KRAS G12S and G12C inhibitors

Abstract

The present invention relates to compounds that inhibit KRas G12S and / or KRas G12C. In particular, the present invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions containing such compounds, and methods of using the same.

Description

[Technical Field]

[0001] This invention relates to compounds that inhibit KRas G12S and / or KRas G12C. In particular, this invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions containing the compounds, and methods of using the same. [Background technology]

[0002] The Carsten rat sarcoma 2 virus oncogene homolog ("KRAS") is a small GTPase and a member of the Ras family of oncogenes. KRas acts as a molecular switch that alternates between inactive (GDP-bound) and active (GTP-bound) states, translating upstream cellular signals received from multiple tyrosine kinases into downstream effectors to regulate a variety of processes, including cell proliferation (see, for example, Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignant tumors was observed more than 30 years ago (see, e.g., Santos et al., (1984) Science 223:661-664). Abnormal KRas expression accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation and downstream signaling of KRas have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038 / nrd428). Single nucleotide substitutions causing missense mutations at codons 12 and 13 of the KRas primary amino acid sequence account for approximately 40% of these KRas driver mutations in lung adenocarcinoma. KRAS G12S mutations were identified in 2% of colorectal cancer patients, 0.6% of ovarian cancer patients, 0.5% of non-small cell lung cancer patients, 0.2% of bladder and gastric cancer patients, and 0.1% of pancreatic ductal adenocarcinoma, breast cancer, and endometrial cancer patients (The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discovery 2017. Cohort v.13.1-public).

[0004] The well-known role of KRas in malignant tumors and the confirmation of these frequent mutations in KRas across various tumor types have made KRas a highly attractive target for cancer treatment in the pharmaceutical industry. Despite 30 years of extensive research efforts to develop KRas inhibitors for cancer treatment, only a few KRas inhibitors have demonstrated sufficient safety and / or efficacy to obtain regulatory approval.

[0005] Compounds that inhibit KRas activity remain in high demand and are under investigation. This includes compounds that inhibit effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358). Furthermore, recent advances have been made regarding the covalent targeting of the allosteric pocket of KRas G12C (see, e.g., Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there is continued interest and effort in the development of KRas inhibitors, particularly inhibitors of active KRas variants, including KRas G12S and KRas G12C.

[0006] Therefore, there is a need to develop novel KRas G12S and / or KRas G12C inhibitors that demonstrate sufficient efficacy in treating KRas G12S-mediated cancer and / or KRas G12C-mediated cancer. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401 [Non-Patent Document 2] Santos et al., (1984) Science 223:661-664 [Non-Patent Document 3] Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038 / nrd428 [Non-Patent Document 4] The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discovery 2017.Cohort v.13.1-public [Non-Patent Document 5] Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358 [Non-Patent Document 6] Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234 [Overview of the project]

[0008] In one embodiment of the present invention, compounds that inhibit the activity of KRas G12S and / or KRas G12C are provided.

[0009] In a particular embodiment, the compound is of formula (Ia) or (Ib): [ka] [In the formula, A is [ka] Selected from; B is [ka] Selected from; X is a bond, N, methylene, ethylene, or propylene; D is either CO or SO2; E is N or CR 10 and; Y is a bond, O, or NR 5 ; Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl, or aryl, and Z is optionally substituted with 1 to 3 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR 12 , N(R 12 )2, COR 12 , and cyano; Each R 2 is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, spirocyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R 5 )2, -CO2R 5 , -CO2N(R 5 )2, =CH2, =CHR 11 , or =C(R 11 )2, and said R 2 may be optionally substituted with one or more R 4 ; R 3 is aryl or heteroaryl, and said aryl or heteroaryl may be optionally substituted with one or more R 8 ; R 4 is hydrogen, halogen, or C1-C3 alkyl; Each R 5 is independently hydrogen or C1-C3 alkyl; Each R 6 is independently hydrogen, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, or heteroaryl, or two R 6 together form C3-C6 cycloalkyl or a heterocycle; Each R 8These are independently halogen, cyano, hydroxy, cycloalkyl, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, or -S-C1-C3 haloalkyl; Each R 9 These are independently hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxy, CH2F, CF2, CF3, C-CN, cyclopropyl, or two R atoms on the same or different carbon atoms. 9 Together they form a C1-C2 alkylene bridge or spiro ring; Each R 10 Hydrogen, halogen, CH2F, CHF2, CF3, C1-C3 alkyl, cyclopropyl, OR 12 , or N(R 12 )2; Each R 11 These are halogens or C1-C3 alkyl groups; Each R 12 is a C1-C3 alkyl group; and Each R 13 [is H, or forms a ring with A] The compound shown, or a pharmaceutically acceptable salt thereof.

[0010] In another embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In yet another embodiment of the present invention, a method for inhibiting the activity of intracellular KRas G12S and / or KRas G12C is provided, comprising contacting cells with a compound represented by formula (Ia) or (Ib) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof. In one embodiment, the contact is performed in vitro. In another embodiment, the contact is performed in vivo.

[0012] Furthermore, the Specified Provisions also provide a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of a compound represented by formula (Ia) or (Ib) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0013] Furthermore, a method for treating cancer in a patient is provided, comprising administering a therapeutically effective amount of a compound, or a pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof, to a patient in need.

[0014] Furthermore, this specification provides a method for treating a KRas G12S-related and / or KRas G12C-related disease or disorder in a patient requiring such treatment, comprising administering to the patient a therapeutically effective amount of a compound represented by formula (Ia) or (Ib) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable

[0015] Furthermore, compounds represented by formula (Ia) or (Ib) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in therapeutic purposes are provided herein.

[0016] Furthermore, compounds represented by formula (Ia) or (Ib) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer are provided herein.

[0017] Furthermore, compounds represented by formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof are provided herein for use in inhibiting KRas G12S and / or KRas G12C.

[0018] Furthermore, compounds represented by formula (Ia) or (Ib) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are provided herein for use in the treatment of KRas G12S-related and / or KRas G12C-related diseases or disorders.

[0019] Furthermore, the use of compounds represented by formula (Ia) or (Ib), as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of cancer is provided herein.

[0020] Furthermore, the use of compounds represented by formula (Ia) or (Ib), as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for inhibiting the activity of KRas G12S and / or KRas G12C is provided herein.

[0021] Furthermore, the use of compounds represented by formula (Ia) or (Ib), as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of KRas G12S-related and / or KRas G12C-related diseases or disorders is provided herein.

[0022] Furthermore, the Specified Method of Treating Cancer in a Patient Requiring Treatment comprises (a) determining whether the cancer is related to a KRas G12S mutation (i.e., KRas G12S-related cancer) or a KRas G12C mutation (i.e., KRas G12C-related cancer); and (b) administering to the patient a therapeutically effective amount of a compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0023] Furthermore, processes for preparing compounds represented by formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof are provided herein.

[0024] Furthermore, compounds represented by formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof, obtained by the process of preparing the compound as defined herein, are also provided herein. [Modes for carrying out the invention]

[0025] The present invention relates to inhibitors of KRas G12S and / or KRas G12C. In particular, the present invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising a therapeutically effective amount of the compound, and methods of using the same.

[0026] (definition) Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. All patents, patent applications, and publications referenced herein are incorporated by reference.

[0027] As used herein, "KRas G12S" refers to a mutant mammalian KRas protein in which glycine is replaced with serine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp.

[0028] As used herein, "KRas G12S inhibitor" refers to the compounds of the present invention represented by formula (Ia) or (Ib) as described herein. These compounds can negatively modulate or inhibit all or part of the enzymatic activity of KRas G12S.

[0029] As used herein, "KRas G12S-related disease or disorder" refers to a disease or disorder associated with, mediated by, or involving a KRas G12S mutation. An example of a KRas G12S-related disease or disorder, not limited to KRas G12S-related diseases or disorders, is KRas G12S-related cancer.

[0030] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein in which glycine is replaced with cysteine ​​at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Cys.

[0031] As used herein, "KRas G12C inhibitor" refers to the compounds of the present invention represented by formula (Ia) or (Ib) as described herein. These compounds can negatively modulate or inhibit all or part of the enzymatic activity of KRas G12C.

[0032] As used herein, "KRas G12C-related disease or disorder" refers to a disease or disorder associated with, mediated by, or involving a KRas G12C mutation. An example of a KRas G12C-related disease or disorder, not limited to KRas G12C-related diseases or disorders, is KRas G12C-related cancer.

[0033] As used herein, the terms “subject,” “individual,” and “patient” are used interchangeably and refer to any animal (including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans). In some embodiments, the patient is human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been determined or diagnosed with cancer having a KRas G12S or KRas G12C mutation (e.g., determined using a regulatory-approved assay or kit, e.g., FDA-approved). In some embodiments, the subject has a tumor that is KRas G12S or KRas G12C mutation-positive (e.g., determined using a regulatory-approved assay or kit). The subject may be a subject having a tumor that is KRas G12S or KRas G12C mutation-positive (e.g., determined to be positive using a regulatory-approved assay or kit, e.g., FDA-approved). A subject may have a tumor that is associated with the KRas G12S or KRas G12C mutation (for example, the tumor is determined to be so using a regulatory-approved kit or assay, e.g., an FDA-approved kit or assay). In some embodiments, a subject is suspected to have a KRas G12S gene-associated cancer or a KRas G12C gene-associated cancer. In some embodiments, a subject has a clinical record indicating that they have a tumor with the KRas G12S or KRas G12C mutation (and, where appropriate, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0034] In any of the methods or embodiments of use described herein, assays are used to determine whether a patient has a KRas G12S or KRas G12C mutation using a sample (e.g., a biological or biopsy sample (e.g., paraffin-embedded biopsy specimen)) from a patient (e.g., a patient suspected of having KRas G12S-related or KRas G12C-related cancer, a patient with one or more symptoms of KRas G12S-related or KRas G12C-related cancer, and / or a patient at high risk of developing KRas G12S-related or KRas G12C-related cancer), such as next-generation sequencing, immunohistochemical staining, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification methods (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment.

[0035] The term "regulatory authority" refers to a national agency responsible for approving the medical use of a drug in that country. An example of a regulatory authority that is not limited to this is the U.S. Food and Drug Administration (FDA).

[0036] The term "acyl" refers to -C(O)CH3.

[0037] As used herein, the terms "C1-C6 alkyl," "C1-C4 alkyl," and "C1-C3 alkyl" refer to linear and branched aliphatic groups having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0038] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to C1-C3 alkyl chains or C1-C4 alkyl chains, respectively, as defined herein, in which one or more hydrogen atoms are substituted with halogens. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0039] The "C1-C4 alkylene" group is a C1-C4 alkyl group as defined above herein, located between two other chemical groups and bonding them together. Examples of alkylene groups include, but are not limited to, methylene, ethylene, 2-2-dimethylethylene, propylene, and butylene.

[0040] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, where the alkyl portion is as defined above in this specification.

[0041] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms, for example, 3 to 8 carbon atoms, and more specifically, 3 to 6 carbon atoms, and such cycloalkyl groups further include one or more R groups as defined herein. X The group may be appropriately substituted. The cycloalkyl group may be monocyclic, bicyclic, spirocyclic, or crosslinked ring system. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes crosslinked cycloalkyl groups, such as bicyclo[1.1.1]pentanyl.

[0042] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0043] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0044] The "aryl" group is a C6-C group containing 1 to 3 aromatic rings. 14 This refers to the aromatic moiety, which may be appropriately substituted with one or more substituents as defined herein. In one embodiment, the aryl group is C6-C 10 This refers to an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic system in which one or two rings may be saturated or partially saturated, and if the system contains two saturated rings, the saturated rings may be fused or spirocyclic. An example of an aryl ring system containing two saturated rings and in which the rings are spirocyclic is the following: [ka] These are some examples.

[0045] The "araC1-C6 alkyl" or "arylalkyl" group includes an aryl group covalently bonded to an alkyl group, and both may be independently substituted or unsubstituted as appropriate. An example of an aralkyl group is (C6-C 10 Examples of aralkyl groups include aryl(C1-C6)alkyl-, which include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. Another example of an aralkyl group is (C6-C10)aryl(C1-C3)alkyl-, which again includes, but are not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted araC1-C6 alkyls include those in which the alkyl group is substituted with a hydroxyalkyl group.

[0046] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, for example, 4 to 8 atoms, where one or more atoms are selected from the group consisting of N, O, and S, the ring N atom may be oxidized to NO, the ring S atom may be oxidized to SO or SO2, and the remaining ring atoms are carbon. Heterocyclyls may be monocyclic, dicyclic, spirocyclic, or bridging ring systems. The heterocyclic group has one or more R atoms on the ring carbon or ring nitrogen at one or more positions. 6 It may be replaced as appropriate by the R 6 The formula is as defined for formula I. The heterocyclic group may also be independently substituted with an alkyl, aralkyl, or alkylcarbonyl group on the nitrogen atom, or with a lower alkyl group on the sulfur atom, as appropriate. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, azilidinyl, tetrahydrofuranil, tetrahydropyranil, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianil, dioxolanil, oxazolidinyl, oxazolidinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroindridinyl) Examples include azaspiroheptanil, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine], hexahydro-1H-pyrrolidinil, tetrahydro-1H-pyrrolidinil, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolidinyl, oxazaspirononanil, oxazaspirooctanil, diazaspirononanil, oxazabiocycloheptanil, hexahydropyrrolidinil-4(1H)-oxide, tetrahydro-2H-thiopyranyl-1-oxide, and tetrahydro-2H-thiopyranyl-1,1-dioxide. Compounds having adjacent cyclic oxygen and / or sulfur atoms are explicitly excluded from the scope of this term.

[0047] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, sharing 6, 10, or 14 π electrons in a cyclic arrangement, and having 1 to 3 heteroatoms selected from the group consisting of N, O, and S in addition to carbon atoms, in each ring.Examples of heteroaryl groups include acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carborinyl, chromanil, clomenil, sinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanil, furazanil, imidazolinyl, and imidazolyl. , 1H-indazolyl, indolenyl, indolinyl, indolidine, indolyl, 3H-indolyl, isobenzofuranil, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, o Xazolidinil, pyrimidinil, phenanthrolinil, phenanthrolinil, phenazinil, phenothiazinil, phenoxathiinil, phenoxazinil, phthalazinil, piperonil, pteridinil, purinil, pyranil, pyrazinil, pyrazolidinil, pyrazolinil, pyrazolyl, pyridazinil, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinil, pyridyl, pyrimidinil, pyrrolinil, 2H-pyrrolyl, pyrrrolyl, quinazolinil, quinolinil, 4H-quinolidinil, quinoxalinil, quinuclidinil Examples include tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.A "heteroaryl" is a bicyclic system that, in addition to carbon atoms, has 1 to 3 heteroatoms selected from the group consisting of N, O, and S in each ring, and one of the ring systems may be saturated or partially saturated.

[0048] As used herein, “effective amount” of a compound means an amount sufficient to negatively modulate or inhibit the activity of KRas G12S and / or KRas G12C. Such an amount may be a single dose or administered according to a regimen to produce an effect.

[0049] As used herein, “therapeutic dose” of a compound means an amount sufficient to alleviate or reduce symptoms in any way, halt or reverse the progression of a disease, or negatively modulate or inhibit the activity of KRas G12S and / or KRas G12C. Such a dose may be a single dose or administered according to a regimen to produce an effect.

[0050] As used herein, "treatment" means any method that improves or otherwise beneficially alters the symptoms or pathology of a medical condition, disorder, or disease. Treatment also encompasses any medicinal use of the compositions herein.

[0051] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any relief that may be caused by or associated with the administration of such composition, whether permanent or temporary, sustained or transient.

[0052] (compound) In one embodiment of the present invention, formula (Ia) or (Ib): [ka] [In the formula, A is [ka] Selected from; B is [ka] Selected from; X is a bond, N, methylene, ethylene, or propylene; D is either CO or SO2; E is N or CR 10 and; Y is a bond, O is an NR 5 and; Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl, or aryl, and Z is halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR 12 , N(R 12 )2, COR 12 , and may be appropriately substituted with 1 to 3 substituents selected from cyano; Each R 2 These are independently hydrogen, hydroxyl, halogen, C1-C3 alkyl, spirocyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R) 5 )2, -CO2R 5 , -CO2N(R 5 )2, =CH2, =CHR 11 , or =C(R 11 )2, R 2 is one or more R 4 It may be replaced as appropriate; R 3 is an aryl or heteroaryl, and the aryl or heteroaryl is one or more R 8 It may be replaced as appropriate; R 4 These are hydrogen, halogens, or C1-C3 alkyl groups; Each R 5 These are independently hydrogen or C1-C3 alkyl; Each R 6 R is independently hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl, or heteroaryl, or two R 6They together form a C3-C6 cycloalkyl or heterocyclic ring; Each R 8 These are independently halogen, cyano, hydroxy, cycloalkyl, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, or -S-C1-C3 haloalkyl; Each R 9 These are independently hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxy, CH2F, CF2, CF3, C-CN, cyclopropyl, or two R on the same or different carbon atoms. 9 Together they form a C1-C2 alkylene bridge or spiro ring; Each R 10 Hydrogen, halogen, CH2F, CHF2, CF3, C1-C3 alkyl, cyclopropyl, OR 12 , or N(R 12 )2; Each R 11 These are halogens or C1-C3 alkyl groups; R 12 is a C1-C3 alkyl group; and R 13 [is H, or forms a ring with A] Compounds represented by or pharmaceutically acceptable salts thereof are provided.

[0053] In a particular embodiment, formula (Ia) is formula IA: [ka] That is the case.

[0054] In other embodiments, formula (Ia) is formula IB: [ka] That is the case.

[0055] In a particular embodiment, X is methylene.

[0056] In certain embodiments, X is ethylene.

[0057] In certain embodiments, X is a bond.

[0058] In certain embodiments, X is propylene.

[0059] In certain embodiments, Y is NR 5 is.

[0060] In certain embodiments, Y is a bond.

[0061] In certain embodiments, Y is O.

[0062] In certain embodiments, Z is hydrogen.

[0063] In another embodiment, Z is C1-C4 alkyl, which may be optionally substituted with 1 to 3 halogens.

[0064] In yet another embodiment, Z is aryl, which may be optionally substituted with 1 to 3 halogens, cyano, or C1-C4 haloalkyl. In certain aspects of this embodiment, the aryl is phenyl.

[0065] In yet another embodiment, Z is heteroaryl, which may be optionally substituted with 1 to 2 C1-C4 alkyls. In certain aspects of this embodiment, the heteroaryl is pyrazolyl or pyridinyl.

[0066] In yet another embodiment of the present invention, Z is heterocyclyl, which may be optionally substituted with oxo. In certain aspects of this embodiment, the heterocyclyl is oxazolidine.

[0067] In certain embodiments, two Rs 9 together form a methylene bridge, or two Rs9 They form ethylene crosslinks together.

[0068] In this particular embodiment, R 5 It is hydrogen.

[0069] In this particular embodiment, R 5 The C1-C3 alkyl group is C1-C3 alkyl. In the specific cases of these embodiments, the C1-C3 alkyl group is methyl.

[0070] One reason, R 2 is a halogen. In one embodiment of this embodiment, R 2 It is fluoro.

[0071] In another embodiment, R 2 is = CHR 11 That is the case.

[0072] In yet another embodiment, R 2 is = C(R 11 )2.

[0073] In some embodiments of the compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB), R 3 is an aryl, and one or more R 8 They may be appropriately substituted with R. In certain embodiments, the aryl is selected from the group consisting of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydro-1H-indenyl, each having one or more R 8 It may be replaced as appropriate.

[0074] In one embodiment, the aryl is phenyl, and one or more R 8 It is substituted with a group. In one embodiment, the aryl is phenyl and one or more R groups independently selected from halogens, C1-C3 alkyls, and cycloalkyls. 8 It is substituted with a group. In a particular embodiment, phenyl has two R groups. 8It is substituted with a group. In a particular embodiment, phenyl has two R groups. 8 It is substituted with one R 8 The base is halogen, and the other R 8 The group is C1-C3 alkyl or cycloalkyl.

[0075] In one embodiment, the aryl is 2,3-dihydro-1H-indenyl, and one or more R 8 It may be substituted as appropriate. In one embodiment, the aryl is 2,3-dihydro-1H-indenyl, and one R 8 It may be replaced as appropriate. In one embodiment, R 8 It is a C1-C alkyl group.

[0076] In one embodiment, the aryl is naphthyl, and one or more R 8 It is substituted with a group. In one embodiment, the aryl is naphthyl and independently one or more R groups selected from halogen, cyano, hydroxy, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, cycloalkyl, triazolyl, C1-C3 haloalkyl, and -O-C1-C3 haloalkyl. 8 It is substituted with the base.

[0077] In one embodiment, the aryl is naphthyl and substituted with hydroxyl. In another embodiment, the aryl is naphthyl and substituted with halogen. In a particular embodiment, the halogen is chlorine, fluorine, or bromine. In another embodiment, the halogen is chlorine. In yet another embodiment, the halogen is fluorine.

[0078] In one embodiment, the aryl is naphthyl and is substituted with a C1-C3 alkyl group, where the C1-C3 alkyl group is methyl or ethyl.

[0079] In one embodiment, aryl is naphthyl and is substituted with C2-C4 alkenyl. In certain embodiments, the C2-C4 alkenyl is prop-2-enyl.

[0080] In one embodiment, aryl is naphthyl and is substituted with C2-C4 alkynyl. In certain embodiments, the C2-C4 alkynyl is ethyne or prop-2-ynyl.

[0081] In one embodiment, aryl is naphthyl and is substituted with cycloalkyl. In certain embodiments, the cycloalkyl is cyclopropyl.

[0082] In one embodiment, aryl is naphthyl and is substituted with one or two Rs 8 and each R 8 is halogen, cyano, hydroxy, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, or triazolyl. In one embodiment, aryl is naphthyl and is substituted with two Rs 8 independently selected from halogen, hydroxy, C1-C3 alkyl, and C2-C4 alkynyl. In another embodiment, one R 8 is hydroxy and the other R 8 is C1-C3 alkyl, halogen, or C2-C4 alkynyl, or one R 8 is halogen and the other R 8 is C1-C3 or C2-C4 alkynyl.

[0083] In one embodiment, aryl is naphthyl and is substituted with three Rs 8 where the first R 8 group is halogen, the second R 8 group is hydroxy, and the third R 8 group is C1-C3 alkyl or C2-C4 alkynyl.

[0084] In some embodiments of the compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB), R 3 It is a heteroaryl, and contains one or more R 8 It may be substituted as appropriate. In one embodiment, the heteroaryl is isoquinolinyl, indazolyl, or benzo[d][1,3]dioxolyl, and one or more R 8 It may be substituted as appropriate. In one embodiment, the heteroaryl is indazolyl, and one or more R 8 They may be appropriately substituted with. In one embodiment, the heteroaryl is indazolyl and may be appropriately substituted with a C1-C3 alkyl or a C1-C3 alkyl and halogen. In another embodiment, the heteroaryl is isoquinolinyl and has one or more R 8 They may be appropriately substituted with. In other embodiments, the heteroaryl is isoquinolinyl, which may be appropriately substituted with a halogen or C2-C4 alkynyl. In a particular embodiment, the heteroaryl is benzo[d][1,3]dioxolyl, with two R 8 The group may be appropriately substituted. In a particular embodiment, the heteroaryl is benzo[d][1,3]dioxolyl, and two R groups 8 The base may be appropriately substituted, and each R 8 The group is independently selected from halogens. In one embodiment, the two halogens are gem-difluoro substitutions. In another embodiment, R3 is indazolyl and the two R 8 It is replaced by, and on the other hand, R 8 R is a halogen, and the other R is a halogen. 8 It is a C1-C3 alkyl group.

[0085] In some embodiments of the compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB), R 4 It is hydrogen.

[0086] In some embodiments of the compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB), R 4is a halogen. For one reason, R 4 is fluorine. In one example, R 4 It is chlorine.

[0087] In some embodiments of the compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB), R 4 R is a C1-C3 alkyl group. In one embodiment, 4 It is methyl.

[0088] Examples of compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB) are: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0089] In one embodiment, the compounds represented by formula (Ia) or (Ib), formula (IA), and / or formula (IB) include bis-hydrochloride, formate, bis-formate, tris-hydrochloride, trifluoroacetate, bis-trifluoroacetate, and tris-trifluoroacetate of the above compounds. The compounds represented by formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions.

[0090] (Pharmaceutical composition) In another embodiment, the present invention provides a pharmaceutical composition comprising the KRas G12S and / or KRas G12C inhibitors of the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention may be formulated in any method well known in the art and may be prepared for administration by any route (including, but not limited to, parenteral, oral, sublingual, transdermal, topical, nasal, intratracheal, or rectal). In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In some embodiments, administration may be via the oral route.

[0091] The characteristics of the carrier vary depending on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic substance that is compatible with a biological system (e.g., cells, cell cultures, tissues, or organisms) and does not interfere with the efficacy of the biological activity of the active ingredient. Accordingly, the compositions of the present invention may include, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0092] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound described above that retains the desired biological activity and exhibits minimal or no undesirable toxic effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamonic acid, arginine acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). The compound also includes pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular, of formula -NR + It may be administered as a quaternary ammonium salt represented by Z- (wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion containing chloride ions, bromide ions, iodide ions, -O-alkyl, toluenesulfonate ions, methylsulfonate ions, sulfonate ions, phosphate ions, or carboxylate ions (e.g., benzoate ions, succinate ions, acetate ions, glycolate ions, maleate ions, malate ions, citrate ions, tartrate ions, ascorbate ions, benzoate ions, cinnamate ions, mandelate ions, benzyloate, and diphenylacetate ions)).

[0093] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient without causing serious toxicity to the patient during treatment. In one embodiment, the dose of the active compound for all of the above conditions is in the range of about 0.01 to 100 mg / kg, for example, 0.1 to 50 mg / kg per day, and further, for example, 0.5 to about 25 mg / kg of patient body weight per day. A typical topical dose would be in the range of 0.01 to 3 wt / wt% in a suitable carrier. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound from which it is derived. If the derivative is active on its own, the effective dose can be estimated using the weight of the derivative as described above, or by other methods known to the parties.

[0094] A pharmaceutical composition containing the compound of the present invention may be used in the manner described herein.

[0095] (How to use) In yet another embodiment, the present invention provides a method for inhibiting the activity of KRas G12S and / or KRas G12C in cells, comprising contacting cells in which inhibition of KRas G12S activity is desired with an effective amount of a compound represented by formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contact is performed in vitro. In another embodiment, the contact is performed in vivo.

[0096] As used herein, the term “contact” means attaching the indicated elements (moiety) in an in vitro or in vivo system. For example, “contact” the compound provided herein with KRas G12S includes administering the compound provided herein to an individual or patient (e.g., a human) having KRas G12S, and providing the compound provided herein to a sample containing, for example, a cell preparation or purified preparation containing KRas G12S. For example, “contact” the compound provided herein with KRas G12C includes administering the compound provided herein to an individual or patient (e.g., a human) having KRas G12C, and providing the compound provided herein to a sample containing, for example, a cell preparation or purified preparation containing KRas G12C.

[0097] In one embodiment, cells in which inhibition of KRas G12S and / or KRas G12C activity is desired are exposed to an effective amount of the compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, thereby negatively modulating the activity of KRas G12S and / or KRas G12C.

[0098] The methods described herein are designed to inhibit undesirable cell proliferation resulting from strong intracellular KRas G12S and / or KRas G12C activity by negatively modulating the activity of KRas G12S and / or KRas G12C. Cells may be exposed to single or multi-dose formulations according to a specific therapeutic regimen to influence the desired negative modulation of KRas G12S and / or KRas G12C. The potency of compounds that bind to KRas G12S and / or KRas G12C may be observed in vitro using well-known methods, including those described in Examples A and B below. Furthermore, the inhibitory activity of exemplary compounds in cells may be observed, for example, by inhibiting KRas G12S and / or KRas G12C activity or by measuring the amount of phosphorylated ERK, using the method described in Example C below.

[0099] In another embodiment, a method is provided for treating cancer in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of a compound represented by formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0100] The compositions and methods provided herein may be used for the treatment of KRas G12S-associated cancer and / or KRas G12C-associated cancer in patients requiring treatment, and the methods provided include administering to the patient a therapeutically effective amount of a compound represented by formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the KRas G12S-associated cancer is lung cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0101] The compositions and methods provided herein may be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated with the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds include: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; digestive system: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) ), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary system: gallbladder cancer, ampulla cancer, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cystoma Cell tumors, osteochondroma (chondrodystomas), benign chondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteoosteitis), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymal cell tumors, germ cell tumors (pineal gland tumors), glioblastoma multiforme, oligodendroglioma, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecological: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); blood System: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: may be used to treat neuroblastoma.

[0102] In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0103] The concentration and route of administration to patients vary considerably depending on the type of cancer being treated. Furthermore, the compound, its pharmaceutically acceptable salts, and pharmaceutical compositions containing such compound and salts may be administered in combination with other antitumor compounds (e.g., chemotherapeutic agents) or in combination with other treatments such as radiation therapy or surgical intervention (used as neoadjuvant or adjuvant therapy).

[0104] Furthermore, compounds represented by formula (Ia) or (Ib) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in therapeutic purposes are provided herein.

[0105] Furthermore, compounds represented by formula (Ia) or (Ib) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer are provided herein.

[0106] Furthermore, compounds represented by formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in inhibiting KRas G12S and / or KRas G12C are provided herein.

