Novel tricyclic compounds as KRAS G12D inhibitors and their uses

Abstract

The present application relates to novel tricyclic derivative compounds as KRAS G12D inhibitors and uses thereof. The compounds according to one example of the present application suppress the activity of KRAS G12D mutant proteins and can be used for the prevention or treatment of diseases caused by KRAS G12D mutations.

Description

[Technical Field]

[0001] This application relates to novel tricyclic compounds, pharmaceutical compositions containing same and their use as medicaments. [Background technology]

[0002] Kristen rat sarcoma virus (KRAS) is a protein belonging to the RAS family (NRAS, HRAS, KRAS) that transmits signals important for cell proliferation and differentiation. It receives signals from cell membrane receptors and transmits them to subordinate signaling proteins such as PI3K, Raf, MEK, and ERK.

[0003] The KRAS protein acts as a molecular switch, exchanging GDP for GTP at its nucleotide binding site through endogenous nucleotide exchange, resulting in an "activated (GTP-bound form, turn-on) state" in which signals are transmitted to downstream signaling proteins. Conversely, when the GTP bound to the KRAS protein is endogenously hydrolyzed to GDP, it becomes an "inactivated (GDP-bound form, turn-off) state" in which downstream signaling does not occur. At this time, within the cell, guanine exchange factors (GEFs) promote the exchange of GDP for GTP, and GTPase activating proteins (GAPs) rapidly increase the hydrolysis of GTP to GDP.

[0004] KRAS gene mutations have been shown to play an important role in cancer cell proliferation in many malignant tumors. Approximately 89% of KRAS gene mutations occur due to a mutation in which glycine at codon 12 of the KRAS gene (KRAS G12) is replaced by another amino acid. KRAS G12 mutations are present in 86% of pancreatic adenocarcinoma (PDAC), 41% of colorectal cancer (CRC), and 32% of non-small cell lung cancer (NSCLC). The reported frequency of KRAS G12 mutations is G12D (36%), followed by G12V (23%) and G12C (14%). KRAS G12 mutant proteins inhibit GTP hydrolysis by GAP, maintaining an activated (GTP-bound form) state, which rapidly increases cancer cell proliferation and survival through sustained downstream signaling.

[0005] Previous KRAS inhibitors were developed as competitive inhibitors of GTP binding in order to suppress activated KRAS, but because there is significantly more GTP in the cell than the inhibitor concentration, many KRAS inhibitors have failed. For this reason, it was thought that it was impossible to develop a targeted therapy that directly targets KRAS. As alternatives to suppress KRAS mutant cancers, attempts have been made to indirectly suppress the activity of KRAS mutant cancer cells by inhibiting downstream signaling proteins other than KRAS, such as PI3K, MEK, AKT, and mTOR, or by inhibiting post-translational modification of KRAS protein and inhibiting KRAS fanesyltransferase, but these have not produced any significant clinical effects.

[0006] Recently, by identifying the switch-II pocket, an allosteric binding pocket of the KRAS G12C mutant protein, we have discovered sotorasib (LUMAKRAS), a selective KRAS G12C-targeting small molecule that inhibits KRAS activity through covalent binding with cysteine ​​in the GDP-bound state of KRAS G12C. TM) was developed and approved by the FDA for non-small cell lung cancer.

[0007] However, the development of targeted therapeutic agents targeting the KRAS G12D mutation, which accounts for the largest proportion of KRAS mutations, is still insufficient, and this remains a significant unmet medical need in clinical practice. Summary of the Invention [Problem to be solved by the invention]

[0008] The present inventors have confirmed that a novel tricyclic compound according to one example of the present application has the effect of inhibiting KRAS G12D activity. Therefore, one object of the present application is to provide a novel cyclic ring-based compound of Chemical Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts thereof, which exhibit excellent KRAS G12D activity inhibitory effects.

[0009] Another object of the present application is to provide a pharmaceutical composition containing, as an active ingredient, the novel cyclic ring-based compound, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0010] According to one embodiment of the present application, there is provided a compound of the following chemical formula 1, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof: [Chemical formula 1] JPEG2025540246000001.jpg31148In the above chemical formula 1, JPEG2025540246000002.jpg18147X is C or N; R1 is hydrogen, halogen, C 1-3 Alkyl, or C 1-3 is 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 )2, or -Z1-OR 15 and; R x and R y are, independently of each other, a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, optionally substituted with one or more R7; R7 is H, halogen, hydroxy, or C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, 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 heterocyclyl; wherein R7 is 1 to 3 of cyano, halogen, haloalkyl, amino, -OR 17 , -SR 17 , or -N(R 17 )2 may be substituted; Z1 to Z3 are independently C 1-4 alkyl; optionally hydroxy, C 1-4 optionally substituted with hydroxyalkyl, or 6- to 20-membered heteroaryl; R6, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are, independently of each other, H or C 1-3 is alkyl; R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, optionally substituted with one or more R8; R8 is H, halogen, hydroxy, -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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxyalkyl, C1-4 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; JPEG2025540246000003.jpg32157R9 can be directly bound or C 1-4 is alkyl; R 10 is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl, optionally with one or more R 11 may be substituted with; R 11 is C 1-3 Alkyl, hydroxy, N(R 19 )2, C 1-3 Alkyl-N(R 19 )2, C 1-3 cyanoalkyl, 3- to 10-membered heterocyclyl; R 12 is H, C 1-3 Alkyl, OH, -N(R 20 )2, -CH2N(R 20 )2, cyano, cyanomethyl, or 3- to 10-membered heterocyclyl; R 13 is H or -C(=O)R 14 and; R 14 is 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 0 to 4; R5 is H, halogen, C 1-6 Alkyl, C 1-3Haloalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, cyano, cyanoC 1-3 Alkyl, hydroxy, 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;

[0011] JPEG2025540246000004.jpg19156

[0012] Specifically, R1 is hydrogen, halogen, or C 1-3 It may also be alkyl.

[0013] Specifically, the L may be a direct bond or O.

[0014] Specifically, 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 may be.

[0015] Specifically, the R x and the R y are each independently a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, which may be optionally substituted with one or more R7.

[0016] More specifically, the R x is a 3- to 10-membered heterocyclyl, and y is a 3- to 10-membered cycloalkyl, and x and the Ry may be optionally substituted with one or more R7. More specifically, x may be a 3- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, or a 3- to 10-membered heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of N and O.

[0017] As an example, the above-mentioned R x and R y are, independently of each other, 3- to 5-membered cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidinyl], ne-1,2'-pyrrolizidinyl]), 6-azaspiro[2.5]octanyl, quinolizidinyl, indolinyl, benzimidazolyl, azaspirooctanyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, or acridinyl, optionally substituted by one or more R7.

[0018] As a specific example, the R xis azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, methylenepyrrolizidinyl, tetrahydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizidinyl], or 6-azaspiro[2.5]octanyl, optionally substituted by one or more R7.

[0019] As a specific example, the R y is a 3- to 5-membered cycloalkyl (eg, cyclopropyl or cyclobutyl), which may be optionally substituted with one or more R7.

[0020] For example, in 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 and R x is a 3- to 10-membered heterocyclyl, and y is a 3- to 10-membered cycloalkyl, and x and the R y may be optionally substituted with one or more R7.

[0021] As a specific example, in the above formula 1, R2 is R x , -Z1-R x , -Z1-R y -R x , -Z1-R y -Z2-N(R15 )2, or -Z1-R y -Z2-R x and R x is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl], or 6-azaspiro[2.5]octanyl, and R y is a 3- to 5-membered cycloalkyl, and x and the R y may be optionally substituted with one or more R7.

[0022] As a specific example, in 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 and R y is a 3- to 5-membered cycloalkyl (e.g., cyclopropyl or cyclobutyl), and R x may be a 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or 6-azaspiro[2.5]octanyl).

[0023] Specifically, R7 is H, halogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 2-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, 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 heterocyclyl; 1 to 3 cyano, halogen, haloalkyl (e.g., C 1-4 haloalkyl), amino, -OR 17 , -SR 17 , or -N(R 17 ) 2 may be substituted.

[0024] For example, R7 may be H, halogen, or C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Haloalkynyl, C 1-4 Alkoxy, =C-(R 16 )2, -N(R16 )2, or (C 1-4 Alkoxy)C 1-4 It may be alkyl-, which may be substituted with 1 to 3 halogen atoms.

[0025] For example, R7 may be H, halogen, or C. 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Haloalkynyl, C 1-3 Alkoxy, =C-(R 16 )2, -N(R 16 )2, or (C 1-3 Alkoxy)C 1-3 It may be alkyl-, which may be substituted with 1 to 3 halogen atoms.

[0026] As a specific example, 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 It may also be alkyl-.

[0027] Specifically, R3 may be a 6- to 20-membered aryl or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R8.

[0028] Specifically, R3 may be phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, pyridinyl, anthracenyl, indenyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or indazolyl, and may be optionally substituted with one or more R8.

[0029] More specifically, R3 may be phenyl, naphthyl, naphthalenyl, pyridinyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or indazolyl, which may be optionally substituted with one or more R8.

[0030] Specifically, R8 is H, halogen, hydroxy, -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 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxyalkyl, C 1-4 Alkyl-N(R 18 )2, cyano, oxo, or 3- to 10-membered cycloalkyl.

[0031] More specifically, R8 is H, halogen, hydroxy, -N(R 18 )2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Haloalkyl, C 1-3 It may be hydroxyalkyl, or cyano.

[0032] Specifically, the R 10 is a 3- to 10-membered cycloalkyl, optionally with one or more R 11 It may be substituted with:

[0033] Specifically, the R 11 is C 1-3Alkyl, hydroxy, N(R 19 )2, C 1-3 Alkyl-N(R 19 )2, or cyano C 1-3 It may also be alkyl.

[0034] For example, in Formula 1, R9 is C 1-3 alkyl, and R 10 is a 3- to 5-membered cycloalkyl, and R 11 is N(R 19 )2 may also be used.

[0035] Specifically, the R 12 may be H.

[0036] Specifically, the R 14 may be a 3- to 10-membered heterocyclyl, a 3- to 10-membered heterocyclyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, or a 3- to 5-membered heterocyclyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, such as oxirane.

[0037] Specifically, R5 is H or C 1-3 It may also be alkyl.

[0038] For example, in Chemical Formula 1, L-R2 may be selected from the following structures: When the compound has the following structure, it not only has excellent KRAS G12D inhibitory activity but is also suitable for the various purposes of the present application described above. JPEG2025540246000005.jpg173168

[0039] For example, in Chemical Formula 1, R3 may be selected from the following structures: When the compound has the following structure, it not only has excellent KRAS G12D inhibitory activity but is also suitable for the various purposes of the present application described above. JPEG2025540246000006.jpg215170

[0040] For example, in Chemical Formula 1, R4 may be selected from the following structures: When the compound has the following structure, it not only has excellent KRAS G12D inhibitory activity but is also suitable for the various purposes of the present application described above. JPEG2025540246000007.jpg2795

[0041] The present application provides the aforementioned compounds, their optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0042] 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 Compound 90.

[0043] By way of example, representative compounds of Formula 1 according to one example of the present application include, but are not limited to, those listed in Table 1 below.

[0044] [Table 1] JPEG2025540246000009.jpg248161JPEG2025540246000010.jpg248161JPEG20255402460 00011.jpg248161JPEG2025540246000012.jpg248161JPEG2025540246000013.jpg248162 JPEG2025540246000014.jpg248161JPEG2025540246000015.jpg156167

[0045] Unless otherwise defined, all technical terms used in this application have the same meaning as commonly understood by a person of ordinary skill in the art to which this application pertains. Furthermore, while exemplary methods and samples are described herein, similar or equivalent methods and samples are also included within the scope of this application. Furthermore, numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications referenced herein are incorporated by reference in their entirety.

[0046] In the above Chemical Formula 1, R1 to R 21 , R x , and R y Residues listed as ##STR00001## are used in the same sense as commonly understood by one of ordinary skill in the art.

[0047] Unless otherwise stated, in this application, "halogen" when used alone or in combination with other additional terms (e.g., haloalkyl) refers to fluorine, chlorine, bromine, or iodine, specifically, but not limited to, fluorine and chlorine.

[0048] Unless otherwise stated, in this application the term "alkoxy" refers to alkyloxy, for example, alkyloxy having 1 to 7 carbon atoms.

[0049] Unless otherwise stated, the term "haloalkyl," as used herein, means alkyl, as defined herein, in which one or more hydrogens are replaced with the same or different halogen. Examples of haloalkyl groups include, but are not limited to, -CH2Cl, -CH2CF3, -CH2CCl3, -CF3, and the like.

[0050] Unless otherwise stated, as used herein, the term "hydroxyalkyl" includes the replacement of one or more hydrogen atoms within an alkyl group with one or more hydroxy (-OH), for example, divalent or trivalent hydroxy.

[0051] Unless otherwise stated, the term "aminoalkyl," as used herein, includes replacing one or more hydrogen atoms within an alkyl group with one or more amino (-NH, e.g., divalent or trivalent amino).

[0052] Unless otherwise stated, as used herein, the term "oxo" refers to a group of formula =O (ie, oxygen with a double bond).

[0053] As used herein, unless otherwise specified, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical. For example, the alkyl may be C 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl, or C 1-3 It may also be alkyl.

[0054] As used herein, unless otherwise specified, the term "alkenyl" refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, each of which can have either the E- or Z-configuration. For example, the alkenyl can be C 2-10 Alkenyl, C 2-8 Alkenyl, C 2-6 Alkenyl, or C 2-4 It may also be alkenyl.

[0055] As used herein, unless otherwise specified, the term "alkynyl" refers to a monovalent group derived from an unsaturated, linear or branched hydrocarbon moiety having at least one carbon-carbon triple bond. For example, the alkynyl can be C 2-10 Alkynyl, C 2-8 Alkynyl, C 2-6 Alkynyl, or C 2-4 It may also be alkynyl.

[0056] The terms "alkyl," "alkenyl," and "alkynyl," when used alone or in combination with other additional terms (e.g., haloalkyl), may be straight-chain or branched. Each definition refers to a saturated aliphatic hydrocarbon radical having 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. Examples of common alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, and tert-pentyl, 1-methylpentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, n-hexyl, 3,3-dimethylbutyl, and isohexyl. The double and triple bonds of the alkenyl and alkynyl groups can be substituted at any position. Examples of alkenyl and alkynyl include, but are not limited to, ethenyl, 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, and the like.

[0057] Unless otherwise specified, in this application, "cycloalkyl," "cycloalkenyl," or "cycloalkynyl" refers to a substituted or unsubstituted cyclic alkyl and a hydrocarbon radical forming a single or fused ring that is unsaturated, partially, or fully saturated (e.g., 3 to 24) carbon atoms. Specifically, the cycloalkyl, cycloalkenyl, or cycloalkynyl can 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 includes, but is not limited to, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and bridged carbocyclyl.

[0058] According to one embodiment of the present application, the cycloalkyl is 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, adamant-1-yl, tetrahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, benzene, naphthalenyl, and all possible isomers thereof may be included without limitation, but are not limited thereto.

[0059] Unless otherwise specified, the term "saturated or unsaturated heterocyclyl" as used herein refers to a substituted or unsubstituted 3- to 24-membered hydrocarbon ring that is unsaturated or partially or fully saturated, containing one or more heteroatoms, e.g., 1 to 8 heteroatoms, selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S). Specifically, the heterocyclyl is 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 ring containing 1 to 3 heteroatoms. Examples of the heterocycle include, but are not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl.

[0060] According to one embodiment of the present application, the heterocyclyl is pyrrolidinyl, morpholinyl, pyrrolidinyl, quinolizidinyl, azaspirooctanyl, piperidinyl, pyrrolidinyl, imidazolinyl, piperazinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspirooctanyl, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, tetrahydropyranyl, Examples of suitable azabicyclo[3.2.1]octanyl include, but are not limited to, 2-oxa-6-azaspiroheptanyl, azetidinyl, oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, pyridyl, tetrahydrofuranyl, 8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-7-azaspiro[3.4]octanyl, 2-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, pyrimidinyl, pyrazolyl, oxetane, and similar groups. 2-10 In the case of heterocyclyl, the carbon atom is represented by C 2-10 means the size of a ring of three or more members containing one or more heteroatoms.

