Prodrugs of PAN-KRas inhibitors

Abstract

The present invention relates to specific compounds that inhibit various mutant forms of KRas, i.e. Prodrugs of pan-KRas inhibitors. In particular, the present invention relates to prodrugs of these pan-KRas compounds, pharmaceutical compositions comprising these prodrugs, and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to specific compounds that inhibit multiple mutant forms of KRas, namely prodrugs of pan-KRas inhibitors. In particular, the present invention relates to prodrugs of pan-KRas compounds, pharmaceutical compositions comprising these prodrugs, and methods of use thereof. Background Art

[0002] Kirsten rat sarcoma type 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras oncogene family. KRas acts as a molecular switch that cycles between an inactive (GDP-bound) and an active (GTP-bound) state to convert upstream cellular signals received from a variety of tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancy was observed more than three decades ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas. KRas mutations at codons 12, 13, 61 and other positions in the KRas primary amino acid sequence are present in 88% of all pancreatic cancer patients, 50% of all colon / rectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (e.g., see Prior et al., (2020) Cancer Res 80:2969–74). Recent publications have also suggested that wild-type Kras inhibition may be a therapeutic approach for KRas. WT A viable treatment strategy for cancers with PD-1 dependence (e.g., see Bery et al., (2020) Nat. Commun. 11:3233).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types make KRas a highly attractive target for cancer therapy by the pharmaceutical industry. Despite three decades of extensive discovery efforts to develop KRas inhibitors for the treatment of cancer, no KRas inhibitor has demonstrated sufficient safety and / or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. [Clinical Cancer Research] 21(8): 1797-1801).

[0005] Compounds that inhibit KRas activity remain highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and recent advances in covalently targeting the allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there remains a continuing interest and effort in developing KRas inhibitors, particularly inhibitors that activate KRas mutants.

[0006] Compounds having the formula: 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol Described in PCT International Application No. PCT / US2021 / 010065 (WO 2022 / 132200), as a type of Example 140.

[0007] Similarly, the compound having the formula: (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione Described in PCT International Application No. PCT / US2021 / 063722 (WO 2022 / 133038) as a type of Example 196.

[0008] There is a need in the art to develop prodrugs of these and similar compounds that are converted to these compounds in vivo and thus would be effective for treating KRas-mediated cancers. Summary of the invention

[0009] In one aspect, the present invention provides a prodrug of a compound having the following structure: 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0010] This compound is described in PCT International Application No. PCT / US2021 / 010065 (WO 2022 / 132200) as a species of Example 140.

[0011] In another aspect, the present invention provides a prodrug of a compound having the following structure: (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0012] This compound is described in PCT International Application No. PCT / US2021 / 063722 (WO 2022 / 133038) as a species of Example 196.

[0013] In one aspect, a prodrug is provided having the general structure of Formula (I): or a pharmaceutically acceptable salt thereof, in R 1 and R 2 Independently selected from the group consisting of: H.R 3 -*, R 3 -O-CH 2 -*、 The condition is R 1 and R 2 Only one of them can be H; A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ; or R on nitrogen 3 and R 4 connected to form a heterocyclic ring; and R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0014] In one aspect, R 1 is H and R 2 YesR 3 -*, R 3 -O-CH 2 -*、

[0015] In another aspect, R 2 is H and R 1 YesR 3 -*, R 3 -O-CH 2 -*、

[0016] In one aspect, a prodrug is provided having the structure: and pharmaceutically acceptable salts thereof.

[0017] In another aspect of the invention, a prodrug is provided having the following general structure: or a pharmaceutically acceptable salt thereof, Where R 1 It is H, R 3 -*, R 3 -O-CH 2 -*、 A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ; R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0018] In one aspect, the compound having Formula II is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

[0019] In another aspect of the present invention, a prodrug is provided having the following structure: or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: R 3 -*, R 3 -O-CH 2 -*、 A is CH or N; R3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ;as well as R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0020] In one aspect, the compound having Formula III is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

[0021] In another aspect of the invention, a prodrug is provided having the following general structure: or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: R 3 -*, R 3 -O-CH 2 -*、 A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ;as well as R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0022] In one aspect, the compound having formula IV is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

[0023] In another aspect of the present invention, pharmaceutical compositions are provided, which contain a therapeutically effective amount of a prodrug compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0024] In yet another aspect of the invention, a method for inhibiting the activity of a cell containing wild-type KRas or one or more KRas mutations (e.g., KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H) in the cell is provided, the method comprising contacting the cell with a prodrug of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0025] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a prodrug compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0026] Also provided are methods for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a prodrug compound or pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof.

[0027] Also provided herein is a method of treating a KRas wild-type, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a prodrug compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0028] Also provided herein is a prodrug compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

[0029] Also provided herein is a prodrug compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating cancer.

[0030] Also provided herein are prodrug compounds or pharmaceutically acceptable salts thereof for use in inhibiting KRas wild type or various types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0031] Also provided herein are prodrug compounds as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating KRas wild-type associated diseases or disorders or KRas mutants G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated diseases or disorders.

[0032] Also provided herein is the use of a prodrug compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0033] Also provided herein is the use of a prodrug compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of a wild-type form of KRas or a mutant form of KRas comprising mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0034] Also provided herein is the use of a prodrug compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a KRas wild-type associated disease or disorder or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder.

[0035] Also provided herein are methods for treating cancer in a patient in need thereof, the methods comprising (a) determining that the cancer is associated with KRas wild-type or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations (i.e., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); and (b) administering to the patient a therapeutically effective amount of a prodrug compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0036] One potential utility of the prodrugs of the pan-KRas inhibitors described herein is for the treatment of cancers that develop resistance after long-term treatment with KRas G12C inhibitors. Thus, embodiments of the invention include those in which patients with cancers that have been treated with G12C inhibitors have become ineffective or less effective with the prodrug compounds described herein due to the emergence of resistance-conferring mutations.

[0037] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors such as adagrasib (MRTX849) or sotograciib (AMG510) may result in the incorporation of additional mutations that confer resistance to adagrasib. These mutations may confer resistance through a number of mechanisms.

[0038] The mutation of the mutant cysteine ​​at codon 12 to another amino acid will make the current covalent KRasG12C inhibitor invalid because the current inhibitor forms a covalent bond with the mutant cysteine ​​amino acid side chain. Similarly, in patients with a wild-type KRas allele in addition to the KRas G12C mutant allele, the mutation of the wild-type codon 12 glycine to another codon will allow bypass signaling by novel mutant proteins in these tumors. The library of codon 12 mutations that can occur with single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, G12C. In addition to G12S and G12R, the library of codon 12 mutations that can occur with single nucleotide base substitutions of cysteine ​​codon 12 includes mutations that are not often observed in cancer, G12Y, G12F and G12W.

[0039] Second site mutations can also occur in another position in the KRas G12C mutant gene that confers resistance to KRas G12C inhibitor treatment. These mutations can confer resistance through different mechanisms. RAS proteins are small GTPases that usually cycle between an active GTP-bound state and an inactive GDP-bound state. RAS proteins are loaded with GTP through guanine nucleotide exchange factors (GEFs; e.g., SOS1), which are activated by upstream receptor tyrosine kinases, thereby triggering subsequent interactions with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is significantly enhanced by GTPase activating proteins (GAPs). Mutations at codons 12 and 13 in RAS proteins impair GAP-stimulated GTP hydrolysis, leaving RAS primarily in a GTP-bound active state. In current clinical development, covalent KRas G12C inhibitors only bind to GDP-bound KRas G12C. Mutations such as the Q61 codon mutation (which may or may not occur on the same allele as the G12C mutation) reduce the intrinsic GTPase activity of KRas and may represent a mechanism of resistance to treatment with KRas G12C inhibitors by shifting KRas to a GTP-loaded state where it is less susceptible to covalent inhibition. Co-mutations such as R68, H95, and Y96 may be present with KRas G12C mutations and may reduce the binding affinity of KRas G12C inhibitors to the Switch II binding pocket.

[0040] The prodrug compounds of the invention described herein may exhibit activity against one or more common and uncommon codon 12 mutations occurring in KRas protein that reduce the binding of KRas G12C inhibitors to the KRas protein. DETAILED DESCRIPTION

[0041] The present invention relates to specific compounds that inhibit various mutant forms of KRas, i.e., prodrugs of pan-KRas inhibitors that inhibit KRas wild type and / or various mutant forms of KRas (e.g., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations). In particular, the present invention relates to compounds that are prodrugs of compounds having the formula: 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0042] This compound is described in PCT International Application No. PCT / US2021 / 010065 (WO 2022 / 132200) as a species of Example 140. The PCT application also describes a method for preparing this compound.

[0043] Similarly, the compound having the formula: (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione Described in PCT International Application No. PCT / US2021 / 063722 (WO 2022 / 133038), as a species of Example 196. The PCT application also describes a method for preparing this compound.

[0044] When administered in vivo, the prodrugs of the invention inhibit the activity of KRas wild type and / or KRas mutants such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, pharmaceutical compositions comprising therapeutically effective amounts of these compounds and methods of use thereof. definition

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0046] As used herein, "wild-type KRas" refers to a non-mutated form of the mammalian KRas protein. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "wild-type KRas inhibitor" refers to a compound of the present invention represented by formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of wild-type KRas G12A. As used herein, "wild-type KRas-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having wild-type KRas. A non-limiting example of a wild-type KRas-related disease or disorder is a wild-type KRas-related cancer.

[0047] As used herein, "KRas G12A" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of alanine for glycine 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.Gly12Asp. As used herein, "KRas G12A inhibitor" refers to a compound of the present invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12A. As used herein, "KRas G12A-related disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G12A mutation or having a KRas G12A mutation. A non-limiting example of a KRas G12A-related disease or disorder is a KRas G12A-related cancer.

[0048] As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of cysteine ​​in place of glycine 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.Gly12Asp. As used herein, "KRas G12C inhibitor" refers to a compound of the invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12C. As used herein, "KRas G12C-related disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G12C mutation or having a KRas G12C mutation. A non-limiting example of a KRas G12C-related disease or disorder is a KRas G12CD-related cancer.

[0049] As used herein, "KRas G12D" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of aspartic acid in place of glycine 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.Gly12Asp. As used herein, "KRas G12D inhibitor" refers to a compound of the invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12D. As used herein, "KRas G12D-related disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G12D mutation or having a KRas G12D mutation. A non-limiting example of a KRas G12D-related disease or disorder is a KRas G12D-related cancer.

[0050] As used herein, "KRas G12R" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of arginine for glycine 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.Gly12Asp. As used herein, "KRas G12R inhibitor" refers to a compound of the present invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-associated disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G12R mutation or having a KRas G12R mutation. A non-limiting example of a KRas G12R-associated disease or disorder is a KRas G12R-associated cancer.

[0051] As used herein, "KRas G12S" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of serine for glycine 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.Gly12Asp. As used herein, "KRas G12S inhibitor" refers to a compound of the present invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12S. As used herein, "KRas G12S-related disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G12S mutation or having a KRas G12S mutation. A non-limiting example of a KRas G12S-related disease or disorder is a KRas G12S-related cancer.

[0052] As used herein, "KRas G12V" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of valine for glycine 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. As used herein, "KRas G12V inhibitor" refers to a compound of the present invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12V. As used herein, "KRas G12V-related disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G12V mutation or having a KRas G12V mutation. A non-limiting example of a KRas G12V-related disease or disorder is a KRas G12V-related cancer.

[0053] As used herein, "KRas G13D" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of aspartic acid in place of glycine at amino acid position 13. 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.Gly12Asp. As used herein, "KRas G13D inhibitor" refers to a compound of the invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-associated disease or disorder" refers to a disease or disorder associated with or mediated by a KRas G13D mutation or having a KRas G13D mutation. A non-limiting example of a KRas G13D-associated disease or disorder is a KRas G13D-associated cancer.

[0054] As used herein, "KRas Q61H" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of histidine for glutamine at amino acid position 61. 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.Gly12Asp. As used herein, "KRas Q61H inhibitor" refers to a compound of the present invention represented by Formula (I)-(IV) as described herein, or a metabolite thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas Q61H. As used herein, "KRas Q61H-related disease or disorder" refers to a disease or disorder associated with or mediated by a KRas Q61H mutation or having a KRas Q61H mutation. A non-limiting example of a KRas Q61H-related disease or disorder is a KRas Q61H-related cancer.

[0055] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., as determined using an assay or kit approved by a regulatory agency, such as FDA). In some embodiments, the subject has a tumor that is positive for wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject having one or more tumors that are positive for wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved assay or kit). The subject can be a subject whose tumor has wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., where the tumor is so identified using a regulatory agency-approved, e.g., FDA-approved kit or assay). In some embodiments, the subject is suspected of having a cancer associated with a wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H gene. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0056] As used herein, the term "prodrug" refers to a prodrug compound that undergoes conversion in vivo to produce a parent compound or a pharmaceutically acceptable salt, hydrate or solvate of the parent compound. Conversion can occur through various mechanisms of metabolism or chemical processes. A discussion of the use of prodrugs is provided below: "Prodrugs: Challenges and Rewards, Parts 1 and 2", the Biotechnology: Pharmaceutical Aspects [biotechnology: pharmaceutical aspects] (Ronald T. Borchardt and C. Russel Middaugh, series editors) Volume V, editors Valentino J. Stella, Ronald T. Borchardt, Michael J. Hageman, Reza Oliyai, Hans Maag, Jefferson W. Tilley, American Association of Pharmaceutical Scientists and Springer, 2007. Particularly favored prodrugs are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or enhance the delivery of the parent compound to biological compartments (e.g., the brain or the lymphatic system).

[0057] The compounds of the present invention as prodrugs may themselves have prodrugs. In this case, the term "prodrug" refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of the present invention, which, after administration to a recipient, is capable of directly or indirectly providing a compound of the present invention or a pharmaceutically active metabolite or residue thereof.

[0058] As used herein, the term "metabolite" refers to any substance produced during metabolism (ie, digestion or other body chemical processes).

[0059] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer, a patient having one or more symptoms of a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer, and / or a patient at increased risk of developing a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer. G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations, the assays can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, resolved FISH analysis, Southern blotting, protein immunoblotting, FACS analysis, RNA blotting, and PCR-based amplification (such as RT-PCR and quantitative real-time RT-PCR). As is well known in the art, these assays are typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0060] The term "regulatory body" is an agency that is responsible for the medical use of a drug approved by a country. For example, a non-limiting example of a regulatory body is the U.S. Food and Drug Administration (FDA).

[0061] The term "acyl" refers to -C(O)CH 3 .

[0062] The term "alkyl" as used herein refers to straight and branched aliphatic groups. For example, the terms "C1-C6 alkyl", "C1-C4 alkyl" and "C1-C3 alkyl" as used herein refer to straight and branched aliphatic groups having 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 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.

[0063] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to a C1-C3 alkyl chain or a C1-C4 alkyl chain, respectively, as defined herein, in which one or more hydrogens have been replaced by halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

[0064] "C1-C4 alkylene" is a C1-C4 alkyl group as defined above, which is located between two other chemical groups and is used to connect the two chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0065] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined above.

[0066] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons (e.g., 3 to 8 carbons) and, as a further example, 3 to 6 carbons, wherein the cycloalkyl group is optionally substituted with a C1-C6 alkyl or other group as defined herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyls such as bicyclo[1.1.1]pentyl.

[0067] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0068] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0069] An "aryl" group is a C 6 -C 14 The aromatic moiety is optionally substituted with one or more R as defined herein. 8 or R 9 As an example, the aryl group is C 6 -C 10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, wherein one or both rings of the aryl ring system may be saturated or partially saturated, respectively, and wherein if the ring system includes two saturated rings, the saturated rings may be fused or spirocyclic. Examples of aryl ring systems comprising two saturated rings, wherein the rings are spirocyclic, include the following ring systems:

[0070] An "aryl C1-C6 alkyl" or "aralkyl" group includes an aryl group covalently linked to an alkyl group, either of which may be independently optionally substituted or unsubstituted. Examples of aralkyl groups are (C 6 -C 10 )Aryl (C 1 -C6 )alkyl-, including but not limited to benzyl, phenethyl, and naphthylmethyl. An example of a substituted aryl C1-C6 alkyl is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0071] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, such as 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O and S, wherein the ring N atom can be oxidized to NO and the ring S atom can be oxidized to SO or SO 2 , the remaining ring atoms are carbon. The heterocyclic group can be a monocyclic, bicyclic, spirocyclic or bridged ring system. The heterocyclic group can be optionally substituted by an alkyl, aralkyl, alkylcarbonyl group on the ring nitrogen atom, by a lower alkyl group on sulfur, and by a lower alkyl group on carbon. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxaazepanyl, azabicyclohexane, azabicycloheptane, azabicyclooctanyl, azabicyclononane Compounds with adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0072] 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 the cyclic array; and having, in addition to carbon atoms, one to three heteroatoms per ring, or one to three heteroatoms selected from N, O and S in at least one ring. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidine phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, Quinoxalinyl, quinuclidinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 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, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. "Heteroaryl" also refers to a bicyclic ring system having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O and S, wherein one of the ring systems may be saturated or partially saturated.

[0073] As used herein, an "effective amount" of a compound refers to an amount sufficient to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount can be administered as a single dose or can be administered according to a regimen such that it is effective.

[0074] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some way reduce the symptoms of a disorder or to stop or reverse the progression of a disorder, or to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount can be administered as a single dose or can be administered according to a regimen, such that it is effective.

[0075] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0076] As used herein, relief of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, long-lasting or transient, resulting from or associated with the administration of the composition. Compound

[0077] In one embodiment of the present invention, a prodrug compound of a compound having the following structure is provided: 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0078] This compound is described in PCT International Application No. PCT / US2021 / 010065 (WO 2022 / 132200) as a species of Example 140.

[0079] Similarly, the compound having the formula: (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione Described in PCT International Application No. PCT / US2021 / 063722 (WO 2022 / 133038) as a type of Example 196.

[0080] In one aspect, a prodrug is provided having the general structure of Formula (I): or a pharmaceutically acceptable salt thereof, in R 1 and R 2 Independently selected from the group consisting of: H.R 3 -*, R 3 -O-CH 2 -*、 The condition is R 1 and R 2 Only one of them can be H; A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ;as well as R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0081] In one aspect, R 1 is H and R 2 YesR3 -*, R 3 -O-CH 2 -*、

[0082] In another aspect, R 2 is H and R 1 YesR 3 -*, R 3 -O-CH 2 -*、

[0083] In one aspect, a prodrug is provided having the structure: and pharmaceutically acceptable salts thereof.

[0084] In another aspect of the invention, a prodrug is provided having the following general structure: or a pharmaceutically acceptable salt thereof, Where R 1 It is H, R 3 -*, R 3 -O-CH 2 -*、 A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ; R 5 and R6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0085] In one aspect, the compound having Formula II is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

[0086] In another aspect of the present invention, a prodrug is provided having the following structure: or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: R 3 -*, R 3 -O-CH 2 -*、 A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ;as well as R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C6 alkyl.