[0107] Furthermore, compounds represented by formula (Ia) or (Ib) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are provided herein for use in the treatment of KRas G12S-related and / or KRas G12C-related diseases or disorders.

[0108] Furthermore, the use of compounds represented by formula (Ia) or (Ib), as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of cancer is provided herein.

[0109] Furthermore, the use of compounds represented by formula (Ia) or (Ib), as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for inhibiting the activity of KRas G12S and / or KRas G12C is provided herein.

[0110] Furthermore, the use of compounds represented by formula (Ia) or (Ib), as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of KRas G12S-related and / or KRas G12C-related diseases or disorders is provided herein.

[0111] Furthermore, the Specified Method of Treating Cancer in a Patient Requiring Treatment comprises (a) determining that the cancer is associated with a KRas G12S mutation or a KRas G12C mutation (e.g., KRas G12S-associated cancer or KRas G12C-associated cancer) (e.g., using a regulatory-approved assay or kit, e.g., an FDA-approved assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0112] Those skilled in the art will understand that both in vivo and in vitro studies using generally accepted and appropriate known cell and / or animal models predict the efficacy of a test compound in treating or preventing a particular disease.

[0113] Those skilled in the art will further understand that human clinical trials, including initial human dose studies, dose-ranging studies, and efficacy studies, may be conducted in healthy patients and / or patients with certain diseases, in accordance with methods well known in the clinical and medical fields. [Examples]

[0114] The compounds of the present invention may be prepared from commercially available reagents using the synthesis methods and reaction schemes described herein, or they may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0115] The following embodiments are intended to illustrate more specific embodiments of the present invention and are not intended to limit the scope of the invention. Reagent abbreviations: [ka]

[0116] Example 1 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0117] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) To a solution of (L)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (10.0 mg, 1.5 equivalents) / DCM (1 mL), DMAP (12.3 mg, 1.2 equivalents) and EDCI (19.3 mg, 1.2 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx5μm; A: water (FA), B: ACN, B%: 15%~45%B, 10 minutes] to obtain the title compound (12.1 mg, 22% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=8.96(s, 1H), 8.16(d, J=2.8Hz, 1H), 7.54(dd, J=5.6, 8.8Hz, 1H), 7.23-7.12(m, 2H), 7.09-6.96(m, 1H), 6.29(d, J=2. 8Hz, 1H), 5.44-5.21(m, 1H), 4.71-4.54(m, 2H), 4.42-4.23(m, 2H), 4.01 (dt, J=5.2, 10.4Hz, 1H), 3.63-3.11(m, 6H), 3.08-2.94(m, 1H), 2.46(br d, J=7.6Hz, 1H), 2.36(s, 3H), 2.24-1.99(m, 10H), 0.83-0.74(m, 3H); LCMS(ESI, M+1): m / z=686.4.

[0118] Example 2 [ka] 3-(1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carbonyl)oxazolidine-2-one [ka]

[0119] Step A. 2-(8-fluoronaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 1-bromo-8-fluoronaphthalene (9.00 g, 1.0 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (15.2 g, 1.5 equivalent) / dioxane (100 mL), potassium acetate (11.8 g, 3.0 equivalent) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.93 g, 0.10 equivalent) were added. The reaction mixture was degassed and purged three times with nitrogen. The reaction mixture was stirred at 90°C for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 50 / 1~1 / 1] to obtain the title compound (8.50 g, 78% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=8.04(td, J=2.4, 8.0Hz, 1H), 7.79(d, J=8.0Hz, 1H), 7.64-7 .56(m, 2H), 7.52(dt, J=5.2, 8.0Hz, 1H), 7.35(dd, J=8.0, 12.0Hz, 1H), 1.36(s, 12H).

[0120] Step B. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine:t-BuONa (4.19 g, 1.1 equivalents) was added in several batches at 25°C to a solution of 2,2,2-trifluoroethanol (4.36 g, 1.1 equivalents) / THF (50 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was added at -40°C to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10.0 g, 1.0 equivalent) / THF (100 mL). The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 30 / 1~1 / 1] to obtain the title compound (7.10 g, 80% yield) as a white solid; LCMS (ESI, M+1): m / z = 315.0.

[0121] Step C: 7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: 7.04 g (3.0 equivalents) of Na2CO3 was added to a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (7.00 g, 1.0 equivalent) and 1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethanol (3.13 g, 1.0 equivalent) in THF (70 mL). The reaction mixture was stirred at 40°C for 3 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were dried together over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1~0 / 1] to obtain the title compound (8.50 g, 83% yield) as a white solid; LCMS (ESI, M+1): m / z = 421.1.

[0122] Step D: 8-Fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine:To a solution of 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5.00 g, 1.0 equivalent) / CPME (5.0 mL), 2-(8-fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.23 g, 1.0 equivalent), Cs2CO3 (23.8 mL, 3.0 equivalent), and CataCXium A Pd G3 (865 mg, 0.1 equivalent) were added. The reaction mixture was degassed and purged three times with nitrogen. The reaction mixture was stirred at 90°C for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1] to obtain the title compound (4.60 g, 67% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.20(s, 1H), 8.22-8.18(m, 1H), 7.95(d, J=8.0Hz, 1H), 7.7 8-7.73(m, 1H), 7.65(d, J=6.4Hz, 1H), 7.60(dt, J=5.2, 8.0Hz, 1H), 7.32(dd, J=7.6, 1 3.2Hz, 1H), 5.43-5.31(m, 2H), 4.18(s, 2H), 3.01-2.89(m, 2H), 2.61-2.53(m, 2H), 1 .95-1.87(m, 2H), 1.84-1.75(m, 4H), 1.64-1.56(m, 2H); LCMS(ESI, M+1): m / z=531.4.

[0123] Step E. Tert-butyl-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equivalent) and tert-butylpiperidine-4-carboxylate (627 mg, 3.0 equivalents) / DMF (10 mL) were mixed with N-ethyl-N,N-diisopropylamine (1.10 g, 9.0 equivalents) and 4A molecular sieve (75.0 mg). The reaction mixture was stirred at 50°C for 16 hours. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were washed together with saline solution (2 x 20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC [(SiO2, dichloromethane / methanol) = 12 / 1] to obtain the title compound (400 mg, 69% yield) as a pale yellow solid; LC-MS (ESI, M+1): m / z = 616.4.

[0124] Step F. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid: To a solution of tert-butyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (100 mg, 1.0 equivalent) / DCM (5.5 mL), TFA (1.8 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain the title compound (90.0 mg, crude) as a pale yellow oily substance; LCMS (ESI, M+1): m / z = 560.3.

[0125] Step G. 3-(1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carbonyl)oxazolidine-2-one:To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and oxazolidine-2-one (8.56 mg, 1.1 equivalents) / DCM (0.5 mL), DMAP (13.6 mg, 1.2 equivalents) and EDCI (21.4 mg, 1.2 equivalents) were added. The reaction mixture was stirred at 30°C for 12 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 22%~52%B, 9 minutes] and preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 20%~50%B, 9 minutes] to obtain the title compound (7.42 mg, 13% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=9.04(s, 1H), 7.99(br d, J=7.6Hz, 1H), 7.74(d, J=8.0Hz, 1H), 7.68-7.58(m, 2H), 7.45(dt, J=4.8, 8.0Hz, 1H), 7. 12(dd, J=7.6, 12.8Hz, 1H), 4.77-4.63(m, 2H), 4.57-4.43(m, 4H), 4.07(t, J=8.0Hz, 2H), 4. 02-3.91(m, 1H), 3.60-3.42(m, 4H), 2.79(td, J=6.6, 10.8Hz, 2H), 2.26(td, J=6.4, 12.0Hz, 2H), 2.19-2.09(m, 2H), 2.09-1.92(m, 6H), 1.89-1.77(m, 2H); LCMS(ESI, M+1): m / z=629.3.

[0126] Example 3 [ka] 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-N-(pyridine-2-yl)piperidine-4-carboxamide [ka]

[0127] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-N-(pyridin-2-yl)piperidine-4-carboxamide: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equivalent) / DMF (2 mL), HATU (272 mg, 2 equivalents), DIEA (277 mg, 6.0 equivalents), and pyridine-2-amine (37 mg, 1.1 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN, B%: 34%~64%B for 9 minutes] to obtain the title compound (7.46 mg, 3.2% yield) as a white solid; 1H NMR (400MHz, chloroform-d) δ=9.05(s, 1H), 8.31(dd, J=0.8, 4.8Hz, 1H), 8.24(d, J=8.4Hz, 1H), 8.14(s, 1H), 8.01(td, J=1.8, 7.6Hz, 1H), 7.78-7.71(m, 2H), 7.68-7.60(m, 2H), 7.46(dt, J=5.2, 7.8Hz, 1H), 7.17-7.05(m, 2H), 4.71(br d, J=13.6Hz, 2H), 4.27(s, 2H), 3.53-3.39(m, 2H), 3.16(td, J=5.2, 10.0Hz, 2H), 2.77-2.62( LCMS (ESI, M+1): m / z=636.3.

[0128] Example 4 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(1H-pyrazole-1-yl)methanone [ka]

[0129] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol (1.0g, 1.0 equivalent) and methyl To a solution of piperidine-4-carboxylate (290 mg, 1.2 equivalents) / DMAC (10 mL), K3PO4 (1.07 g, 3.0 equivalents) was added. The reaction mixture was stirred at 60°C for 0.5 hours. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were washed together with saline solution (2 x 30 mL), dried over Na2SO4, and concentrated to obtain the title compound (1.2 g, crude) as a yellow oil.

[0130] Step B.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (1.2g, 1.0 equivalent) / MeOH (4.0mL) solution was mixed with LiOH·H2O (2M, 3.78mL, 4.0 equivalents). The reaction mixture was stirred at 20°C for 0.5 hours. The mixture was filtered and purified by reverse-phase flash [C18, 0.1% formic acid conditions] to obtain the title compound (0.8 g, 65.8% yield) as a white solid; LCMS (ESI, M+1): m / z = 622.3.

[0131] Step C. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) To a solution of (L)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equivalent) and TEA (81.4 mg, 5.0 equivalents) / DMF (2.0 mL), EDCI (38.5 mg, 1.25 equivalents) and HOBt (2.17 mg, 0.10 equivalents) were added. The reaction mixture was stirred at 25°C for 0.5 hours, and then 1H-pyrazole (43.8 mg, 4.0 equivalents) was added. The reaction mixture was stirred at 25°C for 48 hours. The mixture was filtered and purified twice by preparative HPLC [column: Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN; B%: 48%~78% for 9 minutes]. The fraction of interest was extracted with DCM (3x7.0mL). The organic layers were combined, dried over Na2SO4, and concentrated to obtain the title compound (11.3 mg, 9.89% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=8.96(s, 1H), 8.27(d, J=2.8Hz, 1H), 7.77(d, J=0.8Hz, 1H), 7.58-7 .50(m, 1H), 7.22-7.14(m, 2H), 7.06-6.94(m, 1H), 6.50(dd, J=1.2, 2.8Hz, 1H), 5.41-5.20(m, 1H), 4.74-4.53(m, 2H), 4.44-4.23(m, 2H), 4.14-3.98(m, 1H), 3.61-3.10(m, 5H), 3.08-2.94 (m, 1H), 2.56-2.39(m, 1H), 2.38-2.27(m, 1H), 2.26-2.04(m, 7H), 2.00-1.89(m, 3H), 0.82(br t, J=7.6Hz, 3H); LCMS (ESI, M+1): m / z=672.3.

[0132] Example 5 [ka] 2,6-Difluorophenyl (1R,5S,6r)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)Pyrido[4,3-d]pyrimidine-4-yl)-3-Azabicyclo[3.1.1]heptan-6-carboxylate

[0133] Example 6 [ka] 2,6-Difluorophenyl (1R,5S,6s)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate [ka]

[0134] Step A. 2,6-Difluorophenyl (1R,5S,6s)-3-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)Pyrido[4,3-d]Pyrimidine-4-yl)-3-Azabicyclo[3.1.1]Heptan-6-carboxylate and 2,6-Difluorophenyl (1R,5S,6r)-3-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)Pyrido[4,3-d]Pyrimidine-4-yl)-3-Azabicyclo[3.1.1]Heptan-6-carboxylate:3-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro -1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylic acid (150 mg, 1.0 equivalent), EDCI (75.5 mg, 1.5 equivalents), and DMAP (48.1 mg, 1.5 equivalents) / DCM (2 mL) were mixed with 4-fluorophenol (68.3 mg, 2.0 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated. The residue was diluted with H2O (2 mL) and extracted with RINKAN (3 x 2 mL). The organic layers were washed together with saline solution (2 mL), dried over anhydrous sodium sulfate, concentrated, purified by preparative HPLC [column: YMC-Actus Triart C18 150x30mmx7μm; A: water (FA), B: ACN; B%: 20%~50%B 10 minutes], and lyophilized to obtain two isomers.

[0135] 2,6-Difluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate (Example 5, 2.61 mg, 1.3% yield) was obtained as a yellowish-white solid; 1H NMR (400MHz, chloroform-d) δ=9.48-9.43(m, 1H), 8.02-7.98(m, 1H), 7.77-7.73(m, 1H), 7.66-7.60(m, 2H), 7.48-7.41(m, 1H), 7.24-7.17(m, 1H), 7.12(dd, J=7.6, 12.8Hz, 1H), 7.02(s, 2H), 4.66-4.56(m, 2H), 4.50(s, 4H), 3.75-3.63(m, 2H), 3.23(br d, J=6.0Hz, 2H), 3.08(d, J=5.6Hz, 1H), 2.96-2.89(m, 2H), 2.36(br dd, J=6.4, 12.8Hz, 2H), 2.21-2.13(m, 2H), 2.13-2.04(m, 3H), 1.95(br dd, J=6.8, 13.2Hz, 2H), 1.66(br dd, J=6.0, 10.0Hz, 1H); LCMS(ESI, M+1): m / z=684.4.

[0136] 2,6-Difluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate (Example 6, 3.51 mg, 1.8% yield) was obtained as a yellow solid; 1¹H NMR (400MHz, chloroform-d): δ = 9.50–9.43 (m, 1H), 8.03–7.93 (m, 1H), 7.73 (d, J=8.0Hz, 1H), 7.66–7.59 (m, 2H), 7.48–7.41 (m, 1H), 7.17–7.07 (m, 2H), 6.95–6.86 (m, 2H), 4.82–4.66 (m, 2H) , 4.63-4.53(m, 2H), 4.37-4.26(m, 2H), 3.74-3.59(m, 2H), 3.58-3.48(m, 1H), 3.23-3.13(m , 2H), 2.99-2.86(m, 2H), 2.37-2.33(m, 2H), 2.16-2.09(m, 2H), 2.09-2.04(m, 2H), 2.01(br d, J=4.0Hz, 1H), 1.92(br dd, J=6.8, 13.2Hz, 2H), 1.67(d, J=10.0Hz, 1H); LCMS(ESI, M+1): m / z=684.4.

[0137] Example 7 [ka] 4-Fluorophenyl (1R,5S,6r)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate

[0138] Example 8 [ka] 4-Fluorophenyl (1R,5S,6s)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate [ka]

[0139] Step A. Methyl 3-azabicyclo[3.1.1]heptane-6-carboxylate: A mixture of 3-(tert-butyl)6-methyl3-azabicyclo[3.1.1]heptane-3,6-dicarboxylate (950 mg, 1.0 equivalent) / MeCN (10 mL) was mixed with HCl·dioxane (10 mL, 4 M). The reaction was stirred at 0°C for 1 hour. The mixture was concentrated and diluted with MeOH (10 mL). The mixture was adjusted to pH 7 with NaHCO3 solid, filtered, and concentrated to obtain the title compound (570 mg, 99% yield) as a white solid;

[0140] Step B. Methyl 3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate: 8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.95 g, 1.0 equivalent) and methyl 3-azabicyclo[3.1.1]heptan-6-carboxylate (570 mg, 1.0 equivalent) / DMAc (10 mL) were mixed with K3PO4 (2.34 g, 3.0 equivalent). The reaction mixture was stirred at 60°C for 12 hours. The mixture was diluted with H2O (20 mL) and extracted with ELISA (3 x 20 mL). The organic layers were washed together with saline solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (750 mg, 35% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 586.4;

[0141] Step C. 3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid:To a solution of methyl 3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate (100 mg, 1.0 equivalent) / MeOH (1 mL) and H2O (1 mL), LiOH·H2O (179 mg, 25 equivalents) was added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and adjusted to pH=7 with HCl (4 M). The mixture was filtered to obtain the title compound (70.0 mg, 72% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 572.4;

[0142] Step D. 4-Fluorophenyl (1R,5S,6s)-3-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate and 4-Fluorophenyl (1R,5S,6r)-3-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate: 3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (35 mg, 1.0 equivalent), EDCI (17.6 mg, 1.5 equivalents), and DMAP (11.2 mg, 1.5 equivalents) / DCM (1 mL) were mixed with 4-fluorophenol (13.7 mg, 2.0 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated. The residue was diluted with H2O (2 mL) and extracted with ELISA (3 x 2 mL). The organic layers were washed together with saline solution (2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Welch Xtimate C18 150x25mmx5μm; A: water (FA), B: ACN; B%: 30%~50%B 10 minutes] to obtain two isomers.

[0143] 4-Fluorophenyl (1R,5S,6r)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate (Example 7, 2.05 mg, 4.7% yield) was obtained as a yellowish-white solid; 1¹H NMR (400MHz, chloroform-d): δ = 9.50-9.43 (m, 1H), 8.04-7.96 (m, 1H), 7.78-7.72 (m, 1H), 7.67-7.58 (m, 2H), 7.50-7.42 (m, 1H), 7.16-7.11 (m, 3H), 7.10 (d, J=2.4Hz, 2H), 4.90-4.81 (m, 2H), 4.57-4.47 (m, 4H) , 3.96-3.84(m, 2H), 3.24-3.15(m, 2H), 3.03-2.93(m, 3H), 2.86-2.78(m, 1H), 2.51-2.41(m, 2H), 2.3 3-2.21(m, 2H), 2.20-2.10(m, 2H), 2.09-2.00(m, 2H), 1.29-1.24(m, 1H); LCMS(ESI, M+1): m / z=666.4

[0144] 4-Fluorophenyl (1R,5S,6s)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.1.1]heptan-6-carboxylate (Example 8, 2.38 mg, 5.5% yield) was obtained as an off-white solid; 1 H NMR (400MHz, chloroform-d) δ=9.49-9.43(m, 1H), 8.03-7.96(m, 1H), 7.77-7.71(m, 1H), 7.67-7.57(m, 2H), 7.49-7.41(m, 1H), 7. 11(dd, J=7.6, 12.8Hz, 1H), 7.00(s, 2H), 6.93-6.84(m, 2H), 4.91-4.62(m, 4H), 4.44-4.26(m, 2H), 3.98-3.72(m, 2H), 3.47(br d. s, 1H); LCMS (ESI, M+1): m / z=666.4.

[0145] Example 9 [ka] (3,5-dimethyl-1H-pyrazole-1-yl)(1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone [ka]

[0146] Step A. (3,5-dimethyl-1H-pyrazole-1-yl)(1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equivalent) / DCM (0.5 mL), 3,5-dimethyl-1H-pyrazole (25.8 mg, 3.0 equivalent), EDCI (25.7 mg, 1.5 equivalent), and DMAP (16.4 mg, 1.5 equivalent) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was diluted with water (1 mL), neutralized with solid NaHCO3, and extracted with ethyl acetate (2 x 2 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA); B: ACN, B%: 30%~60% for 7 minutes] to obtain the title compound (16.4 mg, 28% yield, HCOOH salt) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.11(s, 1H), 8.19(br d, J=8.4Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.78-7.72(m, 1H), 7.65(d, J=6.8Hz, 1H) , 7.59(dt, J=5.2, 8.0Hz, 1H), 7.32(dd, J=7.6, 13.2Hz, 1H), 6.23(s, 1H), 4.58(br d, J=13.2Hz, 2H), 4.08(s, 2H), 4.07-3.99(m, 1H), 3.57(br t, J=12.8Hz, 2H), 2.98-2.90(m, 2H), 2.59-2.53(m, 2H), 2.49(s, 3H), 2.23(s, 3H), 2.18-2.09 (m, 2H), 1.99-1.87 (m, 4H), 1.85-1.71 (m, 4H), 1.63-1.54 (m, 2H); LCMS (ESI, M+1): m / z=638.4.

[0147] Example 10 [ka] (1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0148] Step A. (1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanoneTo a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equivalent) / DCM (0.5 mL), 5-methyl-1H-pyrazole (22.0 mg, 3.0 equivalents), EDCI (25.7 mg, 1.5 equivalents), and DMAP (16.4 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was diluted with water (1 mL), neutralized with solid NaHCO3, and extracted with ethyl acetate (2 x 2 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA); B: ACN, B%: 28%~58%B, 7 minutes] to obtain the title compound (15.1 mg, 27% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.12(s, 1H), 8.32(d, J=2.8Hz, 1H), 8.19(br d, J=8.4Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.79-7.72(m, 1H), 7.65(d, J=6.4Hz, 1H), 7.5 9(dt, J=5.2, 7.6Hz, 1H), 7.32(dd, J=7.6, 13.2Hz, 1H), 6.50(d, J=2.8Hz, 1H), 4.59(br d, J=13.2Hz, 2H), 4.08(s, 2H), 4.05-3.95(m, 1H), 3.59(br t, J=12.8Hz, 2H), 2.99-2.88(m, 2H), 2.58-2.53(m, 2H), 2.31(s, 3H), 2.19-2.11(m, 2H) , 2.01-1.86(m, 4H), 1.86-1.71(m, 4H), 1.63-1.53(m, 2H); LCMS(ESI, M+1): m / z=624.4.

[0149] Example 11 [ka] (1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(1H-pyrazole-1-yl)methanone TIFF2026519205000080.tif60164

[0150] Step A. (1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(1H-pyrazole-1-yl)methanone To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (150 mg, 1.0 equivalent) / DCM (1.5 mL), 1H-pyrazole (54.7 mg, 3.0 equivalent), EDCI (77.1 mg, 1.5 equivalent), and DMAP (49.1 mg, 1.5 equivalent) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (5 mL) and extracted with DCM (10 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA); B: ACN, B%: 18%~48%B, 10 minutes] to obtain the title compound (14.4 mg, 8% yield) as a white solid; 1 H NMR (400MHz, CDCl3)δ=9.10(s, 1H), 8.29(d, J=4.8Hz, 1H), 7.99(d, J=7.6Hz, 1H), 7.77-7.73(m, 2H), 7.63-7.59(m, 3H), 7.50-7.40(m, 1H), 7.14-7.09(m, 1H), 6.52(s, 1H), 4.76-4.72(m, 2H), 4.29(s, 2H), 4.15-4.00(m, 1H), 3.51(br t, J=12.0Hz, 2H), 3.20-3.18(m, 2H), 2.69-2.68(m, 2H), 2.23-2.22(m, 2H), 2.16 -2.12(m, 4H), 1.93-1.88(m, 4H), 1.71-1.60(m, 2H); LCMS(ESI, M+1): m / z=610.4.

[0151] Example 12 [ka] 2,4,6-Trifluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0152] Step A. Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.00 g, 1.0 equivalent) / DMAC (20 mL), K3PO4 (2.40 g, 3.0 equivalent) and methylpiperidine-4-carboxylate (1.62 g, 3.0 equivalent) were added. The reaction mixture was stirred at 60°C for 1 hour. The mixture was filtered, concentrated, and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (2.07 g, 92% yield) as a white solid; LCMS (ESI, M+1): m / z = 574.3.

[0153] Step B. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid To a solution of methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (2.07 g, 1.0 equivalent) / MeOH (21 mL), LiOH·H2O (757 mg, 5.0 equivalent) and H2O (7 mL) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (1.49 g, 68% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0154] Step C. 2,4,6-Trifluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylateTo a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (80.0 mg, 1.0 equivalent) and 2,4,6-trifluorophenol (63.5 mg, 3.0 equivalents) / DCM (2 mL), DMAP (26.2 mg, 1.5 equivalents) and EDCI (41.1 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 30°C for 1 hour. The mixture was concentrated and purified by preparative HPLC [column: Welch Ultimate XB-SiOH 250x50mmx10μm; A: Hexane, B: EtOH, B%: 5%~45%B 15 minutes] and preparative HPLC [column: Welch Xtimate C18 150x25mmx5μm; A: Water (FA), B: ACN, B%: 25%~55%B 10 minutes] to obtain the title compound (3.52 mg, 3.3% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=9.06(s, 1H), 8.01(br d, J=7.6Hz, 1H), 7.76(d, J=8.0Hz, 1H), 7.69-7.57(m, 2H), 7.47(dt, J=4.8, 8.0Hz, 1H), 7.14(dd, J=7.6, 12.8Hz, 1H), 6.90-6.74(m, 2H), 4.55(br dd, J=4.0, 13.2Hz, 2H), 4.36(s, 2H), 3.77-3.57(m, 2H), 3.34-3.22(m, 2H), 3.20-3.05(m, 1H), 2.83-2.64(m, 2H), 2.44-2.28(m, 2H), 2.27-2.09(m, 4H), 2.07-1.87(m, 4H), 1.83-1.66(m, 2H); LCMS(ESI, M+1): m / z=690.3.

[0155] Example 13 [ka] 2,4-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0156] Step A. 2,4-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,4-difluorophenol (34.9 mg, 3.0 equivalents) / DCM (1 mL), DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 30°C for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined and concentrated, and purified by preparative TLC (dichloromethane:methanol = 8 / 1) and preparative HPLC [column: Welch Xtimate C18 150x25mmx5μm; A: water (FA), B: ACN, B%: 23%~53%B for 10 minutes] to obtain the title compound (2.19 mg, 3.6% yield) as a white solid; 1 ¹H NMR (400MHz, chloroform-d) δ=9.05(s, 1H), 8.05-7.95(m, 1H), 7.75(d, J=8.0Hz, 1H), 7.68-7.57(m, 2H), 7.50-7.41(m, 1H), 7.18-7.07(m, 2H), 7.01-6.84(m, 2H), 4.55(br dd, J=4.4, 9.2Hz, 2H), 4.39-4.23(m, 2H), 3.68-3.54(m, 2H), 3.29-3.01(m, 3H), 2.77-2.61(m, 2H), 2. 38-2.25(m, 2H), 2.24-2.07(m, 4H), 1.96-1.87(m, 4H), 1.74-1.66(m, 2H); LCMS(ESI, M+1): m / z=672.3.

[0157] Example 14 [ka] 4-Fluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0158] Step A. 4-Fluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equivalent) and 4-fluorophenol (80.1 mg, 2.0 equivalents) / DCM (2 mL), DMAP (65.5 mg, 1.5 equivalents) and EDCI (103 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 30°C for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined and concentrated, and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 30%~60%B, 9 minutes], preparative TLC (dichloromethane:methanol=8 / 1), and preparative HPLC [column: Welch Xtimate C18 150x25mmx5μm; A: water (FA), B: ACN, B%: 20%~50%B, 10 minutes] to obtain the title compound (2.88 mg, 1.2% yield) as a white solid; 1¹H NMR (400MHz, chloroform-d) δ=9.05 (s, 1H), 8.00 (br d, J=7.6Hz, 1H), 7.75 (d, J=8.4Hz, 1H), 7.68-7.59 (m, 2H), 7.45 (dt, J=4.8, 8.0Hz, 1H), 7.13 (br d, J=12.4Hz, 1H), 7.09(d, J=2.4Hz, 2H), 7.08(s, 2H), 4.66-4.54(m, 2H), 4.34(s, 2H), 3.63 -3.49(m, 2H), 3.32-3.19(m, 2H), 3.07-2.95(m, 1H), 2.70(td, J=7.2, 10.4Hz, 2H), 2.30(br dd, J=2.8, 13.6Hz, 2H), 2.22-2.07(m, 5H), 1.95-1.91(m, 4H), 1.78-1.69(m, 2H); LCMS(ESI, M+1): m / z=654.2.

[0159] Example 15 [ka] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carbaldehyde [ka]

[0160] Step A. 4-(4-(4-(dimethoxymethyl)piperidine-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (200 mg, 1.0 equivalent), 4-(dimethoxymethyl)piperidine (161 mg, 3.0 equivalent), and 4A molecular sieve (20 mg) / DMF (1 mL) were mixed with DIEA (131 mg, 3.0 equivalent). The reaction mixture was stirred at 60°C for 2 hours. The mixture was filtered, and the filtrate was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (150 mg, 65% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 652.4.

[0161] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carbaldehyde To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (120 mg, 1 equivalent) / DCM (100 μL), TFA (420 mg, 20 equivalents) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated. The residue was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [YMC Triart 30x150mmx7μm; A: water (FA); B: ACN, B%: 25%~55% 8 min] and preparative HPLC [C18 150x30mm; A: water (FA); B: ACN, B%: 20%~50% 7 min] to obtain the title compound (85.0 mg, 75% yield, HCOOH salt) as a white solid; 1¹H NMR (400MHz, methanol-d4) δ 9.09-9.02 (m, 1H), 7.68 (dd, J=5.6, 8.8Hz, 1H), 7.33-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.08-7.03 (m, 1H), 5.51-5.30 (m, 1H), 4.79-4.68 (m, 2H), 4.51-4.38 (m, 2H), 4.38-4.3 2(m, 1H), 3.61-3.37(m, 5H), 3.24-3.14(m, 1H), 2.56-2.33(m, 3H), 2.29-2.08(m, 4H), 2.07-1.88(m, 4H), 1.69-1.53(m, 2H), 0.85-0.76(m, 3H); LCMS(ESI, M+1): m / z=606.3.

