H),5.54(s,0.5H),4.79–4.68(m,2H),4.56(d,J=15.5Hz,1H),4.48(s,1 H),4.19(s,2H),4.14–3.80(m,5H),3.50(td,J=11.0,6.1Hz,1H),2.84–2.5 5(m,3H),2.52(s,4H),2.38(dq,J=11.4,6.4Hz,2H),2.08(d,J=8.3Hz,5H).

[0470] Example 51: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(5-chloro-6-methyl-1H-indazol-4-yl-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazoline.

[0471]

[0472] Step 1: Tert-butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 190 μmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (107 mg, 285 μmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 19 μmol) and tripotassium phosphate (121 mg, 571 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), and degassing and nitrogen purging were repeated three times. Then, the reaction mixture was stirred at 95 ° C for 30 minutes under nitrogen. After the starting material was completely consumed, water was added to the reaction mixture to quench the reaction, and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (1R, 5S) -3- (3-chloro-6- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -5-fluoro-8-methylfuro [3,2-f] quinazolin-1-yl) -3,8-diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (50 mg, 86.3 μmol, yield 45%). LCMS (ES-API, m / z): [M + H] + =696.6.

[0473] Step 2: The compound was synthesized in the same manner as in Step 2 of Example 43 to give tert-butyl (1R,5S)-3-(6-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30.5 μmol, yield 10%). LCMS (ES-API, m / z): [M+H] + =819.4.

[0474] Step 3: tert-Butyl (1R,5S)-3-(6-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30.5 μmol) obtained in step 2 was dissolved in DCM (1 mL) and 4.0 M HCl in 1,4-dioxane (2 mL) was added. The mixture was stirred at room temperature for 1 hour. After confirming complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%) to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazoline (6 mg, 9.46 μmol, yield 31%). LCMS (ES-API, m / z): [M+H] + =630.6; 1 HNMR(400MHz,MeOD)δ7.72(s,1H),7.53(s,1H),6.90(s,1H),5.66(s,0.5H),5.53(s,0.5H),4.75(d,J=2.8Hz,3H),4.60(t,J= 16.6Hz,2H),4.20(s,2H),4.13–3.84(m,7H),2.90–2.57(m,7H),2.47(s,5H),2.38(dq,J=12.2,6.4Hz,3H),2.28–1.92(m,8H).

[0475] Example 52: Synthesis of 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methylpyridin-2-amine.

[0476]

[0477] The compound was synthesized in the same manner as in Example 43 to give 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methylpyridin-2-amine (23 mg, 42% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =690.7; 1 H NMR(400MHz,MeOD)δ7.19(s,1H),6.98(d,J=1.2Hz,1H),6.91(d,J=1.2Hz,1H),5 .69(s,0.5H),5.56(s,0.5H),4.73(s,2H),4.50(t,J=13.1Hz,3H),4.18(s,2H),3 .95(d,J=15.3Hz,5H),2.68(s,1H),2.63(s,1H),2.60(s,3H),2.54(d,J=1.0Hz, 4H), 2.48 (s, 1H), 2.39 (s, 2H), 2.22 (s, 1H), 2.06 (s, 4H), 1.33 (d, J = 17.7Hz, 2H).

[0478] Example 53: Synthesis of 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine.

[0479]

[0480] The compound was synthesized in the same manner as in Example 43 to give 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine (12 mg, yield 23%) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =816.6; 1H NMR(400MHz,MeOD)δ6.86(s,1H),6.78(s,1H),5.69(s,0.5H),5.56(s,0.5H),4.73(s,2H),4.50(t,J=13.1Hz,3H),4.18(s,2H),3.95(d,J=15.3H z,5H),2.68(s,1H),2.63(s,1H),2.60(s,3H),2.54(d,J=1.0Hz,4H),2.4 8(s,1H),2.39(s,2H),2.22(s,1H),2.06(s,4H),1.33(d,J=17.7Hz,2H).

[0481] Example 54: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[d]thiazol-2-amine.

[0482]

[0483] Step 1: Tert-butyl (1R, 5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 190 μmol), intermediate 20 (107 mg, 285 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (24.8 mg, 38 μmol) and tripotassium phosphate (121 mg, 571 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred at 90 ° C under nitrogen for 24 hours. After the starting material was completely consumed, the palladium catalyst was removed by celite filter. The reaction mixture was diluted with water and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (15% ethyl acetate / hexane) to give tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26 mg, 37.4 μmol, 20% yield). LCMS (ES-API, m / z): [M+H] + =696.2.

[0484] Step 2: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (40.1 mg, 252 μmol) and sodium hydride (10.1 mg, 252 μmol) were added to THF (2 mL) and stirred at room temperature for 30 minutes. After 30 minutes, tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 50.3 μmol) obtained in Step 1 was added to the reaction mixture at room temperature and stirred for 1 hour. After the starting material was completely consumed, the reaction was quenched by slowly adding water, and the organic layer was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% methanol / DCM) to give (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 24.5 μmol, 49% yield). LCMS (ES-API, m / z): [M+H] + =833.4

[0485] Step 3: Tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 24.5 μmol) obtained in step 2 was dissolved in DCM (1 mL), 4.0 M HCl in 1,4-dioxane (2 mL) was added, and the mixture was stirred at 50° C. for 1 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 35%) to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[d]thiazol-2-amine (13 mg, 21.04 μmol, yield 86%). LCMS (ES-API, m / z): [M+H] + =618.7; 1 H NMR (400MHz, MeOD) δ7.85 (dd, J=7.9, 1.3Hz, 1H), 7.45 (d, J=7.5Hz, 1H), 7.33 ( t,J=7.8Hz,1H),6.85(d,J=1.2Hz,1H),5.65(s,0.5H),5.52(s,0.5H),4.85–4 .66(m,3H),4.63(s,1H),4.49(d,J=14.5Hz,1H),4.19(s,2H),4.12–3.77(m,4 H),2.79–2.53(m,3H),2.51(s,2H),2.44–2.31(m,2H),2.12(d,J=44.9Hz,4H).

[0486] Example 55: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-amine.

[0487]

[0488] The compound was synthesized using Intermediate 19 in the same manner as in Example 54. Lyophilization was performed to obtain 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-amine (26 mg, 31.4 μmol, 83% yield). LCMS (ES-API, m / z): [M+H] + =636.7; 1 H NMR (400MHz, MeOD) δ7.47 (dd, J=8.5, 5.4Hz, 1H), 7.11 (t, J=8.8Hz, 1H), 6.85 (d, J= 1.3Hz,1H),5.66(s,0.5H),5.53(s,0.5H),4.75(t,J=5.3Hz,2H),4.72–4.57(m,2H) ,4.49(d,J=14.4Hz,1H),4.19(s,2H),4.14–3.82(m,6H),2.78–2.59(m,3H),2.59–2 .45(m,4H),2.38(dq,J=11.7,6.5Hz,3H),2.22–2.13(m,2H),2.04(d,J=9.6Hz,4H).

[0489] Example 56: Synthesis of 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline.

[0490]

[0491] A compound was synthesized in the same manner as in Example 51 using N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline. Purification was performed by preparative HPLC to give 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline (3.3 mg, 4.36 μmol, yield 6%). LCMS (ES-API, m / z): [M+H]+ =642.7; 1 H NMR (400MHz, MeOD) δ7.04 (s, 1H), 6.85 (d, J = 5.3Hz, 2H), 5.67 (s, 0.5H), 5.54 (s, 0.5H) ,4.92(s,1H),4.82–4.62(m,3H),4.53(d,J=14.1Hz,2H),4.17(s,1H),4.15–4.03(m,1H ),3.94(t,J=14.7Hz,3H),3.54(dd,J=10.3,5.6Hz,1H),2.81–2.62(m,2H),2.58(s,1H ),2.49(q,J=3.2Hz,2H),2.40(dt,J=11.3,6.3Hz,1H),2.17(s,1H),2.15–1.93(m,4H).

[0492] Example 57: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0493]

[0494] The compound was synthesized using Intermediate 18 in the same manner as in Example 44. Purification by preparative HPLC and lyophilization gave 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (26 mg, 39.8 μmol, 26% yield). LCMS (ES-API, m / z): [M+H] + =653.8; 1H NMR (400MHz, DMSO-d6, ppm) δ7.73 (dd, J=9.2, 6.0Hz, 1H), 7.28 (t, J=9.0Hz, 1H), 7.09–6.94(m,2H),6.76(s,1H),5.58(s,2H),5.29(s,0.5H),5.15(s,0.5H),4.11 –3.84(m,3H),3.37(d,J=22.7Hz,4H),3.03(d,J=9.2Hz,1H),2.95(s,1H),2.76( d,J=7.1Hz,1H),2.31(s,6H),2.14–1.91(m,4H),1.90–1.64(m,4H),1.51(s,3H).

[0495] Example 58: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0496]

[0497] The compound was synthesized in the same manner as in Example 44 using Intermediate 18 and Intermediate 8. Lyophilization was performed to obtain 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (70 mg, 96.6 μmol, yield 58%). LCMS (ES-API, m / z): [M+H] + =724.8; 1H NMR(400MHz,MeOD,ppm)δ7.79(dd,J=9.2,5.8Hz,1H),7.32–7.23(m,2H),7.15(d,J =2.4Hz,1H),6.87(s,1H),4.60(dd,J=44.9,13.1Hz,2H),4.50–4.32(m,2H),4.20(d ,J=21.3Hz,2H),3.96(dd,J=32.0,14.2Hz,3H),2.91(s,1H),2.46(s,3H),2.28(s, 2H), 2.10 (s, 4H), 1.33 (dt, J = 16.9, 8.3Hz, 3H), 1.01 (s, 2H), 0.90 (d, J = 4.5Hz, 2H).