[0061] In this application, unless otherwise specified, the term "aryl" refers to a substituted or unsubstituted aromatic group, which may have, for example, 6 to 20 members. For example, the aryl may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, or all possible isomers thereof.

[0062] The term "heteroaryl," as used herein, unless otherwise specified, refers to a monocyclic, bicyclic or higher aromatic group containing one or more, e.g., 1 to 4, 1 to 3, or 1 to 2, heteroatoms selected from O, N, and S, and may have, for example, 6 to 20 members. For example, examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, or similar groups. For example, examples of bicyclic heteroaryls include, but are not limited to, pyrrolidinyl, indolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, quinolinyl, isoquinolinyl, azaspirooctanyl, purinyl, propylidinyl, or similar groups. For example, examples of tricyclic heteroaryls include, but are not limited to, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, or similar groups.

[0063] In this application, a numerical range indicated using "~" refers to a range that includes the numerical values ​​before and after "~" as the lower and upper limits, respectively.

[0064] The compounds of the present application can have asymmetric carbon centers and asymmetric axes or planes, and therefore can exist as all optical and stereoisomers, including substantially pure enantiomers such as R and S enantiomers, as well as mixed racemates, and all such isomers and mixtures are included within the scope of the present application. The optical purity of such enantiomers and pharmaceutically acceptable salts thereof, relative to the pure enantiomers and represented by Chemical Formula 1, is preferably 60% ee or greater, more preferably 95% ee or greater, and most preferably 98% ee or greater.

[0065] The term "ee" refers to enantiomeric excess. For example, one enantiomer of a particular compound is present in a mixture of enantiomers of that compound in a greater amount than the other enantiomer. Enantiomer-enriched forms can include mixtures of enantiomers of a particular compound in which the concentration of a single enantiomer relative to the other enantiomers of the compound is 50% or greater, more typically 60%, 70%, 80%, or 90% or greater (e.g., >95%, >97%, >99%, >99.5%).

[0066] For convenience, unless otherwise specified, the compound of Chemical Formula 1 is used herein to include all compounds of Chemical Formula 1, their optical isomers, stereoisomers, isotopic variations, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0067] As used herein, the term "isotopic variant" refers to a compound that contains an unusual ratio of an isotope at one or more of the atoms that constitute the compound. For example, an isotopic variant of a compound can be radiolabeled, e.g., the hydrogen atoms can be selected from hydrogen, deuterium, and tritium, and carbon-13 ( 13 C), nitrogen-15( 15 N) and the like.

[0068] The compound of Formula 1 according to the present application, its optical isomers, stereoisomers, or isotopic variants can form pharmaceutically acceptable salts. The pharmaceutically acceptable salts include acid or base addition salts and all stereochemically isomeric forms thereof. The salts include, but are not limited to, any salt that maintains the activity of the parent compound in the target object and does not induce undesirable effects. Such salts include inorganic and organic salts, such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, oxalic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esylic acid, lactic acid, non-carboxylic acid, non-sulfuric acid, non-tartaric acid, oxalic acid, butyric acid, calcium iodate, cinnamic acid, carboxylic acid, chlorobenzoic acid, citric acid, iodate, toluenesulfonic acid, edicillic acid, esylic acid, fumaric acid, gluceptic acid, benzoic acid, benzoic acid, stearic acid, esylic acid, lactic acid, non-carboxylic acid, non-sulfuric acid, non-tartaric acid, oxalic acid, butyric acid, calcium iodate, cinnamic acid, cinnamic acid, benzoic ... The basic salts may be, for example, pamoic acid, gluconic acid, glycolylarsanilic acid, methylnitrile acid, polygalaturonic acid, hexylresorcinonic acid, malonic acid, hydrabamic acid, hydrochloric acid, hydroiodic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estric acid, mucic acid, naphsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogenphosphate, dihydrogenphosphate, salicylic acid, sulfamic acid, sulfanilic acid, methanesulfonic acid, or teoclic acid. Examples of the basic salts include alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt; salts with organic bases such as penzatine, N-methyl-D-glucamine, and hydrabaminic acid; and salts with amino acids such as arginine and lysine. The salt forms can also be converted into the free forms by treatment with an appropriate base or acid. The term "addition salt" includes solvates that the compounds of Formula 1 and their salts can form. Such solvates are, for example, hydrates and alcoholates.

[0069] Terms and abbreviations used herein have their original meaning unless defined differently.

[0070] The present application also provides a method for preparing a compound of Chemical Formula 1. Hereinafter, to facilitate understanding of the present application, a method for preparing a compound of Chemical Formula 1 will be described based on an exemplary reaction scheme. However, a person skilled in the art to which the present application pertains can prepare a compound of Chemical Formula 1 by various methods using known compounds or compounds that can be easily prepared from the structure of Chemical Formula 1, and all such methods should be construed as being within the scope of the present application. That is, a compound of Chemical Formula 1 can be prepared by any combination of various synthetic methods described herein or disclosed in the prior art. Therefore, the following description of a method for preparing a compound of Chemical Formula 1 is merely an example, and the order of unit operations can be selectively changed as necessary. The scope of the preparation method of the present application is not limited to these methods.

[0071] [Reaction Scheme 1] JPEG2025540246000016.jpg29170

[0072] Step A: Phosphoryl trichloride and N-ethyl-N-isopropylpropan-2-amine are added to compound 1 in the above reaction formula 1, and the mixture is heated to obtain compound 2.

[0073] Step B: Compound 2 of Reaction Scheme 1 undergoes SNAR reaction with a nucleophile having the formula H-Y1-X-R1 to synthesize compound 3 in the presence of a solvent such as dimethyl chloride and a base such as N-ethyl-N-isopropylpropan-2-amine.

[0074] Step C: In Scheme 1 above, the substituent Y2-R2 is introduced via the 2-chlorine substituent of the compound nucleophile having the formula H-Y2-R2 using a strong base such as sodium hydride in a non-polar solvent such as tetrahydrofuran.

[0075] Step D: To synthesize compound 5 of Reaction Scheme 1, in Step D, compound 4 is reacted with a boronic acid or arylstannane using Suzuki reaction or stiliban.

[0076] According to another aspect of the present application, there is provided a pharmaceutical composition for preventing or treating a disease associated with KRAS G12D mutant protein, comprising as an active ingredient a therapeutically effective amount of a compound of Chemical Formula 1 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof. Specifically, the pharmaceutical composition may inhibit the activity of KRAS G12D mutant protein and prevent or treat a disease associated with KRAS G12D mutant protein.

[0077] The compound of Formula 1 according to one embodiment of the present application, or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof, has high binding affinity to GDP- / GppNHp-KRAS G12D mutant protein and can act as a KRAS G12D mutation-specific inhibitor by inhibiting the phosphorylation of extracellular signal-regulated kinases (Phospho-ERK, pERK) induced by KRAS G12D mutation. Therefore, one embodiment of the present application relates to a composition for binding to KRAS G12D mutant protein, including a compound according to one embodiment of the present application, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof. Furthermore, the compound of Formula 1 according to one embodiment of the present application can prevent, ameliorate, or treat KRAS G12D mutant protein-related diseases or conditions, particularly diseases or conditions induced by KRAS G12D mutant protein. For example, the compound of Chemical Formula 1 according to the present application, as an inhibitor of KRAS G12D mutant protein, can effectively suppress the growth signal of cancer cells caused by KRAS G12D mutation, and can be usefully used in pharmaceutical compositions for the prevention or treatment of cancer.

[0078] According to another aspect of the present application, there is provided a pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient a therapeutically effective amount of a compound of Chemical Formula 1 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0079] Also included within the scope of the present application are various forms of prodrugs that are converted in vivo into the compound of Formula 1 according to the intended purpose. The pharmaceutical composition may further comprise one or more additives selected from the group consisting of pharmaceutically acceptable carriers, diluents, and adjuvants.

[0080] As used herein, "treating" means halting, slowing or mitigating the progression of a disease when applied to an object exhibiting a disease symptom.

[0081] As used herein, "prevention" means reducing or eliminating the chance of contracting a disease.

[0082] As used herein, the term "pharmaceutical composition" may contain other chemical components, such as carriers, diluents, excipients, etc., in addition to the active compound of the present application. Therefore, the pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. Such a pharmaceutical composition facilitates administration of the active compound into a living organism. Various techniques for administering pharmaceutical compositions containing a compound are known, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical composition may be sterilized or may further contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifiers, salts for adjusting osmotic pressure, and / or buffers, or may further contain other therapeutically useful substances. The pharmaceutical composition may be formulated by conventional methods such as mixing, granulating, or coating.

[0083] As used herein, the term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into cells or tissues of living organisms.

[0084] As used herein, a "diluent" is defined as a compound diluted with water that dissolves the compound as well as stabilizes the biologically active form of the compound of interest. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, which mimics the salt form of human body fluids. Because buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely alter the biological activity of the compound.

[0085] As used herein, the term "pharmaceutically acceptable" refers to a property that does not impair the biological activity and physical properties of a compound.

[0086] The pharmaceutical composition may also be a composition for preventing and / or treating a disease associated with KRAS G12D mutant protein, where the disease associated with KRAS G12D mutant protein may be, for example, cancer, or any other disease known to be associated with KRAS G12D mutation.

[0087] The cancers include angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated multicellular carcinoma, pulmonary carcinoma, alveolar (bronchiolar) carcinoma, bronchiolar adenoma, sarcoma, lymphoma, chondrohamartoma, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, gallbladder cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma, benign chondroma, chondroblastoma These include, but are not limited to, myeloma, chondromyxoid fibroma, chondroostoma, giant cell tumor, skull osteoma, skull hemangioma, skull granuloma, skull xanthomas, osteitis deformans of the skull, cerebral meningioma, meningeal sarcoma, glioblastoma, astrocytoma, medulloblastoma, ventriculoma, embryonal tumor, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma, endometrial cancer, cervical cancer, ovarian cancer, blood cancer, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, mononuclear leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, psoriatic carcinoma, and neuroblastoma.

[0088] The pharmaceutical composition can be formulated into various oral or parenteral dosage forms, such as tablets, pills, hard or soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc. In addition to the active ingredient, these oral dosage forms may contain pharmaceutically acceptable carriers, such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, and lubricants such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol, depending on the typical composition of each dosage form.

[0089] When the oral dosage form is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and may optionally further contain a disintegrating agent such as starch, agar, alginic acid or a sodium salt thereof, a boiling mixture and / or an absorbent, a coloring agent, a flavoring agent, or a sweetener.

[0090] The pharmaceutical composition may be formulated into a parenteral dosage form, and in such cases, it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In order to formulate the pharmaceutical composition into a parenteral dosage form, the active ingredient, i.e., the compound of Formula 1 or an optical isomer, stereoisomer, isotopic variant, or a pharmaceutically acceptable salt thereof, is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, and the solution or suspension is prepared in a unit dosage form such as an ampule or vial.

[0091] The pharmaceutical composition may be sterilized, or may further contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for adjusting osmotic pressure and / or buffers, or may further contain other therapeutically useful substances, and may be formulated by a conventional method of mixing, granulating, or coating.

[0092] The active ingredient, i.e., the compound of Formula 1 or a pharmaceutically acceptable salt thereof, is 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 for mammals including humans, and such pharmaceutical composition can be administered orally or parenterally once or twice or more times a day.

[0093] The pharmaceutical composition can also be used to treat cancer by additionally containing a compound according to an example of the present application and at least one other therapeutic agent. The compound according to an example of the present application can exhibit synergistic effects when used in combination with a different therapeutic agent. The term "synergistic" refers to a therapeutic combination that is more effective than the additive effect of two or more single formulations. A combination therapy is demonstrated to be "synergistic" by providing a "synergistic effect," i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects achieved when the compounds are used separately. A synergistic effect can be achieved when the active ingredients are: (1) co-formulated in a combined unit dosage form and administered or delivered simultaneously; or (2) delivered as separate dosage forms by substitution. When delivered in substitution therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by different injections from separate syringes. Generally, during substitution therapy, an effective dose of each active ingredient is administered sequentially, i.e., sequentially over time. In some embodiments, synergy is evidenced by lower toxicity of the combination compared to the same dose of any single component at the same total dose. For example, when a compound of Formula 1 is co-administered with a different therapeutic agent, the toxicity of a 50:50 (w / w) combination containing the compound of Formula 1 and the different therapeutic agent is lower than the toxicity of 100% (w / w) of the compound of Formula 1 and / or the toxicity of 100% (w / w) of the different therapeutic agent, and the combination has approximately the same or greater efficacy. That is, the toxicity of the combination of the compound of Formula 1 and the different therapeutic agent is lower than the toxicity of each component alone, and the efficacy of the combination is greater than the efficacy of each component alone. Furthermore, the reason for combining the compound of Formula 1 and the different therapeutic agent is not only to reduce toxicity and provide greater safety, but also to enhance efficacy beyond that provided by a single formulation alone. Increased efficacy is one of the benefits of combination therapy.

[0094] The one or more therapeutic agents 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 damage inducers, EGFR antibodies, or immunological anticancer agents.

[0095] Examples of RTK / Ras-MAPK pathway inhibitors include EGFR inhibitors (Erlotinib, Gefitinib, Afatinib, or Osimertinib), FGFR inhibitors (Pemigatinib or Inglitinib (BGJ398)), ALK / ROS / MET inhibitors (Crizotinib, Carbozantinib, or Foretinib), RAF inhibitors (Vemurafenib, Tablafenib, and dabrafenib or belvarafenib), ERK / MEK inhibitors (trametinib or cobimetinib), SHP-2 inhibitors (TNO155 and RMC4630), PI3K inhibitors (AMG511 and bupalisib), KRAS inhibitors and KRAS-G12C inhibitors (sotorasib, adagrasib, and diverasib), including, but not limited to, one or more of the following inhibitors:

[0096] As an example, chemotherapeutic agents of DNA damage inducers include alkylating agents (platinum-based chemotherapeutic agents: cisplatin, carboplatin, oxaliplatin / nitrogen mustard). Mustard drugs: Mechlorethamine (nitrogenmustard), Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil / Nitrosourea drugs: Carmustine (BCNU), Lomustine (CCNU), Nimustine / Others: Altretamine, Busulfan, Dacarbazine, Procarbazine, Temozolomide, Thiotepa, Lurbinectedin Anti-metabolites (Fluorouracil (5-FU), Capecitabine, Cytarabine, Gemcitabine, Methotrexate, Mercaptopurine (6-MP), Leucovorin, Pemetrexed, etc.), Topoisomerase inhibitors (Epipodophyllotoxin: Etoposide, Tenoposide / Camptothecin: Topotecan, Irinotecan), SN-38 / Antibiotics Antibiotics: Dactinomycin, Doxorubicin, Daunorubicin, Mitomycin, Bleomycin, etc.), microtubule inhibitors (Vinca alkaloidsAlkaloids: including, but not limited to, Vinblastine, Vincristine, Vinorelvine / Taxanes: Paclitaxel, Docetaxel, etc.), hormone antagonist drugs (Tamoxifen, Flutamide, Leuprolide, etc.), and the like.

[0097] Exemplary EGFR antibodies include, but are not limited to, cetuximab.

[0098] Exemplary immunological anti-cancer agents include, but are not limited to, AMG-404, pembrolizumab, or nivolumab. [Effects of the Invention]

[0099] The present application provides a tricyclic derivative compound, or its optical isomer, stereoisomer, isotopic variant, or pharmaceutically acceptable salt thereof, that exhibits excellent KRAS G12D inhibitory effect. Therefore, such a compound, or its optical isomer, stereoisomer, isotopic variant, or pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of diseases associated with KRAS G12D mutant protein, such as cancer.

[0100] In addition, the compounds according to the present application, or optical isomers, stereoisomers or isotopic variations thereof, or pharmaceutically acceptable salts thereof, may have superior efficacy or improved pharmacokinetic properties. DETAILED DESCRIPTION OF THE INVENTION

[0101] The present application will be described in more detail with reference to the following examples, which are merely illustrative and are not intended to limit the scope of the present invention.

[0102] Intermediate1: Synthesis of 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. JPEG2025540246000017.jpg46164

[0103] Step 1: 6-Chloro-3-nitropicolinonitrile (10 g, 54.48 mmol) was dissolved in H2SO4 (276 g, 2.53 mol) and heated at 70 °C for 3.5 hours. After the reaction was completed, the reaction mixture was cooled to 20 °C, and ice water (1200 mL) was added dropwise. The precipitate was filtered, washed with water, dried, and then concentrated under reduced pressure to give 6-chloro-3-nitropicolinamide (9.85 g, unpurified compound) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.54 (d, J = 8.8 Hz, 1H), 8.29 (brs, 1H), 8.03 (brs, 1H) 7.95 (d, J = 8.8 Hz, 1H).