[0162] Example 16 [ka] Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0163] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (100 mg, 1.0 equivalent), methylpiperidine-4-carboxylate (48.3 mg, 2.0 equivalent), and 4A molecular sieve (20 mg) / DMSO (1 mL) were mixed with DIEA (65.4 mg, 3.0 equivalent). The reaction mixture was stirred at 40°C for 12 hours. The mixture was filtered, and the filtrate was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] and preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN, B: 48%~78% for 9 minutes] to obtain the title compound (22.4 mg, 21% yield) as a white solid; 1 ¹H NMR (400MHz, methanol-d4) δ 9.04 (s, 1H), 7.68 (dd, J=6.0, 9.2Hz, 1H), 7.30 (d, J=2.4Hz, 1H), 7.25 (t, J=9.2Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 5.40-5.21 (m, 1H), 4.64-4.53 (m, 2H), 4.35-4.22 (m, 2H), 3.72 (s, 3H), 3.67-3.54(m, 2H), 3.29-3.16(m, 3H), 3.06-2.97(m, 1H), 2.91-2.81(m, 1H), 2.54-2.40(m, 1H), 2.39-2.09(m, 6H), 2.04-1.84(m, 5H), 0.85-0.74(m, 3H); LCMS(ESI, M+1): m / z=636.4.

[0164] Example 17 [ka] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboaldehyde [ka]

[0165] Step A. (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid: (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (780 mg, 1.0 equivalent) and NaOH (221 mg, 1.1 equivalent) / H2O (10.0 mL) were mixed with CbzCl (1.07 g, 1.2 equivalents) at 0°C. The reaction mixture was stirred at 0-10°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were dried together over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (503 mg, 20% yield) as a yellow oil; 1 H NMR (400MHz, chloroform-d) δ=7.37-7.30(m, 5H), 5.14(s, 2H), 4.72(s, 1H), 4.07-3.88(m, 2H), 3.05- 2.91(m, 2H), 2.69-2.56(m, 2H), 1.88-1.75(m, 2H), 1.65-1.45(m, 2H); LCMS(ESI, M+1): m / z=290.0

[0166] Step B. Benzyl (1R,5S,8r)-8-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (300 mg, 1.0 equivalent) / THF (3.00 mL), BH3·Me2S (10 M, 3.0 equivalent) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was quenched with MeOH (5.00 mL) and concentrated under vacuum. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: YMC-Gel SiL-HG 250mm x 70mm x 10μm; A: hexane, B: EtOH, B%: 5%~45% 15 minutes] to obtain the title compound (190 mg, 60% yield) as a colorless oil; LC-MS (ESI, M+1): m / z = 276.1

[0167] Step C. ((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)methanol: To a solution of benzyl (1R,5S,8r)-8-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (170 mg, 1.0 equivalent) / MeOH (5.00 mL), Pd / C (20 mg, 10% purity) was added under an N2 atmosphere. The suspension was degassed and purged three times with H2. The reaction mixture was stirred at 30°C for 2 hours under H2 (15 Psi). The mixture was filtered and concentrated to obtain the title compound (60 mg, crude) as a white solid; LCMS (ESI, M+1): m / z = 142.1

[0168] Step D. ((1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methanol: 8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (130 mg, 1.0 equivalent) and ((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)methanol (51.9 mg, 1.5 equivalents) / DMF (3.00 mL) were mixed with K3PO4 (156 mg, 3.0 equivalents) and 4A molecular sieve (20 mg). The reaction mixture was stirred at 40°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (45 mg, 30% yield) as a white solid; LC-MS (ESI, M+1): m / z = 572.4

[0169] Step E. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboaldehyde:((1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methanol (20.0 mg, 1.0 equivalent) / DCM (1.00 mL) was mixed with DMP (22.3 mg, 1.5 equivalents) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NaHCO3 solution (10.0 mL) and extracted with ethyl acetate (2 x 5 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (7.41 mg, 33% yield, CF3COOH salt) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=9.07(s, 1H), 8.11(br d, J=8.4Hz, 1H), 7.85(d, J=8.0Hz, 1H), 7.74-7.67(m, 1H), 7.60(d, J=7.2Hz, 1H), 7.53(dt, J=5.2, 8.0Hz, 1H), 7.25 -7.14(m, 1H), 4.83-4.70(m, 2H), 4.40(s, 2H), 4.25(d, J=8.4Hz, 1H), 3.68-3.55(m, 2H), 2.97-2.84(m, 2H), 2.50(br s, 2H), 2.23-2.11(m, 2H), 2.11-1.93(m, 5H), 1.92-1.82(m, 2H), 1.82-1.72(m, 2H), 1.65-1.52(m, 2H); LCMS(ESI, M+1): m / z=570.3.

[0170] Example 18 [ka] 2,2,2-Trifluoroethyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0171] Step A. 2,2,2-Trifluoroethyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,2,2-trifluoroethanol (25.6 mg, 3.0 equivalents) / DCM (1 mL) were mixed with DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 equivalent). The reaction mixture was stirred at 30°C for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC [Phenomenex Luna C18 150x25mmx10μm; A: Water (TFA); B: ACN; B%: 15%~45% 9 min]. The desired fraction was collected. The mixture was adjusted to pH=7 with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative HPLC [Phenomenex Luna C18 150x25mmx10μm; A: Water (FA); B: ACN; B%: 28%~58% 9 min] to obtain the title compound (19.1 mg, 31% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=9.22-9.08(m, 1H), 8.19(dd, J=8.0Hz, 1H), 7.94(t, J=7.6Hz, 1H), 7.81-7 .71(m, 1H), 7.68-7.55(m, 2H), 7.36-7.27(dd, J=7.2, 13.2Hz, 2H), 4.82(q, J=9.2Hz, 2H), 4.63(br d, J=10.0Hz, 2H), 4.13(s, 2H), 3.68(br d, J=12.8Hz, 2H), 3.15(s, 1H), 3.07-2.92(m, 2H), 2.74(br s, 2H), 2.67-2.60(m, 2H), 2.00-1.89(m, 2H), 1.88-1.74(m, 4H), 1.74-1.50(m, 6H); LCMS(ESI, M+1): m / z=668.4.

[0172] Example 19 [ka] Methyl (1R,5S,8s)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0173] Step A. Me Tyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (90 mg, 1.0 equivalent), 4-hydroxybenzonitrile (36.6 mg, 2.0 equivalent), and EDCI (44.2 mg, 1.5 equivalent) / DCM (2.00 mL) were mixed with DMAP (28.2 mg, 1.5 equivalent). The reaction mixture was stirred at 40°C for 1 hour. MeOH (1 mL, 160 equivalent) was added to the mixture. The reaction mixture was stirred at 60°C for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (2 x 15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Welch Ultimate XB-SiOH 250x50x10μm; A: hexane-EtOH; B: 10%~50% for 15 minutes] to obtain the title compound (23.7 mg, 25% yield) as a white solid; 1H NMR (400MHz, methanol-d4) δ=9.14-9.07(m, 1H), 8.18(br d, J=8.4Hz, 1H), 7.93(d, J=8.0Hz, 1H), 7.77-7.70(m, 1H), 7.65-7.62(m, 1H), 7.58(dt, J=5.2, 8.0Hz, 1H), 7.31(dd, J=7.6, 13.2Hz, 1H), 4.59(br d, J=12.4Hz, 2H), 4.07(s, 2H), 3.64(s, 4H), 3.62(s, 1H), 2.99-2.91(m, 3H), 2.70(br s, 2H), 2.61-2.52(m, 2H), 1.96-1.86(m, 2H), 1.85-1.71(m, 4H), 1.70-1.64(m, 2H), 1.59(br dd, J=7.2, 12.4Hz, 2H), 1.55-1.47(m, 2H); LCMS (ESI, M+1): m / z=600.3.

[0174] Example 20 [ka] 4-Cyanophenyl (1R,5S,8r)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0175] Step A. 4-Cyanophenyl (1R,5S,8r)-3-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate:(1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50 mg, 1.0 equivalent), 4-hydroxybenzonitrile (30.5 mg, 3.0 equivalent), and a solution of DMAP (15.6 mg, 1.5 equivalent) / DCM (1.00 mL) were mixed with EDCI (24.6 mg, 1.5 equivalent). The reaction mixture was stirred at 10°C for 16 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150x25mmx10μm; A: water (TFA), B: ACN, B%: 30%~60% for 9 minutes] to obtain the title compound (25.5 mg, 42% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) (400MHz, DMSO-d6) δ=9.15(s, 1H), 8.18(br d, J=8.4Hz, 1H), 7.99-7.90(m, 3H), 7.78-7.70(m, 1H), 7.66-7.62(m, 1H), 7 .61-7.55(m, 1H), 7.45-7.39(m, 2H), 7.31(dd, J=7.2, 13.2Hz, 1H), 4.66(br d, J=12.0Hz, 2H), 4.07(s, 2H), 3.71(br d, J=12.4Hz, 2H), 2.93(td, J=5.2, 10.4Hz, 2H), 2.87(br s, 2H), 2.59-2.51(m, 3H), 1.96-1.86(m, 2H), 1.85-1.70(m, 6H), 1.67-1.52(m, 4H); LCMS(ESI, M+1): m / z=687.3.

[0176] Example 21 [ka] 2-Cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0177] Step A. 2-Cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equivalent) and 2-hydroxybenzonitrile (30.5 mg, 3.0 equivalents) / DCM (1 mL) were mixed with DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 equivalent). The reaction mixture was stirred at 30°C for 2 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex Luna C18 150x25mmx10μm; A: Water (TFA); B: ACN; B%: 32%~62% 9 min], followed by preparative HPLC [Phenomenex Luna C18 150x25mmx10μm; A: Water (FA); B: ACN; B%: 33%~53% 10 min] to obtain the title compound (11.0 mg, 18% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.20(s, 1H), 8.19(br d, J=8.8Hz, 1H), 8.01-7.92(m, 2H), 7.83(m, 1H), 7.78-7.71(t, J=7.6Hz, 1H), 7.68-7.56(m, 2H) , 7.55-7.46(m, 2H), 7.32(dd, J=7.2, 13.2Hz, 1H), 4.89-4.59(m, 2H), 4.53-4.32(m, 2H), 3.78(br t, J=12.0Hz, 2H), 3.50-3.36(m, 3H), 3.13-2.87(m, 4H), 2.14-2.06(m, 2H), 2.04-1.81(m, 8H), 1.68-1.50(m, 2H); LCMS(ESI, M+1): m / z=687.3.

[0178] Example 22 [ka] 3-Cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0179] Step A. 3-Cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equivalent) and 3-hydroxybenzonitrile (30.5 mg, 3.0 equivalents) / DCM (1 mL) were mixed with DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 equivalent). The reaction mixture was stirred at 30°C for 2 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: Water (TFA); B: ACN; B%: 30%~60% 9 min], and preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: Water (FA); B: ACN; B%: 25%~55% 10 min], followed by preparative HPLC [YMC-Actus Triart C18 150x30mmx7μm; A: Water (FA); B: ACN; B%: 30%~60% 10 min] to obtain the title compound (14.5 mg, 24% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.15(s, 1H), 8.18(br d, J=8.0Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.84-7.71(m, 3H), 7.69-7.62(m, 2H), 7.61-7.53(m, 2H), 7.32(dd, J=7.2, 13.2Hz, 1H), 4.66(br d, J=10.8Hz, 2H), 4.10(s, 2H), 3.72(br d, J=12.4Hz, 2H), 3.30(s, 1H), 3.01-2.92(m, 2H), 2.87(br s, 2H), 2.58(td, J=6.8, 9.8Hz, 2H), 1.91(m, 2H), 1.87-1.73(m, 6H), 1.66-1.55(m, 4H); LCMS(ESI, M+1): m / z=687.3.

[0180] Example 23 [ka] 3,4-Difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0181] Step A. 3,4-Difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylateEDCI (54.0 mg, 1.5 equivalents) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (110 mg, 1.0 equivalent), 3,4-difluorophenol (48.9 mg, 2.0 equivalents), and DMAP (34.4 mg, 1.5 equivalents) / DCM (1.00 mL). The reaction mixture was stirred at 40°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with DCM (2 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (dichloromethane:methanol = 8 / 1), followed by preparative HPLC [column: YMC Triart C18 150x25mmx5μm; A: water (FA), B: ACN, B%: 32%~62% for 2 minutes] to obtain the title compound (2.90 mg, 2% yield, HCOOH salt) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=9.06(s, 1H), 8.00(br d, J=7.6Hz, 1H), 7.75(d, J=8.4Hz, 1H), 7.67-7.58(m, 2H), 7.50-7.42(m, 1H), 7.24-7.17(m, 1H), 7.1 7-7.09(m, 1H), 7.03-6.95(m, 1H), 6.88-6.82(m, 1H), 4.91-4.80(m, 1H), 4.80-4.71(m, 1H), 4.28(br s, 2H), 3.67-3.51(m, 2H), 3.31-3.14(m, 2H), 3.04(s, 1H), 2.97-2.86(m, 2H), 2.77-2.61(m , 2H), 2.22-2.10(m, 2H), 1.99-1.88(m, 6H), 1.80-1.67(m, 4H); LCMS(ESI, M+1): m / z=698.3.

[0182] Example 24 [ka] 2,6-Difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0183] Step A. 2,6-Difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate EDCI (24.5 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equivalent), 2,6-difluorophenol (33.3 mg, 3.0 equivalent), and DMAP (15.6 mg, 1.5 equivalent) / DCM (1.00 mL). The reaction mixture was stirred at 10°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150x25mmx10μm; A: water (TFA), B: ACN, B%: 65% for 9 minutes] to obtain the title compound (8.80 mg, 17% yield) as a white solid; 1H NMR (400MHz, methanol-d4) δ=9.16(s, 1H), 8.13(br d, J=8.4Hz, 1H), 7.87(d, J=8.4Hz, 1H), 7.76-7.68(m, 1H), 7.62(d, J=6.4Hz, 1H), 7.54(dt, J=5.2, 8.0Hz, 1H), 7.32(tt, J=6.0, 8.4Hz, 1H), 7.20(dd, J=7.6, 13.2Hz, 1H), 7.15-7.08(m, 2H), 4.89(br s, 2H), 4.68(s, 2H), 3.82(br d, J=12.4Hz, 2H), 3.76-3.65(m, 2H), 3.41(s, 1H), 3.30-3.26(m, 2H), 2.98(br s, 2H), 2.42-2.32(m, 2H), 2.30-2.07(m, 6H), 2.03-1.92(m, 2H), 1.76-1.65(m, 2H); LCMS(ESI, M+1): m / z=698.5.

[0184] Example 25 [ka] 2-Fluorophenyl (1R,5S,8s)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0185] Step A. 2-Fluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate:(1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equivalent), 2-fluorophenol (28.7 mg, 3.0 equivalent), and DMAP (15.6 mg, 1.5 equivalent) / DCM (1.00 mL) were mixed with EDCI (24.5 mg, 1.5 equivalent). The reaction mixture was stirred at 10°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150x25mmx10μm; A: water (TFA), B: ACN, B%: 36%~66% for 9 minutes] to obtain the title compound (8.88 mg, 17% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=9.16(s, 1H), 8.13(d, J=8.4Hz, 1H), 7.87(d, J=8.0Hz, 1H), 7.75-7.68(m, 1H), 7.62(dd, J=1.2 , 7.2Hz, 1H), 7.54(dt, J=5.2, 8.0Hz, 1H), 7.33-7.23(m, 2H), 7.23-7.17(m, 3H), 4.91-4.86(m, 2H), 4.68(s, 2H), 3.81(br d, J=12.8Hz, 2H), 3.76-3.66(m, 2H), 3.34(s, 1H), 3.30-3.26(m, 2H), 2.97(br s, 2H), 2.41-2.31(m, 2H), 2.29-2.17(m, 3H), 2.17-2.07(m, 3H), 2.02-1.94(m, 2H), 1.73-1.65(m, 2H); LCMS(ESI, M+1): m / z=680.5.

[0186] Example 26 [ka] Phenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0187] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid To a mixture of (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.01 g, 2.0 equivalents, HCl), K3PO4 (1.68 g, 3.0 equivalents), and 4A molecular sieve (50.0 mg) / DMF (20.0 mL), 8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.40 g, 1.0 equivalent) was added. The reaction mixture was stirred at 60°C for 2 hours. The mixture was filtered, and the filtrate was purified by reverse-phase flash chromatography [C18, 0.1% NH3·H2O conditions] to obtain the title compound (1.1 g, 69% yield) as a brown solid; LCMS (ESI, M+1): m / z = 586.4.

[0188] Step B. Phenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate50.0 mg, 1.0 equivalent of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid, 24.1 mg, 3.0 equivalents of phenol, and 15.6 mg, 1.5 equivalents of DMAP (15.6 mg, 1.5 equivalents) were added to a solution of DMAP (15.6 mg, 1.5 equivalents) / DCM (1.00 mL). The reaction mixture was stirred at 10°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150x25mmx10μm; A: water (TFA), B: ACN, B%: 35%~65% for 9 minutes] to obtain the title compound (10.0 mg, 18% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=9.15(s, 1H), 8.13(br d, J=8.4Hz, 1H), 7.86(d, J=8.4Hz, 1H), 7.74-7.68(m, 1H), 7.62(d, J=6.4Hz, 1H), 7.54(dt, J=5.2, 8.0Hz, 1H), 7.45-7.38 (m, 2H), 7.29-7.24(m, 1H), 7.20(dd, J=7.6, 12.8Hz, 1H), 7.10(d, J=8.0Hz, 2H), 4.90-4.86(m, 2H), 4.62(s, 2H), 3.79(br d, J=12.8Hz, 2H), 3.66-3.56(m, 2H), 3.28(s, 1H), 3.25-3.17(m, 2H), 2.95(br s, 2H), 2.37-2.27(m, 2H), 2.25-2.01(m, 6H), 1.99-1.90(m, 2H), 1.73-1.63(m, 2H); LCMS(ESI, M+1): m / z=662.6.

[0189] Example 27 [ka] 2-Cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0190] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid 8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.0 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0191] Step B. 2-Cyanophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylateA mixture of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2-hydroxybenzonitrile (31.9 mg, 3.0 equivalents) / DCM (2.00 mL) was mixed with DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 37%-67%B for 9 minutes] to obtain the title compound (9.96 mg, 14.6% yield) as an off-white solid; 1 H NMR (400MHz, DMSO-d6) δ=10.26(br s, 1H), 9.19(s, 1H), 8.20(br d, J=8.4Hz, 1H), 7.96(t, J=8.4Hz, 2H), 7.83(t, J=8.0Hz, 1H), 7.76(t, J=7.6Hz, 1H), 7.65(d, J=7.2Hz, 1H), 7.60(br d, J=5.2Hz, 1H), 7.54-7.49(m, 2H), 7.32(dd, J=7.6, 13.1Hz, 1H), 4.58(s, 4H), 3.73-3.64(m, 2H), 3.52(br dd, J=5.6, 11.6Hz, 2H), 3.26-3.18(m, 2H), 2.33-2.27(m, 2H), 2.19(br dd, J=5.6, 11.6Hz, 2H), 2.10(br d, J=6.4Hz, 2H), 2.07-1.94(m, 7H); LCMS (ESI, M+1): m / z=661.3.

[0192] Example 28 [ka] 3-Cyanophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0193] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid 8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.00 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0194] Step B. 3-Cyanophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate A mixture of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3-hydroxybenzonitrile (31.9 mg, 3.0 equivalents) / DCM (2.00 mL) was mixed with DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water(FA)-ACN]; gradient: 25%~55%B 10 min], and then purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water(FA)-ACN]; gradient: 37%~67%B 9 min] to obtain the title compound (7.3 mg, 11% yield) as a yellow solid; 1H NMR (400MHz, DMSO-d6) δ=10.23(br s, 1H), 9.18(s, 1H), 8.20(br d, J=8.4Hz, 1H), 7.95(d, J=8.0Hz, 1H), 7.81-7.73(m, 3H), 7.70-7.63(m, 2H), 7.62-7 .54(m, 2H), 7.32(s, 1H), 4.57(s, 2H), 3.28-3.16(m, 4H), 2.27-1.97(m, 13H), 1.23(br s, 2H), 1.05 (t, J=7.2Hz, 2H); LCMS (ESI, M+1): m / z =661.4.

[0195] Example 29 [ka] 4-Cyanophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0196] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid 8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.0 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LC-MS (ESI, M+1): m / z = 560.3

[0197] Step B. 4-Cyanophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate A mixture of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 4-hydroxybenzonitrile (31.9 mg, 3.0 equivalents) / DCM (2.00 mL) was mixed with DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 36%~66%B for 9 minutes] to obtain the title compound (20.3 mg, 33% yield) as an off-white solid; 1 H NMR (400MHz, DMSO-d6) δ=10.24(br s, 1H), 9.18(s, 1H), 8.20(br d, J=8.8Hz, 1H), 7.98-7.93(m, 3H), 7.75(d, J=8.0Hz, 1H), 7.66-7.57(m, 2H), 7.42(d, J=8.4Hz, 2H ), 7.32(dd, J=7.6, 13.1Hz, 1H), 4.60-4.53(m, 4H), 3.69-3.45(m, 4H), 2.33-2.22(m, 3H), 2.18(br dd, J=5.6, 11.4Hz, 2H), 2.10(br d, J=6.4Hz, 2H), 2.07-1.93(m, 8H); LCMS (ESI, M+1): m / z=661.3.

[0198] Example 30 [ka] 2,6-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0199] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid 8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.0 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0200] Step B. 2,6-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate A mixture of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,6-difluorophenol (34.8 mg, 3.0 equivalents) / DCM (2.0 mL) was mixed with DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water(FA)-ACN]; gradient: 27%~57%B 10 min] and preparative HPLC [column: Phenomenex luna C18 150x40mmx15μm; mobile phase: [water(TFA)-ACN]; gradient: 35%~65%B 10 min] to obtain the title compound (5.6 mg, 9% yield) as a brown solid; 1H NMR (400MHz, DMSO-d6) δ=10.21(br s, 1H), 9.19(s, 1H), 8.20(br d, J=8.4Hz, 1H), 7.95(d, J=8.0Hz, 1H), 7.76(t, J=7.6Hz, 1H), 7.67-7.56(m, 2H) , 7.45-7.37(m, 1H), 7.36-7.28(m, 3H), 4.61-4.51(m, 4H), 3.43(s, 2H), 3.22(br dd, J=4.4, 11.2Hz, 2H), 2.34-2.23(m, 3H), 2.18(br dd, J=6.0, 11.6Hz, 2H), 2.15-2.08(m, 2H), 2.04-1.95(m, 6H), 1.07-1.03(m, 2H); LCMS(ESI, M+1): m / z=672.3.

[0201] Example 31 [ka] 2,2,2-Trifluoroethyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0202] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.00 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0203] Step B. 2,2,2-Trifluoroethyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate A mixture of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,2,2-trifluoroethanol (26.8 mg, 3.0 equivalents) / DCM (2.0 mL) was mixed with DMAP (16.37 mg, 1.5 equivalents) and EDCI (25.69 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 24%~54%B for 10 minutes] to obtain the title compound (16.7 mg, 28% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.09(s, 1H), 8.25(s, 1H), 8.18(br d, J=8.4Hz, 1H), 7.93(d, J=8.4Hz, 1H), 7.79-7.70(m, 1H), 7.66-7.54(m, 2H), 7.31(dd, J=7.6, 13.2Hz, 1H), 4.80(q, J=9.2Hz, 2H), 4.46(br d, J=13.2Hz, 2H), 4.08(s, 2H), 3.52(br t, J=12.0Hz, 2H), 2.97(br s, 3H), 2.61-2.52(m, 2H), 2.17-2.03(m, 2H), 1.95-1.73(m, 8H), 1.65-1.54(m, 2H); LCMS(ESI, M+1): m / z=642.3.

[0204] Example 32 [ka] Pyridine-3-yl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0205] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.0 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LC-MS (ESI, M+1): m / z = 560.3

[0206] Step B. Pyridine-3-yl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate A mixture of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and pyridine-3-ol (25.49 mg, 3.0 equivalents) / DCM (2.0 mL) was mixed with DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 28%~58%B for 10 minutes] to obtain the title compound (27.4 mg, 47% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.19(s, 1H), 8.55-8.45(m, 2H), 8.20(br d, J=8.4Hz, 1H), 7.95(d, J=8.4Hz, 1H), 7.79-7.73(m, 1H), 7.72-7.56(m, 4H), 7.5 2(dd, J=4.8, 8.4Hz, 1H), 7.32(dd, J=7.6, 13.2Hz, 1H), 4.60-4.54(m, 4H), 3.66(br d, J=13.2Hz, 2H), 3.52(br d, J=5.6Hz, 2H), 2.27(br d, J=11.0Hz, 3H), 2.18(br dd, J=5.6, 11.2Hz, 2H), 2.10(br d, J=6.4Hz, 2H), 2.06-1.97(m, 7H); LCMS(ESI, M+1): m / z=637.3.

[0207] Example 33 [ka] 3,5-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0208] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.0 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LC-MS (ESI, M+1): m / z = 560.3

[0209] Step B. 3,5-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,5-difluorophenol (34.9 mg, 3.0 equivalent) / DCM (2.00 mL), DMAP (16.37 mg, 1.5 equivalent) and EDCI (25.69 mg, 1.5 equivalent) were added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 30%~60% B for 10 minutes] to obtain the title compound (8.30 mg, 14% yield) as a yellow solid; 1H NMR (400MHz, DMSO-d6) δ=9.11(s, 1H), 8.31(s, 1H), 8.18(br d, J=8.0Hz, 1H), 7.94(d, J=8.4Hz, 1H), 7.78-7.70(m, 1H), 7.65-7.56(m, 2H), 7.3 1(dd, J=7.6, 13.2Hz, 1H), 7.26-7.18(m, 1H), 7.09(dd, J=2.0, 7.6Hz, 2H), 4.49(br d, J=13.2Hz, 2H), 4.08(s, 2H), 3.64-3.57(m, 2H), 3.19-3.10(m, 2H), 2.96-2.91(m, 2H), 2.21(br dd, J=3.2, 13.2Hz, 2H), 2.05-1.97(m, 2H), 1.93-1.87(m, 2H), 1.78(td, J=6.0, 12.0Hz, 4H), 1.59(br dd, J=7.6, 12.0Hz, 2H), 1.23(br s, 1H); LCMS (ESI, M+1): m / z=672.3.

[0210] Example 34 [ka] 2,3-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0211] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid8-Fluoro-7-(8-Fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.00 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0212] Step B. 2,3-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equivalent) and 2,3-difluorophenol (34.8 mg, 3.0 equivalents) / dichloromethane (2.00 mL), 4-dimethylaminopyridine (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents) were added. The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 28%~58%B for 10 minutes] to obtain the title compound (14.3 mg, 23% yield) as a yellow solid; 1H NMR (400MHz, DMSO-d6) δ=9.12(s, 1H), 8.29(s, 1H), 8.18(br d, J=8.4Hz, 1H), 7.93(d, J=8.0Hz, 1H), 7.78-7.71(m, 1H), 7.66-7.56(m, 2H), 7.48-7.36(m, 1H), 7.35-7.26(m, 2H), 7.22(br dd, J=1.6, 6.8Hz, 1H), 4.50(br d, J=13.6Hz, 2H), 4.08(s, 2H), 3.64-3.56(m, 2H), 3.26-3.21(m, 1H), 2.97-2.91(m, 2H), 2.24(br d, J=10.4Hz, 2H), 2.09-1.72(m, 10H), 1.59(br dd, J=7.6, 12.0Hz, 2H); LCMS(ESI, M+1): m / z=672.3.

[0213] Example 35 [ka] 2-Fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0214] Step A. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid8-Fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4A molecular sieve (100 mg) / DMF (3.00 mL) were mixed with K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl). The reaction mixture was stirred at 60°C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined and dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to obtain the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0215] Step B. 2-Fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2-fluorophenol (30.0 mg, 3.0 equivalents) / dichloromethane (2.0 mL), DMAP (16.4 mg, 1.5 equivalents) and EDCI (25.7 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 250x50mmx15μm; mobile phase: [water (FA)-ACN]; gradient: 38%~68%B for 9 minutes] to obtain the title compound (11.2 mg, 19% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.12(s, 1H), 8.35(s, 1H), 8.18(br d, J=8.2Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.77-7.72(m, 1H), 7.64(dd, J=0.8, 7.2Hz, 1H), 7.59(br dd, J=2.8, 8.0Hz, 1H), 7.40-7.26(m, 5H), 4.49(br d, J=13.6Hz, 2H), 4.08(s, 2H), 3.64-3.58(m, 2H), 3.21(br s, 2H), 2.96-2.90(m, 2H), 2.27-2.21(m, 2H), 1.99(br d, J=10.8Hz, 2H), 1.93-1.87(m, 2H), 1.79(br dd, J=5.2, 11.2Hz, 4H), 1.62-1.55(m, 2H), 1.23(br s, 1H); LCMS(ESI, M+1): m / z=654.3.

[0216] Example 36 [ka] 3,4-Difluorophenyl (3S,4S)-1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-Hydroxypiperidine-4-carboxylate

[0217] Example 37 [ka] 3,4-Difluorophenyl (3R,4R)-1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-Hydroxypiperidine-4-carboxylate [ka]

[0218] Step A. Ethyl 3-oxopiperidine-4-carboxylate:To a solution of 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (40.0 g, 1.0 equivalent) / MeOH (150 mL), HCl·MeOH (4 M, 250 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the title compound (40.0 g, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 172.3.