[0498] Example 59: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0499]

[0500] The compound was synthesized using Intermediate 8 in the same manner as in Example 44. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (16 mg, 22.1 mmol, 58% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =726.8; 1 H NMR (400MHz, CD3OD, ppm): δ10.26(d,J=13.3Hz,1H),8.06–7.98(m,1H),7.54–7.43(m,1H),7.21(s,1H),6.79(s,1H),4.31(s,1H),4.15(s ,4H),3.77(s,2H),3.52(s,1H),2.41(s,3H),1.57(s,1H),1.47(s,2H),1.18(s,1H),0.89(s,1H),0.80(s,1H),0.66(s,1H),0.43(s,1H).

[0501] Example 60: Synthesis of 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.

[0502]

[0503] The compound was synthesized using Intermediate 3 in the same manner as in Example 20. 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (9 mg, 13.9 mmol, 46% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =644.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.49 (br d, J=1.2Hz, 1H), 7.98 (br s,1H),7.75-7.46(m,1H),7.27-7.07(m,1H),6.70(brs,2H),6.50(s,1H),5.39-5.14(m,1H),4.16 -3.93(m,2H),3.76-3.44(m,4H),3.25-3.17(m,1H),3.14-2.94(m,4H),2.90-2.75(m,1H),2.37(br d,J=1.6Hz,3H),2.21-1.94(m,4H),1.90-1.69(m,4H),1.63-1.18(m,3H).

[0504] Example 61: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-8-methyl-3-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0505]

[0506] The compound was synthesized in the same manner as in Example 44 using (S)-1-((S)-1-methylpyrrolidin-2-yl)ethanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (5 mg, 0.008 mmol, 36% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =738.7; 1 H NMR (400MHz, CD3OD, ppm): δ7.90 (ddd, J=8.2, 5.8, 2.0Hz, 1H), 7.43–7.30 (m, 1 H),7.22(d,J=2.5Hz,1H),6.85(d,J=5.1Hz,1H),5.50(s,1H),4.25(s,1H),4. 19(s,2H),4.12–3.96(m,2H),3.83(d,J=8.8Hz,2H),3.72(s,2H),3.64(q,J=7 .2Hz,3H),3.15(s,2H),2.46(s,3H),2.28–2.01(m,2H),1.58(d,J=6.1Hz,3H).

[0507] Example 62: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.

[0508]

[0509] Step 1: Tert-butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 571 μmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (358 mg, 285 μmol), dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (81.6 mg, 393 μmol) and Cs2CO3 (558 mg, 1710 μmol) were added to 1,4-dioxane (4 mL) and water (1 mL), and then degassing and nitrogen purging were repeated three times. Then, the reaction mixture was stirred at 120 ° C under nitrogen for 6 hours. After the starting material was completely consumed, the palladium catalyst was removed using a celite filter. The reaction mixture was diluted with water, and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (1R, 5S) -3- (6- (2- ( (tert- butoxycarbonyl) amino) -3- cyano -7- fluorobenzo [b] thiophene -4- base) -3- chloro -5- fluoro -8- methylfuro [3,2-f] quinazolin -1- base) -3,8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (290 mg, 393 μmol, yield 69%). LCMS (ES-API, m / z): [M + H] + =738.2.

[0510] Step 2: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (111.5 mg, 700 μmol) and NaH (28 mg, 700 μmol) were added to THF (2 mL) and stirred at room temperature for 30 minutes. After 30 minutes, tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 140 μmol) was added to the reaction mixture at room temperature, and the mixture was stirred at 50°C for 2 hours. After the starting material was completely consumed, water was slowly added at room temperature to quench the reaction, and the organic layer was extracted with ethyl acetate. After drying over anhydrous Na2SO4, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 59.8 μmol, 43% yield). LCMS (ES-API, m / z): [M+H] + =836.9.

[0511] Step 3: The compound was synthesized in the same manner as in Step 3 of Example 54 to give 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (17 mg, 25.8 μmol, 43% yield). LCMS (ES-API, m / z): [M+H] + =660.7; 1 H NMR (400MHz, MeOD) δ7.40 (dd, J=8.4, 5.1Hz, 1H), 7.09 (t, J=8.9Hz, 1H), 6.79 (s, 1H), 5.41 (s, 0.5H), 5.28 (s, 0.5H), 4.55 –4.06(m,4H),3.80–3.46(m,3H),3.28(dd,J=29.1,19.7Hz,39H),3.05(d,J=5.5Hz,1H),2.54–1.62(m,11H),1.31(s,1H).

[0512] Example 63: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.

[0513]

[0514] Step 1: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (139 mg, 814 μmol) and sodium tert-butoxide (156 mg, 1,630 μmol) were added to THF (1 mL) and DMF (3 mL) and stirred at room temperature for 30 minutes. After 30 minutes, tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 271 μmol) obtained in Step 2 of Example 62 was added to the reaction mixture at room temperature and stirred for 2 hours. After the starting material was completely consumed, water was slowly added at room temperature to quench the reaction, and the organic layer was extracted with ethyl acetate. After drying over anhydrous Na2SO4, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 126 μmol, 46% yield). LCMS (ES-API, m / z): [M+H] + =873.3.

[0515] Step 2: The compound was synthesized in the same manner as in Step 3 of Example 54. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (32 mg, 45.2 μmol, 39% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =672.7; 1 H NMR (400MHz, MeOD) δ7.41(dd,J=8.4,5.1Hz,1H),7.11(t,J=8.9Hz,1H),6.84(d,J=14.4Hz,1.5H),6.65(s,0.5H),4.68–4.39(m,2H),4.21(d,J=64 .5Hz,2H),3.99–3.60(m,3H),3.22(q,J=7.3Hz,2H),3.14–2.79(m,3H),2 .62(d,J=15.9Hz,1H),2.49(s,3H),2.35–1.70(m,7H),1.44–1.14(m,3H).

[0516] Example 64: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0517]

[0518] A compound was synthesized in the same manner as in Example 2 using (S,Z)-(4-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (32 mg, 0.048 mmol, 39% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =666.7; 1H NMR (400MHz, CD3OD, ppm): δ8.03-7.99(m,1H),7.51-7.44(m,1H),7.22(s,1H), 6.87(d,J=2.6Hz,1H),6.65(s,1H),4.82–4.66(m,3H),4.44–4.35(m,1H),4.27– 4.22(m,1H),4.18–4.14(m,1H),4.09–3.97(m,2H),3.97–3.84(m,3H),3.54–3.4 4(m,1H),2.77–2.58(m,3H),2.47(s,3H),2.43–2.22(m,3H),2.20–1.95(m,4H).

[0519] Example 65: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0520]

[0521] The compound was synthesized using Intermediate 16 in the same manner as in Example 44. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, 70% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =666.7; 1 H NMR (400MHz, CD3OD, ppm): δ7.90-7.87(m,1H),7.38-7.31(m,1H),7.21(s,1H) ),6.78(z,1H),6.65(s,1H),4.82–4.66(m,3H),4.44–4.35(m,1H),4.27–4.22 (m,1H),4.18–4.14(m,1H),4.09–3.97(m,2H),3.97–3.84(m,3H),3.54–3.44( m,1H),2.77–2.58(m,3H),2.43(s,3H),2.43–2.22(m,3H),2.20–1.95(m,4H).

[0522] Example 66: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0523]

[0524] The compound was synthesized in the same manner as in Example 44 using (7aR)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (27 mg, 47% yield) was obtained as an orange solid. LCMS (ES-API, m / z): [M+H] + =684.2; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.28(s,1H),8.01(m,1H),7.48(t,J=8.4Hz,1H),7.44(s,1H),7.21(s,1H),6.84(s,1H),4 .16–3.95(m,3H),3.66(m,1H),3.55-3.46(m,5H),3.00(m,1H),2.68(s,1H),2.38(s,3H),2.33(s,1H),2.00–1.58(m,9H).

[0525] Example 67: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0526]

[0527] The compound was synthesized in the same manner as in Example 57 using tert-butyl (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. 4-(1-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine (50 mg, 62% yield) was obtained as a brown solid. LCMS (ES-API, m / z): [M+H] + =653.2; 1 HNMR (400 MHz, DMSO-d 6, ppm): δ7.80(m,1H),7.35(t,J=9.0Hz,1H),7.08(m,2H),6.85(s,1H),5.65(s,2H),5.36-5.22(m,1H),4.43(s, 2H),4.06(m,2H),3.41(s,1H),3.21-3.03(m,5H),2.84(m,1H),2.68(m,2H),2.41(s,3H),2.16–1.77(m,14H).

[0528] Example 68: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol.

[0529]

[0530] Step 1: Dissolve 4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (300 mg, 0.904 mmol) in DCM (48 mL), add DIPEA (350 mg, 2.71 mmol, 0.501 mL), and then add tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 1.08 mmol). Stir the reaction mixture at room temperature for 1 hour. Dilute the reaction mixture with water (80 mL) and extract with DCM (50 mL*3). Wash the organic material with saturated aqueous NaCl (50 mL*2), dry over NaSO4, filter, and concentrate to obtain a residue. Precipitate the product in hexane, filter, and dry the filtered solid. Tert-butyl (1R,5S)-3-(4-bromo-7-chloro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (437 mg, 0.861 mmol, 95% yield) was obtained as a light beige solid. LCMS (ES-API, m / z): [M+H] + =508.8.

[0531] Step 2: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (480 mg, 3.02 mmol) was dissolved in THF (15 mL), and NaH (120.6 mg, 3.02 mmol) was added at 0°C. The mixture was stirred at room temperature for 20 minutes. To the THF solution (5 mL), tert-butyl (1R,5S)-3-(4-bromo-7-chloro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.302 mmol) obtained in Step 1 was slowly added and allowed to react at room temperature for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with aqueous NaCl (40 mL*2) and dried over Na2SO4. The filtered solution was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (5% DCM / MeOH). (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.283 mmol, 94% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =531.4.