[0104] Step 2: A solution of 6-chloro-3-nitropicolinamide (7.35 g, 36.46 mmol) was dissolved in ethanol (30 mL), followed by dropwise addition of saturated 28% ammonia (27.30 g, 218.09 mmol). The reaction was carried out in a 100 mL sealed tube at 100 °C for 48 hours. After the reaction was complete, the mixture was cooled and concentrated under reduced pressure to obtain a residue. The residue was diluted with aqueous Na2CO3 (100 mL), and the mixture was stirred at 20 °C for 1 hour. It was then filtered and the filter cake was washed with water (50 mL). The mixture was concentrated under reduced pressure to obtain a residue. 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, unpurified 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).

[0105] 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. 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, and the solid was filtered and dried under reduced pressure. 6-amino-3-nitropicolinamide (5.6 g, 21.13 mmol, 79.37% yield) 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).

[0106] Step 4: 6-amino-3-nitropicolinamide (5.9 g, 22.60 mmol) was dissolved in ethanol (59 mL) and distilled water (59 mL), and then 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 h. The reaction mixture was concentrated in vacuo to remove ethanol, and the pH of the residue was adjusted to 8 with aqueous NaHCO3. The solid precipitated and was then filtered. The filter cake was concentrated in vacuo to give a gray 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (5.28 g, 18.14 mmol, 80.26% yield). The results were confirmed by LCMS and HNMR. LCMS (ES-API, m / z): [M+H] + =287.0; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.55 (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).

[0107] 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 stirred at 85 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with 800 mL of EA / MeOH (10:1). The combined organic phases gave a residue. The residue was then washed with saturated sodium bicarbonate, filtered, and the filter cake was concentrated under reduced pressure to give 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 H NMR (400MHz, DMSO-d6, ppm): δ8.21-7.61(m,3H), 7.57-7.20(m,2H), 6.02-5.40(m,2H).

[0108] 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, and distilled water (20 mL) was added and stirred for 10 minutes to terminate the reaction. The mixture was filtered, and the solid was washed with ethyl acetate (200 mL) and dried. A yellow solid, 6-bromoimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine-1,3(2H,4H)-dione (10.7 g, crude compound), was obtained. LCMS (ES-API, m / z): [M+H] + =283.2; 1H NMR (400MHz, DMSO-d6, ppm): δ12.00-11.95(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)

[0109] Step 7: In a 250 mL round, three-necked 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. Subsequently, DIPEA (6.21 g, 48.03 mmol) was slowly added dropwise. The reaction mixture was filled with nitrogen and stirred at 110 °C for 20 h. After the starting material was completely consumed, the solvent and most of the POCl3 were removed under vacuum 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 H NMR (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).

[0110] Intermediate 2: Synthesis of 6-bromo-1,3-dichloro-8-methylfuro[3,2-f]quinazoline. JPEG2025540246000018.jpg36164

[0111] Step 1: 4-bromo-5-fluoro-2-nitrobenzoic acid (50.0 g, 189 mmol) was dissolved in distilled water (600 mL), 12 M KOH (63.8 g, 1.14 mol) was added, and the reaction solution was stirred at 80 °C for one day. The reaction mixture was adjusted to pH 3 with 1 N aqueous HCl, and then ethyl acetate was added to extract the organic layer, which was washed with saturated aqueous NaCl and dried over anhydrous MgSO 4 . The solvent was concentrated to afford 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol, unpurified compound). 1 H NMR (400MHz, DMSO-d6, ppm): δ13.7(s,1H), 12.1(s,1H), 8.27(s,1H), 7.14(s,1H).

[0112] Step 2: 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol) obtained in Step 1 was dissolved in methanol (599 mL), sulfuric acid (51.6 mL) was added at 0 °C, and the reaction solution was stirred at 70 °C for one day. Distilled water was added to the reaction mixture, and the reaction was completed. Ethyl acetate was added to extract the organic layer, which was washed with saturated aqueous NaCl and then dried over anhydrous MgSO4. The solvent was concentrated to yield methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol, unpurified compound).

[0113] 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 h. Purified water was added to the reaction mixture to quench the reaction. DCM was added to extract the organic layer, which was then dried over anhydrous MgSO4. The solvent was concentrated to give methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.1 g, 189 mmol, unpurified compound). 1 H NMR (400MHz, DMSO-d6, ppm): δ8.55(s,1H), 7.94(s,1H), 3.87(s,3H), 2.39(s,3H).

[0114] Step 4: Methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.0 g, 189 mmol) obtained in 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 with 6N aqueous KOH, and the solvent was removed and filtered. Ethyl acetate was added to the filtrate 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 methyl 5-acetoxy-2-amino-4-bromobenzoate (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).

[0115] 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), K2CO3 (2.19 g, 15.8 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N aqueous HCl, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated to afford methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.91 mmol, unpurified 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).

[0116] Step 6: Methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.92 mmol) obtained in Step 5 was dissolved in DMF (50 mL). 9.2 M 3-bromopropane in toluene (1.21 mL, 11.1 mmol) and K2CO3 (2.19 g, 15.8 mmol) were added sequentially, and the reaction solution was stirred at room temperature for one day. Purified 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, and the resulting material was purified by silica gel chromatography to give methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol, 74% yield) as a solid compound. 1H 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).

[0117] Step 7: Methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol) 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 h. The mixture was diluted with ethyl acetate, washed twice with 1N aqueous hydrochloric acid, and then dried over anhydrous MgSO. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to give solid methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol, 85% yield).

[0118] 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 7N ammonia solution (1.69 g, 99.0 mmol) dissolved in methanol was added to the resulting material, and the mixture was stirred at room temperature for one day. The solid 6-bromo-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (1.23 g, 4.17 mmol, 84% yield) was obtained by filtration using methanol. 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).

[0119] 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 to POCl3 (15.4 mL, 165 mmol) and DIPEA (1.80 mL, 10.3 mmol). The reaction mixture was stirred at 110 °C for 1.5 h. The solvent was concentrated, and the reaction mixture was quenched with saturated NaHCO3 solution. The organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was filtered with DCM to remove solids. The filtrate was concentrated and purified by silica gel chromatography to give 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; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.23(s,1H), 7.70(s,1H), 2.68(s,3H).

[0120] Intermediate 3: Synthesis of 6-bromo-1,3-dichloro-5-fluoro-8-methyl-6a,9a-dihydrofuro[3,2-f]quinazoline. JPEG2025540246000019.jpg50161

[0121] 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. The reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO3, and then 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 give 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).

[0122] 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), K2CO3 (4.97 g, 35.9 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. After acidifying the reaction mixture with 1N HCl aqueous solution, the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated to yield methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (4.74 g, 18.0 mmol, unpurified compound). 1 H NMR (400 MHz, DMSO-d 6, ppm): δ9.86(s,1H), 7.19(d,J=2.1Hz,1H), 6.07(s,2H), 3.81(s,3H).

[0123] 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 propargylbromide (1.15 mL, 10.6 mmol) dissolved in toluene and K2CO3 (2.09 g, 15.1 mmol) were added sequentially. The reaction solution was stirred at room temperature for one day. Purified 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, and the resulting material was purified by silica gel chromatography to give 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).

[0124] Step 4: Methyl 2-amino-4-bromo-3-fluoro-5-(prop-2-yn-1-yloxy)benzoate (1.02 g, 3.38 mmol) 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 h. The mixture was diluted with ethyl acetate, washed twice with 1N aqueous HCl, and then dried over anhydrous MgSO. The solvent was concentrated, and the resulting material was purified by silica gel chromatography to give 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).

[0125] Step 5: Methyl 5-amino-7-bromo-6-fluoro-2-methylbenzofuran-4-carboxylate (910 mg, 3.01 mmol) obtained from Step 4 was dissolved in THF (30.3 mL). Trichloroacetyl isocyante (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 material, and the mixture was stirred at room temperature for one day. The resulting white solid, 6-bromo-5-fluoro-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (863 mg, 2.76 mmol, 91% yield), was obtained by filtration with methanol. 1 H NMR (400MHz, DMSO-d6, ppm): δ9.90(s,2H), 7.21(s,1H), 2.53(s,3H).

[0126] 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, POCl3 (8.93 mL, 95.80 mmol) and DIPEA (1.04 mL, 5.99 mmol) were added, and the reaction solution was stirred at 110 °C for 7 h. The reaction mixture was quenched by adding saturated NaHCO3 solution, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. The solvent was concentrated, and the resulting material was filtered with DCM to give a white solid. The filtrate was concentrated and purified by silica gel chromatography to give 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).

[0127] Synthesis of Intermediate4:4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline. JPEG2025540246000020.jpg53163

[0128] Step 1: 7-bromo-5-nitro-1H-indazole (20 g, 82.6 mmol) was dissolved in THF (200 mL), and then NaH (8.3 g, 124 mmol) was added at 0 °C. The mixture was stirred at 20 °C. After stirring at 20 °C for 30 min, MeI (35.2 g, 248 mmol) was added. The reaction mixture was stirred at 20 °C for 1 h under nitrogen. After the reaction was completed, purified water (80 mL) was added to the reaction mixture, and it was 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 give the residue. The residue was stirred with hexane at 20 °C for 30 min, 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.

[0129] Step 2: 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) were added to a solution of ethanol (120 mL), THF (120 mL), and purified water (40 mL) and stirred at 90 °C for 1 h. The reaction mixture was filtered through celite to obtain a residue. The residue was purified by silica gel chromatography to obtain 7-bromo-2-methly-2H-indazole-5-amine (7 g, 31 mmol, 40% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =227.1; 1H NMR (400MHz, CDCl3, ppm): δ7.73(s,1H), 6.85(s,1H), 6.72(s,1H), 4.18(s,3H), 3.52(br, 2H).

[0130] Step 3: 7-bromo-2-methly-2H-indazole-5-amine (6.67 g, 29.5 mmol), chloralhydrate (9.76 g, 29.5 mmol), and NaSO (33.5 g, 236 mmol) were dissolved in purified water (70 mL). HCl (4 mL) was slowly added dropwise and the mixture was stirred at 90 °C for 30 minutes. N-chlorohydroxylamine (11.9 g, 177 mmol) was then added and the mixture was stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, and purified water (70 mL) was added and the mixture was stirred for 10 minutes. The solid was precipitated and then filtered. The filter cake was concentrated in vacuo to give a black solid N-(7-bromo-2-methyl-2H-indazole-5-yl)-2-(N-hydroxyamino)acetamide (8.77 g, 29.5 mmol, 100% yield, unpurified compound). LCMS (ES-API, m / z): [M+H] + =298.1.

[0131] Step 4: N-(7-bromo-2-methyl-2H-indazole-5-yl-2-(N-hydroxyimino)acetamide (9 g, 30.3 mmol) was slowly added dropwise with concentrated sulfuric acid (60 mL), and the reaction mixture was stirred at 90 °C for 30 minutes. The reaction mixture was cooled to room temperature, and then ice was added and stirred for 30 minutes. The solid was allowed to settle, and then filtered. The solid was dried to give black 4-bromo-2-methyl-2H,6H,7H,8H-pyrolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol, 60% yield). 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).

[0132] Step 5: 4-bromo-2-methyl-2H,6H,7H,8H-pyrolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol) was dissolved in 2N aqueous NaOH (7.28 g, 182 mmol), and then HO (3.1 g, 91 mmol) was slowly added dropwise and stirred for 1 hour. The reaction mixture was adjusted to pH 3 with acetic acid at 0 °C, 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; 1 H NMR (400MHz, DMSO-d6, ppm): δ10.81(s,1H), 8.58(s,1H), 7.25(s,1H), 4.19(s,3H).

[0133] Step 6: 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid (962 mg, 3.56 mmol) was dissolved in methanol (14 mL) and toluene (42 mL), and 2 M (diazomethyl)trimethylsilane (488 mg, 4.27 mmol) was added dropwise at 0 °C. The mixture was heated to room temperature and stirred for 5 minutes. The compound was extracted with ethyl acetate (200 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give methyl 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylate (283 mg, 0.996 mmol, 28% yield). 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).

[0134] Step 7: Methyl 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylate (276 mg, 0.971 mmol) was dissolved in THF (13 mL), and trichloroethanecarbonyl isocyanate (220 mg, 1.17 mmol) was added dropwise at 0 °C. The reaction mixture was then allowed to react 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. Methyl 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylate (459 mg, 0.971 mmol, 100% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =473.5

[0135] Step 8: Dissolve methyl 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylate (459 mg, 0.971 mmol) obtained in Step 7 in 100 mL of 7N NH4 in methanol. The resulting suspension was refluxed at 110 °C under nitrogen for 36 h. After the reaction was complete, the mixture 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, 100% yield, unpurified 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).

[0136] 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, and the mixture was filled with nitrogen and stirred at 110 °C for 20 h. After the reaction was complete, the solvent and most of the POCl3 were removed under vacuum 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.

[0137] Synthesis of Intermediate5:4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline JPEG2025540246000021.jpg81158

[0138] Step 1: 7-Bromo-6-fluoro-2H-indazole (40.0 g, 186 mmol) was dissolved in ethyl acetate (500 mL), followed by the addition of Me3OBF4 (41.3 g, 279 mmol) and stirring at room temperature for 12 hours. The reaction was quenched with purified water (500 mL) and extracted with ethyl acetate (500 mL x 2). The extracted organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography to obtain a yellow solid, 7-bromo-6-fluoro-2-methyl-2H-indazole (37.3 g, 163 mmol, 88% yield). 1H 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).

[0139] 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 slowly 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 x 3) and washed with saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a yellow solid, 7-bromo-6-fluoro-2-methyl-5-nitro-2H-indazole (38.0 g, 139 mmol, 86% yield). 1 H NMR (400MHz, DMSO-d6, ppm): δ8.91 (s, 1H), 8.85 (d, J = 7.2Hz, 1H), 4.26 (s, 3H).

[0140] Step 3: 7-bromo-6-fluoro-2-methyl-5-nitro-2H-indazole (38.0 g, 139 mmol) and NHCl (59.3 g, 1.11 mol) were dissolved in EtOH (400 mL) and HO (200 mL), and Fe (62.0 g, 1.11 mol) was added dropwise. The mixture was stirred at 80 °C for 2 h. After confirming the reaction, the resulting solid was filtered, washed with EtOH, and dried. The mixture was purified by silica gel chromatography to give a yellow solid, 7-bromo-6-fluoro-2-methyl-2H-indazol-5-amine (30.0 g, 123 mmol, 89% yield).

[0141] 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 then quenched with cold purified water. The organic layer was extracted with ethyl acetate (400 mL × 2), washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated. Solidification with petroleum ether / EtOAc = 5:1 gave a yellow solid, (E)-2-((benzyloxy)imino)-N-7-bromo-6-fluoro-2-methyl-2H-indazol-5-yl)acetamide (35.5 g, 87.6 mmol, 91% yield). LCMS (ES-API, m / z): [M+H] + =407.0; 1 H NMR (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).

[0142] 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 confirming the reaction, the mixture was cooled and quenched with cold purified water. The organic layer was extracted with ethyl acetate (1.00 L x 5) and lyophilized. The mixture was then solidified with MeOH to give a red solid, 4-bromo-5-fluoro-2-methyl-2,6-dihydropyrrolo[3,2-e]indazole-7,8-dione (11.0 g, 36.9 mmol, 44% yield). LCMS (ES-API, m / z): [M+H] + =320.1; 1H NMR (400MHz, DMSO-d6, ppm): δ11.42(s,1H), 8.63(s,1H), 4.18(s,3H).

[0143] 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). H2O (220.5 g, 180 mmol) was added dropwise to the reaction mixture at 0 °C and stirred at room temperature for 1 hour. After confirming the reaction, the reaction was quenched with aqueous Na2SO3 (500 mL) and concentrated under reduced pressure. The pH was adjusted to 4 using 6N aqueous HCl, and the resulting yellow solid was filtered and dried. A yellow solid, 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylic acid (8.80 g, 30.6 mmol, 86.7% yield), was obtained. LCMS (ES-API, m / z): [M+H] + =287.9; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.26 (s, 1H), 4.09 (s, 3H).