[0219] Step B. 1-Benzyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate: To a mixture of ethyl 3-oxopiperidine-4-carboxylate (30.0 g, 1.0 equivalent) and CbzCl (35.9 g, 1.2 equivalents) / DCM (300 mL), TEA (88.7 g, 5.0 equivalents) was added at 0°C. The reaction mixture was stirred at 20°C for 2 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were washed together with brine (500 mL), dried over Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 20 / 1~5 / 1] to obtain the title compound (23.0 g, 43% yield) as a colorless oil; 1 H NMR (400MHz, chloroform-d) δ=12.09(s, 1H), 7.39-7.32(m, 5H), 5.16(s, 2H), 4.24(q, J=7.2Hz, 2H), 4.12(br s, 2H), 3.58(t, J=5.6Hz, 2H), 2.36(br s, 2H), 1.31(t, J=7.2Hz, 3H).

[0220] Step C. 1-Benzyl 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate: To a solution of 1-benzyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (10.0 g, 1.0 equivalent) / THF (100 mL), NaBH4 (1.95 g, 1.6 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with saturated NH4Cl (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were washed together with saline solution (100 mL), dried over Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1] to obtain the title compound (4.60 g, 46% yield) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ=7.40-7.28(m, 5H), 5.14(br s, 2H), 4.36-4.09(m, 5H), 3.04(br s, 1H), 2.97-2.84(m, 1H), 2.56(br d, J=10.4Hz, 1H), 2.21-2.01(m, 1H), 1.87-1.70(m, 1H), 1.28(t, J=7.2Hz, 3H); LCMS(ESI, M+1): m / z=308.3.

[0221] Step D. 1-Benzyl 4-ethyl (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylate and 1-Benzyl 4-ethyl (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylate: The residue was purified by SFC [column: DAIEL CHIRALPAK IG (250mm x 30mm, 10μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode] to obtain the title compound (1.50g, 33% yield) and (1.50g, 33% yield).

[0222] Step E. Ethyl (3R,4R)-3-hydroxypiperidine-4-carboxylate: To a solution of 1-benzyl 4-ethyl (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylate (700 mg, 1.0 equivalent) / ethyl acetate (8.00 mL), Pd / C (1.00 g, 10% purity) was added under an N2 atmosphere. The reaction mixture was degassed and purged three times with H2. The reaction mixture was stirred at 25°C for 4 hours under H2 (50 psi). The mixture was filtered and concentrated to obtain the title compound (300 mg, crude) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d): δ=4.18 (q, J=7.2Hz, 2H), 4.07 (br s, 1H), 3.13-3.04 (m, 2H), 2.80-2.66 (m, 3H), 2.59 (dt, J=2.8, 12.4Hz, 1H), 2.54-2.47 (m, 1H), 2.02-1.88 (m, 1H), 1.71 (br dd, J=3.6, 13.2Hz, 1H), 1.27 (t, J=7.2Hz, 3H).

[0223] Step F. Ethyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate:8-Fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equivalent) and K3PO4 (240 mg, 3.0 equivalent) / DMF (3.00 mL) were mixed with ethyl (3R,4R)-3-hydroxypiperidine-4-carboxylate (261 mg, 4.0 equivalent) and 4A molecular sieve (50.0 mg). The reaction mixture was stirred at 60°C for 2 hours. The mixture was filtered and purified by preparative HPLC [FA conditions] to obtain the title compound (180 mg, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 604.3.

[0224] Step G. (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylic acid: To a solution of ethyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate (90.0 mg, 1.0 equivalent) / THF (1.50 mL), NaOH (2 M, 224 μL, 3.0 equivalents) was added. The reaction mixture was stirred at 25°C for 3 hours. The mixture was adjusted to pH 6. The mixture was washed with ethyl acetate (2 x 20.0 mL). The aqueous layer was freeze-dried to obtain the title compound (60.0 mg, crude) as an off-white solid; LCMS (ESI, M+1): m / z = 576.3.

[0225] Step H. 3,4-Difluorophenyl (3R,4R)-1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-Hydroxypiperidine-4-carboxylate:(3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,4-difluorophenol (33.9 mg, 3.0 equivalents) / DCM (1.00 mL) were mixed with DMAP (15.9 mg, 1.5 equivalents) and EDCI (25.0 mg, 1.5 equivalents). The reaction mixture was stirred at 20°C for 4 hours. The mixture was diluted with water (20.0 mL) and extracted with DCM (2 x 20 mL). The organic layers were washed together with saline solution (20.0 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water(FA)-ACN]; gradient: 19%~49%B for 10 minutes] to obtain the title compound (Example 36, 2.00 mg, 3.2% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.26(d, J=7.2Hz, 1H), 8.30(br d, J=4.4Hz, 1H), 8.18(br d, J=8.0Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.74(t, J=7.6Hz, 1H), 7.67-7.61(m, 1H), 7.60-7.54 (m, 1H), 7.54-7.47(m, 1H), 7.38-7.28(m, 2H), 7.08-7.00(m, 1H), 4.71-4.54(m, 2H), 4.47(br s, 1H), 4.09(s, 2H), 3.74(br dd, J=4.8, 13.6Hz, 2H), 3.29-3.17(m, 3H), 3.02-2.91(m, 2H), 2.56(br d, J=9.6Hz, 2H), 2.30(br d, J=13.2Hz, 1H), 1.91(br dd, J=6.0, 11.6Hz, 3H), 1.82-1.75(m, 3H), 1.63-1.56(m, 2H); LCMS(ESI, M+1): m / z=688.3.

[0226] Step I. Ethyl (3S,4S)-3-hydroxypiperidine-4-carboxylate:To a solution of 1-benzyl 4-ethyl (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylate (700 mg, 1.0 equivalent) / siRNA (8.00 mL), Pd / C (1.00 g) was added under an N2 atmosphere. The reaction mixture was degassed and purged three times with H2. The reaction mixture was stirred at 25°C for 4 hours under H2 (50 psi). The mixture was filtered and concentrated to obtain the title compound (300 mg, crude) as a yellow solid; 1 H NMR (400MHz, chloroform-d) δ=4.15(q, J=7.2Hz, 2H), 4.05(br s, 1H), 3.06(td, J=3.2, 12.8Hz, 2H), 2.78(br s, 2H), 2.67(dd, J=1.6, 13.2Hz, 1H), 2.56(dt, J=2.8, 12.4Hz, 1H), 2.51-2.41( m, 1H), 1.92 (dq, J=4.4, 12.8Hz, 1H), 1.74-1.64 (m, 1H), 1.24 (t, J=7.2Hz, 3H).

[0227] Step J. Ethyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate: 8-Fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equivalent) and K3PO4 (300 mg, 3.0 equivalent) / DMF (3.00 mL) were mixed with ethyl (3S,4S)-3-hydroxypiperidine-4-carboxylate (245 mg, 3.0 equivalent) and 4A molecular sieve (50.0 mg). The reaction mixture was stirred at 60°C for 2 hours. The mixture was filtered and purified by preparative HPLC [FA conditions] to obtain the title compound (220 mg, 77% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 604.3.

[0228] Step K. (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylic acid:To a solution of ethyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate (90.0 mg, 1.0 equivalent) / THF (1.50 mL), NaOH (2 M, 224 μL, 3.0 equivalents) was added. The reaction mixture was stirred at 25°C for 3 hours. The mixture was adjusted to pH 6. The mixture was washed with ethyl acetate (2 x 20.0 mL). The aqueous layer was freeze-dried to obtain the title compound (60.0 mg, crude) as an off-white solid; LCMS (ESI, M+1): m / z = 576.3.

[0229] Step L. 3,4-Difluorophenyl (3S,4S)-1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-Hydroxypiperidine-4-carboxylate: (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,4-difluorophenol (33.9 mg, 3.0 equivalent) / DCM (1.00 mL) were mixed with DMAP (15.9 mg, 1.5 equivalent) and EDCI (25.0 mg, 1.5 equivalent). The reaction mixture was stirred at 20°C for 4 hours. The mixture was diluted with water (20.0 mL) and extracted with DCM (2 x 20 mL). The organic layers were washed together with saline solution (20.0 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water(FA)-ACN]; gradient: 19%~49%B for 10 minutes] to obtain the title compound (Example 37, 2.00 mg, 3.2% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.27(d, J=7.2Hz, 1H), 8.27(br s, 1H), 8.19(br d, J=8.4Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.75(t, J=8.0Hz, 1H), 7.64(dd, J=7.6, 12.0Hz, 1H), 7.61- 7.56(m, 1H), 7.55-7.48(m, 1H), 7.39-7.29(m, 2H), 7.09-7.00(m, 1H), 4.73-4.55(m, 2H), 4.48(br s, 1H), 4.11(s, 2H), 3.74(br dd, J=4.8, 13.2Hz, 2H), 3.36-3.18(m, 3H), 3.01-2.93(m, 2H), 2.64-2.54(m, 2H), 2.31(br d, J=13.2Hz, 1H), 1.97-1.87(m, 3H), 1.81(br dd, J=6.0, 11.2Hz, 3H), 1.65-1.56(m, 2H); LCMS (ESI, M+1): m / z=688.3.

[0230] Example 38 [ka] 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carbaldehyde [ka]

[0231] Step A. (1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanol8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equivalent) and piperidine-4-ylmethanol (65.1 mg, 3.0 equivalents) / DMF (1.00 mL) were mixed with 4A molecular sieve (20.0 mg) and DIEA (73.1 mg, 3.0 equivalents). The reaction mixture was stirred at 50°C for 12 hours. The mixture was purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; mobile phase: [water (FA)-ACN]; gradient: 17%~47%B for 10 minutes] to obtain the title compound (60.0 mg, 56% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 546.3.

[0232] Step B. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carbaldehyde To a solution of (1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanol (50.0 mg, 1.0 equivalent) / DCM (1.00 mL), Dess-Martin reagent (77.7 mg, 2.0 equivalents) was added. The reaction mixture was stirred at 20°C for 2 hours. The mixture was quenched with Na2SO3 (20.0 mL, 0°C) and extracted with ethyl acetate (3 x 20.0 mL). The organic layers were washed together with saline solution (20.0 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Waters Xbridge 150x25mmx5μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; gradient: 31%~61% B for 9 minutes] to obtain the title compound (5.60 mg, 11% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.67(s, 1H), 9.08(s, 1H), 8.18(br d, J=7.6Hz, 1H), 7.93(d, J=8.0Hz, 1H), 7.78-7.70(m, 1H), 7.66-7.55(m, 2H), 7.31(br dd. s, 2H), 2.15-2.02(m, 2H), 1.94-1.71(m, 9H), 1.60-1.53(m, 2H); LCMS(ESI, M+1): m / z=544.3.

[0233] Example 39 [ka] Phenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0234] Step A. Phenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylateA mixture of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (230 mg, 1.0 equivalent) and phenol (65.0 mg, 2.0 equivalents) / DCM (2.0 mL) was mixed with DMAP (63.3 mg, 1.5 equivalents) and EDCI (99.3 mg, 1.5 equivalents). The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (170 mg, 65.7% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 742.4.

[0235] Step B. Phenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of phenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (150 mg, 1.0 equivalent) / MeCN (1.0 mL), HCl·dioxane (4 M, 39 equivalents) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated. The residue was diluted with water (2.0 mL). The mixture was adjusted to pH=7 with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (3 x 5.0 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA); B: ACN, B%: 25%~55% for 8 minutes] to obtain the title compound (103 mg, 66% yield, 0.33 HCOOH) as a white solid; 1¹H NMR (400MHz, dimethyl sulfoxide-d6) δ = 10.12-9.77 (m, 1H), 9.12 (s, 1H), 7.77 (dd, J=6.0, 9.2Hz, 1H), 7.51-7.39 (m, 2H), 7.38-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.20-7.13 (m, 2H), 7.03 (d, J=2 .4Hz, 1H), 5.42-5.20(m, 1H), 4.60-4.43(m, 2H), 4.19(dd, J=4.4, 10.4Hz, 1H), 4.14-4.05( m, 1H), 3.70-3.53(m, 2H), 3.20-3.04(m, 4H), 2.93-2.80(m, 1H), 2.41-2.31(m, 1H), 2.23(br d, J=10.4Hz, 2H), 2.19-2.07(m, 3H), 2.06-1.92(m, 3H), 1.91-1.75(m, 3H), 0.73(t, J=7.2Hz, 3H); LCMS(ESI, M+1): m / z=698.3.

[0236] Example 40 [ka] 3,4-Difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0237] Step A. Methyl 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:Methyl piperidine-4-carboxylate (408 mg, 0.80 equivalents) was added at -40°C to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (900 mg, 1.0 equivalent) and DIEA (921 mg, 2.0 equivalents) / DCM (18.0 mL). The reaction mixture was stirred at -40°C for 0.5 hours. The mixture was diluted with water (30.0 mL) and extracted with DCM (2 x 20 mL). The organic layers were dried together over sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain the title compound (600 mg, 42% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 359.1.

[0238] Step B. Methyl 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate: To a solution of methyl 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) / DMSO (0.5 mL), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (665 mg, 3.0 equivalents) was added. The mixture was stirred at 100°C for 3 hours. The mixture was filtered and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (600 mg, 88% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 482.2.

[0239] Step C. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:To a mixture of methyl 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (561 mg, 1.5 equivalent) / methoxycyclopentane (9.0 mL) and water (3.0 mL), [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphine methanesulfonate (75.5 mg, 0.10 equivalent) and Cs2CO3 (1.01 g, 3.0 equivalent) were added. The reaction mixture was degassed and purged three times with nitrogen. The reaction mixture was stirred at 90°C for 5 hours. The mixture was filtered, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (650 mg, 90% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 680.5.

[0240] Step D. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid: Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) / water (1.5 mL) and THF (4.5 mL) were mixed with NaOH (2 M aqueous solution, 4.0 equivalents). The reaction mixture was stirred at 25°C for 2 hours. The mixture was adjusted to pH=7 with HCl (2 M) and extracted with ethyl acetate (3 x 10 mL). The organic layers were dried together over sodium sulfate, filtered, and concentrated to obtain the title compound (480 mg, 96% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 666.3.

[0241] Step E. 3,4-Difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:To a mixture of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equivalent) and 3,4-difluorophenol (78.2 mg, 2.0 equivalents) / DCM (2 mL), DMAP (55.1 mg, 1.5 equivalents) and EDCI (86.4 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (200 mg, 81% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 778.4.

[0242] Step F. 3,4-Difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate: 3,4-difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (100 mg, 1.0 equivalent) / MeCN (0.5 mL) was mixed with HCl·dioxane (4 M, 31 equivalents). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated. The residue was diluted with water (2.0 mL). The mixture was adjusted to pH=7 with saturated NaHCO3 aqueous solution and extracted with ethyl acetate (3 x 5.0 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA); B: ACN, B%: 28%~58% 10 minutes] to obtain the title compound (42.6 mg, 41% yield, 0.28 HCOOH) as a white solid; 1¹H NMR (400MHz, dimethyl sulfoxide-d6) δ = 10.19-9.69 (m, 1H), 9.10 (s, 1H), 7.77 (dd, J=6.0, 9.2Hz, 1H), 7.59-7.50 (m, 1H), 7.49-7.41 (m, 1H), 7.39-7.27 (m, 2H), 7.11-7.05 (m, 1H), 7.03 (d, J=2.4Hz, 1H), 5.45-5.14 (m, 1H), 4.62-4.43 (m, 2H), 4.16 (dd , J=4.0, 10.4Hz, 1H), 4.10-4.02(m, 1H), 3.69-3.54(m, 2H), 3.16-2.99(m, 4H), 2.87-2.76(m, 1H), 2.43-2.30(m, 1H), 2.2 6-2.17(m, 2H), 2.17-2.08(m, 2H), 2.08-1.92(m, 4H), 1.90-1.72(m, 3H), 0.80-0.65(m, 3H); LCMS(ESI, M+1): m / z=734.2.

[0243] Example 41 [ka] Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0244] Step A: Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.1 mg, 1.0 equivalent) and methyl piperidine-4-carboxylate (27.0 mg, 2.0 equivalents) / DMF (1 mL) were mixed with N-ethyl-N,N-diisopropylamine (73.2 mg, 6.0 equivalents) and 4A molecular sieve (10.0 mg). The reaction mixture was stirred at 50°C for 16 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layers were washed together with saline solution (2 x 15 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150 x 25 mm x 10 μm; A: water (FA), B: ACN, B%: 22%~52% for 7 minutes] to obtain the title compound (11.4 mg, 20% yield, 0.6 HCCOH) as a white solid; 1 ¹H NMR (400MHz, methanol-d4) δ=9.08 (s, 1H), 8.12 (br d, J=8.4Hz, 1H), 7.86 (d, J=8.4Hz, 1H), 7.76-7.66 (m, 1H), 7.65-7.58 (m, 1H), 7.54 (dt, J=5.2, 8.0Hz, 1H), 7.19 (dd, J=7.6, 13.2Hz, 1H), 4.62 (br d, J=13.6Hz, 2H), 4.52(s, 2H), 3.79-3.70(m, 3H), 3.69-3.60(m, 2H), 3.50-3.42(m, 2H), 3.12-3. 02(m, 2H), 2.92-2.83(m, 1H), 2.28-2.02(m, 8H), 2.02-1.90(m, 4H); LCMS(ESI, M+1): m / z=574.5.

[0245] Example 42 [ka] 4-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0246] Step A. 4-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (45.0 mg, 1.0 equivalent) and 4-(trifluoromethyl)phenol (39.1 mg, 3.0 equivalents) / DCM (5 mL), 4-dimethylaminopyridine (19.7 mg, 2.0 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30.8 mg, 2.0 equivalents) were added. The reaction mixture was stirred at 40°C for 16 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm, A: water (FA), B: ACN, B%: 35%~65% for 7 minutes] to obtain the title compound (23.5 mg, 39% yield, 0.1 HCOOH) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.18(s, 1H), 8.20(br d, J=8.4Hz, 1H), 7.95(d, J=8.0Hz, 1H), 7.84(d, J=8.8Hz, 2H), 7.79-7.72(m, 1H), 7.67-7. 56(m, 2H), 7.43(d, J=8.4Hz, 2H), 7.32(dd, J=7.2, 13.2Hz, 1H), 4.64-4.46(m, 4H), 3.64(br t, J=12.4Hz, 2H), 3.51-3.40(m, 2H), 3.24-3.10(m, 3H), 2.26(br d, J=10.4Hz, 2H), 2.15(br dd, J=6.0, 12.0Hz, 2H), 2.09-1.91(m, 8H); LCMS(ESI, M+1): m / z=704.4.

[0247] Example 43 [ka] 3,4-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0248] Step A. 3,4-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,4-difluorophenol (34.9 mg, 3.0 equivalents) / DCM (3 mL), 4-dimethylaminopyridine (21.8 mg, 2.0 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (34.3 mg, 2.0 equivalents) were added. The reaction mixture was stirred at 35°C for 16 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 32%~62% for 7 minutes] to obtain the title compound (21.5 mg, 33% yield) as a yellow solid; 1H NMR (400MHz, DMSO-d6) δ=9.17(s, 1H), 8.20(br d, J=8.4Hz, 1H), 7.94(d, J=8.4Hz, 1H), 7.82-7.72(m, 1H), 7.66-7.62(m, 1H), 7.61-7.56(m, 1H), 7.55-7.48(m, 1H) , 7.48-7.41(m, 1H), 7.32(dd, J=7.6, 13.2Hz, 1H), 7.12-7.04(m, 1H), 4.62-4.41(m, 4H), 3.69-3.57(m, 2H), 3.38(br s, 2H), 3.18-3.04(m, 3H), 2.23(br d, J=10.4Hz, 2H), 2.13(br dd, J=6.4, 11.6Hz, 2H), 2.08-1.88(m, 8H); LCMS(ESI, M+1): m / z=672.2.

[0249] Example 44 [ka] Phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate [ka]

[0250] Step A. Phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylateTo a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and phenol (25.2 mg, 3.0 equivalents) / DCM (5 mL), 4-dimethylaminopyridine (21.8 mg, 2.0 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (34.3 mg, 2.0 equivalents) were added. The reaction mixture was stirred at 40°C for 16 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 30%~50% for 10 minutes] to obtain the title compound (2.07 mg, 3.6% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.19(s, 1H), 8.21-8.17(m, 1H), 7.98-7.89(m, 1H), 7.81-7.70( m, 1H), 7.68-7.56(m, 2H), 7.50-7.39(m, 2H), 7.36-7.25(m, 2H), 7.17(d, J=8.0Hz, 2H), 4. 60-4.44(m, 2H), 4.28-4.15(m, 2H), 3.66-3.57(m, 2H), 3.15-3.04(m, 3H), 2.80-2.68(m, 2 LCMS (ESI, M+1): m / z=636.5.

[0251] Example 45 [ka] Methyl (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate [ka]

[0252] Step A. Methyl 3-oxopiperidine-4-carboxylate To a solution of 1-(tert-butyl) 4-methyl 3-oxopiperidine-1,4-dicarboxylate (2.00 g, 1.0 equivalent) / ACN (20 mL), HCl·dioxane (4 M, 1.94 mL, 1.0 equivalent) was added. The reaction mixture was stirred at 0°C for 1 hour. The mixture was concentrated to obtain the title compound (1.20 g, crude) as a white oily substance.

[0253] Step B. 1-Benzyl 4-methyl 3-oxopiperidine-1,4-dicarboxylate To a solution of methyl 3-oxopiperidine-4-carboxylate (1.20 g, 1.0 equivalent) and benzyl carbonochloride (1.56 g, 1.2 equivalents) in THF (12 mL), TEA (1.08 g, 1.4 equivalents) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 250 x 50 mm x 10 μm; A: water (FA), B: ACN, B%: 38%~68%B, 21 minutes) to obtain the title compound (1.27 g, 57% yield) as a red oil; LCMS (ESI, M+1): m / z = 292.2.

[0254] Step C. 1-Benzyl 4-methyl 3-hydroxypiperidine-1,4-dicarboxylate To a solution of 1-benzyl 4-methyl 3-oxopiperidine-1,4-dicarboxylate (1.00 g, 1.0 equivalent) / EtOH (10 mL), NaBH4 (64.9 mg, 0.5 equivalent) was added at 0°C. The reaction mixture was stirred at 0°C for 5 minutes. The mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layers were dried together over sodium sulfate, concentrated, and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (500 mg, 44% yield) as a colorless oil; LCMS (ESI, M+1): m / z = 293.9.

[0255] Step D. Methyl 3-hydroxypiperidine-4-carboxylateTo a solution of 1-benzyl 4-methyl 3-hydroxypiperidine-1,4-dicarboxylate (500 mg, 1.0 equivalent) / isopropanol (5 mL), Pd / C (100 mg, 10% purity) was added. The reaction mixture was degassed and purged three times with H2. The reaction mixture was stirred at 25°C for 1 hour under H2 (15 psi). The mixture was filtered and concentrated to obtain the title compound (270 mg, crude) as a yellow oil.

[0256] Step E. Methyl (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate To a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equivalents) / DMF (1 mL), DIEA (164 mg, 5.0 equivalents) and 8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (135 mg, 1.0 equivalent) were added. The reaction mixture was stirred at 40°C for 12 hours. The mixture was filtered and purified by preparative HPLC [column: Phenomenex luna C18 150x40mmx15μm; A: water (FA), B: ACN, B%: 12%~42%B, 11 mins] and SFC separation [column: CHIRALPAK IH, 250x50mm, 10μm; A: CO2, B: MeOH (0.1% NH3H2O), B%: 40%~40%B, 5.1 mins] to obtain the title compound (1.39 mg, 0.86% yield) as a yellow solid; 1H NMR (400MHz, methanol-d4) δ=9.12(s, 1H), 8.12(br d, J=8.4Hz, 1H), 7.86(d, J=8.0Hz, 1H), 7.75-7.66(m, 1H), 7.63-7.49(m, 2H), 7.19(dd, J=7.6, 12.8Hz, 1H), 4.63(br d, J=4.4Hz, 1H), 4.55-4.49(m, 1H), 4.41(s, 2H), 4.15-4.06(m, 1H), 3.75(s, 3H), 3.69-3.58(m, 1H), 3.50-3.34(m, 2H), 2 .96-2.84(m, 2H), 2.74(ddd, J=4.4, 8.8, 10.8Hz, 1H), 2.25-2.13(m, 3H), 2.08-1.80(m, 8H); LCMS(ESI, M+1): m / z=590.5.

[0257] Example 46 [ka] Methyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate

[0258] Example 47 [ka] Methyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate [ka]

[0259] Step A. Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate and methyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-cis-hydroxypiperidine-4-carboxylateTo a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equivalents) / DMF (1 mL), DIEA (164 mg, 5.0 equivalents) and 8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (135 mg, 1.0 equivalent) were added. The reaction mixture was stirred at 40°C for 12 hours. The mixture was filtered and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 18%~48%B 9 minutes] and SFC separation [column: DAISEL CHIRALCEL OX, 250x30mm, 10μm; A: CO2, B: MeOH (0.1% NH3H2O), B%: 50%~50%B 3.7 minutes] to obtain two isomers.

[0260] Methyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate (Example 46, 3.42 mg, 2.0% yield, HCOOH salt) was obtained as an off-white solid; SFC: 94.4% ee. Column: Lux 3 μm Cellulose-4 50x4.6 mm ID, 3 μm, mobile phase 40% (MeOH:ACN=4:1) (0.05% DEA), flow rate: 3 mL / min, detector: 220 nm, t R :2.211 minutes; 1H NMR (400MHz, methanol-d4) δ=9.24(d, J=11.2Hz, 1H), 8.11(br d, J=8.0Hz, 1H), 7.92-7.79(m, 1H), 7.73-7.66(m, 1H), 7.64-7.48(m, 2H), 7.26-7.13(m, 1H), 4.82(br d, J=2.4Hz, 1H), 4.74(br d, J=13.6Hz, 1H), 4.45(br s, 1H), 4.41-4.35(m, 2H), 3.76-3.66(m, 4H), 3.28-3.21(m, 2H), 2.98-2.80(m, 3H), 2 .44-2.28(m, 1H), 2.20-2.10(m, 2H), 2.07-1.76(m, 8H); LCMS(ESI, M+1): m / z=590.6;

[0261] Methyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-hydroxypiperidine-4-carboxylate (Example 47, 6.40 mg, 4.1% yield, HCOOH salt) was obtained as a white solid; SFC: 94.4% ee. Column: Lux 3um cellulose-4 50x4.6mm ID, 3μm, mobile phase 40% (MeOH:ACN=4:1) (0.05%DEA), flow rate: 3mL / min, detector: 220nm, t R :2.719 minutes; 1 ¹H NMR (400MHz, methanol-d4) δ=9.25 (d, J=11.2Hz, 1H), 8.11 (br d, J=8.4Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.73-7.67 (m, 1H), 7.63-7.49 (m, 2H), 7.19 (dd, J=7.6, 13.2Hz, 1H), 4.83-4.78 (m, 1H), 4.74 (br d, J=13.6Hz, 1H), 4.49-4.36(m, 3H), 3.77-3.65(m, 4H), 3.29-3.25(m, 1H), 2.98-2.85(m, 3H), 2.44 -2.28(m, 1H), 2.23-2.12(m, 2H), 2.11-1.93(m, 6H), 1.92-1.82(m, 3H); LCMS(ESI, M+1): m / z=590.5.

[0262] Example 48 [ka] 3,4-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalene-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate [ka]

[0263] Step A: 1-Benzyl 4-ethyl 5-hydroxyazepan-1,4-dicarboxylate 1-Benzyl 4-ethyl 5-oxoazepan-1,4-dicarboxylate (11.0 g, 1.0 equivalent) / THF (110 mL) solution was mixed with NaBH4 (1.39 g, 1.1 equivalent) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched at 0°C with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3 x 80 mL). The organic layers were washed together with saline solution (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1] to obtain the title compound (5.00 g, 44% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6)δ=7.37-7.27(m, 5H), 5.06(s, 2H), 4.81-4.72(m, 1H), 4.11-3.95(m, 2H), 3.57-3.37(m, 3H), 3.33 -3.21(m, 1H), 2.47-2.40(m, 1H), 2.11-1.99(m, 1H), 1.95-1.77(m, 2H), 1.75-1.61(m, 1H), 1.17(dt, J=2.4, 7.2Hz, 3H).

[0264] Step B: 1-Benzyl 4-ethyl 5-((methylsulfonyl)oxy)azepan-1,4-dicarboxylateTo a solution of 1-benzyl 4-ethyl 5-hydroxyazepan-1,4-dicarboxylate (7.00 g, 1.0 equivalent) / DCM (70 mL), TEA (6.61 g, 9.1 mL, 3.0 equivalents) and MsCl (6.47 g, 2.6 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was slowly quenched at 0°C with ice water (50 mL). The mixture was diluted with water (20 mL) and extracted with DCM (3 x 50 mL). The organic layers were washed together with saline solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (10.0 g, crude) as a yellow oil; 1 H NMR (400MHz, DMSO-d6) δ=7.38-7.25(m, 5H), 5.33-5.23(m, 1H), 5.07(s, 2H), 4.16- 3.96(m, 2H), 3.57-3.35(m, 4H), 3.13(d, J=3.6Hz, 2H), 3.10-3.05(m, 1H), 2.92(br d, J=10.0Hz, 1H), 2.32-2.22(m, 1H), 2.10-1.90(m, 3H), 1.20-1.14(m, 3H).