[0087] In one aspect, the compound having Formula III is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

[0088] In another aspect of the invention, a prodrug is provided having the following general structure: or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: R 3 -*, R 3 -O-CH 2 -*、 A is CH or N; R 3 It is C 1 -C 20 Alkyl, (C 1 -C 4 alkyl) 0-1 -cycloalkyl, (C 1 -C 4 alkyl) 0-1 -heterocyclic group or (C 1 -C 4 alkyl) 0-1 -aryl, where R 3 Optionally C 1 -C 4 Alkyl or -OC 1 -C 4 Alkyl substitution; R 4 Is H or R 3 ;as well as R 5 and R 6 Independently selected from the group consisting of: H and C 1 -C 6 alkyl.

[0089] In one aspect, the compound having formula IV is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

[0090] In one embodiment, compounds of formula (I)-(IV) include dihydrochloride, trihydrochloride, trifluoroacetate, bistrifluoroacetate and tristrifluoroacetate of the above compounds. Provided prodrug compounds or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions. Pharmaceutical composition

[0091] In another aspect, the present invention provides pharmaceutical compositions, which include prodrugs of the present invention and pharmaceutically acceptable carriers, excipients or diluents. The prodrug compounds of the present invention can be prepared by any method well known in the art, and can be prepared for administration by any route, including but not limited to parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, oral, sublingual, transdermal, local, intranasal, intratracheal, rectal, subcutaneous and topical administration. In certain embodiments, the compounds of the present invention are intravenously administered in a hospital setting. In one embodiment, administration can be performed by oral route. In certain embodiments, the pharmaceutical composition provided can be administered to a subject in need of treatment by systemic injection (e.g., by intravenous injection); or by injection or application to a relevant site, such as by direct injection via a syringe, or directly applied to the site when the site is exposed during surgery; or by topical administration.

[0092] Parenteral administration may be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative.

[0093] The pharmaceutical composition provided can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the formulation can be modified with suitable polymerization or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or with ion exchange resins, or as a poorly soluble derivative, for example, as a poorly soluble salt.

[0094] If desired, the pharmaceutical composition can be present in a vial, package or medical device, including but not limited to a dispenser device, which can contain one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device can include a syringe having a single dose liquid formulation ready for injection. The syringe can be accompanied by instructions for use.

[0095] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system (such as a cell, cell culture, tissue or organism) and does not interfere with the effectiveness of the biological activity of one or more active ingredients. Therefore, in addition to the inhibitor, the composition according to the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pennsylvania, 1990.

[0096] As used herein, the term pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesirable toxicological 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, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid). These compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which particularly include quaternary ammonium salts of the formula -NR+Z-, wherein R is hydrogen, alkyl or benzyl, and Z is a counterion including chloride, bromide, iodide, -O-alkyl, tosylate, methanesulfonate, sulfonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate and diphenylacetate).

[0097] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing severe toxic effects in the treated patient. In one embodiment, the range of the active compound dosage for all the above-mentioned conditions is about 0.01 to 300 mg / kg, for example 0.1 to 100 mg / kg per day, and as another example 0.5 to about 25 mg / kg recipient body weight / day. In a suitable carrier, a typical local dose range is 0.01%-3% wt / wt. The effective dose range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated by the weight of the derivative as above or by other means known to those skilled in the art.

[0098] Pharmaceutical compositions comprising compounds of the invention can be used in the methods of use described herein. How to use

[0099] In yet another aspect, the invention provides a method of inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity in a cell, the method comprising contacting the cell (where inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity is desired) with an effective amount of a prodrug compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0100] As used herein, the term "contacting" refers to bringing together the indicated parts in an in vitro system or an in vivo system. For example, "contacting" wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H with a compound provided herein includes administering a prodrug compound provided herein to an individual or patient (e.g., a human having wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutations), as well as, for example, introducing a prodrug compound provided herein into a sample containing cells or purified preparations containing wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutations. G12V, KRas G13D, or KRas Q61H mutations.

[0101] In one embodiment, a cell in which inhibition of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity is desired is contacted with an effective amount of a prodrug compound, or a pharmaceutically acceptable salt thereof, to down-regulate the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H.

[0102] The methods described herein are designed to inhibit unwanted cell proliferation caused by enhanced wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H activity in cells by negatively regulating the activity of one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H. Cells can be contacted with a single dose or multiple doses according to a particular treatment regimen to affect the desired negative regulation of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H. The ability of a compound to bind to wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H can be monitored in vitro using well-known methods. In addition, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the inhibition of one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity in a certain amount of phosphorylated ERK.

[0103] In another aspect, methods of treating cancer in a patient in need thereof are provided, comprising administering to the patient a therapeutically effective amount of a prodrug compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0104] The compositions and methods provided herein can be used to treat wild-type KRas-related or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-related cancers in patients in need thereof, the method comprising administering to the patient a therapeutically effective amount of a prodrug compound of Formula (I)-(IV) or a metabolite thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the wild-type KRas-related or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-related cancer is lung cancer.

[0105] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors, such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by 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, and thyroid cancer and sarcoma. More specifically, these compounds can be used to treat: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial lung cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, smooth muscle sarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor Tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant Lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumors, Sertoli-Leydig cell tumors tumor), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. 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.;

[0106] The concentration and route of administration to the patient will vary depending on the cancer to be treated. Prodrug compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (e.g., radiation or surgical intervention), either as an adjunct before or after surgery.

[0107] Also provided herein is a prodrug compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

[0108] Also provided herein is a prodrug compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating cancer.

[0109] Also provided herein are prodrug compounds or pharmaceutically acceptable salts thereof for use in inhibiting KRas wild type or various types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0110] Also provided herein are prodrug compounds as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating KRas wild-type associated diseases or disorders or KRas mutants G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated diseases or disorders.

[0111] Also provided herein is the use of a prodrug compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0112] Also provided herein is the use of a prodrug compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of a wild-type form of KRas or a mutant form of KRas comprising mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0113] Also provided herein is the use of a prodrug compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a KRas wild-type associated disease or disorder or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder.

[0114] Also provided herein are methods for treating cancer in a patient in need thereof, the methods comprising (a) determining that the cancer is associated with KRas wild-type or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations (i.e., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); and (b) administering to the patient a therapeutically effective amount of a prodrug compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0115] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0116] Those skilled in the art will further recognize that human clinical trials (including first-in-human, dose-ranging and efficacy trials) in healthy patients and / or patients suffering from a given disorder can be performed according to methods well known in the clinical and medical arts. Reaction Schemes and Examples

[0117] Prodrug compounds of the present invention can be prepared from commercially available reagents using the well-known synthetic methods and reaction schemes described herein, and using other well-known methods (e.g., similar to those described in PCT / US2021 / 010065 (WO 2022 / 132200)) or using other reagents and routine methods well known to those skilled in the art.

[0118] The compounds of the present invention may have one or more chiral centers and may be synthesized as a mixture of stereoisomers, which have the same constitution but differ in the arrangement of the atoms in space. These compounds may be used as a mixture, or the individual components / isomers may be separated according to the manufacturer's instructions using commercially available reagents and conventional methods for separating stereoisomers and enantiomers well known to those skilled in the art, for example using (Sigma-Aldrich) or (Diacel Corp) chiral chromatography HPLC column. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever the specification (including the claims) refers to the compounds of the present invention, the term "compound" should be understood to cover all chiral (enantiomers and diastereomers) and racemic forms.

[0119] The compounds of the present invention may be in anhydrous, solvated or hydrated form, and all such forms are encompassed within the scope of the present invention.

[0120] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the present invention. Example 1 Acetic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine-7-yl 2-naphthyl ester

[0121] Step A Acetic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine-7-yl 1-[2-[ ...To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (200 mg, 1.0 eq) and TEA (98.0 mg, 3.0 eq) in dichloromethane (2 mL) at -40°C was added acetyl chloride (25.3 mg, 1.0 eq). The reaction was stirred at -40°C for 0.5 h. The mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN, B%: 53%-83% over 8 min] to give the title compound (101 mg, 46% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ = 9.39-9.22 (m, 1H), 8.01 (dd, J = 6.0, 9.2Hz, 1H), 7.90 (d, J = 2.4Hz, 1H), 7.5 2(dt,J=2.4,9.2Hz,1H),7.37(dd,J=2.4,6.4Hz,1H),5.39-5.16(m,1H),4.87-4.67(m,2H),4.57(br d,J=12.0Hz,1H),4.25-4.06(m,2H),4.01(dd,J=1.6,10.4Hz,1H),3.74(br t,J=10.4Hz,1H),3.40-3.32(m,1H),3.17-2.93(m,3H),2.90-2.73(m,1H),2.44-2.37(m,1H),2.36-2.29(m,4H),2.24 -1.97(m,6H),1.88-1.71(m,4H),1.70-1.62(m,1H),1.32-1.19(m,1H),0.83-0.65(m,3H); LCMS(ESI,M+1): m / z=662.4. Example 2 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl propanoate

[0122] Synthesized according to Example 1. The title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.20 (m, 1H), 8.01 (dd, J = 6.0, 9.2 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.52 (dt, J = 2.0, 9.2 Hz, 1H), 7.37 (dd, J = 2.4, 6.0 Hz, 1H), 5.41-5.16 (m, 1H), 4.89-4.68 (m, 2H), 4.57 (br d, J = 11.6 Hz, 1H), 4.26-4.08 (m, 2H), 4.01 (d, J = 10.4 Hz, 1H), 3.74 (br t,J=9.6Hz,1H),3.42-3.32(m,1H),3.16-2.95(m,3H),2.89-2.76(m,1H) ,2.69-2.61(m,2H),2.44-2.37(m,1H),2.36-2.31(m,1H),2.26-1.97(m,6 H),1.88-1.70(m,4H),1.69-1.61(m,1H),1.30-1.20(m,1H),1.16(dt,J= 1.2, 7.6Hz, 3H), 0.75 (dt, J = 2.4, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 676.3. Example 3 Isobutyric acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0123] Synthesized according to Example 1. The title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.18 (m, 1H), 8.01 (dd, J = 6.0, 9.2 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.53 (dt, J = 2.0, 9.2 Hz, 1H), 7.35 (dd, J = 2.4, 5.2 Hz, 1H), 5.45-5.14 (m, 1H), 4.87-4.67 (m, 2H), 4.57 (br d,J=11.2Hz,1H),4.21-4.08(m,2H),4.01(d,J=10.4Hz,1H),3.83-3.67(m,1H),3.40-3 .32(m,1H),3.18-2.95(m,3H),2.95-2.72(m,2H),2.42(td,J=7.6,15.2Hz,1H),2.33(br d,J=2.0Hz,1H),2.26-1.95(m,6H),1.88-1.70(m,4H),1.69-1.61(m,1H),1. 26 (d, J=7.2Hz, 7H), 0.75 (dt, J=2.8, 7.2Hz, 3H); LCMS (ESI, M+1): m / z=690.3. Example 4 Cyclopropanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0124] Step A Cyclopropanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine- 7a-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin pyridin-7-yl)naphthalen-2-yl ester : To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq.) and TEA (49.0 mg, 3.0 eq.) in DCM (2 mL) was added cyclopropanecarbonyl chloride (25.3 mg, 1.5 eq.) at -40 °C. The reaction was stirred at -40 °C for 3 hours. The mixture was concentrated and purified by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH4 HCO 3 ), B: ACN, B%: 58%-88% over 8 min] to give the title compound (66.5 mg, 59% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ=9.43-9.21(m,1H),8.12-7.87(m,2H),7.61-7.45(m,1H),7.43-7.30(m,1H),5.44-5.14(m,1H),4.95-4. 62(m,2H),4.61-4.48(m,1H),4.26-4.05(m,2H),4.04-3.92(m,1H),3.92-3.62(m,1H),3.39-3.32(m,1H),3.19-2.95(m,3H),2.90 -2.75(m,1H),2.36-2.30(m,2H),2.21-2.03(m,5H),2.01-1.92(m,2H),1.90-1.72(m,4H ), 1.69-1.60 (m, 1H), 1.32-0.96 (m, 5H), 0.81-0.65 (m, 3H); LCMS (ESI, M+1): m / z=688.2. Example 5 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl pivalate

[0125] Synthesized according to Example 4. The title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.22 (m, 1H), 8.07-7.96 (m, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.61-7.47 (m, 1H), 7.38-7.25 (m, 1H), 5.43-5.17 (m, 1H), 4.92-4.67 (m, 2H), 4.57 (br d,J=12.0Hz,1H),4.23-4.07(m,2H),4.05-3.96(m,1H),3.80-3.70(m,1 H),3.51-3.35(m,1H),3.15-2.96(m,3H),2.89-2.76(m,1H),2.44-2.31( m,2H),2.25-1.93(m,6H),1.88-1.70(m,4H),1.69-1.59(m,1H),1.33(s ,9H),1.28-1.18(m,1H),0.84-0.67(m,3H); LCMS(ESI,M+1):m / z=704.1. Example 6 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl dimethylcarbamate

[0126] Step A 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole dimethylcarbamate Oxazine-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridin ... [4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq.) in DMF (1 mL) at 0°C was added K 2 CO 3 (111 mg, 5.0 equiv) and N,N-dimethylformamide chloride (26.0 mg, 1.50 equiv). The reaction mixture was stirred at 20°C for 12 hours. The mixture was filtered and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO3 ), B: ACN, B%: 51%-81% over 8 min] to give the title compound as a white solid (33.8 mg, 30% yield); 1H NMR (400 MHz, DMSO-d6) δ = 9.22-9.39 (m, 1H), 8.05-7.94 (m, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.46-7.59 (m, 1H), 7.33 (dd, J = 9.2, 2.4 Hz, 1H), 5.15-5.38 (m, 1H), 4.47-4.92 (m, 3H), 3.94-4.25 (m, 3H), 3.63-3.84 (m, 1H) ,3.39-3.33(m,1H),2.99-3.16(m,6H),2.93(s,3H),2.82(m,1H),2.31-2.39(m,2H),2.10-2.25(m,3H), 1.95-2.10(m,3H),1.59-1.88(m,5H),1.17-1.35(m,1H),0.65-0.84(m,3H); LCMS(ESI,M+1): m / z=691.2. Example 7 Piperidine-1-carboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0127] Synthesized according to Example 6. The title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.23-9.38 (m, 1H), 7.96-8.06 (m, 1H), 7.86-7.95 (m, 1H), 7.44-7.57 (m, 1H), 7.29-7.38 (m, 1H), 5.18-5.39 (m, 1H), 4.67-4.91 (m, 2H), 4.51-4.65 (m, 1H), 4.09-4.22 (m, 2H), 3.97-4.07 (m, 3H). m,1H),3.70-3.81(m,1H),3.53-3.66(m,2H),3.50-3.36(m,3H),2.99-3.15(m,3H),2.76-2.89(m,1H),1 .95-2.29(m,7H),1.47-1.91(m,12H),1.22-1.32(m,1H),0.82-0.70(m,3H); LCMS(ESI,M+1):m / z=731.2. Example 8 (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0128] Step A 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-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 (33.3 g, 1.0 eq.), DIEA (54.5 g, 4.0 eq.) and A mixture of molecular sieves (4.00 g) in THF (340 mL) was added with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (20.1 g, 1.2 eq.). The reaction was stirred at 40 °C for 14 h. The mixture was quenched by adding water and concentrated to remove the organic solvent. The mixture was extracted with EA (2×200 mL) and purified by Na 2 SO 4Dry, concentrate and purify by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile] to give the title compound (28.8 g, 62% yield) as a yellow solid. 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): m / z = 439.1.

[0129] Step B 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine : 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.0 equiv), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.64 g, 2.0 equiv) and Cs 2 CO 3 CataCXium A Pd G3 (332 mg, 0.20 eq.) (1.5 M, 3.0 eq.) was added to a solution of methoxycyclopentane (15 mL). The reaction was stirred at 100 °C for 2 hours. The mixture was quenched by adding water and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (2×10 mL) and purified by Na 2 SO 4 Dried, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (820 mg, 56% yield) as a yellow solid; LCMS (ESI, M+1): m / z=637.3.

[0130] Step C (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-aza Bicyclo[3.2.1]octan-6-ol To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 eq.) in DMF (0.5 mL) was added MS (20.0 mg), (1R, 5R, 6R) -3- azabicyclo [3.2.1] octan-6-ol (31.9 mg, 1.6 equiv) and DIPEA (40.6 mg, 2.0 equiv). The reaction was stirred at 40 ° C for 12 hours. The mixture was filtered and purified by preparative HPLC (column: UniSil 3-100 C18 UItra (150 * 25mm * 3um); mobile phase: [water (FA) -ACN]; B%: 26% -46%, 7min) to give the title compound as a white solid (59.9 mg, FA salt); 1H NMR (400MHz, methanol-d4) δ = 9.25 (d, J = 18.0Hz, 1H), 7.86-7.73 (m, 1H), 7.65-7.55 (m, 1H), 7.39-7.16 (m, 2H), 5.48 -5.26(m,3H),4.59(s,3H),4.45-4.37(m,1H),4.35-4.25(m,2H),3.89-3.72(m,1H),3.54-3.35(m,6H),3.20 -3.07(m,1H),2.55-2.14(m,8H),2.12-2.01(m,2H),2.00-1.88(m,2H),1.87-1.75(m,1H),1.43 -1.26 (m, 2H), 0.86-0.71 (m, 3H); LCMS (ESI, M+1): m / z=664.5. Example 9 Carbonate 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ylmethyl ester

[0131] Step A. Carbonic acid 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- 4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine- 7-yl)naphthalen-2-yl methyl ester: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (500 mg, 1.00 equiv) and TEA (408 mg, 5.00 equiv) in THF (10.0 mL) at 0°C was added dimethyl dicarbonate (216 mg, 2 equiv). The reaction was stirred at 0°C for 0.5 h. The mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (3×10.0 mL). The combined organic layers were washed with brine (2×15.0 mL) and purified by Na 2 SO 4 Dry, filter, concentrate under reduced pressure and triturate with methyl tert-butyl ether at 25° C. for 30 minutes to give the title compound as a white solid (1.05 g, 82% yield); 1H NMR (400 MHz, methanol-d4) δ = 0.82 (br d, J = 7.72 Hz, 3H) 1.40 (br d, J = 14.92 Hz, 1H) 1.78-2.04 (m, 5H) 2.13-2.58 (m, 8H) 3.00 (br s, 1H) 3.21 (br d, J = 18.56 Hz, 2H) 3.35-3.52 (m, 2H) 3.75-3.85 (m, 1H) 3.90 (br s, 3H) 4.17-4.35 (m, 3H) 4.79 (br s, 3H) d,J=10.64Hz,1H)5.00(br s,1H)5.20-5.40(m,1H)7.29-7.49(m,2H)7.89(br s,2H)9.24(br d,J=18.12Hz,1H); LCMS (ESI,M+1): m / z=678.3. Example 10 (1R,5R,6R)-3-(7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0132] Step A 2-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-di Oxaborane: At 0 ° C, to a solution of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (0.500 g, 1.0 eq.) and chloromethoxyethane (224 mg, 1.5 eq.) in DCM (25 mL) was added chloromethoxyethane (224 mg, 1.5 eq.) and DIEA (818 mg, 1.10 mL, 4.0 eq.). The reaction was stirred at 25 ° C for 16 hours. The mixture was diluted with water (25 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue is purified by flash silica gel chromatography ( 20.0g Purification by silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient at 10 mL / min) gave the title compound (204 mg, 86% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 375.1.