[0532] Step 3: (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (53.5 mg, 84.8 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (32 mg, 102 μmol), A Pd G3 (9.2 mg, 12.7 μmol) and Cs2CO3 (54 mg, 255 μmol) were dissolved in toluene (1.5 mL) and water (0.15 mL), and then degassed and purged with nitrogen three times. The reaction mixture was then stirred at 80 ° C for 1 hour under nitrogen. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), and the compound was extracted with ethyl acetate (5 mL * 2). The organic layer was washed with saturated NaCl aqueous solution (5 mL * 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH / DCM). Tert-butyl (1R,5S)-3-(7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 84.8 μmol, yield 64%) was obtained. LCMS (ES-API, m / z): [M+H] + =738.9.

[0533] Step 4: Tert-butyl (1R,5S)-3-(7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 54.2 μmol) obtained in step 3 was dissolved in DCM (1 mL) and HCl in dioxane (4N, 0.3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%). 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol (25 mg, 54.2 μmol, yield 78%) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =594.7; 1 HNMR (400MHz, DMSO-d6, ppm): δ7.84 (d, J=8.3Hz, 1H), 7.50–7.43 (m, 2H), 7.40 ( d,J=8.5Hz,1H),7.32(d,J=2.4Hz,1H),7.24–7.17(m,2H),6.88(s,1H),5.66(s ,0.5H),5.53(s,0.5H),4.61(s,2H),4.37–4.23(m,3H),4.15(s,2H),3.95–3.8 8(m,4H),3.37–3.27(m,2H),2.43(s,3H),2.25–2.13(m,4H),2.11–1.86(m,6H).

[0534] Example 69: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0535]

[0536] Step 1: (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (107 mg, 170 μmol), (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (87 mg, 170 μmol), catalytic Cxium A Pd G3 (18.5 mg, 25.5 μmol) and Cs2CO3 (108 mg, 509 μmol) were added to toluene (1 mL) and water (0.1 mL), and degassing and nitrogen purging were repeated three times. Then, the reaction mixture was stirred at 80 ° C for 3 hours under nitrogen. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with purified water (10 mL), and the compound was extracted with ethyl acetate (5 mL * 2). The organic layer was washed with saturated NaCl aqueous solution (5 mL * 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH / DCM). Tert-butyl (1R,5S)-3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 64.1 μmol, 38% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =937.2.

[0537] Step 2: Tert-butyl (1R,5S)-3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 64.1 μmol) obtained in step 1 was dissolved in THF (0.5 mL), and TBAF (20.1 mg, 76.9 μmol) was added dropwise at 0°C. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with purified water (10 mL), and the compound was extracted with ethyl acetate (5 mL*2). The organic layer was washed with saturated aqueous NaCl (5 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MC:MeOH = 20:1) to give (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 64.1 μmol, 100% yield). LCMS (ES-API, m / z): [M+H] + =780.9.

[0538] Step 3: Tert-butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 53.4 μmol) obtained in step 2 was dissolved in DCM (0.5 mL) and 4N HCl in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%). 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (25 mg, 39.3 μmol, 74% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =636.7; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.33(s,1H),7.98(dd,J=9.2,6.0Hz,1H),7.45(t,J=9.0Hz,1H),7.38( d,J=2.6Hz,1H),7.32(s,1H),7.13(d,J=2.6Hz,1H),5.67(s,0.5H),5.54(s,0.5H),4.64–4.54(m,2H) ,4.39(s,1H),4.20–4.13(m,2H),4.10(s,3H),3.94–3.81(m,3H),3.69–3.60(m,3H),3.44(d,J=4.2Hz ,1H),3.37–3.27(m,2H),2.36–2.32(m,2H),2.24–2.14(m,3H),2.10–2.01(m,2H),1.98–1.89(m,3H).

[0539] Example 70: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalene-2-ol.

[0540]

[0541] The compound was synthesized in the same manner as in Example 68 using 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The residue was purified by preparative-HPLC to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (16 mg, 25.8 μmol, yield 100%) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =630.7; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.37 (s, 1H), 7.76–7.70 (m, 1H), 7.55 (q, J = 9.0Hz, 1H) ,7.40(s,1H),7.37(s,1H),7.13(d,J=2.3Hz,1H),5.67(s,0.5H),5.54(s,0.5H),4.6 0(s,2H),4.33–4.25(m,1H),4.16(s,2H),4.11(s,3H),3.94–3.85(m,3H),3.81–3.76 (m,3H),3.37–3.28(m,2H),2.26–2.14(m,3H),2.13–2.01(m,3H),2.01–1.88(m,4H).

[0542] Example 71: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0543]

[0544] The compound was synthesized using Intermediate 18 in the same manner as in Example 69. After preparative HPLC purification and lyophilization, 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (60 mg, 94.5 μmol, 42% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =635.7; 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.75(dd,J=9.2,6.0Hz,1H),7.30(t,J=9.0Hz,1H),7.16(s,1H),7.01(d,J=2.9Hz,2H),5.57(s,2H),5.36(s,0 .5H),5.22(s,0.5H),4.29–3.87(m,5H),3.78–3.35(m,7H),3.31(s,3H), 3.22–2.96(m,3H),2.84(q,J=8.4Hz,1H),2.21–1.70(m,7H),1.58(s,3H).

[0545] Example 72: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(3-(dimethylamino)azetidin-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0546]

[0547] The compound was synthesized in the same manner as in Example 68 using 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline and N,N-dimethylazetidin-3-amine. Preparative-HPLC purification and lyophilization were performed to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-(dimethylamino)azetidin-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (50.55 mg, 83.67 μmol, 43% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =595.3; 1HNMR(400MHz,DMSO-d6,ppm)δ11.30-10.30(m,2H),9.71-9.51(m,2H),9.41-9.23(m,1H),8. 20-8.10(m,1H),8.08-8.03(m,1H),7.74-7.66(m,1H),7.58-7.53(m,1H),6.18-6.06(m,1H), 5.72-5.61(m,1H),4.98-4.83(m,1H),4.41-4.36(m,4H),4.29-4.18(m,3H),4.03-3.93(m,1 H),2.86(s,6H),2.38-2.23(m,1H),2.05-1.74(m,3H),1.52-1.36(m,1H),1.30-1.18(m,1H).

[0548] Example 73: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0549]

[0550] The compound was synthesized using Intermediate 8 in the same manner as in Example 69. Preparative HPLC purification and lyophilization were performed to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (30 mg, 42.4 μmol, 45%). LCMS (ES-API, m / z): [M+H] + =707.8; 1H NMR (400MHz, DMSO-d6, ppm) δ10.05 (s, 1H), 8.28 (s, 1H), 7.96 (dd, J = 9.2, 6.0Hz, 1H), 7 .43(t,J=9.0Hz,1H),7.35(d,J=2.6Hz,1H),7.22(s,1H),7.13(d,J=2.5Hz,1H),4.27(s ,2H),4.06(s,2H),3.85–3.55(m,3H),3.42(d,J=14.8Hz,2H),2.36(q,J=12.4Hz,7H), 1.99(s,1H),1.83–1.28(m,7H),1.29–1.04(m,3H),0.64(d,J=4.9Hz,2H),0.42(s,2H).

[0551] Example 74: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0552]

[0553] Step 1: (S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (405 mg, 2.36 mmol) and sodium tert-butoxide (454 mg, 4.73 mmol) were added to THF (3 mL) and DMF (9 mL) and stirred at room temperature for 30 minutes. After 30 minutes, tert-butyl (1R,5S)-3-(4-bromo-2,7-dimethyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 778 μmol) was added to the reaction mixture at room temperature, and the mixture was stirred for 2 hours. After complete consumption of the starting material, the reaction was quenched by the slow addition of water at room temperature, and the organic layer was extracted with ethyl acetate. After drying over anhydrous NaSO, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH / DCM) to give tert-butyl (1R,5S)-3-(4-bromo-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (470 mg, 731 μmol, 93% yield). LCMS (ES-API, m / z): [M+H] +=643.6.

[0554] Step 2: (1R,5S)-3-(4-bromo-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 311 μmol), N-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine (295 mg, 467 μmol), cataCXium APd G3 (33.9 mg, 46.6 μmol) and cesium carbonate (304 mg, 934 μmol) were added to toluene (4 mL) and water (1 mL), and degassing and nitrogen purging were repeated three times. Then, the reaction mixture was stirred at 110 ° C under nitrogen for 24 hours. After the starting material was completely consumed, the palladium catalyst was removed by diatomaceous earth filter. The mixture was diluted with water and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH / DCM) to give tert-butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 84.3 μmol, 27% yield). LCMS (ES-API, m / z): [M+H] + =1068.

[0555] Step 3: tert-Butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 84.3 μmol) was dissolved in THF (2 mL) and tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 126 μL, 126 μmol) was added dropwise at 0°C. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH / DCM) to give tert-butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 43.9 μmol, 52% yield). LCMS (ES-API, m / z): [M+H] + =912.1.

[0556] Step 4: Tert-butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 43.9 μmol) was dissolved in DCM (0.5 mL) and 4N HCl in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (5% methanol / DCM, 5% NH4OH) to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (18 mg, 27.8 μmol, 63% yield). LCMS (ES-API, m / z): [M+H] + =647.7; 1H NMR(400MHz,MeOD)δ8.31(s,1H),7.76(dd,J=9.2,5.8Hz,1H),7.42(s,1H),7.3 0–7.09(m,3H),6.92(s,0.5H),6.71(s,0.5H),4.68–4.37(m,3H),4.33–4.08(m, 6H),3.90(d,J=13.8Hz,2H),3.78(d,J=14.1Hz,1H),3.57(s,1H),3.11(s,1H), 2.96(d,J=15.7Hz,1H),2.87(s,1H),2.70(d,J=15.7Hz,1H),2.42–1.93(m,8H).