[0265] Step C: 1-Benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate 1-Benzyl 4-ethyl 5-((methylsulfonyl)oxy)azepan-1,4-dicarboxylate (9.00 g, 1.0 equivalent) / THF (90 mL) was mixed with DBU (6.86 g, 2.0 equivalent). The reaction mixture was stirred at 80°C for 1 hour. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were washed together with saline solution (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1~3 / 1] to obtain the title compound (4.00 g, 54% yield) as a yellow oil; 1 H NMR (400MHz, DMSO-d6)δ=7.40-7.27(m, 5H), 7.02(br d, J=1.6Hz, 1H), 5.10(s, 2H), 4.10(q, J=7.2Hz, 2H), 3.51(br s, 4H), 2.64-2.58(m, 2H), 2.44(br d, J=5.2Hz, 2H), 1.21(t, J=7.2Hz, 3H).

[0266] Step D: Ethyl azepane-4-carboxylate To a solution of 1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (3.00 g, 1.0 equivalent) / THF (50 mL), Pd / C (700 mg, 10% purity) was added. The reaction mixture was degassed and purged three times with H2. The reaction mixture was stirred at 40°C under H2 (50 psi) for 6 hours. The mixture was filtered and concentrated to obtain the title compound (1.50 g, 88% yield) as a yellow oil; 1 H NMR (400MHz, DMSO-d6) δ=4.03(q, J=7.2Hz, 2H), 2.83-2.71(m, 2H), 2.71-2.58(m, 2H), 2.57- 2.52(m, 1H), 1.91-1.79(m, 2H), 1.72-1.57(m, 3H), 1.54-1.39(m, 1H), 1.16(t, J=7.2Hz, 3H).

[0267] Step E: 8-Fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.0 equivalent) and 4A molecular sieve (1.00 g) / DMF (20 mL), K3PO4 (731 mg, 1.8 equivalents) and ethyl azepane-4-carboxylate (1.61 g, 5.0 equivalents) were added. The reaction mixture was stirred at 50°C for 1 hour. The mixture was filtered, concentrated, and purified with a reverse-phase flush [water (0.1% FA) / ACN] to obtain the title compound (730 mg, 61% yield) as a yellow solid; 1H NMR (400MHz, DMSO-d6) δ=9.15(s, 1H), 8.17(br d, J=8.4Hz, 1H), 7.97-7.91(m, 1H), 7.77-7.70(m, 1H), 7.66-7.53(m, 2H), 7.35-7.26(m, 1H), 4.19-4.08(m, 2H), 4.06 -4.03(m, 3H), 3.95-3.83(m, 2H), 2.99-2.87(m, 2H), 2.68-2.60(m, 1H), 2.57-2.52(m, 2H), 2.29-2.17(m, 1H), 2.07(br d, J=11.6Hz, 2H), 1.98-1.84(m, 5H), 1.83-1.65(m, 5H), 1.56(td, J=7.2, 12.0Hz, 2H), 1.16-1.12(m, 3H).

[0268] Step F: 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylic acid. To a solution of ethyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate (390 mg, 1.0 equivalent) / THF (4.0 mL) and MeOH (4.0 mL), NaOH solution (648 μL, 2.0 equivalent, 2 M) was added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was quenched with HCl (3 M) and concentrated to obtain the title compound (500 mg, HCl) as a white solid; 1 H NMR (400MHz, DMSO-d6)δ=9.15(s, 1H), 8.53-8.50(m, 1H), 8.54(s, 1H), 8.17-7.76(m, 1H), 7.66-7.55(m, 2H), 7.30(dd, J= 7.6, 12.8Hz, 1H), 4.21-4.08(m, 2H), 3.92-3.82(m, 2H), 2.95-2.87(m, 2H), 2.56-2.53(m, 2H), 2.47-2.36(m, 1H), 1.94(br s, 5H), 1.88(br dd, J=5.6, 12.0Hz, 3H), 1.83-1.69(m, 5H), 1.60-1.52(m, 3H).

[0269] Step G: 3,4-Difluorophenyl 1-(8-Fluoro-7-(8-Fluoronaphthalen-1-yl)-2-((Tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate:To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylic acid (95.0 mg, 1.0 equivalent) and 3,4-difluorophenol (64.6 mg, 3.0 equivalents) / DCM (1.0 mL), DMAP (40.5 mg, 2.0 equivalents) and EDCI (63.5 mg, 2.0 equivalents) were added. The reaction mixture was stirred at 50°C for 1 hour. The mixture was concentrated and purified by preparative HPLC [column: YMC-Actus Triart C18 150x30mmx7μm; mobile phase: [water(FA)-ACN]; gradient: 30%~60%B 10 min] and preparative HPLC [column: YMC-Actus Triart C18 150x30mmx7μm; mobile phase: [water(FA)-ACN]; gradient: 30%~60%B 10 min] to obtain the title compound (19.5 mg, 17% yield, 0.2 HCOOH) as an off-white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.21-9.16(m, 1H), 8.18(br d, J=8.4Hz, 1H), 7.93(d, J=8.4Hz, 1H), 7.77-7.70(m, 1H), 7.67-7.55(m, 2H), 7.49(br d, J=9.2Hz, 1H), 7.42-7.26(m, 2H), 7.05-6.98(m, 1H), 4.31-4.19(m, 2H), 4.13 -4.05(m, 2H), 4.03-3.84(m, 2H), 3.75-3.62(m, 1H), 3.61-3.46(m, 2H), 2.94(br dd, J=3.2, 5.6Hz, 2H), 2.16-2.02(m, 4H), 1.93-1.86(m, 3H), 1.78-1.65(m, 4H), 1.63-1.54(m, 3H); LCMS(ESI, M+1): m / z=686.4.

[0270] Example 49 [ka] Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate [ka]

[0271] Step A. Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate: 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylic acid (50.0 mg, 1.0 equivalent) / dichloromethane (1 mL) solution was mixed with oxalyl chloride (22.1 mg, 2.0 equivalent) and dimethylformamide (6.37 mg, 1.0 equivalent) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The mixture was concentrated. Methanol (27.9 mg, 10.0 equivalents) was added dropwise to the residue at 0°C. The reaction mixture was stirred at 25°C for 4 hours. The mixture was filtered, and the filtrate was separated and subjected to HPLC [YMC-Actus Triart C18 150]. * 30mm * The compound was purified using a 7 μm mobile phase [water (FA)-ACN] with a B% concentration of 23% to 53% for 4 minutes to obtain the title compound (5.79 mg, 11% yield, 0.3 HCOOH) as a white solid. 1H NMR (400MHz, DMSO+D2O) δ=9.12(s, 1H), 8.15(br d, J=8.4Hz, 1H), 7.90(d, J=8.4Hz, 1H), 7.72(br t, J=8.0Hz, 1H), 7.64-7.52(m, 2H), 7.32-7.24(m, 1H), 4.22-4.14(m, 3H), 4.11-4.07(m, 1H), 3.54(br d, J=6.0Hz, 3H), 3.02(br d, J=4.4Hz, 2H), 2.67-2.63(m, 4H), 2.22-2.18(m, 1H), 2.08-2.04(m, 2H), 2.01-1.87(m, 4H), 1.86-1.81(m, 2H), 1.80-1.72(m, 3H), 1.67-1.59(m, 3H); LCMS(ESI, M+1): m / z=588.5

[0272] Example 50 [ka] 4-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate [ka]

[0273] Step A. 4-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylic acid (60.0 mg, 1.0 equivalent) / dichloromethane (1.0 mL), 4-(trifluoromethyl)phenol (50.9 mg, 3.0 equivalent), 4-dimethylaminopyridine (25.6 mg, 2.0 equivalent), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.1 mg, 2.0 equivalent) were added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated and preparatively HPLC [YMC-Actus Triart C18 150].* 30mm * The compound was purified using a 7 μm mobile phase [water (FA)-ACN] with a B% concentration of 33% to 63% for 4 minutes to obtain the title compound (34.9 mg, 46% yield, 0.6 HCOOH) as a white solid. 1 H NMR (400MHz, DMSO+D2O) δ=9.18(s, 1H), 8.16(br d, J=8.0Hz, 1H), 7.91(d, J=8.4Hz, 1H), 7.79-7.71(m, 3H), 7.62-7.54(m, 2H), 7.32-7.24(m, 3H), 4.33-4.25(m, 3H), 4.14(br s, 1H), 4.07-3.91(m, 3H), 3.16(br d, J=4.8Hz, 1H), 3.00-2.96(m, 1H), 2.83-2.79(m, 2H), 2.28-2.12(m, 4H), 2.03-1.95(m, 3H), 1.91(br dd, J=6.0, 12.0Hz, 2H), 1.86-1.78(m, 3H), 1.78-1.72(m, 2H); LCMS(ESI, M+1): m / z=718.3.

[0274] Example 51 [ka] Phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate [ka]

[0275] Step A. Methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylateTo a solution of 8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1 g, 1.0 equivalent) / DMAC (10 mL), K3PO4 (1.20 g, 3.0 equivalent) and methyl piperidine-3-carboxylate (270 mg, 1.0 equivalent) were added. The reaction mixture was stirred at 60°C for 1 hour. The mixture was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (677 mg, 32% yield) as a red solid; LCMS (ESI, M+1): m / z = 574.3.

[0276] Step B. 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylic acid To a solution of methyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate (567 mg, 1.0 equivalent) / EtOH (3 mL) and H2O (1 mL), LiOH·H2O (207 mg, 5.0 equivalents) was added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (300 mg, 48% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.2.

[0277] Step C. Phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylateTo a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylic acid (100 mg, 1.0 equivalent) / DCM (1 mL), phenol (25.2 mg, 1.5 equivalents), EDCI (51.4 mg, 1.5 equivalents), and DMAP (32.8 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 30%~60% for 7 minutes] to obtain the title compound (20.9 mg, 33% yield, HCOOH salt) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.18(d, J=2.4Hz, 1H), 8.19(br d, J=8.0Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.78-7.70(m, 1H), 7.68-7.54(m, 2H), 7.45-7.38(m, 2H), 7.3-7.22(m, 2H), 7.13-7.06(m, 2H), 4.62-4.49(m , 1H), 4.27-4.15(m, 1H), 4.15-4.06(m, 2H), 4.03-3.91(m, 1H), 3.80-3.67 (m, 1H), 3.24-3.16(m, 1H), 2.98-2.88(m, 2H), 2.60-2.55(m, 1H), 2.23(br d, J=7.2Hz, 1H), 2.08-1.70(m, 10H), 1.64-1.53(m, 2H); LCMS(ESI, M+1): m / z=636.4.

[0278] Example 52 [ka] 2-Fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate [ka]

[0279] Step A. Phenyl 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate To a solution of 1-(8-fluoro-7-(8-fluoronaphthalene-1-yl)-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylic acid (50 mg, 1.0 equivalent) / DCM (0.5 mL), 2-fluorophenol (15.0 mg, 1.5 equivalent), EDCI (25.7 mg, 1.5 equivalent), and DMAP (16.4 mg, 1.5 equivalent) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA); B: ACN, B%: 30%~60% for 7 minutes] to obtain the title compound (20.9 mg, 33% yield, HCOOH salt) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=9.11(d, J=4.4Hz, 1H), 8.01(br d, J=7.6Hz, 1H), 7.82-7.71(m, 1H), 7.68-7.58(m, 2H), 7.46(dt, J=4.8, 8.0Hz, 1H), 7.25-7.10(m, 5H), 4.7-4.62(m, 1H), 4.59-4.48(m, 2H), 4.46-4.32(m, 1H), 4.05-3.86(m, 1H), 3.77-3.60(m, 1H), 3.51(br d, J=4.0Hz, 2H), 3.25-3.15(m, 1H), 2.84-2.77(m, 2H), 2.43-2.36(m, 1H), 2.26(br dd, J=6.0, 12.8Hz, 2H), 2.14-1.91(m, 7H), 1.88-1.77(m, 2H); LCMS(ESI, M+1): m / z=654.4.

[0280] Example 53 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0281] Step A. Azocane-4-carboxylic acid: A solution of 1-(tert-butoxycarbonyl)azocane-4-carboxylic acid (300 mg, 1 equivalent) / HCl·dioxane (2 M, 11.7 mL, 20 equivalents) was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was diluted with methanol (2.0 mL) and neutralized with solid NaHCO3. The mixture was filtered, and the filtrate was concentrated to obtain the title compound (180 mg, 88% yield) as a yellow oil; 1 ¹H NMR (400 MHz, methanol-d4) δ 3.39-3.32 (m, 1H), 3.27-3.10 (m, 3H), 2.77-2.64 (m, 1H), 2.15-2.06 (m, 2H), 1.99-1.85 (m, 4H), 1.80-1.67 (m, 2H).

[0282] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-4-carboxylic acid:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetra To a solution of lahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (280 mg, 1.0 equivalent) and azocane-4-carboxylic acid (148 mg, 2.0 equivalents) / DMF (2.5 mL), DIEA (244 mg, 4 equivalents) and 4A molecular sieve (20 mg) were added. The reaction mixture was stirred at 60°C for 2 hours. Azocane-4-carboxylic acid (150 mg, 1.6 equivalents, HCl salt) and DIEA (244 mg, 4.0 equivalents) were added to the resulting mixture. The reaction mixture was stirred at 60°C for 2 hours. The mixture was filtered and purified by reverse-phase flash chromatography [water (0.1% FA) / acetonitrile] to obtain the title compound (260 mg, 82% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 650.4.

[0283] Step C. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphtha Len-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocane-4-carboxylic acid (50 mg, 1 equivalent) and EDCI (22.1 mg, 1.5 equivalents) / DMF (0.5 mL) were mixed with HOBt (12.5 mg, 1.2 equivalents) and TEA (31.1 mg, 4.0 equivalents). The reaction mixture was stirred at 25°C for 12 hours. The mixture was filtered, and the filtrate was separated and purified by HPLC [Phenomenex Luna C18 150x25mmx10μm; A: water (NH4HCO3), B: ACN, B%: 56%~86% for 10 minutes] to obtain the title compound (4.97 mg, 8.5% yield) as a yellow solid; 1 H NMR (400MHz, DMSO-d6)δ 9.97-9.88(m, 1H), 9.21-9.16(m, 1H), 8.25-8.19(m, 1H), 7.81-7.71(m, 1H), 7.38-7.29(m, 2H), 6.98(s, 1H), 6.44-6.38(m, 1H), 5.37-5.13(m, 1H), 4.35-4.07(m, 4H), 4.05-3.97(m, 2H) ), 3.91-3.81(m, 1H), 3.11-2.95(m, 3H), 2.87-2.75(m, 1H), 2.31-2.25(m, 1H), 2.16-2.00(m , 9H), 1.98-1.92(m, 1H), 1.91-1.65(m, 8H), 0.76-0.65(m, 3H); LCMS(ESI, M+1): m / z=714.5.

[0284] Example 54 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-5-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0285] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-5-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (1g, 1.0 equivalent) and methyl To a solution of azocane-5-carboxylate (309 mg, 1.0 equivalent) / DMF (10 mL), DIEA (699 mg, 3.0 equivalents) and PYBOP (1.41 g, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 10 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with saline solution (2 x 2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (700 mg, 52% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 708.4.

[0286] Step B. To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-5-carboxylate (650 mg, 1.0 equivalent) / MeOH (2 mL), HCl·MeOH (4 M, 2.00 mL, 8.7 equivalents) was added. The reaction mixture was stirred at 0°C for 0.5 hours. The mixture was concentrated. The residue was diluted with water (5 mL), neutralized with solid NaHCO3, and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with brine (2 x 2 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (600 mg, 86% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 664.4.

[0287] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-5-carboxylate (550 mg, 1.0 equivalent) / MeOH (6 mL) solution was mixed with LiOH·H2O (2 M, 1.81 mL, 4.4 equivalents). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (390 g, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 650.4.

[0288] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-5-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-5-carboxylic acid (60 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (22.7 mg, 3.0 equivalents) / DMF (0.5 mL) were mixed with HATU (70.2 mg, 2.0 equivalents) and DIEA (35.8 mg, 3.0 equivalents). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by reverse-phase flash chromatography [C18, neutral conditions] to obtain the title compound (14.4 mg, 21% yield) as a white solid; 1 H(400MHz, chloroform-d)δ=9.08(d, J=12.0Hz, 1H), 8.13(d, J=2.8Hz, 1H), 7.58-7.48(m, 1H), 7.22-7.07(m, 3H), 6.25(d, J=2.8Hz, 1H), 5.39-5.17(m, 1H), 4.23(br d, J=3.2Hz, 4H), 4.02-3.78(m, 3H), 3.38-3.09(m, 3H), 3.04-2.93(m, 1H), 2. 61-2.50(m, 1H), 2.27(s, 4H), 2.24-2.04(m, 10H), 2.02-1.83(m, 4H), 0.85(br t, J=6.8Hz, 3H); LCMS (ESI, M+1): m / z=714.5.

[0289] Example 55 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0290] Step A. Ethyl 3-(buta-3-en-1-ylamino)propanoate To a solution of ethyl 3-aminopropanoate hydrochloride (49.5 g, 1.5 equivalents) in ACN (1000 mL), K2CO3 (87.5 g, 3.0 equivalents) was added. The reaction mixture was stirred at 25°C for 1 hour. 4-bromobuta-1-ene (28.5 g, 1.0 equivalent) was added. The reaction mixture was stirred at 45°C for 17 hours. The reaction mixture was concentrated to obtain the title compound (48.3 g, crude) as a colorless oil; 1 ¹H NMR (400MHz, chloroform-d): δ = 5.91-5.64 (m, 1H), 5.16-4.89 (m, 1H), 4.21-3.97 (m, 2H), 3.00-2.75 (m, 2H), 2.66 (t, J=6.8Hz, 1H), 2.56-2.34 (m, 2H), 2.29-2.09 (m, 1H), 1.34-1.14 (m, 3H).

[0291] Step B. Ethyl 3-(buta-3-en-1-yl(tert-butoxycarbonyl)amino)propanoate To a solution of ethyl 3-(buta-3-enylamino)propanoate (43.3 g, 1.0 equivalent) in DCM (450 mL), TEA (51.1 g, 2.0 equivalents) and Boc2O (82.7 g, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~20:1) to obtain the title compound (40.2 g, 59% yield) as a yellow oil.

[0292] Step C. Ethyl 2-((buta-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)penta-4-enoateThe solution of ethyl 3-(buta-3-en-1-yl(tert-butoxycarbonyl)amino)propanoate (20.0 g, 1.0 equivalent) / THF (200 mL) was degassed and purged three times with nitrogen. LDA (2 M, 1.5 equivalents) was slowly added at -65°C, and the reaction mixture was stirred at -40°C for 1 hour. 3-iodopropa-1-ene (13.6 g, 1.1 equivalents) was added at -65°C. The reaction mixture was stirred at -40°C for 0.5 hours. The mixture was quenched with water (100 mL) at 0°C and extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~20:1) to obtain the title compound (3.90 g, 15% yield) as a yellow oily substance; 1 H NMR (400MHz, chloroform-d) δ=5.81-5.64(m, 2H), 5.11-4.95(m, 4H), 4.16-4.06(m, 2H), 3.50-3.21(m, 3H), 3.17-3.05(m, 1H), 2.95-2.68(m, 1H), 2.39-2.11(m, 4H), 1.44(s, 9H), 1.23(t, J=7.2Hz, 3H).

[0293] Step D. 1-(tert-butyl)3-ethyl (Z)-3,4,7,8-tetrahydroazosin-1,3(2H)-dicarboxylate To a solution of ethyl 2-((buta-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)penta-4-enoate (1.00 g, 1.0 equivalent) / DCM (150 mL), Grubbs catalyst (265 mg, 0.10 equivalent) was added. The reaction mixture was purged three times with nitrogen. The reaction mixture was stirred at 40°C for 1.5 hours. The mixture was filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~20 / 1) to obtain the title compound (650 mg, 71% yield) as a brown oil; 1¹H NMR (400MHz, chloroform-d): δ = 5.96-5.59 (m, 2H), 4.20-4.06 (m, 3H), 3.91-3.75 (m, 1H), 3.42-3.05 (m, 1H), 3.01-2.89 (m, 1H), 2.83-2.58 (m, 1H), 2.49-2.21 (m, 3H), 2.19-2.06 (m, 1H), 1.47 (d, J=3.2Hz, 9H), 1.26 (td, J=7.2, 10.3Hz, 3H).

[0294] Step E. 1-(tert-butyl)3-ethyl azocane-1,3-dicarboxylate To a mixture of Pd / C (200 mg, 10% purity) / EtOH (20 mL), 1-(tert-butyl)3-ethyl (Z)-3,4,7,8-tetrahydroazosin-1,3(2H)-dicarboxylate (650 mg, 1.0 equivalent) was added. The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 25°C for 1 hour under H2 (15 psi). The mixture was filtered and concentrated to obtain the title compound (381 mg, crude) as a brown oil; 1 ¹H NMR (400MHz, chloroform-d): δ = 4.20-4.05 (m, 2H), 3.94-3.60 (m, 2H), 3.16 (ddd, J = 6.8, 11.2, 14.4Hz, 1H), 3.03-2.80 (m, 2H), 1.98-1.82 (m, 1H), 1.77-1.59 (m, 5H), 1.49-1.42 (m, 10H), 1.29-1.20 (m, 4H).

[0295] Step F. Ethyl azocane-3-carboxylate A solution of 1-(tert-butyl)3-ethyl azocane-1,3-dicarboxylate (381 mg, 1.0 equivalent) / HCl·MeOH (2 M, 6.7 equivalents) was stirred at 25°C for 0.5 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH 8 with NaHCO3 solid, filtered, and concentrated to obtain the title compound (236 mg, crude) as a yellow oily substance; 1¹H NMR (400MHz, chloroform-d): δ = 4.18-3.99 (m, 2H), 3.31-3.22 (m, 1H), 3.19-3.13 (m, 2H), 3.02-2.89 (m, 2H), 2.17-2.06 (m, 1H), 1.96-1.81 (m, 4H), 1.68 (br s, 3H), 1.20 (t, J=7.2Hz, 3H).

[0296] Step G. Ethyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (500 mg, 1.0 equivalent), ethyl HATU (514 mg, 1.5 equivalents) was added to a solution of azocane-3-carboxylate (207 mg, 1.2 equivalents) and DIEA (349 mg, 3.0 equivalents) / DMF (5 mL). The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered, concentrated, and purified by preparative HPLC [C18 150x30 mm; A: water (FA), B: ACN, B%: 35%~65% 7 mins] to obtain the title compound (120 mg, 12%, HCOOH) as a white solid; LCMS (ESI, M+1): m / z = 722.4.

[0297] Step H. Ethyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-carboxylate: A solution of ethyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-carboxylate (170 mg, 1.0 equivalent, FA) / HCl·MeOH (2M, 45 equivalents) was stirred at 25°C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), pH adjusted to approximately 8 with NaHCO3 solid, filtered, and concentrated to obtain the title compound (200 mg, crude) as a yellow oily substance; LCMS (ESI, M+1): m / z = 678.4.

[0298] Step I. A solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-carboxylate (180 mg, 1.0 equivalent) / MeOH (5 mL) was mixed with LiOH·H2O (2 M, 38 equivalents). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was filtered, concentrated, and purified by preparative HPLC [C18 150x30mm; A: water (FA), B: FA, B%: 25%~55% for 7 minutes] to obtain the title compound (65.0 mg, 35%, HCOOH) as a white solid.

[0299] Step J. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaph To a solution of talen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azocan-3-carboxylic acid (30.0 mg, 1.0 equivalent, HCOOH) and 3-methyl-1H-pyrazole (10.6 mg, 3.0 equivalents) / DMF (1 mL), DIEA (22.3 mg, 4.0 equivalents) was added. The reaction mixture was stirred at 25°C for 10 minutes. HATU (32.8 mg, 2.0 equivalents) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN, B%: 58%~88% for 9 minutes] to obtain the title compound (6.57 mg, 21%) as an off-white solid; 1 ¹H NMR (400MHz, chloroform-d) δ=9.17-8.93 (m, 1H), 8.17 (t, J=3.2Hz, 1H), 7.51 (td, J=5.6, 9.2Hz, 1H), 7.13 (br s, 3H), 6.32-6.23 (m, 1H), 5.36-5.12 (m, 1H), 4.85-4.62 (m, 1H), 4.59-4.31 (m, 2H), 4.09-3.99 (m, 1H), 3.96-3.72 (m, 1H), 3.70-3.52 (m, 1H), 3.30-2.99 (m, 3H), 2 .97-2.87(m, 1H), 2.64-2.37(m, 2H), 2.34-2.22(m, 4H), 2.19-2.07(m, 3H), 2.04 -1.98(m, 2H), 1.97-1.73(m, 9H), 0.86-0.79(m, 3H); LCMS(ESI, M+1): m / z=714.4.

[0300] Example 56 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)pyrrolidine-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0301] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)pyrrolidine-3-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (1.00 g, 1.0 equivalent), PyBOP (1.41 g, 1.5 equivalents) / DMF (10 mL), to which DIEA (1.40 g, 6.0 equivalents) and methyl Pyrrolidine-3-carboxylate (448 mg, 1.5 equivalents, HCl) was added. The reaction mixture was stirred at 40°C for 12 hours. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (1.20 g, 98% yield) as a yellow solid; 1H NMR (400MHz, DMSO-d6)δ=9.30-9.22(m, 1H), 7.93-7.85(m, 1H), 7.69-7.64(m, 1H), 7.46-7. 39(m, 1H), 7.27-7.10(m, 4H), 5.39-5.19(m, 3H), 4.24-3.89(m, 6H), 3.69(s, 3H), 3.45-3.41 (m, 4H), 3.14-3.08(m, 2H), 3.07-3.06(m, 1H), 2.89-2.79(m, 1H), 2.44-2.31(m, 2H), 2.29(s , 2H), 2.19-2.11(m, 2H), 2.09-1.98(m, 2H), 1.91-1.75(m, 4H); LCMS(ESI, M+1): m / z=666.4.

[0302] Step B. To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)pyrrolidine-3-carboxylate (1.10 g, 1.0 equivalent) / MeOH (10 mL), HCl·MeOH (4 M, 24 equivalents) was added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was concentrated, diluted with MeOH (10 mL), the pH was adjusted to approximately 8 with NaHCO3 solid, filtered, and concentrated to obtain the title compound (1.00 g, crude) as a yellow solid.

[0303] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)pyrrolidine-3-carboxylate (900 mg, 1.0 equivalent) / MeOH (6 mL) and H2O (2 mL) solution to which LiOH·H2O (911 mg, 15 equivalents) was added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated, the pH was adjusted to 4 with HCl (12M), and the mixture was filtered to obtain the title compound (800 mg, 88% yield, HCl) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=10.75-9.69(m, 1H), 9.35-9.22(m, 1H), 7.75(dd, J=6.0, 8.8H z, 1H), 7.39-7.29(m, 2H), 7.10-7.02(m, 1H), 5.50-5.29(m, 1H), 4.40-4.25(m, 2H), 4. 06-3.91(m, 2H), 3.55-3.21(m, 4H), 3.16(s, 1H), 3.04-2.96(m, 3H), 2.36-2.09(m, 6H) , 1.97-1.86(m, 2H), 1.73-1.69(m, 2H), 0.80-0.66(m, 3H); LCMS(ESI, M+1): m / z=608.3.

[0304] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)pyrrolidine-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- To a solution of (yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)pyrrolidine-3-carboxylic acid (200 mg, 1.0 equivalent) and EDCI (94.7 mg, 1.5 equivalents) / DCM (2 mL), DMAP (60.3 mg, 1.5 equivalents) and 3-methyl-1H-pyrazole (50.1 mg, 2.0 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150x40mmx10μm; A: water (NH4HCO3), B: ACN, B%: 40%~70% for 20 minutes] to obtain the title compound (42.3 mg, 18%) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d) δ = 9.18-9.02 (m, 1H), 8.21-8.10 (m, 1H), 7.48-7.41 (m, 1H), 7.15-7.08 (m, 1H), 7.07-7.02 (m, 1H), 6.99-6.83 (m, 1H), 6.33-6.27 (m, 1H), 5.39-5.15 (m, 1H), 4.41-4.17 (m, 5H), 4.11-3.87 (m, 2H), 3.42-3.24 (m, 2H), 3.23-3.12 (m, 1H), 2.99 (br d, J=5.6Hz, 1H), 2.50-2.38(m, 2H), 2.34(s, 3H), 2.33-2.17(m, 3H), 2.16 -2.09(m, 2H), 2.00-1.88(m, 3H), 0.83-0.74(m, 3H); LCMS(ESI, M+1): m / z =672.4.

[0305] Example 57 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(4-methyl-1H-pyrazole-1-yl)methanone [ka]

[0306] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (10g, 1.0 equivalent) and methyl To a solution of piperidine-4-carboxylate (7.7 g, 3.0 equivalents) in DMF (30 mL), DIEA (7.0 g, 3.0 equivalents) and PyBOP (14.1 g, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 25 hours. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (200 mL). The organic layers were washed together with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (10 g, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 680.4.

[0307] Step B. A solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (10 g, 1 equivalent) and HCl·MeOH (2 M, 30 mL, 4.08 equivalents) was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was made basic with saturated NaHCO3 solution (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layers were washed together with saline solution (2 x 2 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (5 g, 41% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 636.4.