[0133] Step B.7 -(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine : 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (117 mg, 1.0 equiv), 2-[3-(ethoxymethoxy)-8-ethyl-7-fluoro-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 g, 1.0 equiv) and K 3 PO 4 [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]methanesulfonate palladium(II) (17.0 mg, 0.10 equiv) (1.5 M, 534 uL, 3.0 equiv) was added to a solution in CPME (5 mL). The reaction was degassed and purged with N2 three times and stirred at 70 °C under N2 atmosphere for 1 hour. The mixture was washed with H 2 O (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with Na 2 SO 4 Dry, filter, concentrate in vacuo and flash silica gel chromatography ( 20.0g Purification by silica flash column, eluent 0-100% ethyl acetate in petroleum ether gradient at 50 mL / min) gave the title compound (158 mg, 64% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 651.2.

[0134] Step C (1R,5R,6R)-3-(7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-aza Bicyclo[3.2.1]octan-6-ol To a solution of 7-[3-(ethoxymethoxy)-8-ethyl-7-fluoro-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.20 g, 1.0 eq) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (93.8 mg, 2.4 eq) in DMF (14 mL) was added Molecular sieves (0.20 g) and DIEA (119 mg, 3.0 equiv.) were added. The reaction was stirred at 40 °C for 12 h. The mixture was washed with H 2 O (14 mL) and extracted with EtOAc (3 x 14 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, filtered, concentrated in vacuo, and purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 21%-51%, min] to give the title compound (0.13 g, 32% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.24 (m, 1H), 7.90 (dd, J = 6.0, 9.0 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.43 (br d, J = 2.1 Hz, 1H), 7.23 (dd, J = 2.6, 9.6 Hz, 1H), 5.42-5.32 (m, 3H), 5.22 (br s,1H),4.93-4.65(m,2H),4.63-4.53(m,1H),4.14(br dd,J=10.3,13.7Hz,2H),4.01(d,J=10.6Hz,1H),3.72(q,J=7.1Hz,3H),3.11-3.01(m,3H),2.83(br d,J=6.6Hz,1H),2.38-2.30(m,2H),2.20-1.99(m,6H),1.88-1.65(m,5H),1.30-1 .20 (m, 1H), 1.16 (t, J = 7.1Hz, 3H), 0.78-0.68 (m, 3H); LCMS (ESI, M+1): m / z = 678.2. Example 11 Butyric acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0135] Step A Butyric acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine-7-yl 2-naphthyl ester To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq) in DCM (1 mL) was added TEA (49.0 mg, 3.0 eq) and butyryl chloride (17.2 mg, 1.0 eq). The reaction was stirred at -40 °C for 0.5 h. The mixture was diluted with water (10 mL) and extracted with DCM (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 58%-88%, 10 min] to give the title compound as a white solid (27.6 mg, 24% yield); 1H NMR (400 MHz, chloroform-d) δ = 9.05 (d, J = 5.2 Hz, 1H), 7.77-7.69 (m, 2H), 7.31 (t, J = 9.2 Hz, 1H), 7.23 (s, 1H), 5.40-5.21 (m, 1H), 5.03 (br t, J = 13.2 Hz, 1H), 4.32 (br dd, J = 5.2, 10.4 Hz, 2H), 4.28-4.17 (m, 2H), 3.83 (br d, J = 12.8 Hz, 1H), 3.47 (br d,J=13.6Hz,1H),3.34-3.17(m,3H),3.04-2.93(m,1H),2.61-2.49(m,3H),2.43-2.19(m,6H),2.14(br d,J=10.0Hz,1H),2.01-1.90(m,3H),1.88-1.83(m,3H),1.82-1.77(m,2H),1.05(t,J=7.2Hz,3H),0.90-0.80(m,3H); LCMS(ESI,M+1):m / z=690.4. Example 12 Ethyl (5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl) carbonate

[0136] Step A. Carbonic acid Ethyl (5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-methyl)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d] pyrimidin-7-yl)naphthalen-2-yl) esterTo a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (500 mg, 1.00 equiv) and TEA (408 mg, 5.00 equiv) in THF (10.0 mL) at 0°C was added diethyl dicarbonate (131 mg, 1.00 equiv). The reaction was stirred at 0°C for 0.5 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×15 mL) and purified by Na 2 SO 4 Dry, filter, concentrate under reduced pressure and triturate with methyl tert-butyl ether at 25° C. for 30 minutes to give the title compound as a white solid (1.06 g, 82% yield); 1H NMR (400 MHz, methanol-d4) δ = 0.82 (br d, J = 7.72 Hz, 3H) 1.32-1.42 (m, 4H) 1.82 (br s, 1H) 1.87-2.05 (m, 4H) 2.14-2.43 (m, 7H) 2.55 (br s, 1H) 3.01 (br s, 1H) 3.18 (br s, 1H) 3.23 (br s, 2H) 3.40-3.51 (m, 1H) 3.80 (br t, J = 14.48 Hz, 1H) 4.17-4.37 (m, 5H) 4.77 (br d,J=10.52Hz,1H)5.02(br d,J=11.00Hz,1H)5.17-5.44(m,1H)7.27-7.50(m,2H)7.84-7.98(m,2H)9.24(br d, J=18.12Hz, 1H); LCMS (ESI, M+1): m / z=692.3. Example 13 Cyclobutanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0137] Step A: Cyclobutanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-yl ester: To a mixture of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq) and TEA (49.0 mg, 3.0 eq) in DCM (1.0 mL) at -40 °C was added cyclobutanecarbonyl chloride (19.1 mg, 1 eq) in one portion under N2. The reaction mixture was stirred at -40 °C for 4 hours. The reaction mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were washed with brine (30 mL), purified by Na 2 SO 4 The mixture was dried, concentrated and purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 29%-49%, 58 min) to give the title compound (20.1 mg, 16.5% yield, HCOOH salt) as a white solid; SFC: ee>95%, column: Chiralpak IC-3 50×4.6 mm I.D., 3 um, mobile phase: phase A, CO 2, and phase B, MeOH + ACN (0.05% DEA); isocratic elution: 40% B in A, flow rate: 3 mL / min; detector: PDA; column temperature: 35 ° C; back pressure: 100 bar, tR = 1.505; 1H NMR (400MHz, methanol-d4) δ = 9.25 (d, J = 17.2Hz, 1H), 7.96-7.87 (m, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.45-7.36 (m, 1H), 7.32-7.24 (m, 1H), 5.48-5.26 (m, 1H), 5.04-4.93 (m, 1H), 4.84-4.75 (m, 1H), 4.38 (br d,J=4.0Hz,1H),4.35-4.26(m,2H),3.90-3.74(m,1H),3.56-3.41(m,3H),3.3 9-3.36(m,1H),3.16-3.04(m,1H),2.61-2.52(m,1H),2.49-2.39(m,4H),2.39 -2.31(m,3H),2.30-2.21(m,4H),2.21-2.16(m,1H),2.15-1.99(m,4H),1.98- 1.91(m,2H),1.85-1.77(m,1H),1.40(brd,J=13.6Hz,1H),0.89-0.80(m,3H); F NMR (400 MHz, methanol-d4) δ = -116.77, -139.11, -173.75; LCMS (ESI, M+1): m / z = 702.2. Example 14 (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-8-fluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0138] Step A 8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl trifluoromethanesulfonate: 3,4-dihydro-2H-pyran (74.6 mg, 1.0 eq.) was added to a solution of 8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl trifluoromethanesulfonate (300 mg, 1.0 eq.) and TsOH (7.64 mg, 0.05 eq.) in DCM (3 mL). The reaction was stirred at 0 ° C for 1 hour. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (500 mg, crude product) as a yellow oil.

[0139] Step B 2-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-4,4,5,5-tetramethyl 1,3,2-dioxaborolane : A mixture of 8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl trifluoromethanesulfonate (50.0 mg, 1.0 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) (60.1 mg, 2.0 equiv), KOAc (34.9 mg, 3.0 equiv) and cyclopentyl(diphenyl)phosphine; palladium dichloride; iron (17.3 mg, 0.2 equiv) in dioxane (1 mL) was degassed and purged with N2 three times. The mixture was stirred at 100° C. under N2 atmosphere for 3 hours. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (2 mL). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to give the title compound (190 mg, 85% yield) as a black solid; 1H NMR (400 MHz, CD3OD) δ = 7.61 (dd, J = 6.0, 9.2 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.21 (t ,J=9.6Hz,1H),5.59-5.48(m,1H),3.96-3.82(m,1H),3.71-3.56(m,1H),3.11(dq,J=2.4,7.6Hz,2H ),2.10-1.97(m,1H),1.96-1.80(m,2H),1.77-1.65(m,2H),1.64-1.54(m,1H),1.26-1.19(m,15H).

[0140] Step C 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4, 3-d]pyrimidineTo a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (105 mg, 1.0 eq) and 2-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (144 mg, 1.5 eq) in methoxycyclopentane (1 mL) was added A Pd G3 (34.9 mg, 0.2 eq.) and Cs2CO3 (1.5 M, 3.0 eq.) in aqueous solution were degassed and purged with N2 three times. The mixture was stirred at 80 °C under N2 atmosphere for 3 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, and purified by reverse phase HPLC (0.1% FA condition) to give the title compound (76.0 mg, 34% yield) as a black solid; LCMS (ESI, M+1): m / z=677.2.

[0141] Step D (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalene-1- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine- 4-yl)-3-azabicyclo[3.2.1]octan-6-ol : To a solution of 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60.0 mg, 1.0 eq) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (16.9 mg, 1.5 eq) in DMF (0.5 ml) was added DIEA (34.4 mg, 3.0 eq). The reaction was stirred at 50° C. for 14 h. The mixture was filtered and purified by reverse phase HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 62%-92%, 9 min) to give the title compound (8.80 mg, 14% yield) as a white solid; 1H NMR (400MHz, CD3OD) δ=9.29-9.18(m,1H),7.84-7.72(m,1H),7.62(d,J=2.6Hz,1H),7.37-7.18(m,2H),5.69-5.59(m,1H),5.43-5.2 0(m,1H),4.83-4.70(m,2H),4.39-4.27(m,2H),4.26-4.18(m,1H),3.99-3.88(m,1H),3.85-3.74(m,1H),3.70-3.61(m,1H),3.47(br dd,J=12.8,19.1Hz,1H),3.28-3.11(m,3H),3.07-2.95(m,1H),2.58-2.44(m,1H),2.44-2.36(m,1H),2.36-2.10(m,6 H),2.06-1.96(m,3H),1.94-1.85(m,4H),1.85-1.77(m,1H),1.76-1.67(m,2H),1.62(dt,J=3.6,7.6Hz,1H),1.40(br d, J=14.4Hz, 1H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m / z=704.5. Example 15 Carbonate 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl isopropyl

[0142] Step A. Carbonic acid 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- 4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine- 7-yl) naphthalen-2-yl isopropyl ester:To a solution of (1R,5R,6R)-3-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-6-ol (50.0 mg, 1.0 eq) and TEA (24.5 mg, 3.0 eq) in DCM (2 mL) was added isopropyl chloroformate (9.89 mg, 1.0 eq). The reaction was stirred at 0° C. for 3.5 h. The mixture was heated at 0° C. by adding H 2 O (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, concentrated and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 65%-95% over 8 min] to give the title compound as a white solid (14.5 mg, 25% yield); 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.25 (m, 1H), 8.08-7.97 (m, 2H), 7.62-7.42 (m, 2H), 5.22 (br s, 1H), 4.99-4.68 (m, 3H), 4.64-4.27 (m, 1H), 4.22-4.09 (m, 2H), 4.15-3.81 (m, 1H), 3.75 (br s,1H),3.40-3.35(m,1H),3.16-2.97(m,3H),2.90-2.44(m,1H),2.38-2.29(m,2H),2.21-1.95(m,6H),1.90-1.73(m,4H),1.68(br s, 1H), 1.41-1.34 (m, 6H), 1.28-1.20 (m, 1H), 0.75 (m, 3H); LCMS (ESI, M+1): m / z=706.4. Example 16 (1R,5R,6R)-3-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0143] Step A 2-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborane : 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (500 mg, 1.0 equiv) was added to CH 3 To a solution in CN (10 mL) was added DIEA (408 mg, 2.0 equiv) and (bromomethyl)benzene (540 mg, 2.0 equiv). The reaction was stirred at 25 °C for 12 h. The mixture was quenched by adding water (10 mL) and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (3 x 10 mL) and purified by Na 2 SO 4 Dry, concentrate and purify by column chromatography to give the title compound (600 mg) as a white solid; LCMS (ESI, M+1): m / z=407.3.

[0144] Step B 7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a solution of 2-(3-(benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 1.0 equiv) and 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (194 mg, 0.90 equiv) in CMPE (5 mL) was added K 3 PO 4 (1.5M, 0.3mL, 1.0 equiv) and CataCXium A Pd G3 (3.58mg, 0.01 equiv). The reaction was stirred at 80°C under N2 atmosphere for 12 hours. The mixture was quenched by adding water (10mL) and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (3×10mL) and purified by Na 2 SO 4 Drying, concentration gave the crude product as brown oil and used in the next step without further purification; LCMS (ESI, M+1): m / z=683.4.

[0145] Step C (1R,5R,6R)-3-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo [3.2.1] Octane-6-ol To a solution of 7-(3-(benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 eq.) in DMF (1 mL) was added MS (20.0 mg), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (29.8 mg, 1.6 eq.) and DIPEA (36.2 mg, 2.0 eq.) The reaction was stirred at 40 °C for 12 hours. The mixture was filtered and purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 μm; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 7 min] to give the title compound (45.1 mg, 41% yield) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.16 (m, 1H), 7.91-7.81 (m, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.47-7.38 (m, 3H), 7.37-7.30 (m, 1H), 7.23 (dd, J = 2.6, 8.2 Hz, 1H), 5.41 -5.19(m,3H),4.88-4.76(m,1H),4.74-4.48(m,2H),4.21-3.97(m,3H),3.80 -3.67(m,1H),3.14-3.02(m,3H),2.89-2.78(m,1H),2.71-2.59(m,1H),2.33(dd,J=1.8,3.4Hz,2H),2.18-2.00(m,6H ), 1.88-1.72 (m, 4H), 1.70-1.61 (m, 1H), 1.27-1.23 (m, 1H), 0.72 (dt, J = 3.8, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 710.3. Example 17 Cyclopentanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0146] Step A Cyclopentanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine- 7a-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin pyridin-7-yl)naphthalen-2-yl ester: To a mixture of (1R, 5R, 6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq.) and TEA (49.0 mg, 3.0 eq.) in DCM (1.0 mL) was added cyclopentanecarbonyl chloride (21.4 mg, 1.0 eq.) in one portion at -40 °C under N2. The reaction mixture was stirred at -40 °C for 0.5 h. The mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were purified by Na 2 SO 4 The mixture was dried, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 10 min) to give the title compound (27.0 mg, 22.8% yield) as a white solid; SFC: ee>95%, column: Chiralpak AS-3 50×4.6 mm ID, 3 um mobile phase: phase A, CO 2, and phase B, MeOH (0.05% DEA); gradient elution: B in A from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar, tR = 1.417; 1H NMR (400 MHz, methanol-d4) δ = 9.24 (d, J = 16.3 Hz, 1H), 7.94-7.87 (m, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.43-7.35 (m, 1H), 7.30-7.23 (m, 1H), 5.40-5.23 (m, 1H), 5.04-4.95 (m, 1H), 4.77 (br d,J=12.4Hz,1H),4.37-4.29(m,2H),4.27-4.20(m,1H),3.85-3.76(m,1H),3.51-3.42(m,1H),3.28- 3.22(m,2H),3.14-2.99(m,2H),2.60-2.49(m,1H),2.44-2.33(m,2H),2.30-2.21(m,4H),2.20-2.12( m, 2H), 2.08-1.98 (m, 5H), 1.97-1.87 (m, 3H), 1.81-1.75 (m, 2H), 1.74-1.64 (m, 2H), 1.43-1.28 (m, 2H), 0.86-0.79 (m, 3H); HNMR (400 MHz, methanol-d4) δ = -116.78, -139.04, -173.73; LCMS (ESI, M+1): m / z = 716.2. Example 18 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl hexanoate

[0147] Step A Hexanoic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- 4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine- 7-yl)naphthalen-2-yl ester: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq) and TEA (49.0 mg, 3.0 eq) in DCM (2 mL) at 0°C was added hexanoyl chloride (32.6 mg, 1.5 eq). The reaction was stirred at 20°C for 6 hours. The mixture was heated at 0°C by adding H 2 O (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with Na 2 SO 4 Dry, concentrate and purify by preparative HPLC [Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 33%-63% over 10 min] to give the title compound (37.5 mg, 31% yield) as a white solid; 1H NMR(400MHz, DMSO-d6)δ=9.40-9.26(m,1H),8.19-8.16(m,1H),8.08-7.97(m,1H),7.97-7.86(m,1H),7.41-7.33(m,1H),5.40-5.16 (m,1H),4.93-4.64(m,2H),4.63-4.51(m,1H),4.25-4.10(m,2H),4.08-3.97(m,1H),3.80-3.71(m,1H),3.31-3.27(m,1H),3.05(br s,2H),3.04-2.99(m,1H),2.88-2.78(m,1H),2.66-2.58(m,2H),2.46-2.31(m,2H),2.26-2.12(m,3H),2.11-1.97(m,3H),1.89-1.72 (m,4H),1.72-1.61(m,3H),1.42-1.30(m,4H),1.29-1.22(m,1H),0.94-0.87(m,3H),0.81-0.71(m,3H); LCMS(ESI,M+1): m / z=718.5. Example 19 Tert-butyl (5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl) carbonate

[0148] Step A tert-Butyl carbonate (5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-yl)ester : (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (50.0 mg, 1.0 equivalent), Boc 2 O (38.7 mg, 2.2 eq), TEA (24.5 mg, 3.0 eq) and K 2 CO 3 1,4,7,10,13,16-hexaoxacyclooctadecane (21.3 mg, 1.0 eq.) was added to a solution of (11.1 mg, 1.0 eq.) in DMF (0.5 mL). The reaction was stirred at 25 °C for 17.5 hours. The mixture was filtered and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3), B: ACN; B%: 62%-92% over 8 min] to give the title compound (39.3 mg, 67% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.24 (m, 1H), 8.11-7.91 (m, 2H), 7.61-7.48 (m, 1H), 7.47-7.38 (m, 1H), 5.39-5.17 (m, 1H), 4.91-4.68 (m, 2H), 4.64-4.52 (m, 1H), 4.23-4.07 (m, 2H), 4.06-3.97 (m, 1H), 3.80-3.66 (m,1H),3.39-3.33(m,1H),3.15-2.96(m,3H),2.89-2.75(m,1H),2.41-2.31(m,2H),2.24-1.93(m,6H), 1.89-1.60 (m, 5H), 1.55-1.42 (m, 9H), 1.29-1.21 (m, 1H), 0.83-0.67 (m, 3H); LCMS (ESI, M+1): m / z=720.4. Example 20 dimethylcarbamate ((5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl) [4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl ester

[0149] Step A Chloromethyl dimethylcarbamate : At -60 ° C, dimethylamine (2M, 6.49 mL, 0.6 eq.) was slowly added to a solution of chloromethyl chloroformate (2.79 g, 1.0 eq.) and DIEA (8.39 g, 3.0 eq.) in THF (10 mL). The reaction was stirred at -60 ° C for 0.5 hours. At 0 ° C, the mixture was quenched by adding water (30 mL) and extracted with ethyl acetate (4 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1] to obtain the title compound (600 mg, 20% yield) as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ = 6.05-5.52 (m, 2H), 3.11-2.83 (m, 6H).