[0557] Example 75: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0558]

[0559] The compound was synthesized in the same manner as in Example 69 using (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. After preparative HPLC purification and lyophilization, 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (62 mg, 95.7 μmol, 84% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =648.7; 1H NMR(400MHz,MeOD,ppm)δ8.31(s,1H),7.87(dd,J=9.2,5.7Hz,1H),7.41(s,1H),7.38– 7.24(m,2H),7.20(d,J=2.6Hz,1H),6.85(s,0.5H),6.64(s,0.5H),4.54–4.36(m,2H), 4.08(d,J=53.9Hz,6H),3.87(d,J=13.7Hz,1H),3.73(t,J=14.1Hz,2H),3.48–3.30(m, 16H), 3.02–2.77 (m, 3H), 2.59 (d, J = 15.6Hz, 1H), 2.33–2.17 (m, 2H), 2.18–1.89 (m, 5H).

[0560] Example 76: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.

[0561]

[0562] The compound was synthesized using Intermediate 8 in the same manner as in Example 74. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (30 mg, 42.4 μmol, 41% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =707.8; 1 H NMR (400MHz, MeOD, ppm) δ8.33 (s, 1H), 7.81 (dd, J = 9.2, 5.8Hz, 1H), 7.44 (s, 1 H),7.34–7.21(m,1H),7.17(d,J=2.4Hz,1H),4.66–4.42(m,2H),4.19(d,J=2 0.4Hz,3H),3.89(dd,J=41.4,14.1Hz,2H),2.91(s,1H),2.22(d,J=67.0Hz,4 H), 1.83 (d, J = 55.1Hz, 2H), 1.51–1.26 (m, 2H), 0.99 (dd, J = 44.0, 5.8Hz, 3H).

[0563] Example 77: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.

[0564]

[0565] The compound was synthesized using Intermediate 4 in the same manner as in Example 62. Lyophilization was performed to obtain 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (5.8 mg, 9.04 μmol, yield 11%) as a white solid. LCMS (ES-API, m / z): [M+H] + =707.8; 1 H NMR (400MHz, MeOD, ppm) δ8.37(s,1H),7.47(s,1H),7.41(dd,J=8.3,5.2Hz,1H),7.08(t,J=8.9Hz,1H),5.69(s,0.5H),5.57(s,0.5H),4.70(d,J=11 .6Hz,3H),4.38–3.74(m,9H),3.50(dq,J=11.2,5.9Hz,1H),2.95–2.27(m ,6H),2.05(d,J=9.9Hz,5H),1.86(s,2H),1.57(s,2H),1.46–1.25(m,3H).

[0566] Example 78: Synthesis of 9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline.

[0567]

[0568] The compound was synthesized using Intermediate 4 in the same manner as in Example 27. 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (23 mg, 53% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =632.3; 1 H NMR (400MHz, MeOD, ppm): δ8.27(S,1H),8.13-8.09(m,1H),7.67-7.61(m,1H),7.44 -7.39(m,1H),7.38(s,1H),6.79(s,0.5H),6.58(s,0.5H),4.34-4.12(m,3H),4.09( s,3H),4.06(m,1H),3.92-3.88(d,1H),3.69-3.50(m,5H),3.21-3.19(m,1H),2.96( s,1H),2.81-2.74(m,2H),2.51-2.47(d,1H),2.20-2.17(m,1H),2.06-1.84(m,8H).

[0569] Example 79: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0570]

[0571] The compound was synthesized using Intermediate 16 in the same manner as in Example 32. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (68 mg, 83% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.7; 1H NMR (400MHz, DMSO-d6, ppm): δ8.27(s,1H),8.13-8.09(m,1H),7.67-7.61(m,1H),7.44-7.38(m,1H),6.79(s,0.5H),6.58(s,0.5H),4.34-4.29 (m,3H),4.12(s,3H),4.09(m,2H),3.92-3.88(d,1H),3.58-3.19(m,5H) ,2.77-2.74(m,2H),2.51(d,1H),2.20-2.17(m,1H),2.06-1.31(m,8H).

[0572] Example 80: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0573]

[0574] Step 1: Dissolve 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (2 g, 5.71 mmol) in ACN (30 mL) and add DIPEA (1.11 g, 8.57 mmol, 1.49 mL) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 1.46 g, 6.86 mmol). Stir the reaction mixture at room temperature for 1 hour. Dilute the reaction mixture with water (40 mL) and extract with ethyl acetate (30 mL*4). Wash the organic material with saturated aqueous NaCl (50 mL*2), dry over NaSO4, filter, and concentrate to obtain a residue. The product was stirred in PE:EtOAc = 2:1 at room temperature for 30 minutes to give tert-butyl (1R,5S)-3-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.1 g, 5.13 mmol, 90% yield) as a pink solid. LCMS (ES-API, m / z): [M+H] + =527.1; 1H NMR (400MHz, DMSO-d6, ppm): δ8.69 (s, 1H), 4.24 (s, 3H), 4.21 (br d, J = 4.0Hz, 2H), 4.13-4.02 (m, 2H), 3.59 (br d,J=11.6Hz,2H),1.69-1.54(m,4H),1.46(s,9H).

[0575] Step 2: Dissolve tert-butyl (1R,5S)-3-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 2.48 mmol) in DMSO (30 mL), and add KF (865.15 mg, 14.89 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.19 g, 7.45 mmol), and 18-crown-6 (2.30 g, 8.69 mmol). The reaction mixture was allowed to react at 120°C for 16 hours. After confirming the disappearance of the starting material, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL*4). The organic material was washed with a saturated aqueous NaCl solution (50 mL*2), dried over Na2SO4, filtered, and concentrated to obtain a residue. The reaction mixture was purified by silica gel chromatography (eluent 0–50% ethyl acetate / petroleum ether, gradient elution) to obtain (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (545 mg, 689.09 μmol, yield 28%) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.54(s,1H),5.40-5.11(m,1H),4.20(s,5H),4.15-4.10(m,1H),4.06-4.00(m,2H),3.58-3.50(m,2H),3 .12-3.06(m,2H),3.01(s,1H),2.87-2.78(m,1H),2.16-2.10(m,1H),2.08-2.04(m,1H),2.03-1.99(m,1H),1.90-1.71(m,4H),1.65(br s,4H),1.45(s,9H).

[0576] Step 3: (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 379.31 μmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (233.29 mg, 455.18 μmol), Pd(dtbpf)Cl2 (24.72 mg, 37.93 μmol) and K3PO4 (241.55 mg, 1.14 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.75 mL), then degassed and purged with nitrogen three times. The reaction mixture was allowed to react at 80°C for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL*3). Purification by silica gel chromatography gave tert-butyl (1R,5S)-3-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (229 mg, 225.59 μmol, 59% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =954.5; 1H NMR (400MHz, DMSO-d6, ppm): δ8.42(brs,1H),8.14-8.02(m,1H),7.72(d,J=2.4Hz,1H),7.54(br t,J=8.8Hz,1H),7.28(br d,J=1.6Hz,1H),5.35(s,2H),5.22(br s,1H),4.66-4.41(m,1H),4.34-4.28(m,1H),4.21(brd,J=4.8Hz,1H),4.15-4.08(m ,1H),4.03-3.92(m,2H),3.83-3.75(m,1H),3.58-3.48(m,3H),3.43(s,3H),3.10(br d,J=6.8Hz,2H),3.02(br s,1H),2.88-2.80(m,1H),2.28-2.15(m,2H),2.10-2.00(m,2H),1.86-1.73(m ,4H),1.47(s,9H),1.28-1.20(m,2H),0.88-0.80(m,4H),0.69-0.60(m,18H).

[0577] Step 4: Dissolve tert-butyl (1R,5S)-3-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (229 mg, 225.59 μmol) in DMF (4 mL), add CsF (514.02 mg, 3.38 mmol), and allow the mixture to react at room temperature for 40 minutes. After completion of the reaction, extract with ethyl acetate (10 mL*4) and saturated aqueous NaCl solution. Separation by preparative TLC gave tert-butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (174 mg, 209.36 μmol, 93% yield) as an orange solid. LCMS (ES-API, m / z): [M+H] + =798.4; 1H NMR (400MHz, DMSO-d6, ppm): δ8.41(s,1H),8.10(dd,J=6.0,9.2Hz,1H),7.74(d,J=2.8Hz,1H),7.53(t,J=9.2Hz,1H),7.35(d,J=2.0Hz,1H),5.22(br s,3H),4.27(br s,2H),4.13(br dd,J=6.0,10.4Hz,2H),4.05(s,4H),3.98-3.90(m,1H),3.64-3.50(m,3H),3.45(s,3H),3.14-3.06(m,2H),3.02(br s,1H),2.88-2.80(m,1H),2.15(br dd,J=4.4,6.8Hz,1H),2.09-2.00(m,2H),1.89-1.67(m,7H),1.47(s,9H).

[0578] Step 5: To tert-butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (174 mg, 209.36 μmol) was added HCl in 1.4-dioxane (2 M, 2.5 mL) and reacted at 0°C for 1 hour. After the reaction was completed, the product was purified by preparative HPLC to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (47.05 mg, 71.26 μmol, 34% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =654.3; 1H NMR (400MHz, DMSO-d6, ppm): δ10.28-9.91(m,1H),8.32(s,1H),7.97(dd,J=6.0,9.2Hz,1H),7.44(t,J=9.2Hz,1H),7.38(d,J=2.4Hz,1 H),7.16(d,J=2.4Hz,1H),5.39-5.18(m,1H),4.11(dd,J=5.6,10.4Hz,1H),4.05(s,3H),4.04-3.98(m,2H),3.89-3.80(m,1H),3.55(br d,J=13.2Hz,1H),3.45(br d,J=8.0Hz,5H),3.15-3.07(m,2H),3.05-3.00(m,1H),2.87-2.79(m,1H),2 .18-2.11(m,1H),2.09-1.98(m,2H),1.88-1.71(m,4H),1.69-1.52(m,3H).