[0144] 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 CHCl (5.10 g, 35.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After confirming the reaction, the mixture was quenched with aqueous NH4Cl (500 mL) and the organic layer was extracted with ethyl acetate (300 mL x 3). The mixture was dried over anhydrous Na2SO4 and concentrated to give a yellow solid, methyl 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylate (10.0 g, unpurified mixture). LCMS (ES-API, m / z): [M+H] + =303.9; 1H NMR (400MHz, DMSO-d6, ppm): δ8.31(s,1H), 7.15(s,2H), 4.11(s,3H), 3.89(s,3H).

[0145] Step 8: Methyl 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylate (9.70 g, 32.1 mmol) was dissolved in THF (100 mL) and 2,2,2-trichloroacetyl isocyanate (12.1 g, 64.2 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and then concentrated after confirmation of the reaction. The resulting white solid was dissolved in NH₃·H₂O (91.0 g, 727 mmol) and MeOH (100 mL) and stirred at 40 °C for 2 h. The reaction mixture was concentrated and solidified with MeOH (100 mL) to give a yellow solid, 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). LCMS (ES-API, m / z): [M+H] + =314.8; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.72 (s, 1H), 4.19 (s, 3H).

[0146] 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 added dropwise. The reaction mixture was stirred at 115 °C for 40 h. After confirming the reaction, the mixture was cooled and quenched with purified water. The organic layer was extracted with ethyl acetate (500 mL × 2). The extracted organic layer was dried over anhydrous Na2SO4 and concentrated to give a yellow solid, 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (9.00 g, 25.12 mmol, 97% yield). LCMS (ES-API, m / z): [M+H] + =350.8; 1 H NMR (400MHz, CDCl3, ppm): δ8.80(s,1H), 4.37(s,3H).

[0147] Intermediate 6: Synthesis of 1-(morpholinomethyl)cyclopropyl)methanol JPEG2025540246000022.jpg16152

[0148] Step 1: 1-(Methoxycarbonyl)cyclopropane-1-carboxylic acid (1 g, 6.94 mmol) was dissolved in DCM (10 mL), and then oxalyl chloride (1.76 g, 13.88 mmol) and DMF (50.72 mg, 694.00 μmol) were added dropwise at 0 °C. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. Methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate (1.1 g, crude mixture) was obtained as a yellow oil without further purification.

[0149] Step 2: Methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate (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. Morpholine (884.22 mg, 10.15 mmol) was then added and stirred at room temperature for 16 hours. After the reaction was complete, purified water was added and the mixture was extracted with ethyl acetate. Purification by silica gel chromatography afforded methyl 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylate (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).

[0150] Step 3: Methyl 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylate (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 for 16 hours under nitrogen. Purified water was slowly added to terminate the reaction, and saturated aqueous NaOH 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).

[0151] Intermediate7: Synthesis of (R)-1-(3-methylmorpholino)methyl)cyclopropyl)methanol. JPEG2025540246000023.jpg14151

[0152] (R)-3-Methylmorpholine was synthesized in a similar manner to Intermediate 6 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(br d, J = 11.2 Hz, 1 H).

[0153] Intermediate8: Synthesis of 1-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol. JPEG2025540246000024.jpg19151

[0154] 1,1-difluoro-6-azaspiro[2.5]octane was synthesized in a similar manner to Intermediate 6 to give (1-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol (820 mg, unpurified 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).

[0155] Intermediate9: Synthesis of (1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol. JPEG2025540246000025.jpg12150

[0156] (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane was synthesized in a similar manner to Intermediate 6 to give (1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol (470 mg, unpurified 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).

[0157] Synthesis of Intermediate10:(R)-(1-((2-methylmorpholino)methyl)cyclopropyl)methanol. JPEG2025540246000026.jpg17149

[0158] (R)-2-Methylmorpholine was synthesized in a similar manner to Intermediate 6 to give (R)-(1-((2-methylmorpholino)methyl)cyclopropyl)methanol (760 mg, unpurified mixture) as a yellow oil. 1H 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).

[0159] Intermediate11: Synthesis of (1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol. JPEG2025540246000027.jpg12148

[0160] (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane was synthesized in a similar manner to Intermediate 6 to give (1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol (542 mg, unpurified mixture) as a yellow oil. LCMS (ES-API, m / z): [M+H] + =200.2.

[0161] Intermediate 12: Synthesis of (S)-(1-((3-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol. JPEG2025540246000028.jpg13147

[0162] (S)-3-fluoropiperidine was synthesized in a similar manner to Intermediate 6 to give (S)-(1-((3-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol (352 mg, unpurified 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).

[0163] Intermediate 13: Synthesis of 1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol. JPEG2025540246000029.jpg12145

[0164] Pyrrolidine was synthesized in a similar manner to Intermediate 6 to give 1-(pyrrolidin-1-ylmethyl)cyclopropylmethanol (328 mg, 2.11 mmol, 67% yield) as a yellow oil. LCMS (ES-API, m / z): [M+H] + =174.2; 1 H NMR (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).

[0165] Intermediate14: Synthesis of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol. JPEG2025540246000030.jpg10150

[0166] (R)-3-Fluoropyrrolidine was synthesized in a similar manner to Intermediate 6 to give (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (837 mg, unpurified 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).

[0167] Intermediate15: Synthesis of (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methanol. JPEG2025540246000031.jpg14147

[0168] (R)-3-Fluoropyrrolidine was synthesized in a similar manner to Intermediate 6 to give (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methanol (1.8 g, unpurified 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).

[0169] Synthesis of Intermediate16:((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. JPEG2025540246000032.jpg51159

[0170] 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), followed by the addition of imidazole (1.73 g, 25.48 mmol) and stirring at 0 °C for 10 min. TBSC (1.84 g, 12.23 mmol) was then slowly added and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the product was purified by silica gel chromatography to give 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).

[0171] 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 min. Then, 3-chloro-2-(chloromethyl)prop-1-ene (1.89 g, 15.16 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was purified by silica gel chromatography to give 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. 1 H 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).

[0172] Step 3: 1-(tert-butyl)2-methyl(2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (4 g, 8.93 mmol) was dissolved in THF (40 mL), and then TBAF·3HO (1 M, 10.71 mL) was added and stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was purified by silica gel chromatography. 1-(tert-butyl)2-methyl(2R,4R)-2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 7.82 mmol, 88% yield) was obtained 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).

[0173] Step 4: 1-(tert-Butyl) 2-methyl(2R,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 8.69 mmol) was dissolved in DCM (30 mL), and BAST (2.88 g, 13.03 mmol, 2.85 mL) was added dropwise at -78 °C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was purified by silica gel chromatography. 1-(tert-butyl) 2-methyl(2R,4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.82 g, 4.88 mmol, 56% yield) was obtained as a pale 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).

[0174] 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 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 methyl(2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (950 mg, 4.29 mmol, 80% yield) as a pale 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).

[0175] 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 h. Once the starting material was consumed, the reaction was quenched with water and 15% aqueous NaOH. ((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (720 mg, 3.78 mmol, 80% yield) was obtained as a white oil. 1 H 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).

[0176] Synthesis of Intermediate17:((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. JPEG2025540246000033.jpg49160

[0177] Step 1, 2: 1-(tert-butyl) 2-methyl(S)-5-oxopyrrolidine-1,2-dicarboxylate (40 g, 164.44 mmol) was dissolved in DCM (600 mL). DIBAL-H (1 M, 500 mL) was added dropwise at -68 °C and stirred for 30 minutes. The reaction was then continued 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, and the organic layer was extracted and dried over anhydrous MgSO4. The reaction residue was separated by silica gel chromatography to give 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).

[0178] Step 3: A solution of NaH (6.58 g, 164.44 mmol) in DMF (190 mL) was added to tert-butyl(2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-1-carboxylate (19 g, 82.15 mmol) at 0 °C and stirred for 15 min. Then, MeI (23.32 g, 164.30 mmol, 10.23 mL) was added at 0 °C and stirred at 20 °C for 2 h. After completion of the reaction, purified water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. Purification by silica gel chromatography afforded tert-butyl(5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylate (10.7 g, 43.62 mmol, 53% yield) as a yellow oil.1 H NMR (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).

[0179] Step 4: tert-Butyl(5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylate (10.7 g, 43.62 mmol) was dissolved in DCM (100 mL), and TMSOTf (969.44 mg, 4.36 mmol) was added dropwise at 0 °C. After stirring for 15 min, TMSCN (6.49 g, 65.43 mmol, 8.19 mL) was slowly added dropwise and the mixture was allowed to react at 0 °C for 2 h. After completion of the reaction, purified water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. Purification by silica gel chromatography afforded tert-butyl(5S)-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylate (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).

[0180] Step 5: tert-butyl(5S)-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylate (3 g, 12.48 mmol) was added to HCl / MeOH (2 M, 30.00 mL) and reacted at 20 °C for 12 h. 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. 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 H NMR (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).

[0181] Step 6: Methyl(5S)-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol) and BocO (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 MgSO. Purification afforded 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).

[0182] 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 then LiHMDS (1 M, 17.56 mL) was added and stirred at -68 °C for 0.5 h. (2.2 g, 17.56 mmol, 2.04 mL) was added to the reaction mixture and the reaction was continued at room temperature for 12 h. 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 MgSO4. Purification afforded 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).

[0183] 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), and TFA (2.4 mL) was added at 0°C. The reaction mixture was allowed to react 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, unpurified mixture) as a brown oil. LCMS (ES-API, m / z): [M+H] + =490.2.

[0184] 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 completion of the reaction, purified water 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. Purification afforded 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).

[0185] 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). LiAlH4 (2.5 M, 415.48 μL) was added at 0 °C and stirred at room temperature for 1 h. After completion of the reaction, purified water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. After removal of the solvent, ((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (190 mg, 963.13 μmol, 93% yield) was obtained as a yellow oil.

[0186] Synthesis of Intermediate18:6-fluoro-4-methyl-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine. JPEG2025540246000034.jpg28159

[0187] 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 TfO (4.13 g, 14.64 mmol) were added dropwise at 0 °C. The reaction mixture was stirred under nitrogen at 0 °C for 3 hours. Purified water was added to quench the reaction, and the reaction mixture was extracted with DCM. Purification by silica gel chromatography afforded 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 (400 MHz, DMSO-d 6,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).

[0188] Step 2: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate) (4.6 g, 7.39 mmol) obtained in Step 1, diphenylmethaneimine (1.34 g, 7.39 mmol, 1.24 mL), Pd2(dba)3 (1.35 g, 1.48 mmol), Xantphos (1.71 g, 2.96 mmol), and Cs2CO3 (7.22 g, 22.16 mmol) were dissolved in toluene (46 mL) and purged with nitrogen three times. The mixture was then stirred under nitrogen at 100 °C for 12 hours. After the reaction was completed, purified water was added and the resulting mixture was eluted with ethyl acetate. The residue was extracted with acetate several times and purified by silica gel chromatography to give 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonate (3.5 g, 5.35 mmol, 72% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6, ppm): δ7.96-7.90(m,1H), 7.75-7.67(m,3H), 7.54(br s,4H), 7.41-7.39(m,1H), 7.32-7.28(m,3H), 7.23-7.19(m,2H), 1.13(br s,21H).

[0189] Step 3: 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonate (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-yltrifluoromethanesulfonate (1.78 g, 3.35 mmol, 73% yield). LCMS (ES-API, m / z): [M+H] + =490.2; 1 H NMR (400 MHz, DMSO-d 6, 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).

[0190] Step 4: 3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonate (800 mg, 1.63 mmol) obtained in Step 3 was dissolved in toluene 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). The mixture was then purged with nitrogen three times. The reaction mixture was stirred under nitrogen at 110 °C for 12 h. After silica gel chromatography purification, 6-fluoro-4-methyl-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (360 mg, 671.26 μmol, 41% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =468.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ7.63(dd,J=6.0, 9.0Hz,1H), 7.33-7.24(m,1H), 7.23-7.19(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).

[0191] Intermediate19: Synthesis of 2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic acid. JPEG2025540246000035.jpg26150

[0192] 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 BocO (476.97 mg, 2.19 mmol), diethylamine (353.07 mg, 2.73 mmol), and DMAP (4.45 mg, 36.42 μmol). The mixture was purged with nitrogen three times. The reaction mixture was stirred for 2 h, concentrated, and purified by silica gel chromatography to give 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).

[0193] Step 2: tert-butyl(4-bromo-7-fluorobenzo[d]thiazol-2-yl)carbamate (250 mg, 720.04 μmol), the compound obtained in Step 1, was dissolved in THF (2 mL). n-BuLi (2.5 M in THF, 351.38 μL) was added dropwise at -15 °C and stirred for 30 min. Triisopropyl borate (338.55 mg, 1.80 mmol) was added at -65 °C and stirred for 30 min. MeLi (1.6 M, 540.03 μL) was then added at -65 °C and purged with nitrogen three times. The reaction mixture was incubated at 0 °C under nitrogen for 1 h. After completion of the reaction, the compound was extracted with NH4Cl solution and ethyl acetate. The water was dried over Na2SO4, and the solvent was 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).

[0194] Synthesis of Intermediate20:tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate. JPEG2025540246000036.jpg30155

[0195] Step 1: 4-Bromobenzo[d]thiazol-2-amine (1 g, 4.36 mmol) was dissolved in THF (4 mL) and DCM (6 mL) and cooled to 0 °C. At 0 °C, di-tert-butyldicarbonate (1.1 mL, 4.8 mmol), TEA (1.16 mL, 8.73 mmol), and DMAP (53.3 mg, 436 μmol) were added and stirred for 2 h. After complete consumption of the starting material, water was added to terminate the reaction, and the organic layer was extracted with ethyl acetate. The mixture was dried over anhydrous Na2SO4, 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

[0196] Step 2: tert-butyl(4-bromobenzo[d]thiazol-2-yl)carbamate (1.2 g, 3.65 mmol) obtained in Step 1 was dissolved in 1,4-dioxane (10 mL). Potassium acetate (1.07 g, 10.9 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) were added. The mixture was heated to 100 °C and stirred for 24 h. After completion of the reaction, the reaction temperature was lowered to room temperature. The palladium catalyst was removed using a Celite filter, 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 (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

[0197] Intermediate21: Synthesis of (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid. JPEG2025540246000037.jpg43162

[0198] Step 1: 1-Bromo-5-fluoro-2-iodo-3-methylbenzene (3 g, 9.53 mmol) was dissolved in DMF (60 mL), followed by the addition of 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 h. 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. The organic layer was washed with saturated aqueous NaCl (150 mL × 2) and then dried over anhydrous MgSO. The resulting residue was purified by silica gel chromatography to give 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).

[0199] Step 2: 1-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.7 g, 6.61 mmol) was dissolved in THF (34 mL). LDA (2 M, 6.61 mL) was added dropwise slowly under nitrogen at -60 °C and stirred for 30 min. 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 h. After the reaction was complete, saturated aqueous NH₄Cl solution (40 mL) was added dropwise to the reaction mixture, and the organic layer was extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated aqueous NaCl solution (100 mL × 2) and dried over anhydrous MgSO₄. The resulting residue was purified by silica gel chromatography to give 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (860 mg, 3.02 mmol, 46% yield) as a yellow oil. 1H NMR (400MHz, CDCl3, ppm): δ10.35(s,1H), 7.08(d,J=10.5Hz,1H), 2.61(q,J=4.0Hz,3H).

[0200] 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 purged with nitrogen three times. The reaction mixture was incubated at 60 °C for 2 hours. After completion of the reaction, purified water (20 mL) was added dropwise to the reaction mixture, and ethyl acetate (20 mL × 3) was added to extract the organic layer. The organic layer was washed with saturated aqueous NaCl (30 mL × 2) and dried over anhydrous MgSO4. The resulting residue was purified by silica gel chromatography to give 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (618 mg, 2.21 mmol, 73% yield) 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).

[0201] Step 4: 4-Bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (618 mg, 2.21 mmol) was dissolved in DCM (12 mL), followed by TsOH·HO (42.13 mg, 221.46 μmol). This was followed by a solution of DHP (745.14 mg, 8.86 mmol) in acetonitrile (3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, purified water (60 mL) was added dropwise to the reaction mixture, and the organic layer was extracted with ethyl acetate (20 mL × 3). The extract was washed with saturated aqueous NaCl (30 mL × 2) and dried over anhydrous MgSO4. The resulting reaction residue was purified by silica gel chromatography to give 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (800 mg, 2.20 mmol, 99% yield) as a pale 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).