[0150] Step B Dimethylcarbamic acid ((5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidone) Alloxan-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridin ... [4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)methyl ester : (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (60.0 mg, 1.0 equiv) and K 2 CO 3 To the mixture of chloromethyl dimethylcarbamate (40.2 mg, 3.0 eq.) in DMF (1.0 mL) was added chloromethyl dimethylcarbamate (14.7 mg, 1.10 eq.). The reaction was stirred at 20 °C for 12 h. The mixture was filtered and analyzed by preparative HPLC [Waters Xbridge C18 150×50 mm×10 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 55%-58% over 9 min] to give the title compound as a white solid (38.0 mg, 53% yield); 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.22 (m, 1H), 7.96-7.92 (m, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.48-7.43 (m, 1H), 7.26-7.23 (m, 1H), 5.89 (s, 2H), 5.39-5.15 (m, 1H), 4.88-4.75 (m, 1H), 4.75-4.66 (m, 1H), 4.64-4.51 (m, 1H), 4.23-4.07 (m, 2H), 4.03 -3.99(m,1H),3.81-3.66(m,1H),3.40-3.35(m,1H),3.12-2.98(m,3H),2.85(d,J=7.6Hz,6H),2.83-2.74(m,1H),2.40 -2.30(m,2H),2.19-1.97(m,6H),1.89-1.60(m,5H),1.31-1.20(m,1H),0.79-0.67(m,3H); LCMS(ESI,M+1): m / z=721.6. Example 21 Cyclohexanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0151] Step A Cyclohexanecarboxylic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine- 7a-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin pyridin-7-yl)naphthalen-2-yl ester : To a mixture of (1R, 5R, 6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq.) and TEA (49.0 mg, 3.0 eq.) in DCM (1.0 mL) was added cyclohexanecarbonyl chloride (23.7 mg, 1.0 eq.) in one portion at -40 °C under N2. The reaction mixture was stirred at -40 °C for 0.5 h. The mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were purified by Na 2 SO 4 The mixture was dried, concentrated, and purified by preparative HPLC {column: Phenomenex luna C18 150×25 mm×10 um; mobile phase [water (FA)-ACN]; B%: 28%-58%, 10 min} to give the title compound (14.5 mg, 11.9% yield) as a white solid; SFC: ee>95%, column: Chiralpak AS-3 50×4.6 mm ID, 3 μm; mobile phase: phase A, CO 2, and phase B, MeOH (0.05% DEA); gradient elution: B in A from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar, tR = 1.453; 1H NMR (400 MHz, methanol-d4) δ = 9.25 (d, J = 16.5 Hz, 1H), 7.93-7.87 (m, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.43-7.36 (m, 1H), 7.29-7.22 (m, 1H), 5.49-5.31 (m, 1H), 5.05-4.94 (m, 1H), 4.76 (br s,1H),4.49-4.42(m,1H),4.39-4.28(m,2H),3.87-3.75(m,1H),3.61-3.51(m,1H),3.5 0-3.43(m,3H),3.21-3.13(m,1H),2.71-2.62(m,1H),2.60-2.46(m,2H),2.42-2.34(m,2 H),2.28-2.20(m,4H),2.14-2.06(m,4H),2.01-1.91(m,2H),1.86-1.79(m,3H),1.74-1. 67(m,1H),1.64-1.56(m,2H),1.45-1.37(m,3H),1.35-1.29(m,1H),0.86-0.79(m,3H); F NMR (400MHz, methanol-d4) δ = -116.74, -139.20, -173.84; LCMS (ESI, M+1): m / z = 730.4. Example 22 1-((5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)ethyl dimethylcarbamate

[0152] Step A 1-Chloroethyl dimethylcarbamate: At 0°C, add 1-chloroethyl chloroformate (6.00 g, 1.0 d To a solution of 100 g (2 M, 0.7 eq.) and TEA (4.25 g, 1.0 eq.) in DCM (20 mL) was added N-methylmethanamine (2 M, 0.7 eq.) The mixture was stirred at 0°C for 1 hour. The mixture was quenched by adding water (10 mL) and extracted with DCM (3×20 mL). 2 SO 4Dry, concentrate and purify by column chromatography (SiO2, petroleum ether / ethyl acetate 50 / 1 to 20 / 1) to give the title compound (210 mg, 3.3% yield) as a yellow oil; 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.57 (q, J = 6.0 Hz, 1H), 2.95 (d, J = 5.6 Hz, 6H), 1.81 (d, J = 6.0 Hz, 3H).

[0153] Step B 1-((5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentyl)-2-nitropropanecarbamate 2-Pentaborane-2-yl)naphthalen-2-yl)oxy)ethyl ester To a solution of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (430 mg, 1.0 eq.) and 1-chloroethyl dimethylcarbamate (206 mg, 1.0 eq.) in acetonitrile (5 mL) was added K 2 CO 3 (563 mg, 3.0 equiv.). The reaction was stirred at 25 °C for 16 h. The mixture was quenched by the addition of water (5 mL) and extracted with EA (3 x 5 mL). 2 SO 4 Dry, concentrate and purify by column chromatography (SiO2, petroleum ether / ethyl acetate 15 / 1 to 10 / 1) to give the title compound (290 mg, 44% yield) as a yellow oil; 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.58 (dd, J = 6.0, 9.2 Hz, 1H), 7.39-7.31 (m, 2H), 7.20 (t, J = 9.2 Hz, 1H), 6.64 (q, J = 5.2 Hz, 1H), 3.12 (m, 2H), 2.97-2.82 (m, 6H), 1.66 (d, J = 5.2 Hz, 3H), 1.44 (s, 12H), 1.27 (t, J = 7.6 Hz, 3H).

[0154] Step C 1-((5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-dimethylcarbamic acid pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl) 2-(2-(2-oxy)ethyl)ester : 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (230 mg, 1.0 equiv), dimethylcarbamic acid 1-((5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)ethyl ester (282 mg, 1.2 equiv), CataCXium A Pd G3 (38.0 mg, 0.1 equiv) and Cs 2 CO 3A mixture of (1.5 M in water, 0.6 mL) in methoxycyclopentane (3 mL) was degassed and heated with N 2 The reaction was heated at 80 °C under N 2 The mixture was quenched by adding water and extracted with EtOAc and then purified by Na 2 SO 4 Dry, concentrate and purify by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] to give the title compound as a yellow oil (200 mg, 52% yield); 1 H NMR (400MHz, DMSO-d6) δ = 9.21 (s, 1H), 7.90 (dd, J = 6.0, 8.8Hz, 1H), 7.69 (dd, J = 2.8, 7.2Hz, 1H),7.47(t,J=9.2Hz,1H),7.23(dd,J=2.4,4.8Hz,1H),6.64-6.54(m,1H),5.35-5.19(m,1H ),4.30-4.15(dd,J=2.8,8.0Hz,2H),3.31(s,2H),3.13-3.00(m,3H),2.83-2.75(m,7H),2. 37-2.30(m,1H),2.19-2.07(m,3H),1.91-1.73(m,4H),1.59(dd,J=2.0,5.2Hz,3H),0.71(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=608.3.

[0155] Step D 1-((5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-dimethylcarbamic acid Pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyridine 2-(4,3-d)pyrimidin-7-yl)naphthalen-2-yl)oxy)ethyl ester : (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (18.0 mg, 2.0 equiv), DIEA (27.4 mg, 3.0 equiv) and To a solution of molecular sieves (10 mg) in DMF (0.5 mL) was added 1-((5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)ethyl dimethylcarbamate (50 mg, 1.0 equiv). The reaction was stirred at 40 °C for 16 h. The mixture was filtered and the filtrate was purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3), B: ACN; B%: 58%-88% over 8 min] to give the title compound as a white solid (15.9 mg, 29% yield); SFC: >99% ee, column: (S,S) Whelk-O 150×4.6 mm ID, 3.5 μm, mobile phase: 40% EtOH (0.05% DEA) in CO 2 Flow rate: 3 mL / min, detector: 220 nm, tR1: 1.552 min, tR2: 1.988; 1H NMR(400MHz, DMSO-d6)δ=9.37-9.24(d,J=3.2,1H),7.88(dd,J=6.4,9.0Hz,1H),7.70-7.61(m,1H),7.45(dt,J=2.4,9.6Hz,1H),7.26-7.17(m,1H),6 .63-6.54(m,1H),5.41-5.13(d,J=5.4,1H),4.90-4.76(m,1H),4.75-4.67 (m,1H),4.62-4.53(m,1H),4.21-4.10(m,2H),4.08-3.97(m,1H),3.74(br dd,J=12.0,19.6Hz,1H),3.30(s,2H),3.18-2.99(m,3H),2.87-2.75(m,7H),2.37-2.30(m,2H),2.21-2.03(m,5H),1.91 -1.62(m,5H),1.59(dd,J=2.0,5.2Hz,3H),1.29-1.20(m,1H),0.73(dt,J=3.4,7.3Hz,3H); LCMS(ESI,M+1):m / z=735.4. Example 23 (1R,5R,6R)-3-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0156] Step A 2-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane : 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (500 mg, 1.0 equiv) was added to CH 3To a solution in CN (5.0 mL) was added DIEA (408 mg, 2.0 equiv) and ((chloromethoxy)methyl)benzene (495 mg, 2.0 equiv). The reaction was stirred at 25 °C for 12 h. The mixture was quenched by the addition of water and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (2 x 5 mL) and purified by Na 2 SO 4 Dried, concentrated and purified by column chromatography to give the title compound (560 mg, 81% yield) as a colorless liquid.

[0157] Step B 7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a solution of 2-(3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 1.0 eq.) in CMPE (10 mL) was added K 3 PO 4 (1.5M, 0.3mL, 1.0 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and APhos Pd G3 (2.59mg, 0.01 equiv). The reaction was stirred at 70 °C under N2 atmosphere for 12 hours. The mixture was quenched by adding water and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (3×3mL) and purified by Na 2 SO 4 Drying and concentration gave the crude product as brown oil; LCMS (ESI, M+1): m / z=713.4.

[0158] Step C (1R,5R,6R)-3-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-nitrogen Heterobicyclo[3.2.1]octan-6-ol To a solution of 7-(3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) in DMF (1.0 mL) was added MS (20.0 mg), (1R, 5R, 6R) -3- azabicyclo [3.2.1] octan-6-ol (28.5 mg, 1.6 equiv) and DIPEA (36.2 mg, 2.0 equiv). The reaction was stirred at 40 ° C for 12 hours. The mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18150 * 25 mm * 10 um; mobile phase: [water (FA) -ACN]; B%: 27% -57%, 9 min and column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [water (ammonia hydroxide v / v) -ACN]; B%: 68% -98%, 9 min) to give the title compound as a white solid (26.8 mg, 25% yield); 1H NMR (400MHz, DMSO-d6) δ=9.43-9.16(m,1H),7.96-7.83(m,1H),7.71(d,J=2.8Hz,1H),7.50-7.19(m, 7H),5.52-5.44(m,2H),5.38-5.19(m,1H),4.87-4.68(m,4H),4.63-4.53(m,1H),4.28-3.95(m,3H), 3.82-3.69(m,1H),3.19-2.98(m,3H),2.91-2.79(m,1H),2.39-2.31(m,2H),2.21-1.98(m,6H),1.94 -1.71(m,4H),1.69-1.59(m,1H),1.31-1.17(m,2H),0.78-0.60(m,3H); LCMS(ESI,M+1): m / z=740.3. Example 24 Octanoic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0159] Step A Octanoic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine-7-yl 2-naphthyl esterTo a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 eq) in DCM (1 mL) was added TEA (49.0 mg, 3.0 eq) and octanoyl chloride (26.2 mg, 1.0 eq). The reaction was stirred at -40 °C for 0.5 h. The mixture was diluted with water (2 mL) and extracted with DCM (3x1 mL). The combined organic layers were washed with brine (1 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 32%-62%, 10 min) to give the title compound (7.56 mg, 6% yield) as a white solid; 1H NMR (400 MHz, CHLOROFORM-d) δ=9.05 (d, J=4.8 Hz, 1H), 7.76-7.70 (m, 2H), 7.31 (t, J=9.2 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 5.43-5.24 (m, 1H), 5.09 (br t, J=14.8 Hz, 1H), 4.38-4.32 (m, 2H), 4.27 (br t,J=11.2Hz,1H),3.87-3.80(m,1H),3.50-3.27(m,3H),3.27-3.19(m,1H),3.08-2.97(m,1H),2.62-2.50(m,3H),2.37(br d,J=17.6Hz,3H),2.32-2.22(m,3H),2.22-2.15(m,2H),2.00(br dd,J=6.4,11.7Hz,3H),1.85(br s, 2H), 1.80-1.73 (m, 2H), 1.46-1.27 (m, 8H), 1.23-1.07 (m, 1H), 0.92-0.81 (m, 6H); LCMS (ESI, M+1): m / z=746.5. Example 25 Decanoic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl ester

[0160] Step A Decanoic acid 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- 4-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidine- 7-yl) naphthalen-2-yl ester: To a solution of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (3.00 g, 1.0 eq) and TEA (1.47 g, 3.0 eq) in dichloromethane (30 mL) was added decanoyl chloride (1.11 g, 1.2 eq). The reaction was stirred at 0 °C for 2 hours and at 20 °C for 10 hours. The mixture was quenched by the addition of water (20 mL) and extracted with dichloromethane (4×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [Phenomenex luna C18 150×40 mm×15 μm; A: water (FA), B: ACN; B%: 37%-67% over 15 min] to give the title compound (2.28 g, 61% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ=9.39-9.22(m,1H),8.02-7.98(m,1H),7.89(d,J=1.6Hz,1H),7.53-7.49(m,1 H),7.34(s,1H),5.37-5.16(m,1H),4.87-4.67(m,2H),4.59-4.56(m,1H),4.21-4.09(m,2H),4.01(br d,J=10.0Hz,1H),3.72(br t,J=12.0Hz,1H),3.33-3.27(m,1H),3.15-2.97(m,3H),2.87-2.76(m,1H),2.60(br t,J=7.2Hz,2H),2.32(br s,1H),2.27-2.10(m,3H),2.09-1.95(m,3H),1.85-1.70(m,4H),1.64-1.61 (m, 3H), 1.42-1.15 (m, 14H), 0.87-0.71 (m, 6H); LCMS (ESI, M+1): m / z=774.6. Example 26 Decanoic acid 4-(4-((1R,5R,6R)-6-(decanoyloxy)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0161] Step A: Decanoic acid 4-(4-((1R,5R,6R)-6-(decanoyloxy)-3-azabicyclo[3.2.1]octane-3- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine- 7-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester :(1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (0.3 g) was dissolved in DCM (6 mL). Then decanoic acid (4 eq), DMAP (0.4 eq), EDCI (4.4 eq) were added to the reaction in sequence. The reaction was stirred overnight. After completion, the reaction mixture was diluted with DCM (6 mL) and washed with water (10 mL x 2). The organic layer was separated and purified by Na 2 SO 4 The residue was purified by flash column chromatography (using EtOAc / heptane as eluent) to give the title compound (0.25 g, 56% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 9.12 (d, 1H), 7.75-7.70 (m, 2H), 7.30 (t, 1H), 7.20 (dd, 1H), 5.31 (d, 1H), 5.10 (d, 1H), 4.95 (q, 1H), 4.64 (q, 1H), 4.28 (q, 1H), 4.14 (dd, 1H), 3.68 (d, 1H). H), 3.37 (d, 1H), 3.25-3.10 (m, 3H), 3.00-2.94 (m, 1H), 2.59-2.45 (m, 5H), 2.37-2.14 (m, 5H), 2.02-1.72 (m, 10H), 1.56-1.54 (m, 1H), 1.41-1.19 (m, 28H), 0.19-1.81 (m, 10H). MS: ESI-MS calculated for C54H72F3N5O5 [M+H]+ 928.56, found 928.51. Example 27 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl acetate

[0162] Step A Acetic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (46.9 mg, 3.0 eq) in THF (2 mL) was added AcO (48.9 mg, 3.1 eq) at -40 °C. The reaction was stirred at -40 °C for 3.5 h. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN, B%: 19%-49% over 10 min] to give the title compound (50.1 mg, 44% yield) as a white solid; 1H NMR (400 MHz, CD3OD) δ=7.73 (dd, J=5.8, 8.8 Hz, 1H), 7.43 (t, J=2.8 Hz, 1H), 7.29 (t, J=9.4 Hz, 1H), 7.18 (dd, J=2.2, 9.8 Hz, 1H), 5.49-5.23 (m, 1H), 4.72-4.51 (m, 1H), 4.31-3.91 (m, 5H), 3.70 (d, J=17.8 Hz,1H),3.56-3.33(m,7H),3.24-3.11(m,2H),3.10-2.98(m,1H),2.85-2.67(m,1H),2.47-2.32(m, 1H), 2.32-2.29 (m, 3H), 2.28-1.75 (m, 9H), 1.12 (dt, J = 2.0, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 690.3. Example 28 (R)-7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0163] Step A (R)-7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7- Triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (140 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (56.0 mg, 1.6 equiv) in DMF (0.6 mL) were added DIPEA (52.1 mg, 2.0 equiv) and Molecular sieves (20 mg). The reaction mixture was stirred at 40°C for 16 hours. The mixture was filtered and analyzed by preparative HPLC [column: Phenomenex C18 75×30 mm×3 μm; mobile phase: water (FA)-ACN; B%: 20%-50% over 5 minutes] and [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: water (NH 4 HCO 3 )-ACN; B%: 50%-80% over 8 minutes] to give the title compound as a white solid (68.3 mg, 48% yield); 1 H NMR (400MHz, CD 3 OD)δ=7.65-7.59(m,1H),7.28-7.24(m,1H),7.20(t,J=9.2Hz,1H),7.11(dd,J=2.4,10 .8Hz,1H),5.35-5.30(m,1H),5.28(d,J=3.2Hz,2H),4.27-3.91(m,5H),3.65(d,J=17.6 Hz,1H),3.49(d,J=2.4Hz,4H),3.44-3.33(m,3H),3.30-2.90(m,7H),2.83-2.67(m,1H) ,2.33-2.04(m,4H),2.01-1.76(m,6H),1.15-1.05(m,3H); LCMS(ESI,M+1): m / z=692.5. Example 29 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl propanoate