[0579] Example 81: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0580]

[0581] The compound was synthesized using Intermediate 4 in the same manner as in Example 57. The resulting compound was purified by preparative HPLC and then lyophilized to give 4-(9-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-amine (75.99 mg, 115.06 μmol, 49% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =653.4; 1H NMR (400MHz, DMSO-d6, ppm): δ8.35-8.25(m,1H),7.81-7.72(m,1H),7.37-7.25(m,1H),7.09- 6.96(m,2H),5.61-5.50(m,2H),5.41-5.18(m,1H),4.15-3.95(m,6H),3.87-3.77(m,1H),3.5 9-3.50(m,1H),3.49-3.41(m,3H),3.36-3.34(m,2H),3.16-3.06(m,2H),3.05-2.99(m,1H),2 .88-2.78(m,1H),2.20-2.11(m,1H),2.10-1.96(m,2H),1.91-1.70(m,4H),1.70-1.52(m,3H).

[0582] Example 82: Synthesis of 9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline.

[0583]

[0584] The compound was synthesized in the same manner as in Example 80 using ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. The resulting compound was purified by preparative-HPLC and then lyophilized to give 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (32 mg, 49.38 μmol, yield 24%) as a pink solid. LCMS (ES-API, m / z): [M+H] + =638.3; 1H NMR (400MHz, DMSO-d6, ppm): δ8.32(s,1H),8.26-8.13(m,2H),7.74-7.53(m,3H) ),5.39-5.18(m,1H),4.12(dd,J=6.0,10.4Hz,1H),4.07-3.98(m,5H),3.87(br d,J=6.0Hz,1H),3.59-3.43(m,5H),3.21-2.96(m,4H),2.89-2.78(m,1H),2.22-2.12(m,1H),1.99(br s,2H),1.92-1.66(m,5H),1.57(br s,2H).

[0585] Example 83: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0586]

[0587] A compound was synthesized in the same manner as in Example 68 using 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (35 mg, 54.7 mmol, yield 86%) was obtained. LCMS (ES-API, m / z): [M+H] + =640.7; 1H NMR (400MHz, MeOD, ppm): δ8.31(s,1H),7.66(dd,J=9.2,6.0Hz,1H),7.39(s,1H),7.28–7.16(m,1H),7. 05(d,J=2.7Hz,1H),5.40(s,0.5H),5.27(s,0.5H),4.32(d,J=10.2Hz,2H),4.23(d,J=10.3Hz,2H),4.1 3(s,3H),4.09(s,1H),3.73–3.60(m,1H),3.57(s,3H),3.26(s,1H),3.21(s,1H),3.04(s,2H),2.46(s, 2H), 2.30 (s, 1H), 2.17 (s, 1H), 2.03 (s, 3H), 1.92 (d, J = 7.5Hz, 1H), 1.79 (s, 2H), 0.64 (t, J = 7.2Hz, 3H).

[0588] Example 84: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalene-2-ol.

[0589]

[0590] Step 1: Tert-butyl (1R,5S)-3-(4-bromo-7-chloro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.591 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (310 mg, 0.886 mmol), cataCXium APd G3 (44 mg, 0.0591 mmol) and Cs2CO3 (577 mg, 1.77 mmol) were dissolved in toluene (12 mL) and purified water (3 mL), then degassed and purged with nitrogen three times. After stirring at 100°C for 3 hours, the reaction was quenched by adding water. Ethyl acetate was added, the organic layer was extracted, and the mixture was dried over anhydrous MgSO₄. Purification by silica gel chromatography afforded tert-butyl (1R,5S)-3-(7-chloro-4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (286 mg, 0.439 mmol, 74% yield) as a brown oil. LCMS (ES-API, m / z): [M+H] + =651.2.

[0591] Step 2: tert-Butyl (1R,5S)-3-(7-chloro-4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (286 mg, 0.439 mmol) obtained in Step 1 was dissolved in THF (3 mL) and DMF (3 mL), and (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (376 mg, 2.2 mmol) and sodium tert-butoxide (211 mg, 2.2 mmol) were added sequentially and stirred at 40° C. for 3 hours. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO 4 . Purification by silica gel chromatography gave tert-butyl (1R,5S)-3-(4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.191 mmol, 43% yield). LCMS (ES-API, m / z): [M+H]+ =785.9.

[0592] Step 3: To tert-butyl (1R,5S)-3-(4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.191 mmol) was added HCl in 1,4-dioxane (4 M, 2.5 mL) and stirred at 0 °C for 1 hour. After the reaction was completed, the product was purified by preparative HPLC to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (100 mg, 0.16 mmol, 82% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =642.7; 1 H NMR (400MHz, MeOD, ppm): δ8.29(s,1H),7.63-7.59(m,1H),7.39-7.31(m,2H) ,7.31(s,1H),7.19(s,1H),6.78(s,0.5H),6.57(s,0.5H),4.34-4.12(m,3H), 4.09(s,3H),4.06(m,1H),3.92-3.88(d,1H),3.69-3.50(m,5H),3.21-3.19( m,1H),2.96(s,1H),2.81-2.74(m,2H),2.51-2.47(d,1H),2.18-1.87(m,9H).

[0593] Example 85: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0594]

[0595] The compound was synthesized in the same manner as in Example 84 using 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (33 mg, 0.049 mmol, 72% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =670.8; 1 H NMR (400MHz, MeOD, ppm): δ8.33(s,1H),7.70(dd,J=9.1,6.0Hz,1H),7.32(d,J=2.7Hz,1H) ,7.24(t,J=9.3Hz,1H),7.07(d,J=2.7Hz,1H),6.78(s,0.5H),6.56(s,0.5H),4.35–4.26(m ,3H),4.13(s,5H),3.89(d,J=15.1Hz,2H),3.67(d,J=16.5Hz,2H),3.59(s,4H),3.47(s,2H ), 3.32 (s, 2H), 2.50 (s, 2H), 1.92 (s, 2H), 1.80 (s, 3H), 1.31 (s, 2H), 0.68 (t, J = 7.3Hz, 3H).

[0596] Example 86: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalene-2-ol.

[0597]

[0598] The compound was synthesized in the same manner as in Example 84 using 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (46 mg, 0.069 mmol, 56% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =660.7; 1 H NMR (400MHz, MeOD, ppm): δ8.31(s,1H),7.62(dd,J=9.2,4.8Hz,1H),7.44–7.35(m,1H),7.34(d,J=2.2Hz,1H ),7.23(d,J=2.3Hz,1H),6.78(s,0.5H),6.57(s,0.5H),4.38–4.27(m,2H),4.22(s,2H),4.14(s,3H),3.89( d,J=15.0Hz,1H),3.65(dd,J=12.9,6.5Hz,2H),3.59(s,2H),3.49(d,J=14.2Hz,1H),3.19(dd,J=10.4,5.8H z,1H),2.85–2.69(m,2H),2.48(d,J=15.2Hz,1H),2.21(s,1H),2.08–1.84(m,5H),1.80(s,3H),1.31(s,3H).

[0599] Example 87: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0600]

[0601] The compound was synthesized using Intermediate 8 in the same manner as in Example 80. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (26.26 mg, 35.82 μmol, 20% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =726.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.28-9.90 (m, 1H), 8.31 (s, 1H), 7.97 (dd, J = 6.0, 9.2Hz, 1H) ,7.44(t,J=9.2Hz,1H),7.38(d,J=2.4Hz,1H),7.16(d,J=2.4Hz,1H),4.30(s,2H),4.10(br d,J=11.2Hz,1H),4.05(s,3H),3.83(br d,J=12.0Hz,1H),3.57(br d,J=11.6Hz,2H),3.48(brs,3H),3.42(s,3H),2.44(br d,J=1.2Hz,2H),2.36(br d,J=9.6Hz,2H),1.82-1.66(m,2H),1.62-1.53(m,4H),1.49(br s,2H),1.17(br t,J=8.4Hz,2H),0.64(s,2H),0.41(s,2H).

[0602] Example 88: Synthesis of 4-(9-(2,5-diazabicyclo[2.2.2]oct-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0603]

[0604] The compound was synthesized in the same manner as in Example 80 using tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate. 4-(9-(2,5-diazabicyclo[2.2.2]oct-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (23.80 mg, 35.68 μmol, 18% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =654.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.72-9.56(m,1H),8.33(d,J=9.2Hz,1H),7.97(dd,J=6.0,9.2Hz, 1H),7.44(t,J=8.8Hz,1H),7.39(d,J=2.4Hz,1H),7.20-7.07(m,1H),5.40-5.17(m,1H),4.34(br d,J=13.2Hz,1H),4.16-4.08(m,1H),4.06(d,J=4.4Hz,3H),3.99(br d,J=10.4Hz,1H),3.80(br d,J=10.4Hz,1H),3.58(br d,J=11.2Hz,2H),3.53-3.48(m,1H),3.20(br d,J=9.2Hz,1H),3.09(br d,J=9.2Hz,2H),3.03-2.98(m,2H),2.86-2.79(m,1H),2.43-2.31(m,1H),2.30-2.18(m,1H),2.14(br d,J=5.6Hz,1H),2.08-1.94(m,3H),1.92-1.72(m,6H).

[0605] Example 89: Synthesis of 9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-(5-chloro-3,6-dimethyl-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline.

[0606]

[0607] Step 1: Intermediate 22 (100 mg, 324.08 μmol), (1R,5S)-tert-butyl 3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (199.67 mg, 307.87 μmol), K3PO4 (206.37 mg, 972.23 μmol) and cataCXium A Pd G4 (21.12 mg, 32.41 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), degassed and purged with nitrogen three times, and the mixture was stirred at 90°C for 2 hours. After the reaction was completed, purified water was added to the reaction mixture to quench the reaction, and ethyl acetate was added to extract the organic layer, which was then dried over anhydrous MgSO4. The reaction residue was purified by preparative-TLC to give (1R,5S)-3-(4-(5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (87 mg, 99.19 μmol, yield 31%). LCMS (ES-API, m / z): [M+H] + =832.3.