[0308] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (5g, 1.0 equivalent) / MeOH (15mL) solution was mixed with LiOH·H2O (2M, 15.7mL, 4 equivalents). The reaction mixture was stirred at 25°C for 1 hour. The mixture was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (3 g, 57% yield) as a white solid; LCMS (ESI, M+1): m / z = 622.4.

[0309] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(4-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) 4-methyl-1H-pyrazole (79.2 mg, 3.0 equivalents) was added to a solution of (200 mg, 1.0 equivalent) (L)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equivalent), DIEA (208 mg, 5.0 equivalents), and HATU (147 mg, 1.2 equivalents) / DMF (3.0 mL). The reaction mixture was stirred at 30°C for 2 hours. The mixture was filtered and purified by reverse-phase flush [C18, H2O conditions] followed by [column: Phenomenex Luna 150x25mmx10μm; A: water (NH4HCO3), B: ACN; B%: 54%~84% for 10 minutes] to obtain the title compound (11.0 mg, 4.8% yield) as a white solid; 1 ¹H NMR (400MHz, methanol-d4) δ = 9.09-9.05 (m, 1H), 8.09 (s, 1H), 7.71-7.64 (m, 2H), 7.33-7.21 (m, 2H), 7.06 (d, J=2.4Hz, 1H), 5.46-5.22 (m, 1H), 4.79-4.66 (m, 2H), 4.41-4.25 (m, 2H) ), 4.14-4.03(m, 1H), 3.773.61(m, 2H), 3.28-3.17(m, 2H), 3.11-3.00(m, 1H), 2.58-2.4 5(m, 1H), 2.40-2.18(m, 5H), 2.13(s, 4H), 2.11-2.01(m, 4H), 2.00-1.86(m, 2H), 0.81(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=686.4.

[0310] Example 58 [ka] (3-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone [ka]

[0311] Step A. N,N-dimethyl-1H-pyrazole-3-amine: AcOH (361 mg, 1.0 equivalent) was added to a solution of 1H-pyrazole-3-amine (500 mg, 1.0 equivalent) and formaldehyde (542 mg, 3.0 equivalents) / MeOH (5 mL). The reaction mixture was stirred at 25°C for 0.5 hours. NaBH3CN (227 mg, 0.6 equivalents) was added to the mixture. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was diluted with water (10 mL), neutralized with solid NaHCO3, and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with brine (2 x 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain the title compound (150 mg, 19% yield) as a colorless oil;

[0312] Step B. (3-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) HATU (245 mg, 2.0 equivalents) and DIEA (125 mg, 3.0 equivalents) were added to a solution of )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equivalent) and N,N-dimethyl-1H-pyrazole-3-amine (53.6 mg, 1.5 equivalents) / DMF (1 mL). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (ammonium hydroxide v / v)-ACN; B: ACN, B%: 45%~75% 10 min] to obtain the title compound (36.8 mg, 15% yield) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d) δ=8.96 (d, J=2.4Hz, 1H), 8.08 (d, J=3.2Hz, 1H), 7.57-7.49 (m, 1H), 7.21-7.12 (m, 2H), 7.07-6.96 (m, 1H), 6.03 (d, J=3.2Hz, 1H), 5.40-5.18 (m, 1H), 4.60 (br d, J=12.4Hz, 2H), 4.33-4.22(m, 2H), 3.98-3.85(m, 1H), 3.57-3.42(m, 2H), 3.38-3.12 (m, 3H), 2.98(s, 6H), 2.55-2.42(m, 1H), 2.40-2.04(m, 9H), 2.00-1.87(m, 3H), 0.83(br t, J=7.6Hz, 3H); LCMS (ESI, M+1): m / z=715.4.

[0313] Example 59 [ka] ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)(1H-pyrazole-1-yl)methanone [ka]

[0314] Step A. 3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate: (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.15 g, 1.0 equivalent) / DCM (10 mL) and MeOH (10 mL) were mixed with TMSCHN2 (2 M, 7.95 mL, 4.0 equivalents) dropwise at 0°C. The reaction mixture was stirred at 20°C for 3 hours. The mixture was quenched with CH3COOH (10 mL) at 0°C. The mixture was concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 100 / 1~2 / 1] to obtain the title compound (1.1 g, 44% yield, 96% purity) as a colorless oil; LCMS (ESI, M+1): m / z = 304.2.

[0315] Step B. 3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate: 3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (1.1 g, 1.0 equivalent) was purified by SFC [column: DAIEL CHIRALPAK IK (250 mm x 30 mm, 10 μm); mobile phase: CO2-i-PrOH; B%: 30%, isocratic elution mode] and two peaks were obtained.

[0316] Peak 1: 3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (652 mg, crude) was obtained as a colorless oil; SFC: Column: Chiralpak IC-3 50x4.6mm ID, 3μm Mobile phase: Phase A CO2, Phase B IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) / CO2 5%~40% Flow rate: 3mL / min; Detector: PDA; Column temperature: 35C; Back pressure: 100Bar. R :1.533 minutes.

[0317] Peak 2: 3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (400 mg, crude, RT=1.773 min) was obtained as a colorless oily substance; t R :1.777 minutes.

[0318] Step C. Methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylate: To a solution of 3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (652 mg, 1.0 equivalent) / MeOH (10 mL), Pd / C (100 mg, 10% purity) was added under an N2 atmosphere. The reaction mixture was degassed and purged three times with H2. The reaction mixture was stirred at 20°C for 2 hours under H2 (15 psi). The mixture was filtered through Celite and concentrated to obtain the title compound (310 mg, crude) as a colorless oil.

[0319] Step D. Methyl (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol (300 mg, 1.0 equivalent) and methyl To a solution of (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylate (128 mg, 1.5 equivalents) / DMAc (1 mL), DIEA (261 mg, 4.0 equivalents) was added. The reaction mixture was stirred at 80°C for 2 hours. The mixture was purified by reverse-phase flush [0.1% FA conditions] to obtain the title compound (275 mg, 61% yield) as an off-white solid; LCMS (ESI, M+1): m / z = 662.3.

[0320] Step E. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid:methyl (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (255 mg, 1.0 equivalent) / MeOH (1 mL) was mixed with LiOH·H2O (2 M / H2O, 433 μL, 3.0 equivalents). The mixture was stirred at 20°C for 2 hours. The pH of the mixture was adjusted to 8 with 1N HCl at 0°C. The mixture was purified by reverse-phase flash [0.1% FA conditions] to obtain the title compound (180 mg, 70% yield) as an off-white solid; LC-MS (ESI, M+1): m / z = 648.4.

[0321] Step F. ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)(1H-pyrazole-1-yl)methanone:(1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphtha Len-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (60 mg, 1.0 equivalent) and 1H-pyrazole (50 mg, 8.0 equivalents) / DMF (1 mL) were mixed with TEA (75 mg, 8.0 equivalents), HOBt (19 mg, 1.5 equivalents), and EDCI (27 mg, 1.5 equivalents). The reaction mixture was stirred at 40°C for 12 hours. The mixture was purified by preparative HPLC [column: Waters Xbridge 150x25mmx5μm; mobile phase: water (NH4HCO3)-ACN; gradient: 50%~80% B for 53 minutes] to obtain the title compound (9.1 mg, 13.6% yield) as a white solid; 1 H NMR(400MHz,CD3OD)δ=9.11(s, 1H), 8.35(d, J=2.8Hz, 1H), 7.84(d, J=1.2Hz, 1H), 7.68(dd, J=6.0, 9.2Hz, 1H), 7. 30(d, J=2.8Hz, 1H), 7.25(t, J=9.2Hz, 1H), 7.08-7.03(m, 1H), 6.56(dd, J=1.6, 2.8Hz, 1H), 5.40-5.23(m, 1H), 4.4 0-4.21(m, 2H), 4.15-4.02(m, 1H), 3.99-3.62(m, 2H), 3.29-3.12(m, 3H), 3.07-2.96(m, 1H), 2.93-2.76(m, 2H), 2 .61-2.09(m, 6H), 2.08-1.75(m, 6H), 1.74-1.58(m, 2H), 0.80(dt, J=2.0, 7.2Hz, 3H); LCMS(ESI, M+1): m / z=698.4.

[0322] Example 60 [ka] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazine-1-yl)(1H-pyrazole-1-yl)methanone [ka]

[0323] Step A. 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (100 g, 1.0 equivalent) / toluene (300 mL), POCl3 (356 g, 5.0 equivalents) and DIEA (132 g, 2.2 equivalents) were added at -40°C. The reaction mixture was stirred at 110°C for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was quenched by adding saturated NaHCO3 (2000 mL) at 0°C. The mixture was filtered, and the filtered cake was dissolved in ethyl acetate (1000 mL). The organic layer was washed with saturated NaHCO3 (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was triturated with petroleum ether (500 mL) at 25°C for 30 minutes to obtain the title compound (50 g, 81% yield) as a yellow solid.

[0324] Step B. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine:t-BuONa (2M, 261mL, 1.1 equivalents) was added at 25°C to a solution of 2,2,2-trifluoroethanol (52g, 1.1 equivalents) / THF (200mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was added at -40°C to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (120g, 1.0 equivalent) / THF (1200mL). The reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched with H2O (500mL) and extracted with ethyl acetate (3 x 300mL). The organic layers were washed together with saline solution (400mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was triturated with n-heptane (200 mL) and MTBE (20 mL) at 25°C for 60 minutes to obtain the title compound (120 g, crude) as a yellow solid; LC-MS (ESI, M+1): m / z = 315.9.

[0325] Step C. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120 g, 1.0 equivalent) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidine-8-yl]methanol (66.5 g, 1.1 equivalents) / THF (1200 mL) were mixed with Na2CO3 (121 g, 3.0 equivalents). The reaction mixture was stirred at 40°C for 12 hours. The mixture was filtered and purified by reverse-phase flash chromatography [water (FA, 0.1%) / acetonitrile] to obtain the title compound (100 g, 2 steps: 57% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 439.1.

[0326] Step D. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol:7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)-4-(2,2,2-tri Ad2nBuP-Pd-G3 (7.07 g, 0.15 equivalents) was added to a solution of fluoroethoxy)pyrido[4,3-d]pyrimidine (28.4 g, 1.0 equivalent), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (25.6 g, 1.25 equivalents), and Cs2CO3 (1.5 M / H2O, 129 mL, 3.0 equivalents) / methoxycyclopentane (300 mL). The reaction mixture was degassed and purged three times with nitrogen. The reaction mixture was stirred at 100°C for 3 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [water (0.1% FA) / acetonitrile] to obtain the title compound (16.8 g, 40% yield) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d) δ=9.19 (d, J=10.4Hz, 1H), 7.54 (dd, J=5.6, 8.8Hz, 1H), 7.26-7.21 (m, 1H), 7.16-7.11 (m, 1H), 6.96-6.84 (m, 1H), 5.46-5.22 (m, 1H), 5.05 -4.71(m, 2H), 4.56-4.32(m, 2H), 3.48-3.21(m, 3H), 3.13-3.01(m, 1H), 2.47-2. 32(m, 4H), 2.32-2.08(m, 4H), 0.78(t, J=7.2Hz, 3H); LCMS(ESI, M+1): m / z=593.2.

[0327] Step E. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(piperazine-1-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol: To a solution of piperazine (727 mg, 5.0 equivalents) / DMF (10 mL), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (1.00 g, 1.0 equivalent) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was purified by reverse-phase flash chromatography [water (neutral) / acetonitrile = 1 / 1] to obtain the title compound (914 mg, 90% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 579.4.

[0328] Step F. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperazin-1-yl)(1H-pyrazole-1-yl)methanone: A mixture of 1H-pyrazole (20.0 mg, 1.0 equivalent) and DIEA (151 mg, 4.0 equivalents) / DCM (0.3 mL) was mixed with bis(trichloromethyl) carbonate (120 mg, 1.4 equivalents) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (153 mg, 0.9 equivalents) and DIEA (56.9 mg, 1.5 equivalents) / DCM (0.7 mL) were added dropwise to the mixture at 0°C. The reaction mixture was stirred at 20°C for 14 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (5 mL) and extracted with DCM (4 x 3 mL). The organic layers were washed together with saline solution (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Waters Xbridge 150x25mmx5 μm; mobile phase: water (ammonium hydroxide v / v)-acetonitrile; gradient: 42%~72% B for 10 minutes] to obtain the title compound (75.7 mg, 38% yield) as a white solid; 1H NMR (400MHz, DMSO-d6)δ=9.95(br s, 1H), 9.18(s, 1H), 8.28(d, J=2.4Hz, 1H), 7.82(s, 1H), 7.77(dd, J=6.0, 9.0Hz, 1H), 7.40-7.30(m, 2H), 7.02(d, J=1.6Hz, 1H), 6.53(br d, J=1.6Hz, 1H), 5.39-5.17(m, 1H), 4.24-3.97(m, 10H), 3.12-3.03(m, 2H), 3.02-2.90(m, 1H), 2.85 -2.79(m, 1H), 2.42-2.30(m, 1H), 2.20-2.09(m, 2H), 2.08-1.95(m, 2H), 1.89-1.71(m, 3H), 0.73(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=673.2.

[0329] Example 61 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methoxy-1H-pyrazole-1-yl)methanone [ka]

[0330] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methoxy-1H-pyrazole-1-yl)methanone; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- To a solution of (yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (350 mg, 1.0 equivalent) and 3-methoxy-1H-pyrazole (55.2 mg, 1.0 equivalent) / DMF (4 mL), HATU (428 mg, 2.0 equivalent) and DIEA (364 mg, 5.0 equivalent) were added. The reaction mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (4 mL) and extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN, B%: 54%~84% for 9 minutes] to obtain the title compound (15.5 mg, 4% yield) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ=8.97(s, 1H), 8.08(d, J=3.2Hz, 1H), 7.60-7.51(m, 1H), 7.23-7.16(m, 2H), 7.06-6.97(m, 1H), 6.02(d, J=2.8Hz, 1H), 5.35(br s, 1H), 4.69-4.55(m, 2H), 4.29(br d, J=6.4Hz, 2H), 3.99(s, 3H), 3.90(br dd. t, J=7.2Hz, 3H) LCMS (ESI, M+1): m / z =702.4.

[0331] Example 62 [ka] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-N-methyl-N-(pyridine-2-yl)piperidine-4-carboxamide [ka]

[0332] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (2.00 g, 1.0 equivalent) and methyl To a solution of piperidine-4-carboxylate (1.03 g, 2.0 equivalents) in DMF (20 mL), PyBOP (2.82 g, 1.5 equivalents) and DIEA (1.40 g, 3.0 equivalents) were added. The reaction mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (2.1 g, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 680.3.

[0333] Step B. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid:methyl To a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (2.0 g, 1.0 equivalent) / MeOH (6.2 mL), LiOH·H2O (2 M / H2O, 6.2 mL, 4.2 equivalents) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (600 mg, 30% yield) as a white solid; LCMS (ESI, M+1): m / z = 666.4.

[0334] Step C. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-N-methyl-N-(pyridine-2-yl)piperidine-4-carboxamide:1-(7-(8-ethyl-7-fluoro-3-(Me To a solution of toxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (300 mg, 1.0 equivalent) and N-methylpyridine-2-amine (195 mg, 4.0 equivalents) / THF (3 mL), 2-chloro-1-methylpyridinium iodide (460 mg, 4.0 equivalents) and DIEA (349 mg, 6.0 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (ammonium hydroxide), B: ACN, B%: 40%~70% for 10 minutes] to obtain the title compound (112 mg, 32% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 756.4.

[0335] Step D. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-N-methyl-N-(pyridine-2-yl)piperidine-4-carboxamide:1-(7-(8-ethyl-7-fluoro-3-(methoxy) To a solution of methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-N-methyl-N-(pyridine-2-yl)piperidine-4-carboxamide (112 mg, 1.0 equivalent) / MeOH (1 mL), HCl·MeOH (4 M, 1 mL, 27 equivalents) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated, basicized with saturated NaHCO3 solution (6 mL), and extracted with ethyl acetate (3 x 5 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (FA), B: ACN, B%: 15%~45% for 10 minutes] to obtain the title compound (71.4 mg, 67% yield, 0.23 HCOOH) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d) δ=8.86 (s, 1H), 8.56-8.50 (m, 1H), 7.82 (br t, J=7.8Hz, 1H), 7.52-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.24 (s, 1H), 7.17-7.08 (m, 2H), 7.02-6.90 (m, 1H), 5.42-5.16 (m, 1H), 4.59-4.41 (m, 2H), 4.39-4.21 (m, 2H), 3.52 (br d, J=14.0Hz, 1H), 3.36(s, 3H), 3.33-2.94(m, 5H), 2.86-2.71(m, 1H), 2.48-1.83(m, 12H), 0.77(br t, J=7.2Hz, 3H); LCMS(ESI, M+1): m / z=712.4.

[0336] Example 63 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0337] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (400 mg, 1.0 equivalent) and benzotriazole-1-yloxy-tris-(pyrrolidino)-phosphonium To a mixture of hexafluorophosphate (751 mg, 2.0 equivalents) / DMSO (4 mL), TEA (301 μL, 3.0 equivalents) and methyl azepane-4-carboxylate (340 mg, 3.0 equivalents) were added. The reaction mixture was stirred at 35°C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with saline solution (15 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (380 mg, 76% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 694.4.

[0338] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate (260 mg, 1.0 equivalent) / ACN (2 mL), HCl·dioxane (4 M, 3.5 mL, 37 equivalents) was added at 0°C. The reaction mixture was stirred at 15°C for 1 hour. The mixture was adjusted to pH=7 with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated to obtain the title compound (300 mg, crude) as a yellow oil.

[0339] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylate (300 mg, 1.0 equivalent) / MeOH (3 mL) solution was mixed with LiOH (2 M, 923 μL, 4.0 equivalents). The reaction mixture was stirred at 15°C for 2 hours. The mixture was adjusted to pH=8 with HCl (1M) and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (190 mg, 64% yield) as a white solid; LCMS (ESI, M+1): m / z = 636.4.

[0340] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-4-carboxylic acid (30.0 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (7.75 mg, 2.0 equivalents) / DMF (0.3 mL) were mixed with HATU (35.9 mg, 2.0 equivalents) and TEA (19.7 μL, 3.0 equivalents). The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Waters xbridge 150 x 25 mm x 10 μm; A: water (NH4HCO3), B: ACN; B%: 53%~73% for 8 minutes] to obtain the title compound (9.07 mg, 27% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=9.18 (d, J=2.4Hz, 1H), 8.19 (t, J=3.2Hz, 1H), 7.68 (dd, J=6.0, 9.2Hz, 1H), 7.34-7. 19(m, 2H), 7.07(dd, J=2.4, 7.6Hz, 1H), 6.37(d, J=1.2Hz, 1H), 5.37-5.20(m, 1H), 4.49-4.22(m, 4H), 4.14(br s, 1H), 4.02(br d, J=9.2Hz, 1H), 3.88(br s, 1H), 3.21(br d, J=19.8Hz, 3H), 3.08-2.96(m, 1H), 2.57-2.41(m, 2H), 2.39-2.31(m, 1H), 2.31-2.10(m, 1 0H), 2.05-1.94(m, 2H), 1.92-1.77(m, 2H), 0.87-0.77(m, 3H); LCMS(ESI, M+1): m / z=700.4.

[0341] Example 64 [ka] (4-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone [ka]

[0342] Step A. tert-butyl 4-(dimethylamino)-1H-pyrazole-1-carboxylate: AcOH (164 mg, 1.0 equivalent) was added to a solution of tert-butyl 4-aminopyrazole-1-carboxylate (500 mg, 1.0 equivalent) and formaldehyde (2.22 g, 37% purity, 10 equivalents) / MeOH (10 mL). The reaction mixture was stirred at 25°C for 0.5 hours. Sodium cyanoborohydride (514 mg, 3.0 equivalents) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated, basicized with NaHCO3 (10 mL), and extracted with ethyl acetate (2 x 30 mL). The organic layers were washed together with saline solution (2 x 2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain the title compound (500 mg, 81% yield) as a white oil; LC-MS (ESI, M-99, M-55): m / z = 112.0, 156.0

[0343] Step B. N,N-dimethyl-1H-pyrazole-3-amine:To a solution of tert-butyl 4-(dimethylamino)-1H-pyrazole-1-carboxylate (250 mg, 1 equivalent) / DCM (0.5 mL), TFA (767 mg, 5.7 equivalents) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated. The residue was basicized with NaHCO3 (2 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layers were washed together with saline solution (2 x 2 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (130 mg, 99% yield) as a colorless oil.

[0344] Step C. (3-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl HATU (183 mg, 2.0 equivalents) and DIEA (93.5 mg, 3.0 equivalents) were added to a solution of )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (150 mg, 1.0 equivalent) and N,N-dimethyl-1H-pyrazole-4-amine (53.6 mg, 2.0 equivalents) / DMF (1 mL). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by reverse-phase flash chromatography [C18, water / ACN] to obtain the title compound (10.3 mg, 5% yield) as a white solid; 1¹H NMR (400MHz, chloroform-d) δ=8.94 (d, J=7.2Hz, 1H), 7.53-7.46 (m, 3H), 7.19-7.08 (m, 2H), 7.06-6.94 (m, 1H), 5.39-5.19 (m, 1H), 4.60 (br dd, J=4.4, 8.4Hz, 2H), 4.34-4.23(m, 2H), 4.05-3.95(m, 1H), 3.54-3.08(m, 6H), 3.05-2.95(m, 1H), 2.80(s, 6H), 2.51-2.03(m, 9H), 2.00-1.88(m, 3H), 0.86-0.78(m, 3H); LCMS(ESI, M+1): m / z=715.3.

[0345] Example 65 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0346] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (300 mg, 1.0 equivalent), TEA (164 mg, 3.0 equivalent), and benzotriazole-1-yloxy-tris-(pyrrolidino)-phosphonium To a solution of hexafluorophosphate (422 mg, 1.5 equivalents) / DMSO (3 mL), methyl piperidine-3-carboxylate (155 mg, 2.0 equivalents) was added. The reaction mixture was stirred at 30°C for 6 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were washed together with saline solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (300 mg, 81% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 680.4.

[0347] Step B. To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate (150 mg, 1.0 equivalent) / MeCN (0.5 mL), HCl·dioxane (4 M, 1.0 mL) was added. The reaction mixture was stirred at 0°C for 0.5 hours. The mixture was adjusted to a pH greater than 8 with saturated NaHCO3 aqueous solution (5 mL) at 0°C and extracted with DCM (3 x 5 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (120 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 636.3.

[0348] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylic acid:methyl To a solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylate (70.0 mg, 1.0 equivalent) / THF (0.2 mL) and MeOH (0.3 mL), LiOH·H2O (13.9 mg, 3.0 equivalents) / H2O (0.2 mL) was added. The reaction mixture was stirred at 20°C for 1 hour. The mixture was adjusted to approximately 6 pH with HCl (4M, 0.8 mL) at 0°C and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (50.0 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 622.3.

[0349] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-3-carboxylic acid (80.0 mg, 1.0 equivalent), EDCI (37.0 mg, 1.5 equivalents), HOBt (26.1 mg, 1.5 equivalents), and DIEA (49.9 mg, 3.0 equivalents) / DMF (1.0 mL) were mixed with 3-methylpyrazole (21.1 mg, 2.0 equivalents). The reaction mixture was stirred at 20°C for 12 hours.

[0350] The mixture was filtered and purified by reverse-phase flash chromatography [C18, neutral conditions] to obtain the title compound (18.5 mg, 20% yield) as a yellow solid; 1 H NMR (400MHz, DMSO-d6)δ=9.94(br d, J=5.2Hz, 1H), 9.30(d, J=5.6Hz, 1H), 8.31-8.30(m, 1H), 7.79-7.50(m, 1 H), 7.45-7.26(m, 2H), 7.07-6.98(m, 1H), 6.48-6.46(m, 1H), 5.40-5.14(m , 1H), 4.73-4.68(m, 1H), 4.45-4.42(m, 1H), 4.17-4.09(m, 1H), 4.07-4.03 (m, 1H), 3.76-3.65(m, 1H), 3.56-3.43(m, 2H), 3.12-3.04(m, 2H), 3.00(br s, 1H), 2.85-2.78(m, 1H), 2.33(br s, 1H), 2.27(d, J=10.4Hz, 3H), 2.21-2.10(m, 3H), 2.05(br s, 2H), 1.95(br d, J=8.8Hz, 2H), 1.88-1.72(m, 4H), 0.75-0.67(m, 3H); LCMS(ESI, M+1): m / z=686.4.

[0351] Example 66 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-vinyl-1H-pyrazole-1-yl)methanone [ka]

[0352] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-vinyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- To a solution of (yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (300 mg, 1.0 equivalent) and 3-vinyl-1H-pyrazole (300 mg, 6.6 equivalents) / DMF (3 mL), HATU (367 mg, 2.0 equivalents) and DIEA (312 mg, 5.0 equivalents) were added. The mixture was stirred at 25°C for 0.5 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150x40mmx10μm; A: water (NH4HCO3), B: ACN, B%: 45%~75% for 20 minutes] to obtain the title compound (4.94 mg, 1.4% yield) as an orange solid; 1 H NMR (400MHz, chloroform-d) δ=8.98(s, 1H), 8.20(d, J=3.0Hz, 1H), 7.63-7.51(m, 1H), 7.23-7.13(m, 2H) ), 7.03(dd, J=2.4, 18.6Hz, 1H), 6.77(dd, J=11.2, 17.8Hz, 1H), 6.63(d, J=2.8Hz, 1H), 5.91(d, J=1 7.8Hz, 1H), 5.58(d, J=11.3Hz, 1H), 5.41-5.19(m, 1H), 4.70-4.58(m, 2H), 4.36-4.21(m, 2H), 4.09 -3.96(m, 1H), 3.61-3.42(m, 2H), 3.37-3.12(m, 3H), 3.05-2.94(m, 1H), 2.57-2.40(m, 1H), 2.31(br s, 1H), 2.28-2.06 (m, 7H), 2.02-1.92 (m, 3H), 0.83 (br t, J=7.4Hz, 3H); LCMS (ESI, M+1): m / z=698.4.

[0353] Example 67 [ka] (1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0354] Step A. 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of POCl3 (187 g, 5.0 equivalents) / toluene (150 mL), 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (52.6 g, 1.0 equivalent) and DIEA (69.4 g, 2.2 equivalents) were added. The reaction mixture was stirred at 110 °C for 27 hours. The solvent was concentrated under vacuum. The mixture was poured into a cold saturated NaHCO3 solution (2.5 L), maintained at pH 8, and then filtered. The filtered cake was dissolved in ethyl acetate (1.5 L) and washed with saturated NaHCO3 aqueous solution (1 L) and saturated brine (1 L). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (50 g, 81% yield) as a brown solid.

[0355] Step B. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine:To a solution of 2,2,2-trifluoroethanol (15.0 g, 0.9 equivalents) in THF (150 mL), NaH (7.98 g, 60% purity, 1.2 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Next, the mixture was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (42.0 g, 1.0 equivalent) in THF (840 mL) at -40°C. The reaction mixture was stirred at -40°C for 1 hour. The mixture was quenched with H2O (500 mL) and extracted with ethyl acetate (3 x 300 mL). The organic layers were washed together with saline solution (400 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 10 / 1~5 / 1] to obtain the title compound (34.4 g, 53% yield) as a yellow solid; LCMS [ESI, M+1]: 315.9.

[0356] Step C. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (33.3 g, 1.0 equivalent), DIEA (54.5 g, 4.0 equivalent), and 4A molecular sieve (4.0 g) / THF (340 mL), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methanol (20.1 g, 1.2 equivalents) was added. The reaction mixture was stirred at 40°C for 14 hours. The reaction mixture was diluted with H2O (20 mL), extracted with ELISA (3 x 20 mL), the organic layers were dried together over Na2SO4, filtered, concentrated under vacuum, and purified by reverse-phase flash chromatography [water (FA, 0.1%) / acetonitrile] to obtain the title compound (28.8 g, 62% yield) as a yellow solid; 1 ¹H NMR (400 MHz, chloroform-d): δ 8.98 (s, 1H), 5.40-5.19 (m, 1H), 5.02 (q, J=8.0 Hz, 1H, 2H), 4.40-4.27 (m, 2H), 3.34-3.12 (m, 3H), 3.05-2.94 (m, 1H), 2.32-2.06 (m, 3H), 2.03-1.84 (m, 3H); LCMS [ESI, M+1]: 439.1.

[0357] Step D. 8-Fluoro-7-(7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethinyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine:7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine To a solution of -7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.20 g, 1.0 equivalent) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethinyl-triisopropyl-silane (3.85 g, 1.5 equivalent) / methoxycyclopentane (25 mL), CataCxium(R)A Pd G3 (365 mg, 0.1 equivalent) and Cs2CO3 (1.5 M / water, 2.5 equivalents) were added. The reaction mixture was stirred at 100 °C under an N2 atmosphere for 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (2.80 g, 64% yield) as a brown solid. LC-MS (ESI, M+1): m / z = 789.4.

[0358] Step E. Methyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.20g, 1.0 equivalent) and methyl To a solution of piperidine-4-carboxylate (653 mg, 3.0 equivalents) / DMF (12 mL), DIEA (590 mg, 3.0 equivalents) and 4A molecular sieve (1.00 g) were added at 25°C. The reaction mixture was stirred at 70°C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (800 mg, 56% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 832.5.