[0164] Step A Propionic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (110 mg, 1.0 eq) and TEA (51.5 mg, 3.0 eq) in THF (1.5 mL) was added propionic anhydride (22.1 mg, 1.0 eq) in THF (0.5 mL) dropwise at -40°C. The reaction was stirred at -40°C for 1 hour and at 25°C for 15 hours. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (4×3 mL). The organic layer was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: water (FA)-ACN; B%: 25%-55% over 10 min] to give the title compound (44.0 mg, 35% yield) as a white solid; 1H NMR (400 MHz, CD3OD) δ=7.73 (dd, J=6.0, 8.8 Hz, 1H), 7.43 (t, J=2.4 Hz, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.17 (dd, J=2.4, 9.2 Hz, 1H), 5.43-5.22 (m, 1H), 4.29-3.88 (m, 5H), 3.70 (br d,J=17.6Hz,1H),3.61-3.33(m,7H),3.28-2.97(m,4H),2.65(dq,J=2.0,7.6Hz,3H),2.46-1.80 (m, 10H), 1.25 (dt, J = 2.0, 7.6Hz, 3H), 1.12 (dt, J = 2.4, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 704.5. Example 30 Carbonic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylmethyl ester

[0165] Step A Carbonic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl-2-fluoronaphthalen-2-yl methyl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.00 equiv) and TEA (15.6 mg, 2.0 equiv) in THF (2.00 mL) was added dimethyl dicarbonate (20.7 mg, 2.0 equiv). The reaction was stirred at 0°C for 1 hour. The mixture was washed with NH at 25°C. 4 The solution was quenched with Cl (10.0 mL), diluted with water (5.00 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 The product was dried, filtered, concentrated under reduced pressure and purified by preparative HPLC (Xtimate C18 150*40mm*10um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 10 min). The collected fractions were purified by NaHCO 3 (2.00 M, 2.00 mL), extracted with ethyl acetate (2 × 10 mL), and washed with Na 2 SO 4Dry, filter and concentrate under reduced pressure to give the title compound (4.36 mg, 7.6% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (br s, 1H), 8.68-8.43 (m, 1H), 7.86 (br s, 1H), 7.73-7.58 (m, 1H), 7.54-7.22 (m, 2H), 5.32-5.15 (m, 1H), 4.07-3.77 (m, 9H), 3.76-3.53 (m, 2H), 3.27-2.64 (m, 10H), 2.06-1.89 (m, 5H), 1.83-1.69 (m, 5H), 1.07 (br s, 3H); LCMS (ESI, M+1): m / z = 706.2. Example 31 (R)-7-(7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0166] Step A 8-Ethyl-7-fluoro-3-hydroxy-8,8a-dihydronaphthalen-1-yl trifluoromethanesulfonate : At 0°C, 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (5.0 g, 1.0 equiv) was added in portions to HCl·MeOH (4M, 50.0 mL). The reaction mixture was stirred at 0°C for 2 hours. The mixture was concentrated at room temperature. The residue was dissolved in ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL). The mixture was washed with H 2 O (100 mL) and extracted with ethyl acetate (4×50 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, and concentrate to give the title compound as a red oil (4.4 g, 99% yield, crude).

[0167] Step B 3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate: To a solution of (8-ethyl-7-fluoro-3-hydroxy-8,8a-dihydronaphthalen-1-yl) trifluoromethanesulfonate (2 g, 1.0 eq.) and DIPEA (2.28 g, 3.0 eq.) in dichloromethane (20 mL) was added chloromethoxyethane (833 mg, 1.5 eq.) dropwise at 0°C. The reaction mixture was stirred at 20°C for 1 hour. The mixture was washed with H 2O (60 mL) and extracted with dichloromethane (3 x 20 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, concentrate and column chromatography [SiO 2 , petroleum ether / ethyl acetate=20 / 1] to give the title compound (2.2 g, 94% yield) as a light yellow oil; 1 H NMR (400 MHz, CDCl 3 )δ=7.59(dd,J=5.6,9.2Hz,1H),7.40(d,J=2.4Hz,1H),7.33(d,J=2.4Hz,1H),7.26-7.21(m,1H ), 5.29 (s, 2H), 3.74 (q, J = 7.2Hz, 2H), 3.20 (dq, J = 2.8, 7.2Hz, 2H), 1.21 (dt, J = 5.2, 7.2Hz, 6H).

[0168] Step C 7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizine-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine: To a mixture of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (1.0 g, 1.0 equiv), 3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (1.48 g, 1.2 equiv) in dioxane (10 mL) was added Cs 2 CO 3 (2.53 g, 2.5 eq.) and molecular sieves (50 mg). 2 Under a nitrogen atmosphere, Xantphos Pd G4 (298 mg, 0.1 eq.) was added, and the reaction mixture was stirred at 90 °C for 14 h. The mixture was washed with H 2 O (30 mL) and extracted with ethyl acetate (4×15 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dried, concentrated and purified by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile = 1 / 1] to give the title compound (346 mg, 19% yield) as a brown gum; LCMS (ESI, M+1): m / z = 569.4.

[0169] Step D 7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol:To a solution of 7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (340 mg, 1.0 eq) in DMF (5 mL) was added (176 mg, 3.5 eq). The mixture was stirred at 60 °C for 2 h. The mixture was washed with H 2 O (40 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dried, and concentrated to give the title compound (330 mg, crude) as a brown oil; LCMS (ESI, M+1): m / z=555.2.

[0170] Step E 7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4-methylbenzenesulfonic acid 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl ester: To a solution of 7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (300 mg, 1.0 eq), DIEA (209 mg, 3.0 eq) in THF (7 mL) at 0°C was added DMAP (6.61 mg, 0.1 eq) and 4-methylbenzenesulfonyl chloride (155 mg, 1.5 eq). The reaction was stirred at 20°C for 1.5 h. The mixture was washed with H 2 O (20 mL) and extracted with ethyl acetate (4×20 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, concentrate and column chromatography [Al 2 O 3 , ethyl acetate] to give the title compound (270 mg, 67% yield) as a brown gum; LCMS (ESI, M+1): m / z=709.2.

[0171] Step F (R)-7-(7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7- Triazaspiro[4.5]decane-2,4-dione:To a solution of 7-(3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (150 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (64.4 mg, 1.8 equiv) in DMF (2 mL) were added DIEA (54.7 mg, 2.0 equiv) and Molecular sieves (20 mg). The reaction mixture was stirred at 40°C for 14 hours. The mixture was filtered and subjected to reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile = 2 / 3] and preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: water (NH 4 HCO 3 )-ACN; B%: 54%-84% over 8 minutes] to give the title compound as a white solid (34.3 mg, 22% yield); 1 H NMR(400MHz, DMSO-d6)δ=10.87-10.63(m,1H),8.60-8.48(m,1H),7.83-7.64(m,1H),7.38-7. 27(m,2H),7.20-7.06(m,1H),5.37-5.31(m,2H),5.31-5.14(m,1H),4.07-3.76(m,5H),3.74- 3.59(m,3H),3.50-3.34(m,2H),3.27-3.11(m,3H),3.09-2.93(m,4H),2.93-2.58(m,3H),2.1 0-1.67 (m, 10H), 1.19-1.11 (m, 3H), 1.06 (dt, J = 2.4, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 706.5. Example 32 Cyclopropanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0172] Step A Cyclopropanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (200 mg, 1.0 equiv) and TEA (93.7 mg, 3.0 equiv) in DCM (2 mL) at -40°C was added cyclopropanecarbonyl chloride (38.7 mg, 1.2 equiv). The reaction was stirred at 0°C for 5 h. The reaction mixture was quenched by the addition of H2O (5 mL) at 0°C and extracted with DCM (3×5 mL). The combined organic layers were purified by Na2SO4 (5 mL). 2 SO 4 The mixture was dried, concentrated and purified by preparative HPLC [Phenomenex Luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 20%-50% over 9 min] to give the title compound (73.2 mg, 32% yield) as a white solid; 1H NMR (400 MHz, Methanol-d4) δ = 7.78-7.69 (m, 1H), 7.48-7.36 (m, 1H), 7.32-7.25 (m, 1H), 7.19-7.11 (m, 1H), 5.39-5.18 (m, 1H), 4.22-3.93 (m, 5H), 3.75-3.63 (m, 1H), 3.54-3.37 (m, 5H). m,4H),3.29-3.14(m,4H),3.14–2.95(m,2H),2.91-2.68(m,2H),2.39-2.07(m,4H),2 .04–1.73(m,6H),1.39-1.27(m,5H),1.19-1.07(m,3H); LCMS(ESI,M+1): m / z=716.5. Example 33 Butyric acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0173] Step A Butyric acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl: To a solution of (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (46.9 mg, 3.0 eq) in DCM (2 mL) at 0°C was added butyryl chloride (24.7 mg, 1.5 eq). The reaction was stirred at 0°C for 8 h. The mixture was heated at 0°C by adding H 2 O (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, concentrated and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 60%-90%, 8 min] and [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 53%-83%, 8 min] to give the title compound as a pink solid (6.70 mg, 6.0% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.78-7.72 (m, 1H), 7.52-7.46 (m, 1H), 7.35-7.26 (m, 1H), 7.23-7.16 (m, 1H), 5.37-5.20 (m, 1H), 4.23-3.95 (m, 5H), 3.76-3.67 (m, 1H), 3.59-3.36 (m, 5H), 3.27-3.18 ( m,3H),3.16-2.94(m,3H),2.84-2.71(m,1H),266-2.59(m,2H),2.37-2.20(m,1H),2.20-2.07 (m,3H),2.04-1.77(m,8H),1.18-1.11(m,3H),1.10-1.01(m,3H); LCMS(ESI,M+1): m / z=718.2. Example 34 Isobutyric acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0174] Step A Isobutyric acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (200 mg, 1.0 eq) and TEA (93.7 mg, 3.0 eq) in DCM (2 mL) at -40°C was added 2-methylpropanoyl chloride (39.5 mg, 1.2 eq). The reaction was stirred at 20°C for 6.5 hours. The mixture was heated at 0°C by adding H 2 O (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with Na 2 SO 4 Dry, concentrate and purify by preparative HPLC [Phenomenex Luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 23%-53% over 9 min] to give the title compound (90.6 mg, 40% yield) as a white solid; 1H NMR (400MHz, methanol-d4)δ=7.83-7.67(m,1H),7.47-7.38(m,1H),7.34-7.23(m,1H) ,7.19-7.11(m,1H),5.41-5.16(m,1H),4.22-3.92(m,5H),3.80-3.65(m,1H),3. 57-3.33(m,5H),3.29-2.97(m,6H),2.92-2.67(m,2H),2.37-2.07(m,4H),2.04– 1.97 (m, 6H), 1.42-1.31 (m, 6H), 1.20-1.10 (m, 3H); LCMS (ESI, M+1): m / z=718.5. Example 35 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl dimethylcarbamate

[0175] Step A 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-(dimethylcarbamate) 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine pyridin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (110 mg, 1.0 eq) and TEA (51.5 mg, 3.0 eq) in THF (1.5 mL) was added dimethylcarbamoyl chloride (27.4 mg, 1.5 eq) in THF (0.5 mL) dropwise at -10°C. The reaction was stirred at -40°C for 1 hour and at 25°C for 14 hours. At 0°C, K was added 2 CO 3 (47.0 mg, 2.0 eq.), and the mixture was stirred at 25 °C for 36 h. The mixture was washed with H 2 O (5 mL) and extracted with ethyl acetate (4×3 mL). The combined organic layers were concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: water (FA)-ACN; B%: 24%-54% over 10 min] to give the title compound (50.1 mg, 40% yield) as a pink solid; 1H NMR (400 MHz, CD3OD) δ=7.72 (dd, J=5.6, 8.8 Hz, 1H), 7.42 (t, J=2.0 Hz, 1H), 7.28 (t, J=9.2 Hz, 1H), 7.19 (dd, J=2.0, 7.2 Hz, 1H), 5.55-5.16 (m, 1H), 4.27-3.95 (m, 5H), 3.71 (br dd,J=5.2,17.6Hz,1H),3.59-3.34(m,7H),3.24-3.08(m,4H),3.01(s,3H),2.91-2.65 (m, 2H), 2.42-1.81 (m, 10H), 1.12 (dt, J = 2.0, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 719.4. Example 36 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylethyl carbonate

[0176] Step A Carbonic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ylethyl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.00 equiv) and TEA (15.6 mg, 2.00 equiv) in THF (1 mL) at 0°C was added diethyl dicarbonate (12.5 mg, 1.00 equiv). The reaction was stirred at 0°C for 0.5 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×4 mL). The combined organic layers were washed with brine (2×5 mL) and purified by Na 2 SO 4 The mixture was dried, filtered, concentrated under reduced pressure and HPLC (Xbridge Prep OBD C18 150 mm*30 mm*5 um column (eluent: 30% to 60% CH 3 CN, and H 2 The collected fractions were purified by saturated NaHCO 3 (5 mL) and extracted with ethyl acetate (3×3 mL). The combined organic layers were washed with brine (2×5 mL) and purified by Na 2 SO 4The reaction mixture was dried, filtered and concentrated under reduced pressure to give the title compound (5.00 mg, 8.5% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.07 (br s, 3H) 1.23 (br s, 3H) 1.28-1.35 (m, 4H) 1.68-1.83 (m, 5H) 1.90-2.08 (m, 5H) 2.82 (br d, J = 15.76 Hz, 2H) 2.88-3.00 (m, 2H) 3.05 (br s, 2H) 3.17 (br d, J = 12.96 Hz, 2H) 3.71-3.87 (m, 2H) 3.90 (br s,2H)3.94-4.03(m,2H)4.25-4.31(m,2H)5.16-5.32(m,1H)7.38-7.51(m,2H)7.63-7.69(m,1H)7.86(br s, 1H) 8.52-8.62 (m, 1H) 10.72-10.83 (m, 1H); LCMS (ESI, M+1): m / z=720.2. Example 37 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl azetidine-1-carboxylate

[0177] Step A: Azetidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane- 7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d] Pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a mixture of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (1 mL) at -10 °C was added (4-nitrophenyl)chloroformate (31.1 mg, 1.0 eq). After stirring at -10 °C for 20 min, azetidine (8.81 mg, 1.0 eq) was added to the above mixture. The reaction was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were purified by Na 2 SO4 Dry, concentrate, and purify by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 10min) to give the title compound (7.15mg, 6.32% yield) as a white solid. SFC: ee=18.7%, column: Chiralcel OD-3 50x4.6mm ID, 3um, mobile phase: phase A, CO 2 , and phase B, MeOH (0.05% DEA); isocratic elution: 40% B in A, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar, tR1 = 0.659, tR2 = 1.849. 1H NMR (400 MHz, DMSO-d6) δ = 10.80-10.69 (m, 1H), 8.58-8.49 (m, 1H), 7.82 (br s,1H),7.53(d,J=2.0Hz,1H),7.40(s,1H),7.28-7.17(m,1H),5.32-5.15(m,1H),4.25-4.16( m,2H),4.02-3.89(m,6H),3.81(m,1H),3.66(m,1H),3.17(m,1H),3.11-3.02(m,5H),2.97(br F NMR (400MHz, DMSO-d6) δ = -117.30, -172.08; LCMS (ESI, M+1): m / z = 744.5. Example 38 (5R)-7-(7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0178] Step A 8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl trifluoromethanesulfonate: At 0 ° C, HCl dioxane (4M, 50 mL) was added to a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate (10.0 g, 1.0 equiv.) in ACN (50 mL). The reaction was stirred at 25 ° C for 1 hour. The mixture was concentrated under reduced pressure and dissolved in water (20 mL). At 0 ° C, the residue was adjusted to pH = 10 with 10% NaOH aqueous solution. The mixture was extracted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (8.8 g, crude product) as a yellow solid.

[0179] Step B 8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl trifluoromethanesulfonate: To a mixture of 8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl trifluoromethanesulfonate (5.00 g, 1.0 equiv) and 3,4-dihydro-2H-pyran (2.49 g, 2.0 equiv) in DCM (50 mL) was added TsOH (127 mg, 0.05 equiv). The mixture was stirred at 0 ° C for 0.5 hours. The reaction mixture was concentrated and purified by column chromatography [petroleum ether / ethyl acetate=1 / 0 to 50 / 1] to give the title compound (5.00 g, two-step yield: 74%) as a yellow oil; 1 H NMR (400 MHz, methanol-d 4 )δ=7.68-7.62(m,1H),7.50-7.45(m,1H),7.38-7.33(m,1H),7.30-7.22(m,1H),5.51(s,1H),3.93-3.76(m,1H ),3.70-3.46(m,1H),3.26-3.11(m,2H),2.04-1.81(m,3H),1.61-1.52(m,1H),1.57(m,2H),1.22-1.14(m,3H).

[0180] Step C 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d] Pyrimidine: In N 2 To a mixture of 8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.00 g, 1.0 equiv) and 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (916 mg, 1.2 equiv) in toluene (10 mL) was added Cs 2 CO 3 (1.54 g, 2.0 eq.), Xantphos (342 mg, 0.25 eq.), and Pd 2 (dba)3 (352 mg, 0.15 eq.). The reaction mixture was heated at 110 °C under N 2 The reaction mixture was stirred under a 4% CO atmosphere for 12 h. 2 O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (1.00 g, 60% yield) as a yellow solid; LCMS (ESI, M+1): m / z=595.3.

[0181] Step D 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol: To a solution of EtSH (0.780 g, 8.3 eq.) in DMAc (10 mL) was added NaH (484 mg, 60% purity, 8.0 eq.) at 0°C. The reaction mixture was stirred at 20°C for 1 hour. And then 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (900 mg, 1.0 eq.) was added to the mixture. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was heated to 40°C by adding H 2 O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (800 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 581.4.