[0608] Step 2: Tert-butyl (1R,5S)-3-(4-(5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (77 mg, 92.51 μmol) was dissolved in DCM (1 mL), TFA (3.07 g, 26.92 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, purified water was added to the reaction mixture to quench the reaction, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The reaction residue was purified by preparative HPLC to give 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-chloro-3,6-dimethyl-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (15.36 mg, 23.63 μmol, 26% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =832.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ12.84 (br s,1H),8.39(s,1H),7.58(s,1H),5.38-5.19(m,1H),4.17-4.10(m,1H),4.0 6(s,2H),4.09-4.00(m,1H),4.05-4.00(m,1H),3.92-3.84(m,1H),3.59(br d,J=11.6Hz,1H),3.53-3.43(m,3H),3.16-3.05(m,2H),3.04-2.98(m,1H),2.87-2.79(m ,1H),2.52(s,4H),2.22-2.12(m,1H),2.09-1.97(m,2H),1.89-1.72(m,4H),1.58(s,6H).

[0609] Example 90: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0610]

[0611] The compound was synthesized in the same manner as in Example 80 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (115.52 mg, 166.43 μmol, 53% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =684.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.22-9.95(m,1H),8.32(s,1H),7.97(s,1H),7.48-7.40(m,1H),7.39(d,J=2.0Hz,1H),7.16(d,J=2.0Hz ,1H),4.21-4.06(m,3H),4.05(s,3H),3.91-3.78(m,1H),3.72-3.61(m,1H),3.59-3.51(m,1H),3.44(m,4H),3.06-2.95(m,1H),2.66(br d,J=15.6Hz,1H),2.62-2.52(m,2H),2.48-2.34(m,2H),1.99(m,1H),1.91-1.70(m,4H),1.69-1.50(m,3H).

[0612] Example 91: Synthesis of an isomer of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0613]

[0614] The compound of Example 90 was separated under isocratic elution conditions (retention time: 1.160 min) using a DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO₂-ACN / i-PrOH (0.1% NH₃ H₂O)]; B%: 55% to obtain a single atropisomer (ee% = 98.5%) (126.94 mg, 182.88 μmol, 44% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =684.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.36-9.85 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 8.8 Hz,1H),7.44(s,1H),7.40-7.36(m,1H),7.16(d,J=2.4Hz,1H),4.19-4.02(m,6H),3 .90-3.79(m,1H),3.71-3.61(m,1H),3.59-3.52(m,1H),3.44(brd,J=12.0Hz,5H),3 .04-2.96(m,1H),2.69-2.52(m,3H),2.45-2.37(m,1H),2.04-1.93(m,1H),1.78(br s,4H),1.56(br s,3H).

[0615] Example 92: Synthesis of an isomer of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0616]

[0617] The compound of Example 90 was separated under isocratic elution conditions (retention time: 1.605 min) using a DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO₂-ACN / i-PrOH (0.1% NH₃ H₂O)]; B%: 55% to obtain a single atropisomer (ee% = 96.5%) as a yellow solid (98.73 mg, 141.7 μmol, 34% yield). LCMS (ES-API, m / z): [M+H] + =684.3; 1H NMR (400MHz, DMSO-d6, ppm): δ10.37-9.83(m,1H),8.32(s,1H),7.97(dd,J=6.0,8.8Hz,1H),7.51-7.35(m,2H),7.16(d,J=2.4Hz ,1H),4.17-4.01(m,6H),3.90-3.79(m,1H),3.71-3.62(m,1H),3.59-3.52(m,1H),3.51-3.41(m,5H),3.06-2.95(m,1H),2.53(br s,3H),2.43(br s,1H),2.04-1.93(m,1H),1.92-1.71(m,4H),1.70-1.51(m,3H).

[0618] Example 93: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0619]

[0620] The compound was synthesized in the same manner as in Example 83 using 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline. The reaction residue was purified by preparative HPLC and lyophilized to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalene-2-ol (40 mg, 0.061 mmol, 49% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =658.7; 1H NMR (400MHz, MeOD, ppm): δ8.33 (s, 1H), 7.72 (dd, J = 9.2, 5.8Hz, 1H), 7.31 (s, 1H), 7 .27(t,J=8.9Hz,1H),7.06(d,J=2.6Hz,1H),5.41(s,0.5H),5.27(s,0.5H),4.36-4 .18(m,4H),4.13(s,3H),3.71-3.59(m,4H),3.27-3.22(m,2H),3.05-3.04(m,1H), 2.31-2.21(m,4H),2.05-2.03(m,5H),1.99-1.80(m,4H)1.31(m,2H),0.68(m,3H).

[0621] Example 94: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0622]

[0623] The compound was synthesized in the same manner as in Example 80 using (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. The compound was purified by preparative HPLC to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (12 mg, 0.617 mmol, 29% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =666.7; 1H NMR (400MHz, MeOD, ppm): δ8.29 (s, 1H), 7.88 (dd, J=9.2, 5.8Hz, 1H), 7.36 (d, J=2.6Hz, 1H),7.31(t,J=8.9Hz,1H),7.22(d,J=2.6Hz,1H),6.78(s,0.5H),6.57(s,0.5H),4.39 –4.25(m,2H),4.21(t,J=14.2Hz,2H),4.13(s,3H),3.90(d,J=15.1Hz,4H),3.67(d,J= 7.3Hz, 2H), 3.52 (s, 2H), 2.85–2.70 (m, 2H), 2.48 (d, J = 15.2Hz, 1H), 1.94–1.85 (m, 3H).

[0624] Example 95: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalene-2-ol.

[0625]

[0626] The compound was synthesized in the same manner as in Example 83 using 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The reaction residue was purified by preparative-HPLC to give 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (56 mg, 0.086 mmol, 62% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =648.7; 1H NMR (400MHz, MeOD, ppm): δ8.31(s,1H),7.62(dd,J=9.3,4.8Hz,1H),7.44–7.35(m,1H),7.33(d ,J=2.3Hz,1H),7.23(d,J=2.4Hz,1H),5.41(s,0.5H),5.28(s,0.5H),4.35(d,J=10.4Hz,1H),4. 30–4.20(m,3H),4.18(s,3H),3.67(s,3H),3.60(s,2H),3.05(q,J=9.0Hz,1H),2.42(dd,J=15.0 ,4.7Hz,3H),2.37–2.25(m,2H),2.21(dd,J=18.9,11.4Hz,2H),2.03(m,2H),1.94–1.84(m,4H).

[0627] Example 96: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0628]

[0629] The compound was synthesized using Intermediate 17 in the same manner as in Example 80. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (28.22 mg, 40.06 μmol, 34% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =692.3; 1H NMR (400MHz, DMSO-d6, ppm): δ10.20-9.99 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 9. 2Hz,1H),7.44(t,J=9.2Hz,1H),7.39(d,J=2.4Hz,1H),7.19-7.12(m,1H),4.89(br s,2H),4.12-4.00(m,5H),3.93(br dd,J=6.0,10.0Hz,1H),3.89-3.81(m,1H),3.60-3.48(m,5H),3.48-3.42(m,2H),3.28-3.19(m,6H),2.94-2.84(m,1H),2.62- 2.54(m,1H),2.33(brd,J=15.6Hz,1H),2.12-2.04(m,1H),1.96(td,J=2.8,5.6Hz,1H),1.82-1.73(m,1H),1.73-1.55(m,5H).

[0630] Example 97: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0631]

[0632] The compound was synthesized in the same manner as in Example 83 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (42 mg, 0.998 mmol, 61% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =688.7; 1H NMR (400MHz, MeOD,,ppm): δ8.33(s,1H),7.70(dd,J=9.0,5.9Hz,1H),7.32(d,J=2.7Hz,1H),7.24(t,J=9.4Hz,1H),7.07(d,J=2.6H z,1H),4.40(dd,J=10.5,5.1Hz,1H),4.31(dd,J=10.5,3.1Hz,2H),4.25(s,1H),4.13(s,3H),3.84(d,J=14.4Hz,1H),3.72–3.63(m ,2H),3.60(s,3H),3.45(d,J=14.5Hz,1H),3.22–3.15(m,1H),2.86(d,J=16.2Hz,1H),2.73(d,J=8.3Hz,1H),2.54(d,J=16.0Hz,3H ),2.26(s,1H),2.17(d,J=5.5Hz,1H),2.00(d,J=17.7Hz,1H),1.94(s,3H),1.99–1.88(m,1H),1.81(s,4H),0.68(t,J=7.3Hz,3H).

[0633] Example 98: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0634]

[0635] The compound was synthesized using Intermediate 15 in the same manner as in Example 80. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (5.24 mg, 7.46 μmol, 25% yield) was obtained as an off-white solid. LCMS (ES-API, m / z): [M+H] + =682.4; 1H NMR (400MHz, DMSO-d6, ppm): δ10.23-9.97(m,1H),7.44(t,J=9.2Hz,1H),7.39(d ,J=2.4Hz,1H),5.24-5.01(m,1H),4.48-4.37(m,2H),4.14-4.01(m,4H),3.86(br d,J=10.8Hz,1H),3.56(br d,J=12.0Hz,1H),3.47(br d,J=17.6Hz,4H),2.81-2.61(m,5H),2.42-2.29(m,1H),2.05-1.83(m,7H),1.80-1.52(m,5H),1.23(s,1H).

[0636] Example 99: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0637]

[0638] The compound was synthesized in the same manner as in Example 81 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-amine (45 mg, 65.91 μmol, 26% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =683.3; 1H NMR (400MHz, DMSO-d6, ppm): δ8.32(s,1H),7.77(dd,J=6.0,9.2Hz,1H),7.31(t,J=9.2Hz,1H),7 .06-7.00(m,2H),5.57(s,2H),4.17-4.03(m,7H),3.87-3.77(m,1H),3.70-3.62(m,1H),3.56(br d,J=12.0Hz,1H),3.49-3.44(m,3H),3.06-2.97(m,1H),2.70-2.56(m,3H),2.41(br d,J=15.6Hz,1H),2.04-1.67(m,6H),1.66-1.52(m,3H).