[0359] Step F. Methyl 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:methyl To a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (1.00 g, 1.0 equivalent) / MeOH (10 mL), HCl / MeOH (2 M, 20 mL, 33.28 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The mixture was concentrated under vacuum. The mixture was basicized with NaHCO3 (10 mL) and extracted with ethyl acetate (10 mL). The organic layers were combined and dried over sodium sulfate, then concentrated to obtain the title compound (900 mg, crude) as a yellow solid. LCMS(ESI, M+1): m / z = 788.4.

[0360] Step G. Methyl 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate: To a solution of methyl 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (900 mg, 1.0 equivalent) / DMF (9 mL), CsF (2.26 g, 13 equivalents) was added. The reaction mixture was stirred at 40°C for 14 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated to obtain the title compound (900 mg, crude) as a yellow solid. LC-MS (ESI, M+1): m / z = 632.3.

[0361] Step H. A solution of 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) / MeOH (5 mL) was mixed with LiOH·H2O (1.5 M / water, 2.11 mL, 4.0 equivalents). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated, diluted with water (5 mL), and extracted with ethyl acetate (7 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (300 mg, 58% yield) as a yellow solid. LC-MS (ESI, M+1): m / z = 618.2.

[0362] Step I. (1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8- To a solution of fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (150 mg, 242.87 μmol, 1 eq) and 3-methyl-1H-pyrazole (39.9 mg, 2.0 equivalents) / DCM (0.5 mL), EDCI (69.8 mg, 1.5 equivalents) and DMAP (44.5 mg, 1.5 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was concentrated, diluted with water (5 mL), and extracted with ethyl acetate (7 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150x40mmx10μm; A: water (10mM NH4HCO3), B: ACN, B%: 38%~68% for 20 minutes] to obtain the title compound (31.5 mg, 18% yield) as an orange solid. 1H NMR (400MHz, chloroform-d) δ=8.94(d, J=4.4Hz, 1H), 8.15(d, J=2.8Hz, 1H), 7.68-7. 56(m, 1H), 7.24-7.09(m, 3H), 6.29(d, J=2.8Hz, 1H), 5.40-5.13(m, 1H), 4.64(br d, J=13.2Hz, 2H), 4.31-4.19(m, 2H), 4.07-3.97(m, 1H), 3.52(br t, J=11.2Hz, 2H), 3.33-3.10(m, 3H), 3.04-2.90(m, 1H), 2.80(s, 1H), 2.35(s, 3H), 2.33-2.27(m, 1H), 2.21(br d, J=10.0Hz, 3H), 2.11(br d, J=12.8Hz, 3H), 2.03-1.90(m, 3H); LCMS (ESI, M+1): m / z=682.4.

[0363] Example 68 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0364] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (500 mg, 1.0 equivalent) / DMSO (5 mL) was mixed with TEA (456 mg, 5.0 equivalent) and PyBOP (938 mg, 2.0 equivalent). The reaction mixture was stirred at 30°C for 0.5 hours. Methyl azepane-3-carboxylate (262 mg, 1.5 equivalents, HCl) was then added to the mixture. The reaction mixture was stirred at 30°C for 12 hours. The mixture was filtered, washed with DMSO (1 mL), and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (265 mg, 41% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 694.3.

[0365] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-carboxylate (143 mg, 1.0 equivalent) / ACN (1 mL), HCl·dioxane (4 M, 2 mL, 39 equivalents) was added. The reaction mixture was stirred at 20°C for 0.5 hours. The mixture was adjusted to pH 8 with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (3 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated to obtain the title compound (160 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0366] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-carboxylic acid:methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-carboxylate (160 mg, 1.0 equivalent) / THF (0.6 mL), MeOH (0.4 mL), and H2O (0.6 mL) were mixed with LiOH·H2O (31.0 mg, 3.0 equivalents) at 0°C. The reaction mixture was stirred at 20°C for 2 hours. The mixture was filtered and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (100 mg, 63% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 636.3.

[0367] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azepan-3-carboxylic acid (100 mg, 1.0 equivalent), DIEA (61.0 mg, 3.0 equivalents), HOBt (31.9 mg, 1.5 equivalents), and EDCI (45.2 mg, 1.5 equivalents) / DMF (0.5 mL) were mixed with 3-methyl-1H-pyrazole (25.8 mg, 2.0 equivalents). The reaction mixture was stirred at 20°C for 12 hours. The mixture was filtered and purified by reverse-phase flush [C18, H2O conditions] to obtain the title compound (17.6 mg, 15% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=9.93(s, 1H), 9.26(s, 1H), 8.34(d, J=2.7Hz, 1H), 7.76(dd, J=6.0, 8.8Hz, 1H), 7.43-7.28(m, 2H), 7.01(dd, J=2.4, 14.0Hz, 1H), 6.50(d, J=2.8Hz, 1H), 5.30-5.04(m, 1H), 4.63-4.48(m, 1H), 4.26-4.06(m, 3H), 4.01-3.70(m, 3H), 3.05-2.87(m, 3H), 2.75(br s, 1H), 2.40-2.31(m, 1H), 2.26(s, 3H), 2.20-2.13(m, 1H), 2.12-2.01(m, 3H), 1.97-1.8 9(m, 2H), 1.88-1.49(m, 7H), 0.73(td, J=7.6, 17.2Hz, 3H); LCMS(ESI, M+1): m / z=700.3.

[0368] Example 69 [ka] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-diazepan-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0369] Step A. 4-(4-(1,4-diazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 1,4-diazepan (169 mg, 2.5 equivalents) / DMF (3.5 mL), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (400 mg, 1.0 equivalent). The reaction mixture was stirred at 25°C for 2 hours. The mixture was purified by reverse-phase flush [water (0.1% formic acid) / acetonitrile = 1 / 4] to obtain the title compound (370 mg, 85.7% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 593.3.

[0370] Step B. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-diazepan-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone: To a solution of 5-methyl-1H-pyrazole (30.0 mg, 1.0 equivalent) and DIEA (189 mg, 4.0 equivalents) / DCM (0.5 mL), bis(trichloromethyl) carbonate (320 mg, 2.9 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. 4-(4-(1,4-diazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol (195 mg, 0.9 equivalents) and DIEA (70.8 mg, 1.5 equivalents) were added at 0°C, and the reaction mixture was stirred at 20°C for 14 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (4 x 10 mL). The organic layers were washed together with saline solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flush [water (0.1% formic acid) / acetonitrile = 1 / 1] and preparative HPLC [column: Waters Xbridge 150x25mmx5μm; mobile phase: (water (ammonium hydroxide v / v)-acetonitrile); gradient: 46%~76%B for 10 minutes] to obtain the title compound (23.1 mg, 9% yield) as a white solid; 1H NMR (400MHz, DMSO-d6)δ=9.90(br s, 1H), 9.18(s, 1H), 7.98(s, 1H), 7.76(dd, J=6.0, 9.2Hz, 1H), 7.39-7.29(m, 2H), 7.02(d, J=2.4Hz, 1H), 6.25(d, J=2.4Hz, 1H), 5.37-5.16(m, 1H), 4.41-4.26(m, 2H), 4.25-4.00(m, 6H), 3.97-3.69(m, 2H), 3.14-3.02(m, 2H), 3.00(s, 1H), 2.86-2.76(m, 1H), 2.39-2.26(m, 1H), 2.22-1.93(m, 9H), 1.89-1.67(m, 3H), 0.76-0.64(m, 3H); LCMS(ESI, M+1): m / z=701.5.

[0371] Example 70 [ka] (S,Z)-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0372] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol:To a mixture of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (150 g, 1.0 equivalent) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 g, 1.1 equivalent) / dimethylformamide (1500 mL) and water (300 mL), cataCXium® A Pd G3 (25.3 g, 0.05 equivalent) and potassium phosphate (295 g, 2.0 equivalent) were added. The reaction mixture was degassed, purged three times with nitrogen, and stirred under a nitrogen atmosphere at 100°C for 12 hours. The mixture was filtered, and the filtered cake was washed with dimethylformamide (300 mL). The filtrate was concentrated, triturated with water (2000 mL), filtered, and washed with water (1000 mL) and ethanol (500 mL). The crude product was triturated with methyl tert-butyl ether (600 mL), filtered, and washed with methyl tert-butyl ether (200 mL) to obtain 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (102 g, 34.0% yield) as a yellow solid; 1 H NMR (400MHz, DMSO-d6)δ=12.29-11.37(m, 2H), 8.84(s, 1H), 7.90(dd, J=6.0, 8.8Hz, 1H), 7.68(d, J=2.8Hz, 1H), 7.44(t, J= 9.2Hz, 1H), 7.21(d, J=2.4Hz, 1H), 5.34(s, 2H), 3.42(s, 3H), 2.42-2.29(m, 1H), 2.25-2.12(m, 1H), 0.79(t, J=7.2Hz, 3H).

[0373] Step B. 2,4-Dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine:To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.80 g, 1.0 equivalent) / toluene (30.0 mL), POCl3 (3.34 g, 5.0 equivalents) and DIEA (2.28 mL, 3.0 equivalents) were added dropwise at 0°C. The reaction mixture was stirred at 100°C for 1 hour. The mixture was concentrated and then poured into a saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layers were dried together over sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 20 / 1~5 / 1) to obtain the title compound (1.60 g, 81% yield) as a yellow oil; 1 ¹H NMR (400MHz, chloroform-d): δ = 9.54 (s, 1H), 7.73 (dd, J=6.0, 9.2Hz, 1H), 7.59 (d, J=2.8Hz, 1H), 7.30 (t, J=9.2Hz, 1H), 7.20 (d, J=2.8Hz, 1H), 5.31 (d, J=2.0Hz, 2H), 3.53 (s, 3H), 2.48-2.35 (m, 1H), 2.21-2.07 (m, 1H), 0.81 (t, J=7.4Hz, 3H).

[0374] Step C. Methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate: To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (610 mg, 1.0 equivalent) / DCM (12 mL), TEA (411 mg, 3 equivalents) was added at -40°C. A solution of methyl piperidine-4-carboxylate (155 mg, 0.8 equivalents) / DCM (3 mL) was added dropwise to the mixture at -40°C. The reaction mixture was stirred at -40°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with dichloromethane (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate 20 / 1-2 / 1) to obtain the title compound (940 mg, 56% yield) as a yellow solid;1 H NMR (400MHz, methanol-d4)δ 9.18(s, 1H), 7.84-7.76(m, 1H), 7.63(d, J=2.8Hz, 1H), 7.32(t, J=9.2Hz, 1H), 7.23(d, J=2.8Hz, 1H), 5.33(s, 2H), 4.68-4.59(m, 2H), 3.73( s, 3H), 3.72-3.63(m, 2H), 3.50(s, 3H), 2.93-2.83(m, 1H), 2.54-2.40(m, 1H), 2.27-2.13(m, 3H), 2.02-1.89(m, 2H), 0.81(t, J=7.6Hz, 3H).

[0375] Step D. Methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate:(S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (169 mg, 1.1 equivalents) / THF (10 mL) was mixed with NaH (89.8 mg, 60% purity, 2.5 equivalents) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. Methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (500 mg, 1 equivalent) was added to the mixture. The reaction mixture was stirred at 0-20°C for 1 hour. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (300 mg, 43% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 692.4.

[0376] Step E. Methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate: HCl·dioxane (2M, 5.06mL, 20 equivalents) was added dropwise to a mixture of methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (350 mg, 1 equivalent) / ACN (1.25 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated. The residue was basicized with saturated NaHCO3 solution (6 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated to obtain the title compound (300 mg, 82% yield) as a yellow solid; LC-MS (ESI, M+1): m / z = 648.4.

[0377] Step F. A solution of (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylate (300 mg, 1.0 equivalent) / EtOH (4.5 mL) was mixed with a solution of NaOH (92.6 mg, 5 equivalents) / H2O (1.5 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was filtered and purified by reverse-phase flash chromatography [water (NH3·H2O) / acetonitrile] to obtain the title compound (200 mg, 67% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 634.3.

[0378] Step G. (S,Z)-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:(S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8 To a solution of -fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (100 mg, 1 equivalent) and EDCI (45.4 mg, 1.5 equivalents) / DMF (1 mL), HOBt (25.6 mg, 1.2 equivalents) and TEA (63.9 mg, 4.0 equivalents), followed by 3-methyl-1H-pyrazole (38.9 mg, 3.0 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was filtered and purified by preparative HPLC [Phenomenex Luna C18 150x25mmx10μm; A: water (NH4HCO3), B: ACN, B%: 56%~86% 10 min], followed by preparative HPLC [Phenomenex Luna C18 150x25mmx10μm; A: water (FA), B: ACN, B%: 20%~50% 1 min]. The fraction of interest was diluted with water (60 mL) and extracted with dichloromethane (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound (2.50 mg, 2.2% yield) as a white solid; 1¹H NMR (400MHz, chloroform-d3) δ 9.03-8.96 (m, 1H), 8.19-8.14 (m, 1H), 7.61-7.54 (m, 1H), 7.25-7.19 (m, 2H), 7.08-7.02 (m, 1H), 6.65-6.37 (m, 1H), 6.33-6.28 (m, 1H), 4.72-4.61 (m, 2H), 4.36-4.19 (m, 2H), 4.09-3.99 (m, 1H), 3.98-3.85 (m, 1H), 3.61- 3.49(m, 2H), 3.48-3.40(m, 1H), 3.30-3.15(m, 1H), 2.82-2.72(m, 1H), 2.72-2.62(m, 1H), 2.56-2.45(m, 1H), 2.40-2.32 (m, 4H), 2.28-2.06 (m, 7H), 1.98-1.91 (m, 2H), 0.84 (t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=698.5.

[0379] Example 71 [ka] ((3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0380] Step A. 3S,4R)-3-methylpiperidine-4-carboxylic acid: To a solution of (3S,4R)-1-(tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid (250 mg, 1.0 equivalent) / ACN (0.5 mL), HCl·dioxane (2 M, 0.5 ml, 1.0 equivalent) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated to obtain the title compound (120 mg, 73% yield) as a white solid; MS (ESI, M+1): m / z = 144.4

[0381] Step B. (3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylic acid:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS) To a solution of -2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (130 mg, 1.0 equivalent) / DMF (1.5 mL), (3S,4R)-3-methylpiperidine-4-carboxylic acid (62.8 mg, 2.0 equivalents) and K3PO4 (279 mg, 6.0 equivalents) were added. The reaction mixture was stirred at 60°C for 0.5 hours. The mixture was purified by preparative HPLC [Phenomenex luna C18 150x25mmx10μm; A: water (FA)-ACN; B: CAN, B%: 15%~45% for 9 minutes] to obtain the title compound (35 mg, 24% yield) as a white solid; LCMS (ESI, M+1): m / z = 636.4.

[0382] Step C. ((3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:(3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaph To a solution of talen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylic acid (30 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (11.6 mg, 3.0 equivalent) / DMF (0.5 mL), HATU (35.9 mg, 2.0 equivalent) and DIEA (18.3 mg, 3.0 equivalent) were added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by reverse-phase flash chromatography [C18, water / ACN] to obtain the title compound (18.0 mg, 54% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=8.97(d, J=5.6Hz, 1H), 8.20(d, J=2.8Hz, 1H), 7.62-7.52(m, 1H), 7.25-7.17(m, 2H), 7.05(dd, J=2.8, 6 .4Hz, 1H), 6.33(d, J=2.8Hz, 1H), 5.40-5.21(m, 1H), 4.77-4.69(m, 1H), 4.64-4.55(m, 1H), 4.29(d, J=3.6Hz, 2H), 3.84(tt, J=3.6 , 11.2Hz, 1H), 3.43-3.34(m, 1H), 3.33-3.16(m, 3H), 3.15-3.04(m, 1H), 3.04-2.96(m, 1H), 2.55-2.36(m, 5H), 2.36-2.29(m, 1H) , 2.27-2.18(m, 3H), 2.17-2.11(m, 1H), 2.01-1.90(m, 4H), 1.01(t, J=7.2Hz, 3H), 0.88-0.80(m, 3H); LCMS(ESI, M+1): m / z=700.4.

[0383] Example 72 [ka] (4-(tert-butyl)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone [ka]

[0384] Step A. (4-(tert-butyl)-3H-2l4-pyrazole-2-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-flu To a solution of oro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 4-tert-butyl-1H-pyrazole (20.0 mg, 2.0 equivalents) / DMF (1 mL), EDCI (23.1 mg, 1.5 equivalents), HOBt (5.43 mg, 0.5 equivalents), and TEA (24.4 mg, 3.0 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge C18 150x25mmx5μm; A: water (10mM NH4HCO3), B: ACN, B%: 62%~92% for 9 minutes] to obtain the title compound (11.8 mg, 19% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ=9.93(s, 1H), 9.10(s, 1H), 8.16(d, J=0.4Hz, 1H), 7. 97(d, J=0.4Hz, 1H), 7.76(dd, J=6.0, 9.2Hz, 1H), 7.37-7.30(m, 2H), 7.02(d, J =2.4Hz, 1H), 5.41-5.14(m, 1H), 4.63-4.52(m, 2H), 4.20-4.11(m, 1H), 4.09-3 .95(m, 2H), 3.67-3.50(m, 2H), 3.16-2.98(m, 4H), 2.87-2.77(m, 1H), 2.14(br d, J=10.0Hz, 4H), 2.08-1.97(m, 3H), 1.97-1.88(m, 2H), 1.86-1.75(m, 3H), 1.26(s, 9H), 0.72(t, J=7.2Hz, 3H)LCMS(ESI, M+1): m / z=728.5.

[0385] Example 73 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3,4,5-trimethyl-1H-pyrazole-1-yl)methanone [ka]

[0386] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3,4,5-trimethyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) HATU (61.2 mg, 2.0 equivalents) and DIEA (31.2 mg, 3.0 equivalents) were added to a solution of (L)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equivalent) and 3,4,5-trimethyl-1H-pyrazole (26.6 mg, 3.0 equivalents) / DMF (1 mL). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 50%~80% B for 15 minutes] to obtain the title compound (6.31 mg, 11% yield) as a white solid; 1 H NMR (400MHz, chloroform-d) δ=8.99(s, 1H), 7.61-7.53(m, 1H), 7.25-7.18(m, 2H), 7.06(dd, J=2.8, 16.8Hz, 1H), 5.41-5.20(m, 1H), 4.65(br d. d, J=6.0Hz, 1H), 2.24(s, 4H), 2.21-2.12(m, 3H), 2.11-2.02(m, 3H), 2.01-1.92(m, 6H), 0.84(t, J=7.6Hz, 3H); LCMS(ESI, M+1): m / z=714.4.

[0387] Example 74 [ka] (3,5-dimethyl-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone [ka]

[0388] Step D. (3,5-dimethyl-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) To a solution of (L)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equivalent) and 3,5-dimethyl-1H-pyrazole (46.4 mg, 3.0 equivalents) / DMF (1 mL), HATU (122 mg, 2.0 equivalents) and DIEA (62.4 mg, 3.0 equivalents) were added. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by reverse-phase flash chromatography [C18, neutral conditions] to obtain the title compound (28.3 mg, 24% yield) as a yellow solid; 1¹H NMR (400MHz, chloroform-d) δ = 8.99 (s, 1H), 7.64-7.51 (m, 1H), 7.25-7.18 (m, 2H), 7.10-7.00 (m, 1H), 6.02 (s, 1H), 5.41-5.20 (m, 1H), 4.71-4.61 (m, 2H), 4.34-4.21 (m, 2H), 4.17-4.03 (m, 1H), 3.59-3.46 (m, 2H) H), 3.35-3.14(m, 3H), 3.06-2.95(m, 1H), 2.57(s, 3H), 2.54-2.44(m, 1H), 2.33-2.27(m, 4H), 2.26-2 .12(m, 5H), 2.11-2.04(m, 2H), 2.01-1.87(m, 3H), 0.84(t, J=7.6Hz, 3H); LCMS(ESI, M+1): m / z=700.4.

[0389] Example 75 [ka] (3-(tert-butyl)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone [ka]

[0390] Step A. (3-(tert-butyl)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- To a solution of (100 mg, 1.0 equivalent) and 3-tert-butyl-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equivalent) and 3-tert-butyl-1H-pyrazole (59.9 mg, 3.0 equivalent) / DMF (1 mL), HATU (91.7 mg, 1.5 equivalent) and DIEA (62.4 mg, 3.0 equivalent) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150x25 mmx5 μm; A: water (NH4HCO3), B: ACN, B%: 54%~84% 15 minutes]. The aqueous solution was extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated to obtain the title compound (27.0 mg, 23% yield) as a yellow solid; 1 H NMR (400MHz, chloroform-d) δ=8.99(s, 1H), 8.15(d, J=2.8Hz, 1H), 7.57(dd, J=5.6, 9.2Hz, 1H), 7.24-7.17(m, 2H), 7 .08-7.00(m, 1H), 6.39(d, J=2.8Hz, 1H), 5.41-5.20(m, 1H), 4.70-4.57(m, 2H), 4.34-4.22(m, 2H), 4.09-3.98(m , 1H), 3.62-3.46(m, 2H), 3.42-3.10(m, 3H), 3.06-2.94(m, 1H), 2.56-2.43(m, 1H), 2.38-2.29(m, 1H), 2.28-2.2 0(m, 3H), 2.20-2.07(m, 4H), 2.02-1.90(m, 3H), 1.35(s, 9H), 0.83(t, J=7.2Hz, 3H); LCMS(ESI, M+1): m / z=728.4.

[0391] Example 76 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-isopropyl-1H-pyrazole-1-yl)methanone [ka]

[0392] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(3-isopropyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) To a solution of (L)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equivalent) and 3-isopropyl-1H-pyrazole (53.2 mg, 3.0 equivalents) / DMF (1 mL), HATU (91.7 mg, 1.5 equivalents) and DIEA (62.4 mg, 3.0 equivalents) were added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN, B%: 50%~80% 15 minutes] to obtain the title compound (13.9 mg, 12% yield) as a yellow solid; 1¹H NMR (400MHz, chloroform-d) δ=8.97 (s, 1H), 8.16 (d, J=2.8Hz, 1H), 7.58-7.51 (m, 1H), 7.22-7.14 (m, 2H), 7.07-6.96 (m, 1H), 6.34 (d, J=2.8Hz, 1H), 5.41-5.18 (m, 1H), 4.70-4.55 (m, 2H), 4.36-4.24 (m, 2H), 4.10-3.95 (m, 1H), 3.6 0-3.45(m, 2H), 3.40-3.11(m, 3H), 3.09-2.94(m, 2H), 2.55-2.43(m, 1H), 2.38-2.28(m, 1H), 2.27-2.17(m, 4H), 2.17-2.08(m, 3H), 2.00-1.90(m, 3H), 1.31(d, J=6.8Hz, 6H), 0.82(t, J=7.2Hz, 3H); LCMS(ESI, M+1): m / z=714.3.

[0393] Example 77 [ka] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0394] Step A. Methyl 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 To a solution of -yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (100 mg, 1.0 equivalent) / DMF (2 mL), DIEA (70.0 mg, 3.0 equivalents) and PyBOP (141 mg, 1.5 equivalents) were slowly added at 25°C, and the reaction mixture was stirred at 25°C for 20 minutes. Then, methyl 1,4-oxazepan-6-carboxylate (34.4 mg, 1.2 equivalents) was slowly added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered, concentrated, and purified by preparative HPLC [C18 150x25mmx10μm; A: water (ammonium hydroxide v / v), B: ACN, B%: 40%~70% 10 min] to obtain the title compound (96.0 mg, 77% yield) as a white solid; LCMS (ESI, M+1): m / z = 696.5.

[0395] Step B. Methyl 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-carboxylate:methyl 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-carboxylate (50.0 mg, 1.0 equivalent) / MeOH (0.9 mL) was mixed with HCl·MeOH (2 M, 2 mL, 111 equivalents) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), pH adjusted to approximately 7 with NaHCO3 solid, filtered, and concentrated to obtain the title compound (45.0 mg, 78% yield) as a white solid; LCMS (ESI, M+1): m / z = 652.3.

[0396] Step C.4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-carboxylate:methyl 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-carboxylate (35.0 mg, 1.0 equivalent) / MeOH (1 mL) solution was mixed with LiOH·H2O (2 M, 1 mL, 37 equivalents). The reaction mixture was stirred at 25°C for 1 hour. The mixture was filtered and purified by reverse-phase flash (0.1% FA conditions) to obtain the title compound (18.0 mg, 48% yield, HCOOH) as a white solid; LCMS (ESI, M+1): m / z = 638.2.

[0397] Step D. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-yl)(3-methyl-1H-pyrazole-1-yl)methanone:4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-1,4-oxazepan-6-carboxylic acid (16.0 mg, 1.0 equivalent, HCOOH), 3-methyl-1H-pyrazole (5.76 mg, 3.0 equivalents), and DIEA (15.1 mg, 5.0 equivalents) / DMF (0.5 mL) were mixed with HATU (17.8 mg, 2.0 equivalents). The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN, B%: 40%~70% for 9 minutes] to obtain the title compound (4.65 mg, 26%) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d): δ=8.83 (t, J=3.6Hz, 1H), 8.11-7.98 (m, 1H), 7.67-7.52 (m, 1H), 7.23-7.09 (m, 2H), 6.84-6.62 (m, 1H), 6.29-6.17 (m, 1H), 5.43-5.20 (m, 2H), 4.51-4.31 (m, 1H), 4.28-4.17 (m, 1H), 4.04-3. 85(m, 2H), 3.83-3.54(m, 4H), 3.43-3.14(m, 3H), 3.09-2.98(m, 1H), 2.53-2.38(m, 2H), 2.36-2.31(m, 2H) , 2.30-2.23(m, 3H), 2.22-2.08(m, 5H), 2.02-1.99(m, 2H), 0.82-0.72(m, 3H); LCMS(ESI, M+1): m / z=702.2.

[0398] Example 78 [ka] (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0399] Step A. Add tert-butyl 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol (500 mg, 1.0 equivalent) / DMF (6 mL) to a mixture of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (627 mg, 3.5 equivalents) and DIEA (218 mg, 2.0 equivalents) were added. The reaction mixture was stirred at 35°C for 10 hours. The mixture was filtered and purified by reverse-phase flush [C18, 0.1% formic acid conditions] to obtain the title compound (450 mg, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 705.4.

[0400] Step B. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4,7-diazaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol:tert-butyl To a solution of 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 1.0 equivalent) / MeOH (1 mL), HCl·MeOH (2 M, 3 mL) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was adjusted to pH=7 with saturated NaHCO3 (10 mL) and extracted with DCM (2 x 10 mL). The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (120 mg, crude) as a white solid.

[0401] Step C. (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone: To a solution of 3-methyl-1H-pyrazole (20.0 mg, 1.0 equivalent) and DIEA (126 mg, 4.0 equivalents) / DCM (0.5 mL), bis(trichloromethyl) carbonate (120 mg, 1.7 equivalents) was added. The reaction mixture was stirred at 0°C for 1 hour. To the mixture, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(4,7-diazaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (118 mg, 0.8 equivalents) and DIEA (47.2 mg, 1.5 equivalents) / DCM (0.5 mL) were added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (4 x 10 mL). The organic layers were washed together with saline solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Phenomenex luna C18 150x25mmx10 μm; A: water (FA), B: ACN; B%: 20%~50% 10 minutes] and SFC [column: DAISEL CHIRALCEL OX (250 mm x 30 mm, 10 μm); A: CO2-ACN, B: MeOH (0.1% NH3·H2O); B%: 40%, isocratic elution mode] to obtain two peaks.

[0402] Peak 1: (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)(5-methyl-1H-pyrazole-1-yl)methanone: The residue was separated and purified by HPLC [column: Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN; B%: 22%~52% 10 min] to obtain the title compound (6.63 mg, 3.8% yield) as an off-white viscous substance; 1 H NMR (400MHz, DMSO-d6)δ=10.00(s, 1H), 9.16(s, 1H), 7.77(dd, J=6.0, 9.2Hz, 1H), 7.54(s, 1H), 7.4 1-7.29(m, 2H), 7.04(d, J=2.4Hz, 1H), 6.26(s, 1H), 5.59-5.34(m, 1H), 4.41-4.14(m, 6H), 3.89(br d, J=3.6Hz, 2H), 3.46(br d. ID, 3μm Mobile phase: Phase A CO2, Phase B MeOH+ACN(0.05%DEA); Gradient elution: 30% MeOH+ACN(0.05%DEA) / CO2 flow rate: 3mL / min; Detector: PDA column temperature: 35℃; Back pressure: 100Bar, t R :2.315 minutes;

[0403] Peak 2: (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone: The residue was separated and purified by HPLC [column: Phenomenex luna C18 150x25mmx10μm; A: water (FA), B: ACN; B%: 22%~52% 10 min] to obtain the title compound (11.8 mg, 6.6% yield) as an off-white viscous substance; 1 H NMR (400MHz, DMSO-d6)δ=10.03(br s, 1H), 9.13(s, 1H), 8.07(d, J=2.4Hz, 1H), 7.76(dd, J=6.0, 8.8Hz, 1H), 7.39-7.28(m, 2H), 7.05(s, 1H), 6.31(d, J=2.4Hz, 1H), 5.47-5.26(m, 1H), 4.32-4.08(m, 8H), 2.97(br d, J=5.2Hz, 2H), 2.33(br s, 2H), 2.26-1.76(m, 11H), 1.05-0.95(m, 2H), 0.90(br s, 2H), 0.71(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=713.3; SFC: 97.3%de, Column: Chiralcel OX-3 50x4.6mm ID, 3μm Mobile phase: Phase A CO2, Phase B MeOH+ACN(0.05%DEA); Gradient elution: 30% MeOH+ACN(0.05% DEA) / CO2 flow rate: 3mL / min; Detector: PDA Column temperature: 35℃; Back pressure: 100Bar, t R :2.765 minutes;

[0404] Example 79 [ka] ((3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0405] Step A. cis-1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate: 800 mg, 1.0 equivalent of cis-methyl (3R,4R)-3-methylpiperidine-4-carboxylate and 16 mL of TEA (1.54 g, 3.0 equivalents) in a solution of DCM (16 mL) were mixed with benzylcarbonochloride (1.04 g, 1.2 equivalents). The reaction mixture was stirred at 0°C for 1 hour. The mixture was concentrated and purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain the title compound (1.1 g, 69% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=7.46-7.23(m, 5H), 5.07(s, 2H), 3.91(br d, J=13.2Hz, 1H), 3.72(br d, J=12.0Hz, 1H), 3.61(s, 3H), 3.23-3.06(m, 1H), 3.02-2.80(m, 1H), 2.71(td, J=4.8, 10.0Hz, 1H), 2.15(br dd, J=3.6, 6.8Hz, 1H), 1.73-1.50(m, 2H), 0.75(d, J=6.8Hz, 3H).