[0182] Step E 4-Methylbenzenesulfonic acid 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine Pyridin-4-yl esters: To a mixture of 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (500 mg, 1.0 eq) and 4-methylbenzene-1-sulfonyl chloride (246 mg, 1.5 eq) in DCM (5 mL) was added DIEA (334 mg, 3.0 eq) and DMAP (10.5 mg, 0.1 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was washed with H 2The reaction mixture was quenched with 4% paraformaldehyde (5 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [petroleum ether / ethyl acetate=10 / 1 to 0 / 1] to give the title compound (400 mg, 58% yield) as a yellow solid; LCMS (ESI, M+1): m / z=735.2.

[0183] Step F (5R)-7-(7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine Pyridine-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a solution of 7-(8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (200 mg, 1.0 equiv) and DIEA (52.8 mg, 1.5 equiv) in DMF (1.0 mL) was added (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (92.1 mg, 2.0 equiv). The reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was concentrated and purified by preparative HPLC [Waters Xbridge C18 150×50 mm×10 μm; A: water (NH 4 HCO 3 ), B: ACN, B%: 64%-94% after 10 min] and [Waters Xbridge C18 150×25mm×5μm; A: water (NH 4 HCO 3 ), B: ACN, B%: 58%-88% over 10 min] to give the title compound as a white solid (20.4 mg, 10% yield); 1 H NMR (400 MHz, methanol-d 4 )δ=7.65-7.59(m,1H),7.30-7.26(m,1H),7.23-7.16(m,1H),7.16-7.09(m,1H), 5.59-5.52(m,1H),5.36-5.17(m,1H),4.22-4.06(m,4H),4.05-3.87(m,2H),3.7 3-3.58(m,2H),3.52-3.36(m,4H),3.28-2.94(m,7H),2.82-2.68(m,1H),2.21-1 .80(m,13H),1.78-1.56(m,3H),1.13-1.02(m,3H); LCMS(ESI,M+1):m / z=732.3. Example 39 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivalate

[0184] Step A 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-nitropropanoic acid (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : Under N2 atmosphere, at -40 ° C, to a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (62.0 mg, 4.0 eq) in THF (2 mL) was added pivaloyl chloride (19.0 mg, 1.0 eq) dropwise. The reaction mixture was stirred at -40 ° C for 2 hours. At -40 ° C, the mixture was quenched with anhydrous methanol (1 mL) and stirred for 10 minutes. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×3 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried, concentrated and purified by preparative HPLC [column: Phenomenex C18 75×30 mm×3 μm; mobile phase: water (FA)-ACN; B%: 25%-55% over 7 min] to give the title compound (64 mg, 55% yield) as a white solid; 1H NMR (400 MHz, CD3OD) δ=7.74 (dd, J=6.0, 8.8 Hz, 1H), 7.40 (t, J=2.4 Hz, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.12 (dd, J=2.4, 7.6 Hz, 1H), 5.46-5.27 (m, 1H), 4.33-3.92 (m, 5H), 3.70 (dd, J= 6.4,17.6Hz,1H),3.60-3.38(m,7H),3.28-2.99(m,4H),2.87-2.67(m,1H),2.46-1.80( m, 10H), 1.39 (d, J = 2.0Hz, 9H), 1.13 (dt, J = 2.4, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 732.5. Example 40 Carbonic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl isopropyl ester

[0185] Step A Carbonic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 5-ethyl-6-fluoronaphthalen-2-yl isopropyl ester : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (200 mg, 1.00 equiv) and TEA (62.5 mg, 2.00 equiv) in THF (6 mL) at -68°C was added isopropyl chloroformate (18.9 mg, 0.50 equiv). The reaction was stirred at -68°C for 30 min. The mixture was washed with NH at 25°C. 4 The solution was quenched with Cl (5 mL), diluted with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, filter, concentrate under reduced pressure and use preparative HPLC (Xtimate C18150*40mm*10um; mobile phase: [water (NH 3)-ACN]; B%: 30%-60%, 7 min) to give the title compound as a white solid (22.4 mg, 9.6% yield); 1H NMR (400 MHz, DMSO-d6) δ = 10.72 (br s, 1H), 8.63-8.47 (m, 1H), 7.86 (br dd,J=5.6,8.8Hz,1H),7.71-7.62(m,1H),7.48-7.29(m,2H),5.31-5.14(m,1H),4.90(qd,J=6.4,12.5Hz,1H),4.03- 3.89(m,4H),3.86-3.80(m,1H),3.77-3.61(m,2H),3.25-3.10(m,3H),3.08-2.94(m,4H),2.94-2.67(m,3H),2.05(br s,1H),2.01-1.86(m,4H),1.86-1.63(m,6H),1.36-1.29(m,6H),1.07(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=734.3. Example 41 (R)-7-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0186] Step A (R)-7-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexa Hydrogen-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro [4.5]Decane-2,4-dione To a mixture of 7-(3-(benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (80.0 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (27.4 mg, 1.5 equiv) in DMF (1 mL) were added DIEA (83.7 mg, 6.0 equiv) and Molecular sieves (10 mg). The reaction mixture was stirred at 60 ° C for 12 hours. The mixture was filtered and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 8 min) to give the title compound (41.0 mg, 47% yield) as an off-white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.63 (br dd, J = 6.0, 8.8 Hz, 1H), 7.48 (br d, J = 6.8 Hz, 2H), 7.38 (br t, J = 7.2 Hz, 2H), 7.34-7.28 (m, 1H), 7.23-7.15 (m, 2H), 7.09 (br d,J=9.2Hz,1H),5.44-5.23(m,1H),5.17(s,2H),4.28-3.92(m,5H),3.65(br dd,J=4.4,17.6Hz,1H),3.55-3.33(m,7H),3.26-2.98(m,4H),2.83-2.67(m,1H),2. 46-2.22 (m, 2H), 2.21-1.80 (m, 8H), 1.17-1.06 (m, 3H); LCMS (ESI, M+1): m / z=738.4. Example 42 Cyclopentanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0187] Step A: Cyclopentanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl esterTo a mixture of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1 eq.) and DIEA (59.9 mg, 3 eq.) in THF (1.0 mL) was added cyclopentanecarbonyl chloride (10.2 mg, 0.5 eq.) in one portion under N2. The mixture was stirred at -68 °C for 1.5 h. The mixture was diluted with water (3 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were purified by Na 2 SO 4 The mixture was dried, filtered, concentrated and purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 29%-59%, 10 min) to give the title compound (12.1 mg, 10.0% yield) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ = 10.77 (br s, 1H), 8.58-8.48 (m, 1H), 7.88-7.80 (m, 1H), 7.58-7.52 (m, 1H), 7.42 (t, J = 9.3 Hz, 1H), 7.29-7.17 (m, 1H), 5.33-5.15 (m, 1H), 3.98-3.89 (m, 3H), 3.81 (br d,J=10.4Hz,1H),3.67(br d,J=17.6Hz,1H),3.23(br s,4H),3.14-3.01(m,6H),2.97(br F NMR (400MHz, DMSO-d6) δ = 116.97, -172.09; LCMS (ESI, M+1): m / z = 744.5. Example 43 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl pyrrolidine-1-carboxylate

[0188] Step A Pyrrolidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine pyridin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 equiv) in DMF (1 mL) at 0°C was added K 2 CO 3 (111 mg, 5.0 equiv) and pyrrolidine-1-carbonyl chloride (32.3 mg, 1.5 equiv). The reaction was stirred at 20 ° C for 12 hours. The mixture was filtered, concentrated and purified by preparative HPLC [UniSil 3-100 C18 UItra 150×25mm×3μm; A: water (FA), B: ACN; B%: 31%-51%, 7min] to give the title compound as a white solid (31.1 mg, 36% yield); 1H NMR (400 MHz, methanol-d4) δ=7.76-7.66 (m, 1H), 7.47-7.41 (m, 1H), 7.33-7.24 (m, 1H), 7.23-7.15 (m, 1H), 5.40-5.23 (m, 1H), 4.30-3.87 (m, 5H), 3.77-3.60 (m, 3H), 3.59 -3.35(m,8H),3.30-2.96(m,5H),2.85-2.69(m,1H),2.42-2.20(m,2H),2.18-2.0 8 (m, 2H), 2.06-1.81 (m, 10H), 1.12 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 745.3. Example 44 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl hexanoate

[0189] Step A Hexanoic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl: To a solution of (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (46.9 mg, 3.0 eq) in DCM (2 mL) at 0°C was added hexanoyl chloride (31.2 mg, 1.5 eq). The reaction was stirred at 0°C for 6 h. The mixture was heated at 0°C by adding H 2 O (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, concentrated and purified by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 70%-100%, 8 min] and [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 65%-95%, 8 min] to give the title compound as an off-white solid (4.89 mg, 4.0% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.78-7.72 (m, 1H), 7.52-7.44 (m, 1H), 7.32-7.23 (m, 1H), 7.21-7.09 (m, 1H), 5.36-5.17 (m, 1H), 4.21-4.07 (m, 4H), 4.06-3.94 (m, 1H), 3.77-3.65 (m, 1H), 3.56-3.48 (m, 1H), 3.47-3.37 (m, 3H), 3.22-3.11 (m, 4H), 3. 08–2.92(m,2H),2.83–2.68(m,1H),2.64–2.55(m,2H),2.36–2.20(m,1H),2.18–2.06(m,3H),2.03–1.81(m,6H),1.79– 1.72(m,2H),1.55–1.45(m,4H),1.35–1.26(m,1H),1.17–1.08(m,3H),1.00–0.91(m,3H); LCMS(ESI,M+1): m / z=746.3. Example 45 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl diethylcarbamate

[0190] Step A 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-diethylcarbamate 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (80.0 mg, 1.0 eq.) in DCM (4 mL) was added DMAP (15.1 mg, 1.0 eq.). After 5 minutes, TEA (18.8 mg, 1.5 eq.) and diethylcarbamoyl chloride (25.1 mg, 1.5 eq.) were added dropwise to the above mixture. The reaction was stirred at 40 °C for 5 hours. The mixture was quenched with water (4.0 mL) and extracted with DCM (2 mL x 3) at 0-5 °C. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 33%-53%, 58 min) to give the title compound (26.8 mg, 5.42% yield) as an off-white solid; SFC: ee=23.5%, column: Chiralcel OD-3 50×4.6 mm ID, 3 um, mobile phase: phase A, CO 2, and phase B, MeOH (0.05% DEA); gradient elution: B in A from 5% to 40%, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar, tR1=1.788, tR2=2.508; 1H NMR (400 MHz, DMSO-d6) δ=10.84-10.63 (m, 1H), 8.61-8.46 (m, 1H), 7.90-7.77 (m, 1H), 7.58-7.48 (m, 1H), 7.44-7.35 (m, 1H), 7.30-7.16 (m, 1H), 5.37-5.12 (m, 1H), 3.96-3.89 (m, 3H), 3.81 (br d,J=10.0Hz,1H),3.69-3.65(m,1H),3.49-3.46(m,2H),3.19(br d,J=12.4Hz,2H),3.11-3.02(m,4H),2.97(br s,1H),2.85-2.76(m,2H),2.71-2.57(m,2H),2.11-2.04(m,2H),2.02-1.88(m,5H),1.86-1.78(m,2H),1.78-1.67(m,4H),1.23(br d,J=6.4Hz,4H),1.16-1.11(m,3H),1.07(br t,J=7.2Hz,3H); F NMR (400MHz, DMSO-d6) δ = -117.423, -172.136; LCMS (ESI, M+1): m / z = 747.1. Example 46 Tert-butyl (4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl) carbonate

[0191] Step A tert-Butyl carbonate (4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl)ester: To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) and TEA (15.6 mg, 2.00 equiv) in THF (2.00 mL) at 0°C was added (Boc)2O (33.7 mg, 2.0 equiv). The reaction was stirred at 25°C for 12 h. The mixture was washed with NH at 25°C. 4 The solution was quenched with Cl (2.00 mL), diluted with water (5.00 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 The mixture was dried, filtered, concentrated under reduced pressure and purified by preparative HPLC (Xtimate C18 150*40mm*10um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 10 min). The collected fractions were neutralized with saturated aqueous NaHCO3 solution (2 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound as a white solid (7.58 mg, 13% yield). 1H NMR (400MHz, DMSO-d6)δ=10.86-10.67(m,1H),8.67-8.47(m,1H),7.87(br s,1H),7.71-7.59(m,1H),7.43(br t,J=8.8Hz,1H),7.37-7.23(m,1H),5.32-5.13(m,1H),4.10-3.51(m,6H),3.28-2.94(m, 8H),2.94-2.62(m,3H),2.11-1.88(m,5H),1.86-1.59(m,6H),1.57-1.48(m,9H),1.07(br s, 3H); LCMS (ESI, M+1): m / z=748.5. Example 47 Cyclohexanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0192] Step A Cyclohexanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((2R,7aS)-2-Fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- 6-Fluoronaphthalen-2-yl)-5-ethyl : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (80.0 mg, 1.0 eq) and DIEA (47.9 mg, 3.0 eq) in THF (0.80 mL) at -68 °C was added cyclohexanecarbonyl chloride (9.05 mg, 0.50 eq). The reaction was stirred at -68 °C for 1 hour. The mixture was quenched with water (2 mL) and extracted with DCM (1 mL x 3) at 0-5 °C. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 10 min) to give the title compound (29.9 mg, 10.3% yield) as an off-white solid; SFC: ee=21.572%, column: Chiralcel OD-3 50×4.6 mm ID, 3 um, mobile phase: phase A, CO 2, and phase B, MeOH + ACN (0.05% DEA); isocratic elution: 40% B in A, flow rate: 3 mL / min; detector: PDA; column temperature: 35 ° C; back pressure: 100 bar, tR1 = 0.507, tR2 = 1.126; 1H NMR (400MHz, DMSO-d6) δ = 10.87-10.63 (m, 1H), 8.60-8.47 (m, 1H), 7.90-7.80 (m, 1H), 7.57-7.49 (m, 1H), 7.46-7.37 (m, 1H), 7.28-7.14 (m, 1H), 5.36-5.13 (m, 1H), 4.05-3.85 (m, 4H), 3.81 (br d,J=10.4Hz,1H),3.71-3.63(m,1H),3.13-3.02(m,4H),2.99-2.95(m,1H),2.94 -2.85(m,1H),2.85-2.74(m,2H),2.72-2.57(m,2H),2.10-2.00(m,3H),1.99(br F NMR (400MHz, DMSO-d6) δ = -116.943; -172.150; LCMS (ESI, M+1): m / z = 758.4. Example 48 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl piperidine-1-carboxylate

[0193] Step A Piperidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50 mg, 1.0 equiv) and K 2 CO 3To a solution of 4-nitro-1-yl-2-nitro-2-yl-4 ... NMR (400 MHz, methanol-d4) δ = 7.73 (dd, J = 6.0, 8.8 Hz, 1H), 7.41 (t, J = 2.4 Hz, 1H), 7.28 (t, J = 9.6 Hz, 1H), 7.17 (dd, J = 2.4, 7.2 Hz, 1H), 5.45-5.23 (m, 1H), 4.28-3.93 (m, 5H), 3.80-3.62 (m, 3H), 3.5 8-3.35(m,9H),3.25-2.98(m,4H),2.85-2.67(m,1H),2.46-2.21(m,2H),2.21-2.08(m,2H),2 .07-1.78(m,6H),1.75-1.58(m,6H),1.12(dt,J=2.4,7.2Hz,3H); LCMS(ESI,M+1):m / z=759.6. Example 49 (R)-7-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0194] Step A 3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate : To a solution of 8-ethyl-7-fluoro-3-hydroxy-8,8a-dihydronaphthalen-1-yl trifluoromethanesulfonate (2.00 g, 1.0 eq.) in dichloromethane (15 mL) was added DIEA (2.28 g, 3.0 eq.) and ((chloromethoxy)methyl)benzene (1.38 g, 1.5 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The organic layer was washed with anhydrous Na 2 SO 4Dry, concentrate and purify by column chromatography [SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1] to give the title compound (2.40 g, 88% yield) as a colorless oil; 1H NMR (400 MHz, CD3OD) δ = 7.72 (dd, J = 5.6, 9.2 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.38-7.34 (m, 1H), 7.33-7.28 (m, 4H), 7.27-7.23 (m, 2H), 5.42 (s, 2H), 4.74 (s, 2H), 3.27-3.17 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H).

[0195] Step B 7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrafluoroethylene Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine: To a mixture of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (600 mg, 1.0 eq) and 3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (1.02 g, 1.2 eq) in dioxane (5 mL) were added Xantphos Pd G4 (179 mg, 0.1 eq) and Cs 2 CO 3 (1.82 g, 3.0 eq.). The reaction mixture was heated at 90 °C under N 2 The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dried, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (160 mg, 13% yield) as a yellow oil; LCMS (ESI, M+1): m / z=631.5.

[0196] Step C 7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrafluoroethylene Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol: In N 2To a mixture of NaH (20.1 mg, 60% purity, 2.0 equiv) in DMAC (2 mL) was added EtSH (87.2 mg, 5.5 equiv) slowly under a 4% CO atmosphere at 0°C. The mixture was stirred at 25°C for 10 min. 7-(3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (160 mg, 1.0 equiv) was added at 0°C and the reaction mixture was stirred at 60°C for 1 h. The mixture was washed with saturated NH 4 The mixture was quenched with aqueous Cl solution (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 Dry, and concentrate to give the title compound (220 mg, crude) as a yellow solid.

[0197] Step D 7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(4-methylbenzenesulfonic acid (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine Pyridin-4-yl esters: To a solution of 7-(3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (200 mg, 1.0 eq.) and DIEA (126 mg, 3.0 eq.) in dichloromethane (2 mL) at 0°C was added DMAP (3.96 mg, 0.1 eq.) and 4-methylbenzenesulfonyl chloride (92.7 mg, 1.5 eq.). The reaction mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2 x 5 mL). The organic layer was washed with brine (5 mL) and purified by anhydrous Na 2 SO 4 Dry, and concentrate to give the title compound (80.0 mg, crude) as a yellow oil.