[0202] Step 5: Hypoboric 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) were dissolved in MeOH (3 mL), and DIEA (266.90 mg, 2.07 mmol) was added dropwise slowly under nitrogen. After degassing with nitrogen for 10 minutes, the mixture was stirred at 60 °C for 40 minutes. After completion of the reaction, 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, unpurified mixture) as a black solid. LCMS (ES-API, m / z): [M+H] + =245.1

[0203] Intermediate22: Synthesis of (5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid. JPEG2025540246000038.jpg25163

[0204] 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. The mixture was stirred at room temperature for 2 hours under nitrogen. 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 MgSO4. Purification by silica gel chromatography afforded 4-bromo-5-chloro-3-iodo-6-methyl-1H-indazole (2.9 g, 7.73 mmol, 95% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =372.8; 1H NMR (400 MHz, DMSO-d 6, ppm): δ14.24-13.32(m,1H), 7.60(s,1H), 2.50(s,3H).

[0205] 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), and DHP (90.59 mg, 1.08 mmol) were dissolved in DCM (2.5 mL). The mixture was degassed and purged with nitrogen three times, then stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, purified water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. Trituration with ethyl acetate afforded 4-bromo-5-chloro-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (120 mg, 252.90 μmol, 47% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =454.9; 1 H NMR (400 MHz, DMSO-d 6, 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).

[0206] 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·CHCl₂ (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 h. After completion of the reaction, purified water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO₄. The residue was purified using silica gel chromatography to give 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 931.19 μmol, 42% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =260.8; 1 H 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(d t,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(br dd,J=3.2, 12.8Hz,1H), 1.82-1.70(m,2H), 1.69-1.62(m,1H).

[0207] Step 4: 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 651.83 μmol), hypoboric acid (175.31 mg, 1.96 mmol), DIEA (252.73 mg, 1.96 mmol), and cataCXium Pd G4 (47.54 mg, 65.18 μmol) were dissolved in MeOH (4 mL), degassed, purged with nitrogen three times, and then stirred at 60 °C for 40 min. After completion of the reaction, purified water 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 purified by silica gel chromatography to give (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).

[0208] Intermediate23: Synthesis of N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine. JPEG2025540246000039.jpg21155

[0209] Step 1: 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (110.67 mg, 190.78 μmol) and SuBu (110.67 mg, 190.78 μmol) were dissolved in 1,4-dioxane (1 mL). Pd(dba) (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 h. After the reaction was completed, the product was purified by silica gel chromatography 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 (400 MHz, DMSO-d 6, 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).

[0210] Intermediate24: Synthesis of N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine. JPEG2025540246000040.jpg19150

[0211] Step 1: 6-Bromo-5-(trifluoromethyl)pyridin-2-amine (700 mg, 2.9 mmol) was dissolved in DMF (10 mL) and cooled to 0 °C. Sodium hydride (290 mg, 7.26 mmol) was added at 0 °C and stirred for 30 minutes. After 30 minutes, 4-methoxybenzyl chloride (1.07 mL, 7.26 mmol) was added to the reaction mixture and stirred at room temperature for 4 hours. After the reaction was complete, the temperature was lowered to 0 °C, and water was slowly added to quench the reaction. The organic layer was extracted with ethyl acetate. The mixture was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was 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

[0212] 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 mixture was cooled to room temperature. The palladium catalyst was removed using a Celite filter, and the organic layer was extracted with ethyl acetate. The mixture 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

[0213] Intermediate25: Synthesis of N,N-bis(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine. JPEG2025540246000041.jpg26150

[0214] Step 1: 3-Bromo-4-(trifluoromethyl)aniline (500 mg, 2.08 mmol) was dissolved in DMF (10 mL) and cooled to 0 °C. NaH (416 mg, 10.41 mmol) was added at 0 °C and stirred for 30 minutes. After 30 minutes, 4-methoxybenzylchloride (1.4 mL, 10.41 mmol) was added to the reaction mixture and stirred at room temperature for 24 hours. After completion of the reaction, the reaction temperature was lowered to 0 °C, and water was slowly added to quench the reaction. The organic layer was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate / hexane) to give 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

[0215] Step 2: 3-bromo-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline (160 mg, 333 μmol) from 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-dioxaborolane (102 mg, 400 μmol), and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (24.4 mg, 33.3 μmol) were added and the mixture was heated to 90°C and stirred for 24 hours. After the starting material was completely consumed, 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. The extract was dried over anhydrous MgSO4 and 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

[0216] Intermediate 26: Synthesis of 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. JPEG2025540246000042.jpg23154

[0217] Step 1: 2,3,4,5-Tetrafluoroaniline (5 g, 30.3 mmol) was dissolved in acetonitrile (20 mL), and then NBS (5.93 mg, 33.3 mmol) was added at room temperature and stirred at 60 °C for 2 hours. The reaction temperature was lowered to room temperature, and the reaction was quenched with saturated aqueous sodium thiosulfate, followed by extraction with ethyl acetate. Purification by silica gel chromatography afforded 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).

[0218] Step 2: 2-bromo-3,4,5,6-tetrafluoroaniline (0.5 g, 2.05 mmol) obtained in Step 1, B2pin2 (1.30 g, 5.12 mmol), Pd(dppf)Cl2 (149.95 mg, 204.93 μmol), and potassium acetate (402.25 mg, 4.10 mmol) were added to 1,4-dioxane (5 mL) and purged with nitrogen three times. The reaction was then carried out at 100 °C under nitrogen for 2 h. 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, 31% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =210.0; 1 H NMR (400 MHz, DMSO-d 6, ppm):δ 1.19-1.15(m, 12H).

[0219] Example 1: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- Synthesis of 7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol. JPEG2025540246000043.jpg58156

[0220] Step 1: 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2.4 g, 7.55 mmol) was dissolved in DCM (48 mL), followed by the addition of 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). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with purified water (80 mL) and extracted with DCM (50 mL × 3). The organic layer was washed with aqueous NaCl (50 mL × 2), dried over Na2SO4, filtered, and concentrated to give a residue. The product was stirred with petroleum ether (50 mL) and EA (20 mL) at 25 °C for 30 min, after which the solid was filtered and dried. 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 H NMR (400 MHz, DMSO-d 6,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).

[0221] 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 NaH (395.28 mg, 9.88 mmol) was added at 0 °C. The reaction mixture was heated at room temperature for 30 min, and then a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (865.35 mg, 5.44 mmol) in THF (5 mL) was added. The reaction mixture was stirred at room temperature under nitrogen for 16 h. Purified water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was 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 RP-HPLC (0.1% FA condition). tert-Butyl(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-carboxylate (920 mg, 1.58 mmol, 32% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =572.5; 1 H NMR (400 MHz, DMSO-d 6,ppm):δppm8.19(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)。

[0222] Step 3: tert-butyl(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-carboxylate (470 mg, 821.57 μmol) obtained in Step 2, 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), and 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), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred under nitrogen at 80 °C for 16 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The compound was extracted with ethyl acetate (5 mL × 2). The organic layer was washed with saturated aqueous NaCl (5 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-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.

[0223] LCMS (ES-API, m / z): [M+H] + =770.4; 1 H NMR (400 MHz, DMSO-d 6,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,1H)、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)。

[0224] 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 4 N HCl in ethyl acetate solution (650 μL) was added. The reaction mixture was stirred at 25 °C for 1 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, and 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 saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-HPLC. 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-ethyl-6-fluoronaphthalen-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; 1 H NMR (400 MHz, DMSO-d 6,ppm): δ 9.86 (s, 1H), 8.11 - 7.99 (m, 1H), 7.75 (d, J = 2.4 Hz, 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, 1H), 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 = 6.8 Hz, 3H).

[0225] Example 2: Synthesis of 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-ol JPEG file: JPEG2025540246000044.jpg, size: 30167

[0226] Step 1: tert-Butyl(1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-y l)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-c arboxylate (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), followed by degassing and nitrogen purging three times. The mixture was then stirred under nitrogen at 80 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the ethanol. The unpurified residue was then diluted with purified water (15 mL) and extracted with ethyl acetate (10 mL × 2). The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-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; 1 H NMR (400 MHz, 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)。

[0227] 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 DMF (1.2 mL), and then 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 layer was washed with saturated aqueous NaCl (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by prep-TLC to give 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, 91.17 μmol, 70% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =766.5; 1H NMR(400MHz,CDCl3、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)。

[0228] 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). Then, 4N HCl in dioxane (700 μL) was added and stirred at 0 °C under nitrogen for 1 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (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 separated and purified by Prep-HPLC. 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-ol (27.37 mg, 43.79 μmol, 48% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =622.4; 1 H NMR (400 MHz, DMSO-d 6,ppm): δ 10.33 - 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 = 7.2 Hz, 1H), 2.20 - 1.98 (m, 4H), 1.93 - 1.68 (m, 5H), 1.57 - 1.42 (m, 1H).

[0229] Example 3: Synthesis of 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. JPEG2025540246000045.jpg38161

[0230] Step 1: tert-butyl(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-carboxylate (150mg, 262.20μmol), 2-(7,8-d ifluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110.18 mg, 314.65 μmol), PdCl2(dtbpf) (17.09 mg, 26.22 μmol), and K3PO4 (166.97 mg, 786.61 μmol) were added to 1,4-dioxane (2.4 mL) and water (0.6 mL), followed by degassing and purging with nitrogen three times. The mixture was then stirred under nitrogen at 80 °C for 1 h. After complete consumption of the starting material, 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 aqueous NaCl (5 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-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 (400 MHz, DMSO-d 6,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).

[0231] 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). HCl in dioxane (4 M, 1.30 mL) was added at 0 °C, followed by stirring at 0 °C for 1 h. 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 aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was separated 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 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.21 (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 = 9.2 Hz, 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, 4H), 2.88 - 2.78 (m, 1H), 2.20 - 1.95 (m, 4H), 1.92 - 1.60 (m, 5H), 1.58 - 1.36 (m, 2H).

[0232] 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-fluoronaphthalen-2-ol. JPEG2025540246000046.jpg26160

[0233] Step 1: 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2 g, 6.29 mmol) was dissolved in DCM (40 mL), and DIPEA (1.22 g, 9.44 mmol) and 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amine (967.79 mg, 7.55 mmol) were added sequentially. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (80 mL) and extracted with DCM (50 mL × 2). The organic layer was washed with saturated aqueous NaCl (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The product was stirred with petroleum ether (15 mL) and ethyl acetate (45 mL) at 25 °C for 30 min, then 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 (400 MHz, DMSO-d 6, 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).

[0234] 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), followed by the addition of NaH (1.42 g, 35.59 mmol) at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 10 min. The reaction mixture was then stirred at 70 °C under nitrogen for 16 h. The mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL x 3), dried, and concentrated under reduced pressure to give the product. The residue was purified by silica gel chromatography and then by prep-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 (400 MHz, DMSO-d 6, 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).

[0235] 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) obtained in Step 2, 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). After purging with nitrogen three times, the mixture was stirred under nitrogen at 80 °C for 1.5 h. After completion of the reaction, 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 (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 (400 MHz, DMSO-d 6,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)。

[0236] 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), and then HCl in dioxane (4 M, 0.5 mL) was added at 0 °C and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and 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, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was separated and purified by Prep-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-ethyl-6-fluoronaphthalen-2-ol (30.44 mg, 46.40 μmol, 32% yield) as a white solid. LCMS (ES-API, m / z): [M+H] + =488.2; 1 H NMR (400 MHz, DMSO-d 6,ppm): δ 9.86 (br s, 1H), 8.39 (s, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.38 - 7.26 (m, 3H), 6.99 (d, J = 2.4 Hz, 1H), 5.40 - 5.17 (m, 1H), 4.16 - 4.01 (m, 2H), 3.92 (br s, 1H), 3.75 (br s, 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 = 7.2 Hz, 3H).

[0237] 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. JPEG2025540246000047.jpg37152

[0238] The synthesis was carried out in a similar manner to Example 4, except that 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 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 (400 MHz, DMSO-d 6, 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).

[0239] 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-fluoronaphthalen-2-ol. JPEG2025540246000048.jpg28162

[0240] 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 (150mg, 307.38μmol), ((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), and K3PO4 (195.74 mg, 922.13 μmol) were added to dioxane (2.4 mL) and water (0.6 mL) and purged with nitrogen three times. The reaction mixture was stirred under nitrogen at 80 °C for 1.5 h. After completion of the reaction, 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 (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 H NMR (400 MHz, DMSO-d 6,ppm):δ8.14-8.05(m,1H)、7.83-7.74(m,1H)、7.71-7.65(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)。

[0241] 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). CsF (394.20 mg, 2.60 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (15 mL × 3). The organics were washed with saturated aqueous NaCl (15 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by prep-TLC to give 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 (90 mg, 128.62 μmol, 74% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =838.6; 1H NMR(400MHz,CDCl3、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)。

[0242] 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). Then, HCl in dioxane (4 M, 800 μL) was added at 0 °C and stirred for 1 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated NaHCO3 solution (15 mL). The compound was extracted with ethyl acetate (10 mL × 3). The organic layer was washed with saturated aqueous NaCl (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-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-fluoronaphthalen-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 H NMR (400 MHz, DMSO-d 6,ppm): δ10.34-9.88(m,1H), 8.32(s,1H), 7.95(dd,J=6.0, 9.2Hz,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).

[0243] Example 7: Synthesis of 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. JPEG2025540246000049.jpg36152

[0244] The synthesis was carried out in the same manner as in Example 2 using Intermediate 6. 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 (400 MHz, DMSO-d 6,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).

[0245] Example 8: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-methylmorpholino)methyl)cyclop Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000050.jpg35143

[0246] The synthesis was carried out in the same manner as in Example 2 using Intermediate 7. 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 (400 MHz, DMSO-d 6,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,3 H), 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).

[0247] Example 9: Synthesis of 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. JPEG2025540246000051.jpg35148

[0248] The synthesis was carried out in the same manner as in Example 2 using Intermediate 8. 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 (400 MHz, 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), 7.4 6-7.35(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).

[0249] Example 10: 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diaz Synthesis of abicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000052.jpg41147

[0250] The synthesis was carried out in the same manner as in Example 2 using Intermediate 9. 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-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-fluoronaphthalen-2-ol (39 mg, 59.19 μmol, 31% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =646.2; 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.21 - 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).

[0251] Example 11: Synthesis of 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. JPEG2025540246000053.jpg40153

[0252] The synthesis was carried out in the same manner as in Example 2 using Intermediate 10. 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; 1 H 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).

[0253] Example 12: 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diaz Synthesis of abicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol JPEG2025540246000054.jpg41155

[0254] The synthesis was carried out in the same manner as in Example 2 using Intermediate 11. 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-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-fluoronaphthalen-2-ol (62 mg, 91.22 μmol, 40% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =646.5; 1 H 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).

[0255] Example 13: Synthesis of 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. JPEG2025540246000055.jpg35154

[0256] Step 1: The synthesis was carried out in the same manner as in Step 1 of Example 2, except that 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. 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 mg, 103.82 μmol, 27% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =701.4; 1 H 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).

[0257] 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 (4 M, 0.8 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. Saturated aqueous NaHCO3 was added, followed by extraction with ethyl acetate. The crude compound was purified by prep-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; 1 H 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).

[0258] Example 14: Synthesis of 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. JPEG2025540246000056.jpg38148

[0259] This compound was synthesized in the same manner as in Example 2 using tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 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; 11H NMR (400 MHz, CDCl3, ppm): δ 8.78 - 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, 6.4 Hz, 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).

[0260] Example 15: Synthesis of 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. JPEG20,255,402,460,000,057.jpg 31,153

[0261] Step 1: (2-((tert-Butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic The acid (220 mg, 563.88 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 (280 mg, 489.45 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Then, K3PO4 (311.68 mg, 1.47 mmol) and Pd(amphos)Cl2 (31.90 mg, 48.94 μmol) were added and the mixture was purged with nitrogen three times. The reaction mixture was then stirred at 80 °C for 12 h. After completion of the reaction, the product was purified by silica gel chromatography to give 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, 65% yield). LCMS (ES-API, m / z): [M+H] + =804.7; 1H 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).