[0639] Example 100: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0640]

[0641] The compound was synthesized using Intermediate 16 in the same manner as in Example 80. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (18 mg, 46% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =666.7; 1H NMR (400MHz, MeOD, ppm): δ8.29(s,1H),7.88(dd,J=9.2,5.7Hz,1H),7.37(d,J=2.6Hz,1H),7.31(t,J=8.9Hz ,1H),7.22(d,J=2.6Hz,1H),5.45(s,0.5H),5.31(s,0.5H),5.01(s,2H),4.36–4.18(m,3H),4.13(s,3H),3.8 2(d,J=13.5Hz,1H),3.68(t,J=11.9Hz,3H),3.45(d,J=15.1Hz,1H),3.27–3.17(m,1H),2.91(d,J=11.4Hz,1H ), 2.80 (s, 2H), 2.32 (dd, J = 24.0, 14.7Hz, 1H), 2.05 (d, J = 9.3Hz, 1H), 1.92 (s, 1H), 1.86 (s, 3H), 0.91 (s, 3H).

[0642] Example 101: Synthesis of 9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline.

[0643]

[0644] The compound was synthesized using ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane and (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol in the same manner as in Example 80. 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (22 mg, yield 56%) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =666.7; 1H NMR (400MHz, MeOD, ppm): δ8.31(s,1H),8.17–8.09(m,1H),7.73–7.61(m,1H),7.43(t,J=8.9Hz,1H),4.40(dd ,J=10.6,7.7Hz,1H),4.32(dd,J=10.6,6.8Hz,1H),4.24(d,J=13.0Hz,2H),4.12(s,3H),3.86(d,J=14.5Hz,1H ),3.74–3.67(m,4H),3.46(s,1H),3.23–3.15(m,1H),2.99(s,1H),2.87(d,J=15.8Hz,1H),2.75(q,J=8.2Hz, 1H),2.55(d,J=16.1Hz,1H),2.04(d,J=9.2Hz,1H),2.01–1.92(m,1H),1.95(s,4H),1.87(s,2H),1.31(s,2H).

[0645] Example 102: Synthesis of (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-1-yl)(oxirane-2-yl)methanone.

[0646]

[0647] Step 1: 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (500 mg, 1.43 mmol, 1 eq) was dissolved in ACN (8 mL) and DIPEA (369.29 mg, 2.86 mmol, 497.70 μL, 2 eq) and tert-butyl piperazine-1-carboxylate (319.31 mg, 1.71 mmol, 1.2 eq) were added dropwise. The reaction mixture was stirred at room temperature for 1 hour, filtered, washed with PE, and dried under vacuum. tert-Butyl 4-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (570 mg, crude mixture) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =501.0; HNMR (400MHz, DMSO-d6, ppm): δ8.73 (s, 1H), 4.28 (s, 3H), 3.56-3.54 (m, 8H), 1.45 (s, 9H).

[0648] Step 2: A compound was synthesized in the same manner as in Step 2 of Example 80 using tert-butyl 4-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate. tert-Butyl 4-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (384 mg, 561.96 μmol, 74% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =624.0; HNMR (400MHz, DMSO-d6, ppm): δ8.64 (s, 1H), 5.33 (d, J = 53.6Hz, 1H) 4.29 (s, 3H), 4.20-4.07 (m, 2H), 3.63 (s ,3H),3.55-3.50(m,4H),3.15-3.06(m,3H),2.93-2.77(m,2H),2.20-2.03(m,3H),1.93-1.83(m,3H),1.48(s,9H).

[0649] Step 3: A compound was synthesized in the same manner as in Step 3 of Example 80 using tert-butyl 4-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate. Tert-butyl 4-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (300 mg, 323.22 μmol, 59% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =928.5.

[0650] Step 4: A compound was synthesized in the same manner as in Step 4 of Example 80 using tert-butyl 4-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate. Tert-butyl 4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (310 mg, crude mixture) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =772.4.

[0651] Step 5: A compound was synthesized in the same manner as in Step 5 of Example 80 using tert-butyl 4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]pyrrolizin-9-yl)piperazine-1-carboxylate. 5-Ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(piperazin-1-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol (64 mg, 101.35 μmol, 46% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =628.3.

[0652] Step 6: Potassium oxirane-2-carboxylate (19.29 mg, 152.95 μmol, 2.4 eq) was dissolved in DMF (0.5 mL) and HATU (29.08 mg, 76.47 μmol, 1.2 eq) was added dropwise. To the reaction mixture was added 5-ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(piperazin-1-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol (40 mg, 63.73 μmol, 1 eq) and DIPEA (24.71 mg, 191.19 μmol, 33.30 μL, 3 eq) and stirred at room temperature for 1 hour. Preparative HPLC (neutral conditions; column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 9 minutes) was performed to obtain (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-1-yl)(oxirane-2-yl)methanone (10.77 mg, 14.74 μmol, 12% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =698.4; HNMR (400MHz, DMSO-d6, ppm): δ10.51-9.83(m,1H),8.63-8.39(m,1H),8.07-7.87( m,1H),7.49-7.31(m,2H),7.22-7.12(m,1H),5.42-5.14(m,1H),4.18-4.02(m,5H),4.01-3. 88(m,3H),3.85-3.74(m,2H),3.65-3.41(m,5H),3.13-3.06(m,2H),3.04-2.99(m,1H),2.9 8-2.94(m,1H),2.87-2.80(m,2H),2.19-2.13(m,1H),2.10-1.99(m,2H),1.90-1.72(m,3H).

[0653] Example 103: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0654]

[0655] The compound was synthesized in the same manner as in Example 80 using 3-Boc-3,8-diazabicyclo[3.2.1]octane. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (38 mg, 58.1 μmol, 71% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =654.3; 1 HNMR (400MHz, CD3OD, ppm): δ8.28(s,1H),7.88(dd,J=9.1,5.8Hz,1H),7.37(d,J=2.5Hz,1H),7.31(t,J=8.9Hz,1H),7.24(d,J=2.6Hz,1H),5.42(m ,0.5H),5.29(m,0.5H),4.62(m,3H),4.41-4.25(m,1H),4.31(m,1H),4.1 5(s,3H),2.90-2.82(m,3H),2.05-1.99(m,7H),1.92(m,3H),1.32(m,6H).

[0656] Example 104: Synthesis of 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.

[0657]

[0658] The compound was synthesized using Intermediate 5 in the same manner as in Example 62. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (82 mg, 124.29 μmol, 76% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =660.3; 1 HNMR (400MHz, DMSO-d6, ppm): δ8.34(s,1H),7.99-7.88(m,2H),7.38(dd,J=5.2,8.4Hz,1H),7.20-7.09(m,1H),5.38-5.18(m,1H),4.16-3.9 9(m,6H),3.90-3.78(m,1H),3.56-3.36(m,4H),3.14-3.00(m,3H),2. 90-2.75(m,1H),2.18-2.00(m,3H),1.94-1.59(m,5H),1.51(brs,3H).

[0659] Example 105: Synthesis of 4-(9-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0660]

[0661] The compound was synthesized in the same manner as in Example 80 using (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. 4-(9-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (78 mg, 122.0 μmol, 77% yield) was obtained as an off-white solid. LCMS (ES-API, m / z): [M+H] + =640.3; 1H NMR (400MHz, DMSO-d6, ppm): δ10.16(s,1H),8.32(d,J=28.0Hz,1H),7.99–7.96(m,1H),7.44(t,J=8.0Hz,1H),7.39(m,1H), 5.29(d,J=54.0Hz,1H),4.86(d,J=55.2Hz,1H),4.13-3.99(m,5H),3.67-3.48(m,2H),3.14-2.80(m,5H),2.16-1.72(m,9H).

[0662] Example 106: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-ol.

[0663]

[0664] The compound was synthesized in the same manner as in Example 2 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, 29.5 μmol, 15% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =652.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.12 (br d,J=0.8Hz,1H),8.81-8.55(m,1H),7.97(dd,J=6.0,9.1Hz,1H),7.53-7.33(m,4H ),7.22(s,1H),4.45-4.06(m,4H),3.98-3.87(m,1H),3.72-3.46(m,2H),3.26(br s,1H),3.05-2.97(m,1H),2.84-2.55(m,4H),2.43(br d,J=15.6Hz,2H),2.18-1.73(m,8H).

[0665] Example 107: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0666]

[0667] The compound was synthesized in the same manner as in Example 1 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (15 mg, 22.12 μmol, 16% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =656.4; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.79-8.59(m,1H),7.70-7.64(m,1H),7.60(s,1H),7.56-7.53(m,1H),7.52-7.47(m,3H),7.22(br d,J=3.6Hz,5H),5.27(s,3H),4.26(br d,J=2.4Hz,6H),3.99-3.78(m,3H),3.50(s,6H),3.44-3.24(m,4H),2.97-2.63(m,3H),1.53-1.47(m,9H),0.67-0.56(m,5H).

[0668] Example 108: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalene-2-amine.

[0669]

[0670] The compound was synthesized in the same manner as in Example 14 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1′,2′:1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (17.17 mg, 26.29 μmol, 17% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =651.3; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.71 (br s,1H),7.81-7.71(m,1H),7.53-7.46(m,1H),7.37-7.26(m,2H),7.11-7.02(m,2H),5.75-5.48(m,2H),4.49-4.05(m,4H),4.02- 3.86(m,1H),3.74-3.61(m,1H),3.56-3.44(m,1H),3.38-3.34(m,2H),3.04-2.54(m,6H),2.47-2.38(m,1H),2.34-1.65(m,9H).

[0671] Example 109: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalene-2-ol.

[0672]

[0673] The compound was synthesized in the same manner as in Example 1 using (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrol...