[0198] Step E (R)-7-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- 1,3,7-triazaspiro[4.5]decane-2,4-dione:To a solution of 7-(3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (70 mg, 1.0 equiv) and (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (30.7 mg, 2.0 equiv) in DMF (0.5 mL) were added DIEA (23.5 mg, 2.0 equiv) and The reaction mixture was stirred at 40°C for 12 hours. The mixture was filtered and analyzed by reverse phase flash chromatography [C18, 0.1% formic acid conditions] and preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN, B%: 65%-95% over 8 minutes] to give the title compound (18.4 mg, 26% yield); 1 H NMR (400MHz, CD 3 OD)δ=7.62(dd,J=6.0,8.8Hz,1H),7.38-7.08(m,8H),5.41(d,J=4.0Hz,2H),5.35-5.16(m,1H),4.75(d,J=3.2Hz,2H),4.27-3.87(m,5H),3.65(br d,J=17.6Hz,1H),3.48(br d,J=9.6Hz,1H),3.45-3.35(m,3H),3.30-2.93(m,7H),2.83-2.66(m,1H),2.37-2.06 (m, 4H), 2.04-1.75 (m, 6H), 1.11 (dt, J = 3.2, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 768.5. Example 50 Octanoic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0199] Step A Octanoic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl: To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) and TEA (15.6 mg, 2.0 equiv) in THF (2 mL) at 0°C was added octanoyl chloride (25.1 mg, 2.0 equiv). The reaction was stirred at 25°C for 12 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (3×10 mL) at 25°C. The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, filter, concentrate under reduced pressure and analyze by preparative HPLC (Xbridge Prep OBD C18 150mm*30mm*5um column (eluent: 30% to 60% CH 3 CN, and H 2 The collected fractions were neutralized with aqueous NaHCO3 (2M, 2 mL), extracted with ethyl acetate (3×10 mL), and purified by Na 2 SO 4 The reaction mixture was dried, filtered and concentrated under reduced pressure to give the title compound (4.02 mg, 6.8% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (br s, 1H), 8.66-8.47 (m, 1H), 7.85 (br s, 1H), 7.57-7.50 (m, 1H), 7.42 (br t, J = 9.0 Hz, 1H), 7.29-7.20 (m, 1H), 5.31-5.16 (m, 1H), 4.06-3.87 (m, 4H), 3.86-3.79 (m, 1H), 3.74-3.62 (m, 1H), 3.21-2.94 (m, 7H), 2.92-2.71 (m, 3H), 2.62 (br d,J=7.2Hz,2H),2.09-1.89(m,6H),1.83-1.62(m,8H),1.28(br s,6H),1.07(br s,3H),0.86(br d,J=7.2Hz,5H); LCMS(ESI,M+1):m / z=774.2. Example 51 Decanoic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0200] Step A Decanoic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- 6-Fluoronaphthalen-2-yl)-5-ethyl : Under N2 atmosphere, to a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq.) and TEA (63 mg, 4.0 eq.) in THF (1.5 mL) at -40 °C was added decanoyl chloride (24 mg, 0.8 eq.). The reaction mixture was stirred at -40 °C for 2 hours. The mixture was quenched with anhydrous methanol (1 mL) at -40 °C and stirred for 10 minutes. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×3 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried, concentrated and purified by preparative HPLC [column: Phenomenex C18 75×30 mm×3 μm; mobile phase: water (FA)-ACN; B%: 35%-65% over 5 min] to give the title compound (30 mg, 24% yield) as a pink solid; 1H NMR (400 MHz, CD3OD) δ=7.71 (dd, J=6.0, 8.8 Hz, 1H), 7.41 (dd, J=2.4, 3.6 Hz, 1H), 7.27 (t, J=9.6 Hz, 1H), 7.14 (dd, J=2.4, 13.2 Hz, 1H), 5.40-5.16 (m, 1H), 4.26-3.90 (m, 5H), 3.69 (br d,J=17.6Hz,1H),3.55-3.32(m,5H),3.29-2.96(m,6H),2.80-2.56(m,3H),2.36-1.67(m,12H), 1.50-1.23(m,12H),1.12(dt,J=1.6,7.2Hz,3H),0.96-0.81(m,3H); LCMS(ESI,M+1):m / z=802.6. Example 52 ((4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl)oxy)methyl dimethylcarbamate

[0201] Step A Chloromethyl dimethylcarbamate : At -60 ° C, dimethylamine (2M, 6.49 mL, 0.60 equiv) was slowly added to a solution of chloromethyl chloroformate (2.79 g, 1.0 equiv) and DIEA (8.39 g, 3.0 equiv) in THF (10 mL). The reaction was stirred at -60 ° C for 0.5 hours. At 0 ° C, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (4 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1] to obtain the title compound (600 mg, 20% yield) as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ = 6.05-5.52 (m, 2H), 3.11-2.83 (m, 6H).

[0202] Step B. ((4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl)oxy)methyl dimethylcarbamate Esters: (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (200 mg, 1.0 equiv) and K 2 CO 3(128 mg, 3.0 equiv.) was added to a mixture in DMF (1.0 mL) with chloromethyl dimethylcarbamate (33.9 mg, 0.80 equiv.). The reaction was stirred at 20°C for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC [SiO2, dichloromethane: methanol = 10 / 1] and preparative HPLC [Phenomenex luna C18 150×25mm×10μm; A: water (FA), B: ACN; B%: 15%-45% over 10 min]. The product was further purified by SFC [DAICEL CHIRALPAK AS 250mm×30mm, 10μm; A: ACN, B: EtOH (0.1% NH 3 H 2 O), B%: over 3.8 min, 30%-30%] and purified by preparative HPLC [Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: over 10 min, 16%-46%] to give the title compound (3.44 mg, 1.5% yield, 0.18HCOOH) as a white solid; 1H NMR(400MHz, DMSO-d6)δ=11.00-10.44(m,1H),8.63-8.47(m,1H),7.84-7.72(m,1H),7.46-7.28(m,2H), 7.24-7.06(m,1H),5.90-5.77(m,2H),5.36-5.11(m,1H),4.05-3.74(m,6H),3.73-3.55(m,2H),3.21(br s,3H),3.09-2.91(m,5H),2.80-2.78(m,8H),2.10-1.88(m,5H),1.84-1.69(m,5H),1.11-1.00(m,3H); LCMS(ESI,M+1): m / z=749.4. Example 53 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl azepane-1-carboxylate

[0203] Step A Azacycloheptane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane- 7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d] Pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (1.0 mL) was added 4-nitrophenyl chloroformate (31.1 mg, 1.0 eq) at -10°C. The mixture was stirred at this temperature for 0.5 h, and then azepane (76.6 mg, 5.0 eq) was added at -10°C. The reaction was stirred at 20°C for 12 h. The mixture was diluted with water (5.0 mL) and extracted with DCM (5.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN, B%: 60%-90% over 9 min] to give the title compound as a white solid (8.35 mg, 6.7% yield); 1H NMR (400 MHz, DMSO-d6) δ = 10.87-10.70 (m, 1H), 8.67-8.44 (m, 1H), 7.96-7.81 (m, 1H), 7.59-7.50 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H), 7.32-7.12 (m, 1H), 5.75-5.13 (m, 1H), 4.05-3.70 (m, 5H), 3.67-3. 53(m,3H),3.50-3.40(m,4H),3.31-2.97(m,7H),2.95-2.67(m,3H),2.11-1.99(m,2H),1.99-1.9 2(m,2H),1.92-1.61(m,10H),1.60-1.48(m,4H),1.11-1.03(m,3H); LCMS(ESI,M+1): m / z=773.4. Example 54 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl heptamethine-1-carboxylate

[0204] Step A Heptamethine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine pyridin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (150 mg, 1.0 eq) and TEA (46.7 mg, 2.0 eq) in DCM (1.0 mL) at -10°C was added 4-nitrophenyl chloroformate (46.7 mg, 1.0 eq). The mixture was stirred at this temperature for 0.5 h, and then heptamethine (26.2 mg, 1.0 eq) was added at -10°C. The reaction was stirred at 20°C for 12 h. The mixture was diluted with water (5.0 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [Waters Xbridge 150 x 25 mm x 5 μm; A: water (NH 4 HCO 3 ), B: ACN, B%: 64%-94% over 9 min] to give the title compound as an off-white solid (28.2 mg, 15% yield); 1H NMR (400 MHz, DMSO-d6) δ = 10.89-10.64 (m, 1H), 8.65-8.42 (m, 1H), 7.98-7.76 (m, 1H), 7.56-7.46 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 7.26-7.08 (m, 1H), 5.39-5.09 (m, 1H), 4.10-3.75 (m, 5H), 3.75-3. 49(m,3H),3.48-3.36(m,4H),3.30-2.94(m,7H),2.94-2.65(m,3H),2.12-1.98(m,2H),1.97-1.9 1 (m, 2H), 1.90-1.64 (m, 10H), 1.63-1.44 (m, 6H), 1.16-1.02 (m, 3H); LCMS (ESI, M+1): m / z=787.4. Example 55 (S)-4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 2-methylpiperidine-1-carboxylate

[0205] Step A (S)-2-Methylpiperidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane alkyl-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3, 4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (3.0 mL) at -10°C was added 4-nitrophenyl chloroformate (31.1 mg, 1.0 eq). The mixture was stirred at -10°C for 30 minutes, and then (S)-2-methylpiperidine (15.3 mg, 1.0 eq) was added to the mixture. The reaction was stirred at 20°C for 12 hours. The mixture was diluted with water (5.0 mL) and extracted with dichloromethane (5.0 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and analyzed by preparative HPLC [Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 26%-56% over 10 min] and [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3), B: ACN; B%: 9 min, 61%-91%] to give the title compound as a white solid (23.3 mg, 19% yield); 1H NMR (400 MHz, DMSO-d6) δ = 10.79-10.53 (m, 1H), 8.63-8.46 (m, 1H), 7.89-7.78 (m, 1H), 7.59-7.48 (m, 1H), 7.42-4.40 (m, 1H), 7.31-7.15 (m, 1H), 5.35-5.11 (m, 1H), 4.56-4.36 (m, 1H), 3.81 (s, 6H), 3.71-3.64 (m, 1H), 3.22-3.13 (m ,2H),3.14-3.11(m,6H),2.87-2.56(m,6H),2.11-2.04(m,1H),2.03-1.87(m,4H),1.83-1.80(m,1H),1.70-1.67 (m,6H),1.61-1.53(m,2H),1.48-1.35(m,1H),1.25-1.23(m,3H),1.09-1.05(m,3H); LCMS(ESI,M+1): m / z=773.5. Example 56 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 4-methylpiperidine-1-carboxylate

[0206] Step A 4-Methylpiperidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane- 7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d] Pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl esterTo a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (3.0 mL) at -10°C was added 4-nitrophenyl chloroformate (31.1 mg, 1.0 eq). The mixture was stirred at -10°C for 30 minutes, and then 4-methylpiperidine (15.3 mg, 1.0 eq) was added to the mixture. The reaction was stirred at 20°C for 12 hours. The mixture was diluted with water (5.0 mL) and extracted with dichloromethane (5.0 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and analyzed by preparative HPLC [Phenomenexluna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 27%-57% over 10 min] and [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: after 10 min, 63%-93%] to give the title compound as a white solid (11.1 mg, 9.1% yield); 1H NMR (400 MHz, DMSO-d6) δ = 10.87-10.11 (m, 1H), 8.59-8.42 (m, 1H), 7.85-7.80 (m, 1H), 7.58-7.49 (m, 1H), 7.42-7.38 (m, 1H), 7.29-7.15 (m, 1H), 5.37-5.10 (m, 1H), 4.24-4.12 (m, 1H), 4.02-3.80 (m, 6H), 3.73-3.6 6(m,1H),3.21-3.15(m,2H),3.09-2.95(m,6H),2.93-2.75(m,6H),2.06-2.01(m,1H),1.99-1.86(m,4H), 1.93-1.81(m,8H),1.25-1.21(m,1H),1.12-1.02(m,4H),0.99-0.91(m,3H); LCMS(ESI,M+1): m / z=773.3. Example 57 (R)-4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 2-methylpiperidine-1-carboxylate

[0207] Step A (R)-2-Methylpiperidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane alkyl-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3, 4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (1.0 mL) at -10°C was added 4-nitrophenyl chloroformate (31.1 mg, 1.0 eq). The mixture was stirred at -10°C for 0.5 h, and then (R)-2-methylpiperidine (76.7 mg, 5.0 eq) was added. The reaction was stirred at 20°C for 12 h. The mixture was diluted with water (5.0 mL) and extracted with DCM (5.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 4 HCO 3), B: ACN, B%: 9 min, 61%-91%] to give the title compound as a white solid (24.7 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6) δ = 10.85-10.52 (m, 1H), 8.68-8.35 (m, 1H), 7.93-7.75 (m, 1H), 7.60-7.48 (m, 1H), 7.40 (t, J = 9.2 Hz, 1H), 7.31-7.14 (m, 1H), 5.39-5.09 (m, 1H), 4.57-4.37 (m, 1H), 4.11-3.59 (m, 7H), 3.42 (br s,1H),3.27-2.95(m,8H),2.92-2.74(m,3H),2.68-2.62(m,1H),2.09-1.92(m,4H),1.92-1.70 (m,6H),1.69-1.35(m,6H),1.32-1.22(m,3H),1.15-0.97(m,3H); LCMS(ESI,M+1): m / z=773.4. Example 58 (R)-4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 3-methylpiperidine-1-carboxylate

[0208] Step A: (R)-3-Methylpiperidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane alkyl-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3, 4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl esterTo a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (1.0 mL) at -10°C was added (4-nitrophenyl)chloroformate (31.1 mg, 1.0 eq). The mixture was stirred at -10°C for 20 minutes, and then (R)-3-methylpiperidine hydrochloride (31.29 mg, 1.5 eq) was added. The reaction was stirred at 20°C for 12 hours. The mixture was diluted with water (5.0 mL) and extracted with DCM (5.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 26%-56%, 10 min] to give the title compound (30.2 mg, 23.5% yield, 0.33HCOOH) as a white solid. NMR (400MHz, DMSO-d6) δ = 10.90-10.65 (m, 1H), 8.63-8.49 (m, 1H), 7.89-7.80 (m,1H),7.58-7.50(m,1H),7.41(t,J=9.2Hz,1H),7.32-7.15(m,1H),5.34-5 .15(m,1H),4.04-3.63(m,8H),3.27-3.11(m,5H),3.10-2.94(m,5H),2.94-2 .67(m,4H),2.16-1.87(m,5H),1.86-1.52(m,9H),1.22-1.12(m,1H),1.08(br t, J=7.2Hz, 3H), 0.91 (br s, 3H); LCMS (ESI, M+1): m / z=773.4. Example 59 (S)-4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 3-methylpiperidine-1-carboxylate

[0209] Step A: (S)-3-Methylpiperidine-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane alkyl-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3, 4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) and TEA (31.2 mg, 2.0 eq) in DCM (1.0 mL) at -10°C was added (4-nitrophenyl)chloroformate (31.1 mg, 1.0 eq). The mixture was stirred at -10°C for 20 minutes, and then (S)-3-methylpiperidine hydrochloride (31.29 mg, 1.5 eq) was added. The reaction was stirred at 20°C for 12 hours. The mixture was diluted with water (5.0 mL) and extracted with DCM (5.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; gradient: 27%-57% B over 10 min) to give the title compound (30.0 mg, 23.2% yield, 0.2HCOOH) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 10.87 (s, 1H), 8.62-8.50 (m, 1H), 7.88-7.78 (m, 1H), 7.60-7.49 (m ,1H),7.46-7.36(m,1H),7.31-7.16(m,1H),5.35-5.13(m,1H),4.03-3.63(m,8H),3.14(br s,5H),3.10-2.94(m,5H),2.92-2.66(m,4H),2.10-1.87(m,5H),1.86-1.57(m,9H),1 .22-1.12(m,1H),1.11-1.03(m,3H),0.95-0.86(m,3H); LCMS(ESI,M+1):m / z=773.4. Example 60 Morpholine-4-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0210] Step A Morpholine-4-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a mixture of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 equiv) and morpholine-4-carbonyl chloride (23.1 mg, 1.0 equiv) in DMF (2 mL) was added K 2 CO 3 (64.0 mg, 3.0 equiv.). The reaction was stirred at 20 °C for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: YMC-Actus Triart C18 150×30 mm×7 μm; mobile phase: water (FA)-ACN; gradient: 25%-55% B over 10 min] to give the title compound (61.2 mg, 49% yield, HCOOH) as an off-white solid; 1H NMR (400MHz, DMSO-d6)δ=10.88-10.63(m,1H),8.66-8.43(m,1H),8.14(s,1H),7.83(m,1H),7.59-7.53(m,1H),7.41(t, J=9.2Hz,1H),7.33-7.20(m,1H),5.36-5.14(m,1H),4.07-3.77(m,5H),3.48-2.77(m,21H),2.08-1.69(m,10H),1.07(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=761.4. Example 61 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 1-methylcyclobutane-1-carboxylate

[0211] Step A 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-1-methylcyclobutanecarboxylic acid alkyl-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3, 4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 eq) and TEA (37.0 mg, 5.0 eq) in DCM (1 mL) was added 1-methylcyclobutanecarboxylic acid (47.3 mg, 5.7 eq) and isobutyl chloroformate (47.3 mg, 4.7 eq). The reaction was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×5 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [Phenomenex luna C18 150×25 mm×10 um; mobile phase: water (FA)-ACN; gradient: 25%-55% B over 10 min] to give the title compound (10.2 mg, 18% yield, HCOOH) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ=10.00-9.87 (m, 1H), 7.78-7.65 (m, 1H), 7.33 (s, 1H), 7.08-7.07 (m, 1H), 7.02 (br s,1H),6.86-6.70(m,1H),6.64-6.54(m,1H),6.52-6.35(m,1H),4.50-4.32(m,1H),3.23-2.79 (m,7H),2.39-1.73(m,13H),1.26-1.06(m,8H),0.99-0.88(m,4H),0.74-0.70(m,2H),0.24(br s, 2H), 0.12 (br d, J = 6.0Hz, 2H); LCMS (ESI, M+1): m / z = 744.6. Example 62 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 3-methyloxetane-3-carboxylate

[0212] Step A 3-Methyloxetane-3-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5] Decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido [3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of 3-methyloxetane-3-carboxylic acid (20.0 mg, 1.0 eq) in DCM (1 mL) was added TEA (87.2 mg, 5.0 eq) and isobutyl chloroformate (23.5 mg, 1.0 eq). The reaction was stirred at 0 °C for 0.5 h and (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (112 mg, 1.0 eq) was added. The reaction was stirred at 0 °C for 0.5 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: YMC-Actus Triart C18 150×30 mm×7 μm; mobile phase: water (formic acid v / v, B: ACN); gradient: 25%-55% B over 10 min] to give the title compound (11.8 mg, 8.7% yield, HCOOH) as a pink solid; 1H NMR (400MHz, DMSO-d6) δ = 10.87-10.68 (m, 1H), 8.65-8.46 (m, 1H), 8.21 (s, 1H) ,7.90-7.81(m,1H),7.69-7.59(m,1H),7.49-7.30(m,2H),5.36-5.12(m,1H), 5.06-4.98(m,2H),4.52-4.44(m,2H),4.06-3.65(m,7H),3.22-2.71(m,11H), 2.07-1.70 (m, 13H), 1.08 (dt, J = 2.4, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 746.3. Example 63 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl (3r,5r,7r)-adamantane-1-carboxylate