[0262] 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, and then HCl in dioxane (4 M, 0.5 mL) was added and stirred at 0 °C for 2 h. After the reaction was completed, the compound was purified by prep-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; 1H 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).

[0263] Example 16: Synthesis of 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. JPEG2025540246000058.jpg38145

[0264] The synthesis was carried out in the same manner as in Example 2 using Intermediate 14. 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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 0.45 (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, 9.07 Hz, 1H), 2.57 (br d, J = 4.4 Hz, 1H), 2.60 - 2.68 (m, 1H), 2.73 - 2.82 (m, 2H), 2.87 (br d, J = 11.2 Hz, 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 = 2.4 Hz, 1H), 7.35 (s, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.42 (t, J = 9.2 Hz, 1H), 7.47 (s, 1H), 7.96 (dd, J = 9.2, 6.00 Hz, 1H), 8.30 - 8.93 (m, 1H), 9.79 - 10.39 (m, 1H).

[0265] Example 17: Synthesis of 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. JPEG2025540246000059.jpg39143

[0266] The synthesis was carried out in the same manner as in Example 2 using Intermediate 13. 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 pale 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).

[0267] Example 18: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H) Synthesis of -yl)methoxy)-6-6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. JPEG2025540246000060.jpg34157

[0268] 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 2 h. After completion of the reaction, the reaction mixture was purified by prep-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; 1H 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)。

[0269] 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 reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was purified by prep-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 H NMR (400MHz, DMSO-d6, ppm): δ13.52-13.32(m,1H), 9.05-8.48(m,1H), 7.74-7.63(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).

[0270] Example 19: Synthesis of 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. JPEG2025540246000061.jpg37150

[0271] The synthesis was carried out in the same manner as in Example 2 using Intermediate 12. 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).

[0272] Example 20: 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 synthesis. JPEG2025540246000062.jpg34150

[0273] 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 simultaneously dissolved in 1,4-dioxane (2 mL) and then purged with nitrogen three times. The reaction mixture was then stirred at 110°C for 12 hours. After completion of the reaction, the product was purified by silica gel chromatography to give 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; 1H 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).

[0274] 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]octane-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 h. The reaction was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The reaction mixture was purified by prep-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).

[0275] Example 21: Synthesis of 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-fluoronaphthalen-2-ol. JPEG2025540246000063.jpg37148

[0276] The synthesis was carried out 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-fluoronaphthalen-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; 11H NMR (400 MHz, MeOD, ppm): δ 8.87 - 8.62 (m, 1H), 7.82 (dd, J = 5.8, 9.1 Hz, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.29 - 7.21 (m, 2H), 5.00 (s, 2H), 4.53 - 4.23 (m, 4H), 3.78 (br d, J = 14.4 Hz, 1H), 3.55 - 3.34 (m, 2H), 3.25 - 3.15 (m, 1H), 3.09 - 2.58 (m, 6H), 2.51 (br d, J = 15.9 Hz, 1H), 2.26 - 1.80 (m, 8H), 1.36 - 1.21 (m, 2H).

[0277] Example 22: Synthesis of 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. JPEG2025540246000064.jpg41157

[0278] This 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(br d,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).

[0279] Example 23: Synthesis of 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 JPEG2025540246000065.jpg41153

[0280] The synthesis was carried out 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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.12 (br s, 1H), 8.86 - 8.56 (m, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.49 (s, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.22 (d, J = 2.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.90 - 6.63 (m, 1H), 5.61 (d, J = 7.6 Hz, 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 = 15.2 Hz, 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).

[0281] Example 24: Synthesis of 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. JPEG2025540246000066.jpg40152

[0282] The synthesis was carried out in the same manner as in Example 2, except that intermediate 18 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. 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 H NMR(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).

[0283] Example 25: Synthesis of 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. JPEG2025540246000067.jpg38157

[0284] The synthesis was carried out 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).

[0285] Example 26: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H) Synthesis of -yl)methoxy)-6-6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. JPEG2025540246000068.jpg37161

[0286] This 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(br s,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).

[0287] Example 27: Synthesis of 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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. JPEG2025540246000069.jpg41151

[0288] This 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-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; 1 H 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).

[0289] Example 28: Synthesis of 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. JPEG2025540246000070.jpg39155

[0290] 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; 1 H 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).

[0291] Example 29: Synthesis of 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. JPEG2025540246000071.jpg38146

[0292] The synthesis was carried out 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; 1 H 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).

[0293] Example 30: Synthesis of 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. JPEG2025540246000072.jpg36151

[0294] The synthesis was carried out in the same manner as in Example 2 using Intermediate 14. 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; 1 H 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).

[0295] Example 31: Synthesis of 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. JPEG2025540246000073.jpg37149

[0296] The synthesis was carried out in the same manner as in Example 2 using Intermediate 12. 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; 1 H 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).

[0297] Example 32: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrol Synthesis of izin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000074.jpg36152

[0298] 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).

[0299] Example 33: Synthesis of 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. JPEG2025540246000075.jpg37154

[0300] The synthesis was carried out in the same manner as in Example 2, except that (R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol was used 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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.36 - 9.87 (m, 1H), 8.45 (br s, 1H), 7.96 (dd, J = 6.0, 9.1 Hz, 1H), 7.54 (br s, 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 = 13.9 Hz, 2H), 3.05 - 2.89 (m, 2H), 2.69 - 2.53 (m, 2H), 2.37 (br d, J = 15.6 Hz, 1H), 2.25 - 2.05 (m, 1H), 1.98 (ddd, J = 4.4, 7.1, 11.7 Hz, 1H), 1.93 - 1.64 (m, 5H), 1.60 - 1.22 (m, 2H).

[0301] Example 34: Synthesis of 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. JPEG2025540246000076.jpg36151

[0302] The synthesis was carried out 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).

[0303] Example 35: Synthesis of 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. JPEG2025540246000077.jpg37156

[0304] The synthesis was carried out in the same manner as in Example 2 using Intermediate 13. 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(br s,1H), 4.26(s,2H), 3.89-4.08(m,1H), 3.54-3.75(m,2H), 3.38-3.53(m,4H), 2.8 2-3.06(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).

[0305] Example 36: Synthesis of 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. JPEG2025540246000078.jpg37152

[0306] 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; 1 H NMR (400MHz, DMSO-d6, ppm): δ8.45 (br s, 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).

[0307] Example 37: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-fluoronaphthalen-2-ol. JPEG2025540246000079.jpg41162

[0308] 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-pyrrolizin-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; 1 H 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), 2.70-2.52(m,3H), 2.42(br d,J=16.0Hz,1H), 2.27-2.06(m,1H), 2.04-1.68(m,6H), 1.59-1.35(m,2H).

[0309] Example 38: Synthesis of 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 JPEG2025540246000080.jpg42153

[0310] This 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; 1 H 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).

[0311] Example 39: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrro Synthesis of lizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol JPEG2025540246000081.jpg42154

[0312] This compound was synthesized in the same manner as in Example 2 using tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 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).

[0313] Example 40: Synthesis of 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. JPEG2025540246000082.jpg38156

[0314] The synthesis was carried out in the same manner as in Example 2 using Intermediate 15. 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; 1 1H NMR (400 MHz, DMSO-d6, ppm): δ 10.36 - 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 = 5.2 Hz, 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 = 2.0 Hz, 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).

[0315] Example 41: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-tetrahydro-2-fluorine-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol JPEG2025540246000083.jpg63165

[0316] 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 min. Purified water was added to the reaction mixture to quench the reaction. The organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. The solvent was concentrated and the resulting material was purified by silica gel chromatography to give solid 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 mg, 0.098 mmol, 81.7% yield). LCMS (ES-API, m / z): [M+H] + =510.1

[0317] 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 min. After stirring, 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 to a solution of the product in THF (1 mL). The reaction mixture was stirred at room temperature for 7 h. Purified water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. The solvent was concentrated and the resulting material was purified by silica gel chromatography to give solid 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 (51 mg, 0.081 mmol, 39% yield). LCMS (ES-API, m / z): [M+H] + =631.6

[0318] 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)naphtalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.9 mg, 0.089 mmol), and KPO (28.3 mg, 0.133 mmol) were dissolved in ethanol (1.50 mL), DMF (0.30 mL), and purified water (0.15 mL). The resulting mixture was added to a 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 terminate 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 solid 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, 93% yield). LCMS (ES-API, m / z): [M+H] + =738.9

[0319] 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 4N hydrochloric acid solution (0.50 mL) dissolved in 1,4-dioxane was added at 0 °C. The reaction solution was stirred at room temperature for 30 minutes. The solvent was concentrated, purified using Prep-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).

[0320] Example 42: Synthesis of 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-fluoronaphthalen-2-ol. JPEG2025540246000084.jpg30168

[0321] Step 1: tert-Butyl(1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-m ethylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (51.0mg, 0.081mmol), ((2-Fluo Ro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (62.2 mg, 0.121 mmol) and K3PO4 (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 Pd G3 (8.82 mg, 0.012 mmol) was added, and the reaction solution was stirred at 80 °C for 1 h. Purified water was added to the reaction mixture to terminate 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 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. LCMS (ES-API, m / z): [M+H] + =937.4

[0322] 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) was added at 0 °C. The reaction solution was stirred at room temperature for 20 min. Purified water was added to the reaction mixture to quench the reaction. The organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. The solvent was concentrated and the resulting material was purified by silica gel chromatography to give 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. LCMS (ES-API, m / z): [M+H] + =780.9

[0323] 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 from Step 2 was dissolved in DCM (1 mL), and 4N HCl solution (0.30 mL) dissolved in 1,4-dioxane was added at 0 °C. The reaction solution was stirred at room temperature for 30 min. The solvent was concentrated, purified using Prep-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-fluoronaphthalen-2-ol (38.0 mg, 0.051 mmol, 79% yield). LCMS (ES-API, m / z): [M+H] + =636.9; 1 H 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).

[0324] Example 43: Synthesis of 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. JPEG2025540246000085.jpg31168

[0325] 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)naphtalen-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane] (53.8 mg, 0.171 mmol), and CsCO (112 mg, 0.342 mmol) were dissolved in toluene (1.00 mL) and purified water (0.25 mL). CataCXium A Pd G (8.3 mg, 0.011 mmol) was added, and the reaction solution was stirred at 100 °C for 2 h. The reaction mixture was quenched with purified water, 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 give solid 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, 28% yield). LCMS (ES-API, m / z): [M+H] + =634.3

[0326] 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 min. 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 was added to the reaction solution, and the reaction solution was stirred at 70 °C for 1 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 MgSO. The solvent was evaporated and the resulting material was purified by silica gel chromatography to give solid 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 (15.0 mg, 0.020 mmol, 63% yield). LCMS (ES-API, m / z): [M+H] + =756.6

[0327] 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 from Step 2 was dissolved in DCM (3.00 mL), and 4N hydrochloric acid solution (0.2 mL) dissolved in 1,4-dioxane was added at 0 °C. The reaction solution was stirred at room temperature for 3 hours. The solvent was concentrated, purified using Prep-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; 1 H 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).

[0328] Example 44: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-py Synthesis of rrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000086.jpg81161

[0329] 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 CsCO (2.21 g, 6.79 mmol) were dissolved in toluene (34.0 mL) and purified water (8.5 mL). CataCXium A Pd G (165 mg, 0.226 mmol) was added, and the reaction solution was stirred at 100 °C for 1 day. The reaction mixture was quenched by adding purified water, 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. The resulting material was concentrated, dissolved in hexane, and then sonicated. The resulting solid was filtered. The resulting solid was washed with hexane to give the solid compound 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 (640 mg, 0.770 mmol, 34% yield). LCMS (ES-API, m / z): [M+H] + =831.4; 1H 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)。

[0330] Step 3: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.05 g, 6.61 mmol) was dissolved in THF (29 mL), NaH (265 mg, 6.61 mmol) was added, and the mixture was stirred for 30 min. After stirring, 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 from Step 2 was slowly added to a solution of the resulting mixture in THF (22.0 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with purified water, 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 give the solid compound 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). LCMS (ES-API, m / z): [M+H] + =954.5; 1H 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)、2.13-2.02(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)。

[0331] 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 from 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. The reaction solution was stirred at room temperature for 20 min. Purified water was added to the reaction mixture to quench the reaction. The organic layer was extracted with ethyl acetate and dried over anhydrous MgSO. The solvent was concentrated and the resulting material 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. LCMS (ES-API, m / z): [M+H] + =798.3; 1H 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).

[0332] 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), and 4 N HCl in 1,4-dioxane (0.06 mL) was added at 0 °C. The reaction solution was stirred at room temperature for 1 h. The solvent was concentrated, purified using Prep-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-fluoronaphthalen-2-ol (6.2 mg, 0.008 mmol, 32% yield). LCMS (ES-API, m / z): [M+H]+ =654.3; 1 1H NMR (400 MHz, CD3OD, ppm): δ 7.91 (dd, J = 9.2, 5.7 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.22 (d, J = 2.6 Hz, 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 - 2.2 ( / s, 3H), 2.20 - 1.95 (m, 4H).

[0333] Example 45: Synthesis of 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. JPEG2025540246000087.jpg38156

[0334] It should be noted that there seems to be an error in the original text where "<4.82 - 4.66 (m, 3H)" is written as "<4.82 - 4.66 (m, 3H)" with an extra "<" at the beginning. This has been corrected in the translation for better readability. Also, "2.43 - 2.2 ( / s, 3H)" seems to have an incorrect " / s" notation which has been left as is in the translation as the exact meaning is unclear from the original text.This 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. Purification by prep-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-ethyl-6-fluoronaphthalen-2-ol (10 mg, 61% yield). 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).

[0335] Example 46: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H Synthesis of -pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol. JPEG2025540246000088.jpg37158

[0336] This 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. Purification by prep-HPLC and lyophilization afforded 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).

[0337] 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. JPEG2025540246000089.jpg39158

[0338] This compound was synthesized in the same manner as in Example 43 using 1-(Aminomethyl)-N,N-dimethyl-cyclobutanamine. Purification by RP-HPLC and lyophilization afforded 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).

[0339] Example 48: 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-p Synthesis of yrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000090.jpg39155

[0340] This compound was synthesized using 1-(aminomethyl)-N,N-dimethyl-cyclobutanamine in the same manner as in Example 44. Purification by prep-HPLC and lyophilization gave 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; 1 H 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).

[0341] Example 49: 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 Synthesis of H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline JPEG2025540246000091.jpg29168

[0342] 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). The mixture was degassed and purged with nitrogen three times. The reaction mixture was then stirred under nitrogen at 110 °C for 5 h. 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. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl(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-carboxylate (70 mg, 82.7 μmol, 29% yield). LCMS (ES-API, m / z): [M+H] + =946.3

[0343] Step 2: Synthesized in a manner similar to Step 2 of 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, 62% yield). LCMS (ES-API, m / z): [M+H] + =970.1

[0344] Step 3: 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 to TFA (4 mL) and stirred at room temperature for 9 hours. After the starting material was completely consumed, 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; 11H NMR (400 MHz, MeOD) δ 7.55 (d, J = 8.7 Hz, 1H), 6.89 - 6.79 (m, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 5.45 (s, 0.5H), 5.25 (s, 0.5H), 4.32 (d, J = 10.3 Hz, 2H), 4.24 (dd, J = 10.3, 2.6 Hz, 2H), 3.64 (q, J = 12.7 Hz, 2H), 3.54 (s, 2H), 3.31 - 3.13 (m, 3H), 3.03 (td, J = 9.6, 5.5 Hz, 1H), 2.46 (s, 4H), 2.35 - 2.13 (m, 3H), 2.01 (dq, J = 12.0, 6.5 Hz, 2H), 1.77 (s, 2H), 1.31 (s, 1H).

[0345] Example 50: Synthesis of 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. JPEG2025540246000092.jpg33164

[0346] 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), and Lithium chloride 1 (9.3 mg, 456 µmol). Copper(I) iodide (5.8 mg, 30.4 µmol) was placed in 1,4-dioxane (2 mL), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred under nitrogen at 130°C 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. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl(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-carboxylate (40 mg, 47.2 μmol, 31% yield). LCMS (ES-API, m / z): [M+H] + =848.3

[0347] Step 2: Synthesized in a manner similar to Step 2 of 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

[0348] Step 3: 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 to TFA (2 mL) and stirred at 40 °C for 9 h. After complete consumption of the starting material, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge C18 150 x 50 mm x 10 μm column; 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, 58% yield). 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).