Claims

1. A compound represented by the following Chemical Formula 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt: [Chemical Formula 1] in, A is X is C or N; R1 is hydrogen, halogen, C 1-3 Alkyl or C 1-3 alkoxy; L is a direct bond, O or NR6; R2 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, R x ,-Z1-R x ,-Z1-R y -R x ,-Z1-R y -Z2-N(R 15 )2.-Z1-R y -Z2-R x 、-N(R 15 )2, -Z1-N(R 15 )2, -Z1-C(O)N(R 15 )2OR-Z1-OR 15 ; R x and R y Each is independently 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 20-membered aryl or 6 to 20-membered heteroaryl, and may be optionally substituted with one or more R7; R7 is independently H, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Alkoxy, C 1-4 Alkyl-N(R 16 )2、=C-(R 16 )2, cyano, C(O)R 16 、C(=O)OR 16 、C(=O)N(R 16 )2, -NHC(O)-6 to 20-membered aryl, -N(R 16 )2、(C 1-4 Alkoxy) C 1-4 Alkyl-, oxo, -OR 16 、-SR 16 、-(C 1-4 alkyl)C(O)R 16 , 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl, 6 to 20-membered heteroaryl, -Z3-3 to 10-membered cycloalkyl, -Z3-3 to 10-membered heterocycloalkyl, -Z3-6 to 20-membered aryl, -Z3-6 to 20-membered heteroaryl, -Z3-OC(O)N(R 16 )2 or -Z3-OC(O)-3 to 10-membered heterocyclic group; and R7 may be 1 to 3 cyano, halogen, haloalkyl, amino, -OR 17 、-SR 17 or -N(R 17 )2; Z1 to Z3 are each independently C 1-4 and optionally substituted by hydroxyl, C 1-4 substituted by hydroxyalkyl or 6- to 20-membered heteroaryl; R6, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 and R 21 Each independently is H or C 1-3 alkyl; R3 is 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl or 6 to 20-membered heteroaryl, and may be optionally substituted with one or more R8; R8 is H, halogen, hydroxyl, -N(R 18 )2、OR 18 ,SH,S(C 1-3 alkyl), S(=O)(C 1-6 alkyl), S(=O)2(C 1-6 alkyl), C(=O)(C 1-6 alkyl), C(=O)OH, C(=O)N(R 18 )2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxyalkyl, C 1-4 Alkyl-N(R 18 )2、C 1-3 Alkoxy, C 1-3 haloalkoxy, cyanoalkyl, cyano, oxo, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl; R4 is or -NH-R9-R 10 ; R9 is a direct key or C 1-4 alkyl; R 10 is a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocycloalkyl group, and may be optionally replaced by one or more R 11 replaced by; R 11 C 1-3 Alkyl, hydroxyl, N(R 19 )2、C 1-3 Alkyl-N(R 19 )2、C 1-3 cyanoalkyl or 3- to 10-membered heterocyclic group; R 12 H, C 1-3 Alkyl, OH, -N(R 20 )2、-CH2N(R 20 )2, cyano, cyanomethyl or a 3- to 10-membered heterocyclic group; R 13 is H or -C(=O)R 14 ; R 14 C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -N(R6)2, -OR6, -SR6, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl; n is an integer from 1 to 4; and R5 is H, halogen, C 1-6 Alkyl, C 1-3 haloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, cyano, cyano C 1-3 Alkyl, hydroxyl, C 1-3 Hydroxyalkyl, C(O)(NR 21 )2, 6 to 20-membered aryl, C 1-3 Alkyl-3 to 6-membered cycloalkyl, C 1-3 Alkyl-3 to 6-membered heterocycloalkyl, C 1-3 Alkyl-6 to 20-membered aryl or C 1-3 Alkyl-6 to 20-membered heteroaryl.

2. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Where A is 3. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Wherein R1 is hydrogen, halogen or C 1-3 alkyl.

4. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Wherein L is a direct bond or O.

5. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, where R x and R y Each is independently a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and may be optionally substituted by one or more R7.

6. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, where R x is a 3- to 10-membered heterocyclic group, R y is a 3- to 10-membered cycloalkyl group, and R x and R y May be optionally substituted with one or more R7.

7. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Wherein R7 is independently H, halogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 1-4 Alkoxy, C 1-4 Alkyl-N(R 16 )2、=C-(R 16 )2、C(O)R 16 、C(=O)OR 16 、C(=O)N(R 16 )2, -NHC(O)aryl, -N(R 16 )2、(C 1-4 Alkoxy) C 1-4 Alkyl-, oxo, -OR 16 、-SR 16 、-(C 1-4 alkyl)C(O)R 16 , 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl, 6 to 20-membered heteroaryl, -Z3-3 to 10-membered cycloalkyl, -Z3-3 to 10-membered heterocycloalkyl, -Z3-6 to 20-membered aryl, -Z3-6 to 20-membered heteroaryl, -Z3-OC(O)N(R 16 )2 or -Z3-OC(O)-3 to 10-membered heterocyclic group; and may be substituted by 1 to 3 cyano, halogen, haloalkyl, amino, -OR 17 、-SR 17 or -N(R 17 )2.

8. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, wherein R3 is 6 to 20-membered aryl or 6 to 20-membered heteroaryl, and may be optionally substituted with one or more R8; and Wherein R8 is H, halogen, hydroxyl, -N(R 18 )2、OR6、SH、S(C 1-3 alkyl), S(=O)(C 1-6 alkyl), S(=O)2(C 1-6 alkyl), C(=O)(C 1-6 alkyl), C(=O)OH, C(=O)N(R 18 )2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxyalkyl, C 1-4 Alkyl-N(R 18 )2, cyano, oxo or 3 to 10-membered cycloalkyl.

9. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, where R 10 is a 3 to 10-membered cycloalkyl group, and may be optionally substituted by one or more R 11 replaced; and where R 11 C 1-3 Alkyl, hydroxyl, N(R 19 )2、C 1-3 Alkyl-N(R 19 )2 or cyano C 1-3 alkyl.

10. The compound according to claim 8 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, wherein R3 is phenyl, biphenyl, naphthyl, toluoyl, naphthalenyl, pyridyl, anthracenyl, indenyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzofuranyl or indazolyl, and may be optionally substituted by one or more R8.

11. The compound according to claim 8 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, wherein R3 is phenyl, naphthyl, naphthalenyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, benzothienyl, benzofuranyl or indazolyl, and may be optionally substituted with one or more R8, and Wherein R8 is H, halogen, hydroxyl, -N(R 18 )2、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Halogenated alkyl, C 1-3 hydroxyalkyl or cyano.

12. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Where R9 is C 1-3 alkyl, where R 10 is a 3- to 5-membered cycloalkyl group, and where R 11 N(R 19 )2.

13. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, where R 12 For H.

14. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Where R5 is H or C 1-3 alkyl.

15. The compound according to claim 5 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, where R x and R y Each is independently 3- to 5-membered cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl], 6-azaspiro[2.5]octyl, quinolizidinyl, indolyl, benzimidazolyl, azaspirooctyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl or acridinyl, and may be optionally substituted with one or more R7.

16. The compound according to claim 6 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, Where R2 is R x ,-Z1-R x ,-Z1-R y -R x ,-Z1-R y -Z2-N(R 15 )2 or -Z1-R y -Z2-R x , where R x is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl] or 6-azaspiro[2.5]octyl, where R y is a 3- to 5-membered cycloalkyl group, where R x and R y may be optionally substituted with one or more R7, and Wherein R7 is independently H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 2-4 Halogenated alkenyl, C 2-4 Haloalkynyl, C 1-4 Alkoxy, =C-(R 16 )2、-N(R 16 )2 or (C 1-4 Alkoxy) C 1-4 Alkyl-, and may be substituted by 1 to 3 halogens.

17. The compound according to claim 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt, The compound of Chemical Formula 1 is selected from the following compounds (1) to (120): Table 5 18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 18 , further comprising a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is an antagonist of KRAS G12D mutant protein. The pharmaceutical composition according to claim 18 , wherein the pharmaceutical composition is used to prevent or treat a disease associated with a KRASG12D mutant protein.

22. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is used for preventing or treating cancer.

23. The pharmaceutical composition of claim 18, wherein the composition is administered by one or more routes selected from oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration.

24. The pharmaceutical composition of claim 18, wherein the composition is formulated into one or more dosage forms selected from the group consisting of tablets, pills, hard or soft capsules, liquids, suspensions, emulsions, syrups, granules, and elixirs.

25. The pharmaceutical composition according to claim 18, further comprising one or more selected from RTK / Ras-MAPK pathway-related protein inhibitors, DNA damaging agents, EGFR antibodies, and immuno-oncology therapeutic agents.

26. The pharmaceutical composition according to claim 25, wherein the RTK / Ras-MAPK pathway-related protein inhibitor is one or more selected from EGFR inhibitors, FGFR inhibitors, ALK inhibitors, ROS inhibitors, MET inhibitors, RAF inhibitors, ERK inhibitors, MEK inhibitors, SHP-2 inhibitors, PI3K inhibitors, KRAS inhibitors, KRAS-G12C inhibitors and SOS1 inhibitors.

27. The pharmaceutical composition of claim 22, wherein the cancer is one or more selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated multicellular carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchiolar adenoma, sarcoma, lymphoma, chondromatosis, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, biliary tract cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell carcinoma tumor, osteochondroma, benign enchondroma, chondromyxoid fibroma, chondroostoma, giant cell tumor, skull tumor, skull hemangioma, skull granuloma, skull xanthomas, skull deforming osteitis, meningioma, meningioma sarcoma, glioblastoma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma, endometrial cancer, cervical cancer, ovarian cancer, blood cancer, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, malignant melanoma, basal cell carcinoma, adenocarcinoma and neuroblastoma.

28. A composition for binding to a KRAS G12D mutant protein, comprising the compound according to any one of claims 1 to 17 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate or pharmaceutically acceptable salt thereof.

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