[0406] Step B. 1-Benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate: Methyl (3R,4R)-3-methylpiperidine-4-carboxylate (1.3 g, 1.0 equivalent) was purified by SFC separation [column: DAIEL CHIRALPAK AD, 250 mm x 50 mm, 10 μm; A: CO2, B: MeOH (0.2% NH3H2O), B%: 15% B, 6.3 minutes] to obtain two isomers.

[0407] Peak 1: 1-Benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate (700 mg, 50% yield) was obtained as a white solid; LC-MS (ESI, M-44): m / z = 248.4; SFC > 99% ee, column: Chiralpak AD-350 x 4.6 mm ID, 3 μm; mobile phase: 5%~40% MeOH (0.05% DEA) / CO2, flow rate: 3 mL / min, detector: PDA, t R :1.054 minutes;

[0408] Peak 2: 1-Benzyl 4-methyl (3S,4S)-3-methylpiperidine-1,4-dicarboxylate (700 mg, 51% yield) was obtained as a white solid; LC-MS (ESI, M-44): m / z = 248.4; SFC > 99% ee, column: Chiralpak AD-350 x 4.6 mm ID, 3 μm; mobile phase: 5%~40% MeOH (0.05% DEA) / CO2, flow rate: 3 mL / min, detector: PDA, t R :1.162 minutes;

[0409] Step C. Methyl (3R,4R)-3-methylpiperidine-4-carboxylate: To a solution of 1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate (600 mg, 1.0 equivalent) / MeOH (12 mL), Pd / C (60 mg, 10% purity) was added. The reaction mixture was degassed and purged three times with nitrogen. The reaction mixture was stirred at 25°C under an H2 atmosphere (15 Psi) for 2 hours. The mixture was filtered and concentrated to obtain the title compound (300 mg, crude) as a yellow oil; 1 H NMR (400MHz, DMSO-d6) δ=3.58(s, 3H), 2.87(td, J=4.0, 12.2Hz, 1H), 2.66(br dd.

[0410] Step D. Methyl (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylate:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol (150 mg, 1.0 equivalent), methyl To a solution of (3R,4R)-3-methylpiperidine-4-carboxylate (47.8 mg, 1.2 equivalents) / DMAC (2 mL), K3PO4 (161 mg, 3.0 equivalents) and 4A molecular sieve (30.0 mg) were added. The reaction mixture was stirred at 60°C for 0.5 hours. The mixture was filtered, the filtrate was diluted with H2O (20 mL), and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with saline solution (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (200 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0411] Step E. (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylic acid:methyl (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylate (200 mg, 1.0 equivalent) / MeOH (2 mL) was mixed with LiOH·H2O (2 M, 2.00 mL, 13 equivalents). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (100 mg, 44% yield) as a white solid; LCMS (ESI, M+1): m / z = 636.5.

[0412] Step F.((3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:(3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxyna To a solution of phthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylic acid (90.0 mg, 1.0 equivalent) and HATU (161 mg, 3.0 equivalents) / DMF (1 mL), 3-methyl-1H-pyrazole (17.4 mg, 1.5 equivalents) and DIEA (91.5 mg, 5.0 equivalents) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3); B: ACN, B%: 55%~85% for 9 minutes] to obtain the title compound (10 mg, 10% yield) as a white solid; 1 ¹H NMR (400MHz, chloroform-d) δ=9.00 (br d, J=4.0Hz, 1H), 8.22-8.13 (m, 1H), 7.64-7.50 (m, 1H), 7.23-7.16 (m, 2H), 7.13-6.95 (m, 1H), 6.36-6.18 (m, 1H), 5.48-5.12 (m, 1H), 4.49-4.23 (m, 3H), 4.21-4.13 (m, 1H), 3.91 (br dd, J=2.4, 12.8Hz, 1H), 3.83-3.65(m, 1H), 3.46-3.09(m, 3H), 3.06-2.91 (m, 1H), 2.75-2.57(m, 1H), 2.56-2.40(m, 1H), 2.39-2.29(m, 4H), 2.24(br s, 1H), 2.14 (br dd, J=3.8, 8.2Hz, 2H), 2.00-1.84 (m, 6H), 1.04-0.92 (m, 3H), 0.82 (q, J=7.6Hz, 3H); LCMS (ESI, M+1): m / z=700.5.

[0413] Example 80 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(4-isopropyl-1H-pyrazole-1-yl)methanone [ka]

[0414] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-yl)(4-isopropyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl HATU (73.4 mg, 1.5 equivalents) and DIEA (49.9 mg, 3.0 equivalents) were added to a solution of )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)piperidine-4-carboxylic acid (80.0 mg, 1.0 equivalent) and 4-isopropyl-1H-pyrazole (42.5 mg, 3.0 equivalents) / DMF (1 mL). The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150x25 mmx5 μm; A: water (NH4HCO3), B: ACN, B%: 62%~92% 15 minutes]. The aqueous solution was extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated to obtain the title compound (4.79 mg, 15% yield) as a white solid; 1¹H NMR (400MHz, chloroform-d) δ=8.99(s, 1H), 8.01(s, 1H), 7.64(s, 1H), 7.58(dd, J=5.6, 9.2Hz, 1H), 7.24-7.18(m, 2H), 7.05(dd, J=2.4, 18.4Hz, 1H), 5.43-5.20(m, 1H), 4.73-4.58(m, 2H), 4.35-4.27(m, 2H), 4.10-3.98(m, 1H), 3.5 8-3.46(m, 2H), 3.41-3.14(m, 3H), 3.08-2.95(m, 1H), 2.91-2.83(m, 1H), 2.57-2.44(m, 1H), 2.39-2.30(m, 1H), 2.27-2.08(m, 7H), 2.04-1.92(m, 3H), 1.26(d, J=6.8Hz, 6H), 0.83(t, J=6.8Hz, 3H); LCMS(ESI, M+1): m / z=714.4.

[0415] Example 81 [ka] ((2S,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0416] Step A. tert-butyl (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate:To a solution of 3-methyl-1H-pyrazole (192 mg, 1.0 equivalent) / DCM (3 mL), bis(trichloromethyl) carbonate (410 mg, 0.59 equivalents) and TEA (472 mg, 2.0 equivalents) were slowly added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. Tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (500 mg, 1.0 equivalent) and TEA (472 mg, 2.0 equivalents) / DCM (3 mL) were added at 0°C. The reaction mixture was stirred at 40°C for 2 hours. The mixture was poured into water (10 mL) and extracted with DCM (3 x 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to obtain the title compound (500 mg, 88%) as a white oily substance; 1 H NMR (400MHz, chloroform-d) δ=8.00(d, J=2.4Hz, 1H), 6.14(d, J=2.4Hz, 1H), 4.82(br d, J=2.4Hz, 2H), 4.06-3.81(m, 2H), 3.29-3.03(m, 2H), 2.30(s, 3H), 1.50(s, 9H), 1.38(d, J=7.2Hz, 6H); LCMS(ESI, M+23): m / z=345.1.

[0417] Step B. ((2R,6S)-2,6-dimethylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone: A solution of tert-butyl (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate (400 mg, 1.0 equivalent) / HCl·MeOH (2 M, 8.00 mL, 12.9 equivalents) was stirred at 25°C for 1 hour. The mixture was concentrated, dissolved in MeOH (5 mL), adjusted to pH=7 with NaHCO3 solid, concentrated under reduced pressure, and dried. The mixture was dissolved in DCM (5 mL) and filtered. The filtrate was concentrated under reduced pressure and dried to obtain the title compound (300 mg, crude) as a white oily substance; LCMS (ESI, M+1): m / z = 223.2.

[0418] Step C. ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone:7-( To a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (600 mg, 1.0 equivalent) / DMF (6 mL), PYBOP (845 mg, 1.5 equivalents) and DIEA (420 mg, 3.0 equivalents) were added. The reaction mixture was stirred at 25°C for 0.5 hours. ((2R,6S)-2,6-dimethylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone (289 mg, 1.2 equivalents) was added to the mixture. The reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture was quenched with water (15 mL) at 0°C and extracted with ethyl acetate (3 x 10 mL). The organic layers were washed together with saturated brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; A: water (NH4HCO3), B%: ACN, B%: 55%~85% 20 minutes] to obtain the title compound (500 mg, 99% yield) as a white solid; LCMS (ESI, M+1): m / z = 759.4.

[0419] Step D. ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone:((2R,6S)-4-(7-(8-ethyl-7-fluorine A solution of lo-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone (150 mg, 1.0 equivalent) / HCl·MeOH (2 M, 3.00 mL, 30 equivalents) was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL), pH adjusted to 7 with NaHCO3 solid, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge 150x25 mmx5 μm; A: water (NH4HCO3), B%: ACN, B%: 52%~82% for 9 minutes] to obtain the title compound (55.3 mg, 96% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=9.92(s, 1H), 9.22(s, 1H), 8.13(d, J=2.4Hz, 1H), 7.77(dd, J=6.0, 9.2Hz , 1H), 7.43-7.29(m, 2H), 7.02(d, J=2.4Hz, 1H), 6.33(d, J=2.8Hz, 1H), 5.42-5.13(m, 1H), 4.66(br s, 2H), 4.36-4.21(m, 2H), 4.20-4.14(m, 1H), 4.12-3.98(m, 3H), 3.15-2.96(m, 3H) ), 2.88-2.76(m, 1H), 2.40-2.31(m, 1H), 2.25(s, 3H), 2.18-1.98(m, 4H), 1.77(br s, 3H), 1.54-1.37 (m, 6H), 0.73 (t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=715.4.

[0420] Example 82 [ka] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0421] Step A. tert-butyl 3-methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate: To a solution of 3-methyl-1H-pyrazole (205 mg, 1.0 equivalent) / DCM (3 mL), bis(trichloromethyl) carbonate (490 mg, 0.66 equivalents) and TEA (505 mg, 2.0 equivalents) were added at 0°C. The reaction mixture was stirred at 0°C for 3 hours. Tert-butyl 3-methylpiperazine-1-carboxylate (500 mg, 1.0 equivalent) and TEA (505 mg, 2.0 equivalents) / DCM (3 mL) were added at 0°C. The reaction mixture was stirred at 40°C for 2 hours. The mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain the title compound (280 mg, 34% yield) as a colorless oil; 1 H NMR (400MHz, chloroform-d) δ=8.05-7.92(m, 1H), 6.13(d, J=2.8Hz, 1H), 4.78(br s, 1H), 4.41(br d, J=12.4Hz, 1H), 4.18-4.03(m, 1H), 3.95-3.74(m, 1H), 3.32(dt, J=3.6, 12.0Hz, 1H), 3.21- 2.88 (m, 2H), 2.28 (s, 3H), 1.46 (s, 9H), 1.30 (d, J=6.8Hz, 3H); LCMS (ESI, M+23): m / z=331.1.

[0422] Step B. (3-methyl-1H-pyrazole-1-yl)(2-methylpiperazine-1-yl)methanone:A solution of tert-butyl 3-methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate (230 mg, 1.0 equivalent) / HCl·MeOH (2 M, 4.6 mL, 12.3 equivalents) was stirred at 25°C for 2 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to approximately pH 7 with NaHCO3 solid, filtered, and concentrated to obtain the title compound (153 mg, 97% yield) as a white solid; LCMS (ESI, M+1): m / z = 209.2.

[0423] Step C. (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone:7-(8-ethyl-7-fluoro-3-(meth To a solution of xymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (380 mg, 1.0 equivalent) / DMF (6 mL), DIEA (266 mg, 3.0 equivalent) and PyBOP (535 mg, 1.5 equivalent) were slowly added at 25°C, and the reaction mixture was stirred at 25°C for 20 minutes. (3-methyl-1H-pyrazole-1-yl)(2-methylpiperazine-1-yl)methanone (150 mg, 1.0 equivalent) was slowly added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered and purified by reverse-phase flush (0.1% FA conditions) to obtain the title compound (700 mg, crude, HCOOH) as a colorless oil; LCMS (ESI, M+1): m / z = 745.4.

[0424] Step D. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone: (4-(7-(8-ethyl-7-fluoro-3-(methoxy) A solution of methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)(3-methyl-1H-pyrazole-1-yl)methanone (300 mg, 1.0 equivalent, HCOOH) / HCl·MeOH (2M, 5 mL, 26 equivalents) was stirred at 25°C for 2 hours. The mixture was concentrated, diluted with MeOH (3 mL), pH adjusted to approximately 7 with NaHCO3 solid, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150x40 mmx10 μm; A: water (NH4HCO3), B: ACN, B%: 40%~70% 20 minutes] to obtain the title compound (81.0 mg, 30% yield, 2 steps) as a white solid; 1 H NMR (400MHz, DMSO-d6)δ=10.04-9.82(m, 1H), 9.20(s, 1H), 8.13(t, J=2.4Hz, 1H), 7.77(dd, J=6.0, 9. 2Hz, 1H), 7.43-7.28(m, 2H), 7.13-6.94(m, 1H), 6.33(d, J=2.8Hz, 1H), 5.44-5.16(m, 1H), 4.85-4.65 (m, 1H), 4.51-4.39(m, 1H), 4.39-4.25(m, 2H), 4.21-3.97(m, 3H), 3.96-3.83(m, 2H), 3.30-3.24(m, 1 H), 3.15-3.06(m, 2H), 2.89-2.74(m, 1H), 2.43-2.32(m, 1H), 2.25(s, 3H), 2.19-1.96(m, 4H), 1.77(br s, 3H), 1.37(dd, J=6.8, 10.0Hz, 3H), 0.79-0.65(m, 3H); LCMS(ESI, M+1): m / z=701.3.

[0425] Example 83 [ka] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0426] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4-methylpiperidine-4-carboxylate:7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-ol (2.3g, 1.0 equivalent) and methyl To a solution of 4-methylpiperidine-4-carboxylate (1.0 g, 1.2 equivalents, HCl salt) / DMF (20 mL), PyBOP (3.24 g, 1.5 equivalents) and DIEA (5.36 g, 10 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was filtered and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (3.4 g, 87% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 694.4.

[0427] Step B. To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4-methylpiperidine-4-carboxylate (3.4g, 1.0 equivalent) / MeOH (15mL), HCl·MeOH (2M, 30mL, 12 equivalents) was added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated. The residue was basicized with saturated NaHCO3 (80 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% NH3·H2O conditions] to obtain the title compound (1.9 g, 55% yield) as a white solid; LCMS (ESI, M+1): m / z = 650.4.

[0428] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4-methylpiperidine-4-carboxylate (1.9g, 1.0 equivalent) / MeOH (15mL) solution was mixed with LiOH·H2O (2M / H2O, 15mL, 10 equivalents). The reaction mixture was stirred at 25°C for 4 hours. The mixture was filtered, and the filtrate was purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (1.12 g, 34% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 636.4.

[0429] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone:1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1- To a solution of (yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-4-methylpiperidine-4-carboxylic acid (300 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (58.1 mg, 1.5 equivalents) / DMF (3 mL), HATU (359 mg, 2.0 equivalents) and DIEA (366 mg, 6.0 equivalents) were added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150x40mmx10μm; A: water (NH4HCO3), B: ACN, B%: 52%~82% for 20 minutes] to obtain the title compound (8.22 mg, 2.4% yield) as a yellow solid; 1 ¹H NMR (400MHz, chloroform-d) δ=8.93 (d, J=2.1Hz, 1H), 8.19 (d, J=2.8Hz, 1H), 7.56-7.48 (m, 1H), 7.20-7.10 (m, 2H), 7.01-6.88 (m, 1H), 6.22 (d, J=2.8Hz, 1H), 5.40-5.17 (m, 1H), 4 .34-4.18(m, 4H), 3.75-3.59(m, 2H), 3.36-3.11(m, 3H), 3.04-2.93(m, 1H), 2.89-2.76 (m, 2H), 2.50-2.41(m, 1H), 2.33(s, 3H), 2.27-2.12(m, 4H), 1.97-1.89(m, 5H), 1.64(br d, J=1.1Hz, 3H), 0.81(t, J=7.4Hz, 3H); LCMS (ESI, M+1): m / z=700.4.

[0430] Example 84 [ka] 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azetidine-3-yl)-1-(3-methyl-1H-pyrazole-1-yl)ethane-1-one [ka]

[0431] Step A. 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azetidine-3-yl)acetic acid: 2-(azetidine-3-yl)acetic acid (154 mg, 2 equivalents, HCl), DIEA (327 mg, 5.0 equivalents) / DMF (3.00 mL) were mixed with 4A molecular sieve (20 mg). The reaction mixture was stirred at 25°C for 10 minutes. Next, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalen-2-ol (300 mg, 1.0 equivalent) was added. The reaction mixture was stirred at 40°C for 3 hours. The mixture was filtered and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to obtain the title compound (320 mg, 96% yield, HCOOH) as a white solid; 1H NMR (400MHz, DMSO-d6)δ 10.25-9.58(m, 1H), 8.93(s, 1H), 7.76(dd, J=6.0, 9.2Hz, 1H), 7.41-7.27(m, 2H), 7.00(d, J=2.4Hz, 1H), 5.46-5.2 2(m, 1H), 5.06-4.89(m, 1H), 4.62-4.38(m, 2H), 4.28-3.96(m, 4H), 3.23-3.08(m, 5H), 2.95-2.85(m, 1H), 2.76(br d, J=7.2Hz, 2H), 2.43-2.28(m, 1H), 2.22-1.98(m, 4H), 1.94-1.74(m, 3H), 0.78-0.63(m, 3H); LCMS(ESI, M+1): m / z=608.3.

[0432] Step B. 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azetidine-3-yl)-1-(3-methyl-1H-pyrazole-1-yl)ethane-1-one:2-(1-(7-(8-ethyl-7-flu To a solution of ruoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)azetidine-3-yl)acetic acid (100 mg, 1.0 equivalent) and HATU (93.9 mg, 1.5 equivalents) / DMF (1.00 mL), DIEA (106 mg, 5.0 equivalents) was added. The reaction mixture was stirred at 25°C for 0.5 hours. Then 3-methyl-1H-pyrazole (27.0 mg, 2.0 equivalents) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 0.5 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150x25mmx5μm; A: water (NH4HCO3), B: ACN; B%: 45%~75% B for 9 minutes] to obtain the title compound (5.05 mg, 4.2% yield) as a white solid; 1¹H NMR (400MHz, chloroform-d) δ=8.79 (s, 1H), 8.15 (d, J=2.8Hz, 1H), 7.60-7.49 (m, 1H), 7.21-7.09 (m, 2H), 6.97-6.78 (m, 1H), 6.30 (d, J=2.8Hz, 1H), 5.42-5.18 (m, 1H), 5 .03-4.51(m, 2H), 4.45-4.07(m, 4H), 3.57-3.14(m, 6H), 3.09-2.95(m, 1H), 2.54- 2.41(m, 1H), 2.34(d, J=1.2Hz, 3H), 2.31-2.21(m, 2H), 2.19-2.07(m, 3H), 1.96(br s, 2H), 0.80 (t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=672.2.

[0433] Example 85 [ka] ((3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-yl)(3-methyl-1H-pyrazole-1-yl)methanone [ka]

[0434] Step A. Methyl (3S,4S)-3-methylpiperidine-4-carboxylate: To a solution of 1-benzyl 4-methyl (3S,4S)-3-methylpiperidine-1,4-dicarboxylate (700 mg, 1.0 equivalent) / MeOH (14 mL), Pd / C (70 mg, 10% purity) was added. The reaction mixture was degassed, purged three times with nitrogen, and stirred at 25°C for 2 hours under an H2 atmosphere (15 Psi). The mixture was filtered and concentrated to obtain the title compound (350 mg, crude) as a yellow oil; 1H NMR (400MHz, DMSO-d6) δ=3.59(s, 3H), 2.88(td, J=4.0, 12.0Hz, 1H), 2.73-2.62(m, 2H), 2.57(td, J=4.4, 10 .8Hz, 1H), 2.46-2.39(m, 1H), 2.00(tdd, J=3.2, 7.2, 10.4Hz, 1H), 1.71-1.39(m, 2H), 0.85(d, J=7.2Hz, 3H).

[0435] Step B. Methyl (3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3-methylpiperidine-4-carboxylate:5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine-7-yl)naphthalene-2-ol (500 mg, 1.0 equivalent) and methyl To a solution of (3S,4S)-3-methylpiperidine-4-carboxylate (199 mg, 1.5 equivalents) / DMF (10 mL), K3PO4 (537 mg, 3.0 equivalents) and 4A molecular sieve (100 mg) were added. The reaction mixture was stirred at 60°C for 0.5 hours. The mixture was filtered, diluted with H2O (50 mL), and extracted with ethyl acetate (2 x 20 mL). The organic layers were washed together with saline solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (400 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 650.5.

[0436] Step C. (3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-...

Claims

1. Formula (Ia) or (Ib): 【Chemistry 1】 [In the formula: A is, 【Chemistry 2】 Selected from; B is, 【Transformation 3】 Selected from; X is a bond, N, methylene, ethylene, or propylene; D is CO or SO ２ And; E is N or CR １０ And; Y is bond, O, or NR ５ And; Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl, or aryl, and Z is halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR １２ , N(R １２ ) ２ COR １２ , and may be substituted with one to three substituents selected from cyano; Each R ２ is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, spirocyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF ２ , HC(=O)-, -OC(O)N(R ５ ), ２ , -CO ２ R ５ , -CO ２ N(R ５ ), ２ , =CH ２ , =CHR １１ , or =C(R １１ ), ２ and the R ２ may be substituted with one or more R ４ ; R ３ is an aryl or heteroaryl, and the aryl or heteroaryl has one or more R ８ It is also fine if it is replaced with; R ４ is hydrogen, halogen, or C1-C3 alkyl; Each R ５ These are independently hydrogen or C1-C3 alkyl; Each R ６ R is independently hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl, or heteroaryl, or two R ６ They together form a C3-C6 cycloalkyl or heterocycle; Each R ８ These are independently halogens, cyano, hydroxy, cycloalkyl, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, or -S-C1-C3 haloalkyl; Each R ９ These are independently hydrogen, C1-C4 alkyl, methoxy, and CH ２ - Methoxy, hydroxy, CH ２ F, CF ２ CF ３ , C-CN, cyclopropyl, or two R on the same or different carbon atoms ９ Together they form a C1-C2 alkylene bridge or spiro ring; Each R １０ Hydrogen, halogens, CH ２ F, CHF ２ CF ３ C1-C3 alkyl, cyclopropyl, OR １２ , or N(R １２ ) ２ And; Each R １１ is a halogen or a C1-C3 alkyl group; R １２ is a C1-C3 alkyl group; and R １３ [is H, or forms a ring with A] The compound indicated by, or a pharmaceutically acceptable salt thereof.

2. Equation (Ia) is Equation IA: 【Chemistry 4】 That is, The compound or salt according to claim 1.

3. Equation (Ia) is Equation IB: 【Transformation 5】 That is, The compound or salt according to claim 1.

4. B 【Transformation 6】 That is, A compound or salt thereof according to any one of claims 1 to 3.

5. A compound or salt according to any one of claims 1 to 4, wherein X is methylene.

6. A compound or salt according to any one of claims 1 to 4, wherein X is ethylene.

7. A compound or salt according to any one of claims 1 to 4, wherein X is a bond.

8. A compound or salt according to any one of claims 1 to 4, wherein X is propylene.

9. A compound or salt according to any one of claims 1 to 8, wherein Y is O.

10. Y is NR ５ The compound or salt according to any one of claims 1 to 8.

11. A compound or salt according to any one of claims 1 to 8, wherein Y is a bond.

12. A compound or salt according to any one of claims 1 to 8, wherein Z is hydrogen.

13. The compound or salt according to any one of claims 1 to 8, wherein Z is a C1-C4 alkyl group and may be substituted with 1 to 3 halogens.

14. The compound or salt according to any one of claims 1 to 8, wherein Z is an aryl compound and may be substituted with 1 to 3 halogens, cyanos, or C1-C4 haloalkyl groups.

15. The compound or salt according to claim 14, wherein the aryl is phenyl.

16. The compound or salt according to any one of claims 1 to 8, wherein Z is a heteroaryl compound and may be substituted with one or two C1-C4 alkyl groups.

17. The compound or salt according to claim 16, wherein the heteroaryl is pyrazolyl or pyridinyl.

18. The compound or salt according to any one of claims 1 to 8, wherein Z is a heterocyclyl and may be substituted with an oxo.

19. The compound or salt according to claim 18, wherein the heterocyclyl is an oxazolidine.

20. Two R ９ The compound or salt according to any one of claims 1 to 8, wherein the compounds together form a methylene crosslink.

21. Two R ９ The compound or salt according to any one of claims 1 to 8, wherein the compounds together form an ethylene crosslink.

22. R ２ The compound or salt according to claim 4, wherein is fluoro.

23. R ２ ga = CHR １１ The compound or salt according to claim 19.

24. R ２ ga = C(R １１ ) ２ The compound or salt according to claim 19.

25. R ３ is an aryl, and one or more R ８ The compound or salt according to any one of claims 1 to 24, which may be substituted with

26. The aryl is naphthyl, and there is one or more R ８ The compound or salt according to claim 25, which may be substituted with

27. Naphthyl has one R ８ It is replaced by the one R ８ The compound or salt according to claim 26, wherein is a hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl.

28. Naphthyl has two R ８ It is replaced by the one R ８ R is hydroxyl, and the other R is ８ R is a C1-C3 alkyl, halogen, or C2-C4 alkynyl, or one of the R ８ One is halogen, and the other R ８ The compound or salt according to claim 26, wherein is a C1-C3 alkyl or C2-C4 alkynyl.

29. Naphthyl has 3 R ８ It is replaced by the first R ８ It is hydroxyl, and the second R ８ It is a halogen, and the third R ８ The compound or salt according to claim 26, wherein is a C1-C3 alkyl or C2-C4 alkynyl.

30. The aryl is phenyl, and there is one or more R ８ The compound or salt according to claim 26, which may be substituted with

31. R with one phenyl group ８ It is replaced by the R ８ The compound or salt according to claim 30, wherein is a C1-C3 alkyl group.

32. Two R's of phenyl ８ It is replaced by the one R ８ One is halogen, and the other R ８ The compound or salt according to claim 30, wherein is a C1-C3 alkyl group.

33. Two R's of phenyl ８ It is replaced by the one R ８ One is halogen, and the other R ８ The compound or salt according to claim 30, wherein is a cycloalkyl group.

34. R ３ A compound or salt according to any one of claims 1 to 24, wherein is a heteroaryl compound.

35. The heteroaryl is indazolyl, and one or more R ８ The compound or salt according to claim 34, which may be substituted with

36. Two R units of indazolyl ８ It is replaced by the one R ８ One is halogen, and the other R ８ The compound or salt according to claim 35, wherein is a C1-C3 alkyl group.

37. R ４ A compound or salt according to any one of claims 1 to 36, wherein is a halogen.

38. The compound or salt according to claim 37, wherein the halogen is fluorine.

39. The compound 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 and selected from its pharmaceutically acceptable salts, The compound or salt according to claim 1.

40. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

41. A method for inhibiting intracellular KRas G12S and / or KRas G12C activity, comprising contacting cells in which inhibition of KRas G12S and / or KRas G12C activity is desired with an effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

42. A method for treating cancer, comprising administering to a patient having cancer a therapeutically effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

43. The method according to claim 42, wherein the therapeutically effective dose of the compound is approximately 0.01 to 100 mg / kg per day.

44. The method according to claim 43, wherein the therapeutically effective dose of the compound is approximately 0.1 to 50 mg / kg per day.

45. Cancers of the heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lungs: Bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; Digestive system: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (cancer, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, bipoma), Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibrous tumor) Organ cancers: colon (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary system: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma (chondrodystostoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymal cell tumor, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecological system: Uterus (endometrial cancer, serous cystadenoma, mucinous cystadenoma, unclassifiable cancer) The method according to claim 42, selected from the group consisting of: granulosa theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma; vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); hematological system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

46. The method according to claim 42, wherein the cancer is a KRas G12S-related cancer.

47. The method according to claim 42, wherein the cancer is a KRas G12C-associated cancer.

48. The method according to claim 46 or 47, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

49. A method of treating cancer in patients who require treatment, (a) confirming that the cancer is associated with a KRas G12S mutation or a KRas G12C mutation (e.g., a KRas G12S-associated cancer or a KRas G12C-associated cancer); and (b) Administering to a patient a therapeutically effective amount of the compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40. A method that includes this.

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