[0349] Example 51: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1H-indazol-4-yl)-5-fluoro- Synthesis of 3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazoline. JPEG2025540246000093.jpg38161

[0350] 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 (100mg, 190μmol), 5-chloro-6-methyl-1 -(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (107mg, 285μmol), Tetrakis(triphenylphosphine)palladium(0)(22mg, 19μmol) and Potassium phosphate Tribasic (121 mg, 571 μmol) was added to 1,4-dioxane (2 mL) and water (0.5 mL), followed by degassing and purging with nitrogen three times. The reaction mixture was then stirred under nitrogen at 95°C for 30 minutes. After complete consumption of the starting material, the reaction mixture was quenched by adding 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 tert-butyl(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-carboxylate (50 mg, 86.3 μmol, 45% yield). LCMS (ES-API, m / z): [M+H] + =696.6

[0351] Step 2: Synthesized in a manner similar to 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, 10% yield). LCMS (ES-API, m / z): [M+H] + =819.4

[0352] 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 then 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 prep-HPLC (Waters Xbridge C18 150 x 50 mm x 10 μm column; 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, 31% yield). LCMS (ES-API, m / z): [M+H] + =630.6; 1 H NMR(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=1 6.6Hz,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).

[0353] Example 52: Synthesis of 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. JPEG2025540246000094.jpg36156

[0354] The synthesis was carried out in a similar manner to 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).

[0355] Example 53: Synthesis of 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. JPEG2025540246000095.jpg37151

[0356] Synthesized in a similar manner to Example 43, 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, 23% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =816.6; 1 H 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).

[0357] Liquid 54:4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro The formula of -1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[d]thiazol-2-amine. JPEG2025540246000096.jpg34165

[0358] 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 potassium phosphate tribasic (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 under nitrogen at 90 °C for 24 h. After complete consumption of the starting material, 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 (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

[0359] 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 complete consumption of the starting material, water was slowly added to quench the reaction, and the organic layer was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% methanol / DCM) to give 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, 49% yield). LCMS (ES-API, m / z): [M+H] + =833.4

[0360] 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), followed by 4.0 M HCl in 1,4-dioxane (2 mL) and stirring 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 prep-HPLC (Waters Xbridge C18 150 x 50 mm x 10 μm column; 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, 86% yield). 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).

[0361] Example 55: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-p Synthesis of yrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-amine. JPEG2025540246000097.jpg38159

[0362] The compound was synthesized in the same manner as in Example 54 using Intermediate 19. 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)-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).

[0363] Example 56: 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyr Synthesis of rolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline. JPEG2025540246000098.jpg39149

[0364] This 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 by prep-HPLC afforded 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, 6% yield). 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).

[0365] Example 57: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyr Synthesis of rolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. JPEG2025540246000099.jpg39156

[0366] This was synthesized using Intermediate 18 in the same manner as in Example 44. Purification by prep-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; 1 H 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).

[0367] Example 58: Synthesis of 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. JPEG2025540246000100.jpg37157

[0368] The compound was synthesized in the same manner as in Example 44 using Intermediate 18 and Intermediate 8. Lyophilization gave 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, 58% yield). LCMS (ES-API, m / z): [M+H] + =724.8; 1 H 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).

[0369] Example 59: 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)meth Synthesis of yl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000101.jpg39150

[0370] The synthesis was carried out in the same manner as in Example 44 using Intermediate 8. 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).

[0371] Example 60: 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol Synthesis of izin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine JPEG2025540246000102.jpg37156

[0372] The compound was synthesized in the same manner as in Example 20 using Intermediate 3. 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(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).

[0373] Example 61: Synthesis of 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. JPEG2025540246000103.jpg37153

[0374] 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).

[0375] Example 62: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizi Synthesis of n-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. JPEG2025540246000104.jpg28166

[0376] 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(300mg, 571μmol), tert-butyl(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxab (Orolan-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), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred under nitrogen at 120 °C for 6 h. After complete consumption of the starting material, 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 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 (290 mg, 393 μmol, 69% yield). LCMS (ES-API, m / z): [M+H] + =738.2

[0377] 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 stirred at 50 °C for 2 hours. After the starting material was completely consumed, the reaction was quenched by slowly adding water at room temperature, and the organic layer was extracted with ethyl acetate. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 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

[0378] Step 3: 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)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (17 mg, 25.8 μmol, 43% yield) in a manner similar to Step 3 of Example 54. 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).

[0379] Example 63: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrro Synthesis of lizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. JPEG2025540246000105.jpg36160

[0380] 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, the reaction was quenched by slowly adding water at room temperature. The organic layer was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 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

[0381] Step 2: The synthesis was carried out 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).

[0382] Example 64: Synthesis of 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. JPEG2025540246000106.jpg42156

[0383] The compound was synthesized in the same manner as in Example 44 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)-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; 1 H 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).

[0384] Example 65: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-((2S,7aR)-2-fluoro-6-methylenetetrahydro Synthesis of -1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol JPEG2025540246000107.jpg37158

[0385] The synthesis was carried out in the same manner as in Example 44 using Intermediate 16. 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-fluoronaphthalen-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).

[0386] Example 66: Synthesis of 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-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-fluoronaphthalen-2-ol. JPEG2025540246000108.jpg39154

[0387] This 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-pyrrolizin-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).

[0388] Example 67: 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyr Synthesis of rolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine JPEG2025540246000109.jpg37153

[0389] The synthesis was carried out 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-fluoronaphthalen-2-amine (50 mg, 62% yield) was obtained as a brown solid. LCMS (ES-API, m / z): [M+H] + =653.2; 1 H NMR (400MHz, DMSO-d6, 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,1) H), 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).

[0390] Example 68: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-p Synthesis of yrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol. JPEG2025540246000110.jpg27162

[0391] Step 1: 4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (300 mg, 0.904 mmol) was dissolved in DCM (48 mL), followed by the addition of DIPEA (350 mg, 2.71 mmol, 0.501 mL), followed by the addition of tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted with DCM (50 mL x 3). The organic layer was washed with saturated aqueous NaCl (50 mL x 2), dried over NaSO, filtered, and concentrated to give a residue. The product was precipitated with hexane, filtered, and the filtered solid was dried. 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

[0392] 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 min. After that, 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 to a solution of the product in THF (5 mL) and reacted at room temperature for 3 h. 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). tert-butyl(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-carboxylate (150 mg, 0.283 mmol, 94% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =531.4

[0393] Step 3: tert-butyl(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-carboxylate (53.5 mg, 84.8 μmol) obtained in Step 2, 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (32 mg, 102 μmol), and cataCXium 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), followed by degassing and purging with nitrogen three times. The reaction mixture was then stirred under nitrogen at 80 °C for 1 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, and 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 aqueous NaCl (5 mL × 2), dried over anhydrous Na2SO4, and then 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, 64% yield) was obtained. LCMS(ES-API,m / z):[M+H] + =738.9

[0394] 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 Prep-HPLC (Column: Waters Xbridge C18 150 x 50 mm x 10 μm; 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, 78% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =594.7; 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).

[0395] Example 69: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin Synthesis of -7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000111.jpg29165

[0396] Step 1: tert-Butyl(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]octan e-8-carboxylate (107mg, 170μmol), (2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (87mg, 170μmol), cataCXium 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), followed by degassing and nitrogen purging three times. The reaction mixture was then stirred under nitrogen at 80 °C for 3 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with purified water (10 mL). The compound was extracted with ethyl acetate (5 mL × 2). The organic layer was washed with saturated aqueous NaCl (5 mL × 2), dried over anhydrous Na2SO4, and then 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-pyrr olizin-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

[0397] 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 complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure, and 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 × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (MC:MeOH = 20:1) to give 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, 64.1 μmol, 100% yield). LCMS (ES-API, m / z): [M+H] + =780.9

[0398] 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 4 N 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 prep-HPLC (Column: Waters Xbridge C18 150 × 50 mm × 10 μm; 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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 8.33 (s, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.32 (s, 1H), 7.13 (d, J = 2.6 Hz, 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 = 4.2 Hz, 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).

[0399] Example 70: Synthesis of 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. JPEG2025540246000112.jpg39157

[0400] The synthesis was carried out 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 prep-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, 100% yield) 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).

[0401] Example 71: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- Synthesis of 7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine JPEG2025540246000113.jpg40158

[0402] This was synthesized using Intermediate 18 in the same manner as in Example 69. After prep-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-d6δ8.28(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).

[0403] Example 72: Synthesis of 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-fluoronaphthalen-2-ol JPEG2025540246000114.jpg33156

[0404] This 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. Purification by prep-HPLC and lyophilization afforded a yellow solid, 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-fluoronaphthalen-2-ol (50.55 mg, 83.67 μmol, 43% yield). LCMS (ES-API, m / z): [M+H] + =595.3; 1 H NMR(400MHz,DMSO-d6,ppm)δ11.30-10.30(m,2H), 9.71-9.51(m,2H), 9.41-9.23(m,1H), 8.2 0-8.10(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).

[0405] Example 73: 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)met Synthesis of hyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000115.jpg37146

[0406] The compound was synthesized in the same manner as in Example 69 using Intermediate 8. Purification by prep-HPLC and lyophilization afforded 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; 1 H 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).

[0407] Example 74: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrroliz Synthesis of in-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. JPEG2025540246000116.jpg86157

[0408] 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 stirred for 2 hours. After complete consumption of the starting material, the reaction was quenched by slowly adding water at room temperature. The organic layer was extracted with ethyl acetate. The mixture 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-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

[0409] Step 2: 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 (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 A Pd G3 (33.9mg, 46.6μmol) and Cesium Carbonate (304 mg, 934 μmol) was added to toluene (4 mL) and water (1 mL), and degassing and nitrogen purging were repeated three times. The reaction mixture was then stirred under nitrogen at 110 °C for 24 hours. After the starting material was completely consumed, the Palladium catalyst was removed through a Celite filter. The residue 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

[0410] 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

[0411] 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; 1 H 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).

[0412] Example 75: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrol Synthesis of izin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000117.jpg40151

[0413] This compound was synthesized in the same manner as in Example 69 using (S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. After purification by prep-HPLC 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; 1 H 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).

[0414] Example 76: 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)methy Synthesis of l)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. JPEG2025540246000118.jpg34156

[0415] The synthesis was carried out in the same manner as in Example 74 using Intermediate 8. 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).

[0416] Example 77: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- Synthesis of yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. JPEG2025540246000119.jpg34155

[0417] This was synthesized in the same manner as in Example 62 using Intermediate 4. Lyophilization afforded 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, 11% yield) 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).

[0418] Example 78: 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2- Synthesis of (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline JPEG2025540246000120.jpg36154

[0419] This was synthesized in the same manner as in Example 27 using Intermediate 4. 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).

[0420] Example 79: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrr Synthesis of olizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000121.jpg38154

[0421] The synthesis was carried out in the same manner as in Example 32 using Intermediate 16. 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-fluoronaphthalen-2-ol (68 mg, 83% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.7; 1 H 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).

[0422] Example 80: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol Synthesis of izin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000122.jpg59157

[0423] Step 1: 4-Bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (2 g, 5.71 mmol) was dissolved in ACN (30 mL), followed by the addition of 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). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL × 4). The organic layer was washed with saturated aqueous NaCl (50 mL × 2), dried over NaSO, filtered, and concentrated to give 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).

[0424] Step 2: 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) was dissolved in DMSO (30 mL). 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) were added. The reaction mixture was heated at 120 °C for 16 h. After confirming that the starting material was gone, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 4). The organic layer was washed with saturated aqueous NaCl (50 mL × 2), dried over NaSO, filtered, and concentrated to give a residue. The reaction mixture was purified by silica gel chromatography (eluent of 0–50% ethyl acetate / petroleum ether gradient) to give tert-butyl(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-carboxylate (545 mg, 689.09 μmol, 28% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =650.3; 1H 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)。

[0425] Step 3: tert-butyl(1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methy l-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 379.31μmol), ((2-fluoro-6-(meth (oxymethoxy)-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). The mixture was degassed and purged with nitrogen three times. The reaction mixture was incubated at 80 °C for 3 h. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). Purification by silica gel chromatography afforded 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(br s,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(br d,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)。

[0426] Step 4: 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) was dissolved in DMF (4 mL), and then CsF (514.02 mg, 3.38 mmol) was added and reacted at room temperature for 40 minutes. After the reaction was complete, the mixture was extracted with ethyl acetate (10 mL × 4) and saturated aqueous NaCl solution. Separation by prep-TLC afforded 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).

[0427] Step 5: 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 to HCl in 1,4-dioxane (2 M, 2.5 mL) and reacted at 0 °C for 1 h. After completion of the reaction, the product was purified by prep-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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.28 - 9.91 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 5.39 - 5.18 (m, 1H), 4.11 (dd, J = 5.6, 10.4 Hz, 1H), 4.05 (s, 3H), 4.04 - 3.98 (m, 2H), 3.89 - 3.80 (m, 1H), 3.55 (br d, J = 13.2 Hz, 1H), 3.45 (br d, J = 8.0 Hz, 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).

[0428] Example 81: Synthesis of 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-amine. JPEG2025540246000123.jpg38152

[0429] The compound was synthesized in the same manner as in Example 57 using Intermediate 4. The resulting compound was purified by prep-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-fluoronaphthalen-2-amine (75.99 mg, 115.06 μmol, 49% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =653.4; 1 H 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).

[0430] Example 82:9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(( Synthesis of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline. JPEG2025540246000124.jpg36152

[0431] This 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 prep-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, 24% yield) as a pink solid. LCMS (ES-API, m / z): [M+H] + =638.3; 1 H 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. s,2H).

[0432] Example 83: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizi Synthesis of n-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. JPEG2025540246000125.jpg38154

[0433] The 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, 86% yield) was obtained. LCMS (ES-API, m / z): [M+H] + =640.7; 1 H 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).

[0434] Example 84: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyr Synthesis of rolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol. JPEG2025540246000126.jpg33165

[0435] 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 A Pd G3 (44 mg, 0.0591 mmol), and Cs2CO3 (577 mg, 1.77 mmol) were dissolved in toluene (12 mL) and purified water (3 mL). The mixture was degassed and purged with nitrogen three times. After stirring at 100 °C for 3 h, the reaction was quenched by adding water. The organic layer was extracted with ethyl acetate and dried over anhydrous MgSO4. Purification by silica gel chromatography afforded a brown oil, 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). LCMS (ES-API, m / z): [M+H] + =651.2

[0436] 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), followed by (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), and the mixture was stirred at 40 °C for 3 h. After the reaction was completed, purified water 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. Purification by silica gel chromatography afforded 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

[0437] Step 3: 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 to HCl in 1,4-dioxane (4 N, 2.5 mL) and stirred at 0 °C for 1 h. After completion of the reaction, the product was purified by prep-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).

[0438] Example 85: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-p Synthesis of yrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. JPEG2025540246000127.jpg41150

[0439] This 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; 11H NMR (400 MHz, MeOD, ppm): δ 8.33 (s, 1H), 7.70 (dd, J = 9.1, 6.0 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.24 (t, J = 9.3 Hz, 1H), 7.07 (d, J = 2.7 Hz, 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 = 15.1 Hz, 2H), 3.67 (d, J = 16.5 Hz, 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 = 7.3 Hz, 3H).

[0440] Example 86: Synthesis of 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. JPEG2025540246000128.jpg40156

[0441] This 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).

[0442] Example 87: 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)c Synthesis of yclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000129.jpg40156

[0443] This was synthesized in the same manner as in Example 80 using intermediate 8. 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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.28 - 9.90 (m, 1H), 8.31 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 4.30 (s, 2H), 4.10 (br d, J = 11.2 Hz, 1H), 4.05 (s, 3H), 3.83 (br d, J = 12.0 Hz, 1H), 3.57 (br d, J = 11.6 Hz, 2H), 3.48 (br s, 3H), 3.42 (s, 3H), 2.44 (br d, J = 1.2 Hz, 2H), 2.36 (br d, J = 9.6 Hz, 2H), 1.82 - 1.66 (m, 2H), 1.62 - 1.53 (m, 4H), 1.49 (br s, 2H), 1.17 (br t, J =​​​​​​​​​The synthesis was carried out 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]octan-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).

[0446] Example 89: 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- Synthesis of (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline. JPEG2025540246000131.jpg35161

[0447] Step 1: Intermediate22 (100mg, 324.08μmol), tert-butyl(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-carboxylate (199.67mg, 307.87μmol), K3PO4 (206.37mg, 972.23μmol), cataCXium A Pd G4 (21.12 mg, 32.41 μmol) was dissolved in 1 mL of 1,4-dioxane and 0.2 mL of water, followed by degassing and nitrogen purging three times and stirring at 90°C for 2 hours. After the reaction was completed, purified water was added to the reaction mixture to terminate 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 prep-TLC to give 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 (87 mg, 99.19 μmol, 31% yield). LCMS (ES-API, m / z): [M+H] + =832.3

[0448] 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), and TFA (3.07 g, 26.92 mmol) was added dropwise. 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 MgSO4. The reaction residue was purified by prep-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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 12.84 (br s, 1H), 8.39 (s, 1H), 7.58 (s, 1H), 5.38 - 5.19 (m, 1H), 4.17 - 4.10 (m, 1H), 4.06 (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 = 11.6 Hz, 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).

[0449] Example 90: Synthesis of 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. JPEG2025540246000132.jpg40148

[0450] The synthesis was carried out 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).

[0451] Example 91: Synthesis of one isomer of 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 JPEG2025540246000133.jpg39157

[0452] The compound of Example 90 was separated (ee% = 98.5%) using a DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: [CO₂-ACN / i-PrOH (0.1% NH₃·H₂O)]; B%: 55% under isosolvent transfer conditions (retention time: 1.160 min) to give a single hindered rotation isomer (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, 8.8Hz,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(br d,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).

[0453] Example 92: Synthesis of one isomer of 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 JPEG2025540246000134.jpg39157

[0454] The compound of Example 90 was separated (ee% = 96.5%) using a DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: [CO₂-ACN / i-PrOH (0.1% NH₃·H₂O)]; B%: 55% under isosolvent transfer conditions (retention time: 1.605 min) to give a single hindered rotation isomer (98.73 mg, 141.7 μmol, 34% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =684.3; 1 H 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).

[0455] Example 93: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro Synthesis of lizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. JPEG2025540246000135.jpg37150

[0456] The synthesis was carried out 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 prep-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-fluoronaphthalen-2-ol (40 mg, 0.061 mmol, 49% yield) as a yellow solid. LCMS (ES-API, m / z): [M+H] + =658.7; 1 H 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).

[0457] Example 94: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-py Synthesis of rrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000136.jpg41152

[0458] This compound was synthesized in the same manner as in Example 80 using (S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. Purification by prep-HPLC afforded 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; 1 H 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).

[0459] Example 95: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyr Synthesis of rolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol. JPEG2025540246000137.jpg38154

[0460] The synthesis was carried out 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 prep-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; 1 H 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).

[0461] Example 96: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydr Synthesis of o-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000138.jpg37155

[0462] The synthesis was carried out in the same manner as in Example 80 using Intermediate 17. 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; 11H NMR (400 MHz, DMSO-d6, ppm): δ 10.20 - 9.99 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 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, 10.0 Hz, 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 (br d, J = 15.6 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.96 (td, J = 2.8, 5.6 Hz, 1H), 1.82 - 1.73 (m, 1H), 1.73 - 1.55 (m, 5H).

[0463] Example 97: Synthesis of 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. JPEG2025,540,246,000,139.jpg 41159

[0464] The synthesis was carried out 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; 1 H 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).

[0465] Example 98: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((R)-3-fluoropyrrolidin-1-yl)meth Synthesis of yl)cyclobutyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000140.jpg39147

[0466] The synthesis was carried out in the same manner as in Example 80 using Intermediate 15. 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; 1 H 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).

[0467] Example 99: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7 Synthesis of a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. JPEG2025540246000141.jpg41157

[0468] The synthesis was carried out 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-fluoronaphthalen-2-amine (45 mg, 65.91 μmol, 26% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =683.3; 1 H 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).

[0469] Example 100: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H Synthesis of -pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. JPEG2025540246000142.jpg39156

[0470] The synthesis was carried out in the same manner as in Example 80 using Intermediate 16. 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-fluoronaphthalen-2-ol (18 mg, 46% yield) was obtained as a yellow solid. LCMS (ES-API, m / z): [M+H] + =666.7; 11H NMR (400 MHz, MeOD, ppm): δ 8.29 (s, 1H), 7.88 (dd, J = 9.2, 5.7 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.31 (t, J = 8.9 Hz, 1H), 7.22 (d, J = 2.6 Hz, 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), 3.82 (d, J = 13.5 Hz, 1H), 3.68 (t, J = 11.9 Hz, 3H), 3.45 (d, J = 15.1 Hz, 1H), 3.27 - 3.17 (m, 1H), 2.91 (d, J = 11.4 Hz, 1H), 2.80 (s, 2H), 2.32 (dd, J = 24.0, 14.7 Hz, 1H), 2.05 (d, J = 9.3 Hz, 1H), 1.92 (s, 1H), 1.86 (s, 3H), 0.91 (s, 3H).

[0471] Example 101: Synthesis of 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. JPEG2025540246000143.jpg41157

[0472] The synthesis was carried out 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 and (S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. 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, 56% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =666.7; 1 H 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).

[0473] Example 102: (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-((2R,7aS)-2-fluorotetrahydro-1H-pyrro Synthesis of lizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-1-yl)(oxiran-2-yl)methanone JPEG2025540246000144.jpg61165

[0474] Step 1: 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (500 mg, 1.43 mmol, 1 equiv.) was dissolved in ACN (8 mL), and DIPEA (369.29 mg, 2.86 mmol, 497.70 μL, 2 equiv.) and tert-butyl piperazine-1-carboxylate (319.31 mg, 1.71 mmol, 1.2 equiv.) were added dropwise. The reaction mixture was stirred at room temperature for 1 h, filtered, washed with PE, and dried under vacuum. A yellow solid, tert-butyl 4-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (570 mg, unpurified mixture), was obtained. 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).

[0475] Step 2: The compound was synthesized using the same procedure 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. A yellow solid, 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. 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).

[0476] Step 3: Synthesized in a similar manner to 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. A yellow solid, 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. LCMS (ES-API, m / z): [M+H] + =928.5

[0477] Step 4: Synthesized in a similar manner to 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. A yellow solid, 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, unpurified mixture) was obtained. LCMS (ES-API, m / z): [M+H] + =772.4

[0478] Step 5: Synthesized in a similar manner to 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]quinazolin-9-yl)piperazine-1-carboxylate. A yellow solid, 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. LCMS (ES-API, m / z): [M+H] + =628.3

[0479] Step 6: Potassium oxirane-2-carboxylate (19.29 mg, 152.95 μmol, 2.4 equiv.) was dissolved in DMF (0.5 mL) and HATU (29.08 mg, 76.47 μmol, 1.2 equiv.) was added dropwise. 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 equivalent) and DIPEA (24.71 mg, 191.19 μmol, 33.30 μL, 3 equivalents) were added to the reaction mixture and stirred at room temperature for 1 hour. Purification by prep-HPLC (neutral condition; column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; gradient: 25%-55% B over 9 min) gave a yellow solid: (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)(oxiran-2-yl)methanone (10.77 mg, 14.74 μmol, 12% yield). 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).

[0480] Example 103: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrro Synthesis of lizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol JPEG2025540246000145.jpg38156

[0481] The synthesis was carried out 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-fluoronaphthalen-2-ol (38 mg, 58.1 μmol, 71% yield) was obtained as a white solid. LCMS (ES-API, m / z): [M+H] + =654.3; 1H NMR (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), 4.15 (s,3H), 2.90-2.82(m,3H), 2.05-1.99(m,7H), 1.92(m,3H), 1.32(m,6H).

[0482] Example 104: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7 Synthesis of a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile JPEG2025540246000146.jpg36152

[0483] This was synthesized in the same manner as in Example 62 using Intermediate 5. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluor...

Claims

1. A compound of the following chemical formula 1, its optical isomers, stereoisomers, racemates, isotopic variations, solvates, hydrates, or pharmaceutically acceptable salts thereof: [Chemical formula 1] In the above Chemical Formula 1, X is C or N; R １ is hydrogen, halogen, C １－３ Alkyl, or C １－３ is alkoxy; L is a direct bond, O, or NR ６ and R ２ is C １－６ Alkyl, C １－６ Alkoxy, C １－６ Hydroxyalkyl, C ２－６ Alkoxyalkyl, C １－６ Haloalkyl, R ｘ , -Z １ -R ｘ , -Z １ -R ｙ -R ｘ , -Z １ -R ｙ -Z ２ -N(R １５ ) ２ , -Z １ -R ｙ -Z ２ -R ｘ , -N(R １５ ) ２ , -Z １ -N(R １５ ) ２ , -Z １ -C(O)N(R １５ ) ２ , or -Z １ -OR １５ and R ｘ and R ｙ are, independently of each other, a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, optionally with one or more R ７ may be substituted with; R ７ are H, halogen, hydroxy, and C, respectively. １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Hydroxyalkyl, C １－４ Haloalkyl, C ２－４ Haloalkenyl, 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, -Z ３ -3- to 10-membered cycloalkyl, -Z ３ -3- to 10-membered heterocycloalkyl, -Z ３ -6- to 20-membered aryl, -Z ３ -6- to 20-membered heteroaryl, -Z ３ -OC(O)N(R １６ ) ２ , or -Z ３ -OC(O)-3- to 10-membered heterocyclyl; ７ represents 1 to 3 of cyano, halogen, haloalkyl, amino, -OR １７ , -SR １７ , or -N(R １７ ) ２ may be substituted with; Z １ ~Z ３ are, independently of each other, C １－４ alkyl; optionally hydroxy, C １－４ optionally substituted with hydroxyalkyl, or 6- to 20-membered heteroaryl; R ６ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ and R ２１ are, independently of one another, H or C １－３ is alkyl; R ３ is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, optionally with one or more R ８ may be substituted with; R ８ is H, halogen, hydroxy, -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 Haloalkyl, 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; R ９ is a direct bond or C １－４ is alkyl; R １０ is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycloalkyl, optionally with one or more R １１ may be substituted with; R １１ is C １－３ Alkyl, hydroxy, N(R １９ ) ２ , C １－３ Alkyl-N(R １９ ) ２ , C １－３ cyanoalkyl, 3- to 10-membered heterocyclyl; R １２ is H, C １－３ Alkyl, OH, —N(R ２０ ) ２ , -CH ２ N (R ２０ ) ２ , cyano, cyanomethyl, or 3- to 10-membered heterocyclyl; R １３ is H or -C(=O)R １４ and R １４ is C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, —N(R ６ ) ２ , -OR ６ , -SR ６ , a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered cycloalkynyl, a 3- to 10-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl; n is an integer from 0 to 4; R ５ is H, halogen, C １－６ Alkyl, C １－３ Haloalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, cyano, cyanoC １－３ Alkyl, hydroxy, 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. A compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or a pharmaceutically acceptable salt thereof.

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

4. L is a direct bond or O; 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

5. R ｘ and R ｙ are each independently a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl, and optionally one or more R ７ may be substituted with, 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

6. R ｘ is a 3- to 10-membered heterocyclyl, and R ｙ is a 3- to 10-membered cycloalkyl, and ｘ and the R ｙ optionally one or more R ７ may be substituted with, 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

7. R ７ are H, halogen, hydroxy, and C, respectively. １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C ２－４ Hydroxyalkyl, C １－４ Haloalkyl, C ２－４ Haloalkenyl, 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, -Z ３ -3- to 10-membered cycloalkyl, -Z ３ -3- to 10-membered heterocycloalkyl, -Z ３ -6- to 20-membered aryl, -Z ３ -6- to 20-membered heteroaryl, -Z ３ -OC(O)N(R １６ ) ２ , or -Z ３ -OC(O)-3- to 10-membered heterocyclyl; 1 to 3 of cyano, halogen, haloalkyl, amino, -OR １７ , -SR １７ , or -N(R １７ ) ２ may be substituted with, 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

8. R ３ is a 6- to 20-membered aryl or a 6- to 20-membered heteroaryl, optionally with one or more R ８ may be substituted with R ８ is H, halogen, hydroxy, -N(R １８ ) ２ , OR ６ , 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 Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Alkoxyalkyl, C １－４ Alkyl-N(R １８ ) ２ , cyano, oxo, or 3- to 10-membered cycloalkyl; 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

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

10. R ３ is phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, pyridinyl, anthracenyl, indenyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or indazolyl, optionally with one or more R ８ may be substituted with, 9. The compound according to claim 8, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

11. R ３ is phenyl, naphthyl, naphthalenyl, pyridinyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or indazolyl, optionally with one or more R ８ may be substituted with The R ８ is H, halogen, hydroxy, -N(R １８ ) ２ , C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－３ Haloalkyl, C １－３ hydroxyalkyl, or cyano; 9. The compound according to claim 8, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

12. R ９ is C １－３ is alkyl, R １０ is a 3- to 5-membered cycloalkyl; R １１ is N(R １９ ) ２ That is, 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

13. R １２ is H, 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

14. R ５ is H or C １－３ is alkyl, 2. The compound according to claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

15. The R ｘ and R ｙ are each independently a 3- to 5-membered cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1′H,3′H-spiro[cyclopropane-1,2′-pyrrolizidinyl], cyclopropane-1,2′-pyrrolizidinyl), 6-azaspiro[2.5]octanyl, quinolizidinyl, indolinyl, benzimidazolyl, azaspirooctanyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, or acridinyl, optionally with one or more R ７ which may be replaced by 6. The compound according to claim 5, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

16. The R ２ is R ｘ , -Z １ -R ｘ , -Z １ -R ｙ -R ｘ , -Z １ -R ｙ -Z ２ -N(R １５ ) ２ , or -Z １ -R ｙ -Z ２ -R ｘ and The R ｘ are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl], tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidinyl], or 6-azaspiro[2.5]octanyl; The R ｙ is a 3- to 5-membered cycloalkyl; The R ｘ and the R ｙ optionally one or more R ７ may be substituted with The R ７ are H, halogen, and C, respectively. １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Haloalkyl, C ２－４ Haloalkenyl, 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-, optionally substituted with 1 to 3 halogens; 7. The compound according to claim 6, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof.

17. The compound of Formula 1 is selected from the group consisting of the following (1) to (120): The compound of claim 1, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof: Table 1

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or a pharmaceutically acceptable salt thereof.

19. 20. The pharmaceutical composition of claim 18, additionally comprising a pharmaceutically acceptable carrier.

20. 19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is an antagonist of KRAS G12D mutant protein.

21. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is for the prevention or treatment of a disease associated with KRAS G12D mutant protein.

22. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is for the prevention or treatment of cancer.

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

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

25. The pharmaceutical composition according to claim 18, further comprising at least one selected from the group consisting of an RTK / Ras-MAPK pathway-associated protein inhibitor, a DNA damage inducer, an EGFR antibody, and an immunotherapeutic anti-cancer agent.

26. 26. The pharmaceutical composition of claim 25, wherein the RTK / Ras-MAPK pathway-associated protein inhibitor is any one or more selected from the group consisting of an EGFR inhibitor, an FGFR inhibitor, an ALK inhibitor, a ROS inhibitor, a MET inhibitor, a RAF inhibitor, an ERK inhibitor, a MEK inhibitor, an SHP-2 inhibitor, a PI3K inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, and an SOS1 inhibitor.

27. The cancers include angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyofibroma, lipoma, teratoma; squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated multicellular carcinoma, pulmonary carcinoma, alveolar (bronchiolar) carcinoma, bronchiolar adenoma, sarcoma, lymphoma, chondrohamartoma, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, gallbladder cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma.

23. The pharmaceutical composition of claim 22, wherein the cancer is one or more selected from the group consisting of: chondroostoma, giant cell tumor, skull osteoma, cranial hemangioma, skull granuloma, skull xanthomas, osteitis deformans of the skull, cerebral meningioma, meningeal sarcoma, glioblastoma, astrocytoma, medulloblastoma, ventriculoma, embryonal tumor, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma, endometrial cancer, cervical cancer, ovarian cancer, blood cancer, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, mononuclear leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, psoriatic cancer, 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, its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or a pharmaceutically acceptable salt thereof.

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