[0213] Step A (3r,5r,7r)-adamantane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro [4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrrolidone Imido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (2.0 g, 1.0 equiv) in DMF (100 mL) was added K 2 CO 3 (3.41 g, 8.0 equiv) and adamantane-1-carbonyl chloride (3.07 g, 5.0 equiv). The reaction was stirred at 40 °C for 18 h. The mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried, concentrated, and purified by preparative HPLC [column: Waters Xbridge Prep OBD C18 150×40 mm×10 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 65%-95% over 15 min] to give the title compound (395 mg, 15% yield) as an off-white solid; 1H NMR(400MHz, DMSO-d6)δ=10.85-10.67(m,1H),8.60-8.46(m,1H),7.91-7.79(m,1H),7.56-7.37(m,2H),7.28-7.12(m,1H),5.34-5.1 3(m,1H),4.02-3.64(m,6H),3.49-3.35(m,2H),3.29-3.00(m,6H),2.99-2.60(m,4H),2.09-2.01(m,10H),2.00-1.87(m,4H),1.82(br s,1H),1.79-1.67(m,10H),1.07(br t, J=7.1Hz, 3H); LCMS (ESI, M+1): m / z=810.4. Example 64 Cyclobutanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0214] Step A Cyclobutanecarboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (200 mg, 1.0 eq) in DMF (3 mL) was added cyclobutanecarbonyl chloride (36.6 mg, 1.0 eq) and K 2 CO 3 (128 mg, 3.0 equiv.). The reaction was stirred at 25 °C for 12 h. The mixture was treated with H 2 O (15 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 Dry, concentrate and purify by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: water (ammonia hydroxide v / v, B: ACN); gradient: 56%-86% B over 9 min] to give the title compound (26.0 mg, 11% yield) as an off-white solid; 1H NMR (400MHz, DMSO-d6) δ = 10.84-10.68 (m, 1H), 8.66-8.43 (m, 1H), 7.86-7.82 (m,1H),7.61-7.53(m,1H),7.42(t,J=9.2Hz,1H),7.34-7.13(m,1H),5.35-5 .08(m,1H),4.04-3.63(m,6H),3.55-3.41(m,2H),3.30-2.93(m,8H),2.92-2 .58(m,3H),2.41-2.25(m,4H),2.10-1.86(m,7H),1.83-1.68(m,5H),1.07(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=730.4. Example 65 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl bis(2-methoxyethyl)carbamate

[0215] Step A Bis(2-methoxyethyl)carbamic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro [4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrrolidone Imido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (36.0 mg, 1.0 eq) in DCM (1 mL) was added (4-nitrophenyl)chloroformate (13.4 mg, 1.2 eq) and TEA (16.9 mg, 3.0 eq). The reaction was degassed and purged with nitrogen three times and stirred at -10 °C for 0.5 h. 2-Methoxy-N-(2-methoxyethyl)ethylamine (5.74 mg, 1.0 equiv) was added dropwise at 20°C and the reaction was stirred at 20°C for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: water (ammonia hydroxide v / v, B: ACN); gradient: 40%-70% B over min, 5 min] to give the title compound (8.92 mg, 9% yield) as an off-white solid; 1H NMR(400MHz, DMSO-d6)δ=11.08-10.23(m,1H),8.27-7.91(m,1H),7.89-7.76(m, 1H),7.58-7.49(m,1H),7.46-7.36(m,1H),7.32-7.13(m,1H),5.39-5.11(m,1H) ,4.08-3.77(m,5H),3.73-3.55(m,5H),3.55-3.46(m,4H),3.32-3.28(m,7H),2. 55 (s, 11H), 2.13-1.58 (m, 10H), 1.20-0.96 (m, 3H); LCMS (ESI, M+1): m / z=807.6. Example 66 Bicyclo[2.2.2]octane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0216] Step A Bicyclo[2.2.2]octane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5] Decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido [3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester : To a solution of bicyclo[2.2.2]octane-1-carboxylic acid (59.5 mg, 2.5 eq) in DCM (2 mL) was added isobutyl chloroformate (37.9 mg, 1.8 eq) and TEA (78.1 mg, 5.0 eq) at 0 °C. The reaction was stirred at 25 °C for 12 h. (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) was added. The reaction was stirred at 40 °C for 12 h. The mixture was washed with H 2 O (15 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: water (formic acid v / v, B: ACN); gradient: 38%-68% B over 9 min] to give the title compound (26.0 mg, 11% yield, HCOOH) as an off-white solid; 1H NMR(400MHz, DMSO-d6)δ=10.84-10.68(m,1H),8.66-8.43(m,1H),7.84(m,1H),7.61-7 .53(m,1H),7.42(t,J=9.2Hz,1H),7.34-7.13(m,1H),5.35-5.08(m,1H),4.04-3.63(m, 6H),3.55-3.41(m,2H),3.30-2.93(m,8H),2.92-2.58(m,3H),2.41-2.25(m,4H),2.10 -1.86 (m, 7H), 1.83-1.68 (m, 5H), 1.07 (brt, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 784.6. Example 67 Bicyclo[2.1.1]hexane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0217] Step A Bicyclo[2.1.1]hexane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5] Decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido [3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl esterTo a solution of bicyclo[2.1.1]hexane-1-carboxylic acid (38.9 mg, 2.0 eq) in DCM (0.5 mL) at 0°C was added isobutyl chloroformate (37.9 mg, 1.8 eq) and TEA (78.1 mg, 5.0 eq). The reaction was stirred at 25°C for 12 hours and (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 eq) was added. The reaction was stirred at 25°C for 24 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: water (ammonium bicarbonate v / v)-ACN; gradient: 63%-93% B over 9 minutes] to give the title compound (9.34 mg, 7.4% yield) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.74 (dd, J = 6.0, 8.4 Hz, 1H), 7.45-7.40 (m, 1H), 7.32-7.26 (m, 1H), 7.17-7.12 (m, 1H), 5.33-5.18 (m, 1H), 4.23-4.16 (m, 1H), 4.15-4.11 (m, 2H), 4 .10-4.06(m,1H),4.06-4.01(m,1H),3.69(brd,J=17.2Hz,1H),3.57-3.48(m,2H),3 .45-3.38(m,3H),3.24-3.17(m,4H),3.04-2.94(m,2H),2.83-2.75(m,1H),2.53(br s,1H),2.21-2.11(m,3H),2.06(br s,5H),1.96-1.82(m,8H),1.48(br s,2H),1.16-1.10(m,3H); LCMS(ESI,M+1): m / z=756.4. Example 68 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 2-oxabicyclo[2.1.1]hexane-4-carboxylate

[0218] Step A 2-Oxabicyclo[2.1.1]hexane-4-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro [4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrrolidone Imido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester: To a solution of 2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (70.0 mg, 2.0 equiv) in DCM (1 mL) was added isobutyl chloroformate (67.2 mg, 1.8 equiv) and TEA (138 mg, 5.0 equiv) at 0°C. The reaction was stirred at 25°C for 12 hours, and then (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (177 mg, 1.0 equiv) was added. The reaction was stirred at 25°C for 3 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Phenomenexluna C18 150×25 mm×10 μm; mobile phase: water (formic acid v / v, B: ACN); gradient: 25%-55% B over 9 min] to give the title compound (82.9 mg, 37% yield, HCOOH) as an off-white solid; 1H NMR (400MHz, DMSO-d6)δ=10.82-10.72(m,1H),8.62-8.49(m,1H),8.17(s,1H),7.91-7.82(m,1H),7.66-7.59(m,1H),7.44 (t,J=9.6Hz,1H),7.38-7.26(m,1H),5.34-5.15(m,1H),4.60-4.58(m,1H),4.07-3.80(m,7H),3.76-3.62(m,2H),3.20(br d,J=13.2Hz,1H),3.15-3.05(m,4H),2.94-2.75(m,3H),2.34-2.28(m,2H),2.12-1.64(m,14H),1.12-1.04(m,3H); LCMS(ESI,M+1):m / z=758.3. Example 69 2,2-Diethylbutyric acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0219] Step A 2,4,6-Trichlorobenzoic acid 2,2-diethylbutyric anhydride : TEA (98.2 mg, 2.0 equiv) and 2,4,6-trichlorobenzoyl chloride (118 mg, 1.0 equiv) were added to a solution of 2,2-diethylbutyric acid (70.0 mg, 1.0 equiv) in DCM (2 mL). The reaction was stirred at 30 ° C for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified with preparative TLC [SiO2, petroleum ether / ethyl acetate=50 / 1] to give the title compound (166 mg, 49% yield) as a white solid; 1HNMR (400 MHz, methanol-d4) δ=7.54 (s, 2H), 1.62-1.55 (m, 6H), 0.76 (t, J=7.6 Hz, 9H).

[0220] Step B 2,2-Diethylbutyric acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine pyridin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of 2,4,6-trichlorobenzoic acid 2,2-diethylbutyric anhydride (120 mg, 1.0 equiv) in toluene (6 mL) was added DMAP (83.4 mg, 2.0 equiv) and (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (221 mg, 1.0 equiv). The reaction was stirred at 90 °C for 12 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: water (NH 4 HCO 3 )-ACN; gradient: 70%-100% B over 9 min] and SFC [column: DAICELCHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: CO 2 -EtOH (0.1% NH 3 ·H 2O); B%: 50%, isocratic elution mode] to give the title compound as an off-white solid (6.30 mg, 2.3% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.75 (td, J = 5.6, 8.4 Hz, 1H), 7.36 (dd, J = 2.0, 6.0 Hz, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.08-6.97 (m, 1H), 5.40-5.1 7(m,1H),4.21-3.94(m,5H),3.78-3.35(m,6H),3.22-2.96(m,6H),2.84-2.63(m,1H),2.29-1.85( m, 10H), 1.81-1.73 (m, 6H), 1.16-1.09 (m, 3H), 0.92 (q, J = 7.2Hz, 9H); LCMS (ESI, M+1): m / z = 774.5. Example 70 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl (3r,5r,7r)-adamantane-1-carboxylate

[0221] Step A (S,Z)-2-((2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxy tert-Butyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate : To a mixture of tert-butyl 2-chloro-4-methoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (7.0 g, 1.0 equiv), (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (4.40 g, 1.1 equiv) and Cs2CO3 (22.8 g, 3.0 equiv) in toluene (70.0 mL) was added 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.91 g, 0.2 equiv). The mixture was degassed and purged with N2 three times. Diacetoxypalladium (524 mg, 0.10 equiv) was added to the mixture. The reaction was degassed and purged with N2 three times. The reaction was stirred at 110 °C for 3 hours. The mixture was filtered, concentrated and purified by preparative HPLC [Phenomenex luna C18 250×70 mm, 10 um; A: water (FA), B: ACN, B%: 22%-50% over 18 min] to give the title compound (9.20 g, 91% yield) as a yellow oil; LCMS (ESI, M+1): m / z=435.2.

[0222] Step B (S,Z)-2-((2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxy 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine : A solution of (S,Z)-tert-butyl 2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8.00 g, 1.0 equiv) in HCl·MeOH (4M, 30 mL, 6.5 equiv) was stirred at 25 °C for 0.5 h. The mixture was concentrated. The residue was diluted with water (30.0 mL). The pH of the mixture was adjusted to 11 with sodium hydroxide solution (15 ml). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (6.00 g, 88% yield) as a yellow oil; LCMS (ESI, M+1): m / z=335.0.

[0223] Step C (S,Z)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine To a solution of (S,Z)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (6.00 g, 1.0 eq.) and 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (8.92 g, 1.3 eq.) in dioxane (100 mL) was added Cs 2 CO 3 (17.5 g, 3.0 eq.). The mixture was degassed and heated to 400 °C with N 2 Purge 3 times. 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; palladium dichloride (872 mg, 0.05 equiv) were added to the mixture. The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 ° C for 16 hours. The mixture was filtered and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (6.00 g, 57.2% yield) as a yellow oil; LCMS (ESI, M+1): m / z=567.2.

[0224] Step D (S,Z)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-olTo a solution of (S,Z)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (5.00 g, 1.0 eq) in DMAC (30.0 mL) was added NaSEt (2.23 g, 3.0 eq). The reaction was stirred at 60 °C for 1 hour. The mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (4.50 g, 86% yield) as a yellow oil; LCMS (ESI, M+1): m / z=553.1.

[0225] Step E (R)-7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((S,Z)-2-(fluoro (methylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)- 1,3,7-Triazaspiro[4.5]decane-2,4-dione To a solution of (S,Z)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (6.00 g, 1.0 eq) in DMSO (60 mL) was added TEA (3.30 g, 3.0 eq) and PyBOP (8.48 g, 1.5 eq). The reaction was stirred at 25 °C for 0.5 h. (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (2.76 g, 1.5 eq) was then added to the mixture. The reaction was stirred at 25 °C for 12 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate=2 / 1 to 0 / 1] to give the title compound (7.2 g, 90% yield) as a red solid; LCMS (ESI, M+1): m / z=704.3.

[0226] Step F (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrakis Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazine Heterospiro[4.5]decane-2,4-dioneTo a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (1.00 g, 1.0 eq.) in DCM (5 mL) was added TFA (7.68 g, 49.1 eq.). The reaction was stirred at 15 °C for 0.1 h. At -40 °C, the mixture was diluted with DCM (10 mL) and quenched with TEA until pH = 8. The mixture was diluted with water (20 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 35%-65% B over 12 min] to give the title compound (175 mg, 19% yield) as a red solid; LCMS (ESI, M+1): m / z=660.3.

[0227] Step G (3r,5r,7r)-adamantane-1-carboxylic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro [4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-5,8-dihydro- Hydrogen pyrido [3,4-d] pyrimidin-7 (6H) -yl) -5-ethyl-6-fluoronaphthalen-2-yl ester: To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (170 mg, 1.0 equiv) in DMF (2 mL) was added K 2 CO 3 (125 mg, 15 equiv) and (3r,5r,7r)-adamantane-1-carbonyl chloride (307 mg, 10 equiv). The reaction was stirred at 50 °C for 5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: water (FA)-ACN; gradient: 35%-65% B over 10 min] to give the title compound (18.2 mg, 16% yield, 0.24HCOOH) as an off-white solid; 1 H NMR (400 MHz, methanol-d4 )δ=7.79-7.73(m,1H),7.41(t,J=2.4Hz,1H),7.31(t,J=9.2Hz,1H),7.12(dd,J=2.0,7.6Hz,1H),6.90 -6.61(m,1H),4.38-4.34(m,1H),4.31-4.20(m,1H),4.19-3.93(m,4H),3.86-3.69(m,2H),3.58-3.38( m,6H),3.25-3.14(m,2H),3.11-2.89(m,2H),2.87-2.71(m,2H),2.64-2.54(m,1H),2.29-2.19(m,1H), 2.12(brs,10H),2.06-1.92(m,4H),1.90-1.82(m,7H),1.19-1.12(m,3H); LCMS(ESI,M+1): m / z=822.5. Example 71 Carbonic acid 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylmethyl ester

[0228] The compound of Example 71 can be prepared by one skilled in the art by methods similar to those described for preparing the compound of Example 30. Example 72 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl acetate

[0229] Step A Acetic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S, Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl esterTo a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (30.0 mg, 1.0 equiv) in DMF (3 mL) was added K 2 CO 3 (16.3 mg, 3.0 equiv) and acetyl chloride (6.18 mg, 2.0 equiv). The reaction was stirred at 50 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 45%-75% B over 9 min] to give the title compound as a yellow solid (5.65 mg, 20% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.73 (dd, J = 6.0, 8.8 Hz, 1H), 7.43 (dd, J = 2.4, 4.8 Hz, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.17 (dd, J = 2.4, 16.2 Hz, 1H), 6.75-6.47 (m, 1H), 4.20-3.90 (m, 5H), 3.86-3.76 (m, 1H), 3.70 (dd, J = 10.8, 17.6Hz,1H),3.53-3.37(m,5H),3.26-2.98(m,4H),2.82-2.62(m,3H),2.42-2.35(m,1H),2.31(d,J=4.0 Hz, 3H), 2.16-2.04 (m, 2H), 2.01-1.75 (m, 6H), 1.12 (dt, J = 2.4, 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 702.4. Example 73 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl piperidine-1-carboxylate

[0230] Step A Piperidine-1-carboxylic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)- 2-(((S,Z)-2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d] Pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.0 mg, 1.0 equiv) in DMF (4 mL) was added K 2 CO 3 (83.8 mg, 10.0 equiv) and piperidine-1-carbonyl chloride (89.5 mg, 10.0 equiv). The reaction was stirred at 50 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 52%-82% B over 9 min] to give the title compound as a yellow solid (3.49 mg, 7.3% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.72 (dd, J = 6.0, 8.8 Hz, 1H), 7.45-7.37 (m, 1H), 7.28 (t, J = 9.6 Hz, 1H), 7.17 (dd, J = 2.0, 12.4 Hz, 1H), 6.76-6.47 (m, 1H), 4.25-4.04 (m, 5H), 3.86-3.66 (m, 4H), 3.52 (br s, 3H), 3.46-3.39 (m, 3H), 3.24-3.10 (m, 3H), 3.03 (br s,1H),2.81-2.64(m,3H),2.39(br d,J=14.8Hz,1H),2.16-2.06(m,2H),2.03-1.75(m,7H),1.68(br d, J=11.2Hz, 6H), 1.14-1.10 (m, 3H); LCMS (ESI, M+1): m / z=771.5. Example 74 Cyclopropanecarboxylic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0231] Step A Cyclopropanecarboxylic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((S,Z)-2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine pyridin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv) in DMF (4 mL) was added K 2 CO 3 (157 mg, 15.0 equiv) and cyclopropanecarbonyl chloride (79.2 mg, 10.0 equiv). The reaction was stirred at 50 °C for 5 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 50%-80% B over 9 min] to give the title compound as a yellow solid (6.18 mg, 11% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.78-7.66 (m, 1H), 7.42 (br s, 1H), 7.29 (br t,J=9.2Hz,1H),7.21-7.10(m,1H),6.75-6.46(m,1H),4.26-4.01(m,5H),3.96-3.81(m,1H),3.76-3.65(m,1H),3.52-3.38(m,5H),3.22- 2.98(m,4H),2.80-2.62(m,3H),2.44-2.35(m,1H),2.16-2.06(m,2H),2.00-1.77(m,7H),1.20-1.00(m,7H); LCMS(ESI,M+1): m / z=728.2. Example 75 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl propanoate

[0232] Step A. Propionic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane -7-yl)-2-(((S, Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (30.0 mg, 1.0 equiv) in DMF (4 mL) was added K 2 CO 3 (94.3 mg, 15.0 equiv) and propionyl chloride (42.1 mg, 10.0 equiv). The reaction was stirred at 50 °C for 5 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH 4 HCO 3)-ACN]; gradient: 48%-78% B over 9 min] to afford the title compound as a pink solid (4.55 mg, 13% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.73 (dd, J = 5.6, 8.8 Hz, 1H), 7.43 (dd, J = 2.4, 4.0 Hz, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.17 (dd, J = 2.0, 13.6 Hz, 1H), 6.77-6.47 (m, 1H), 4.18-4.07 (m, 4H), 3.97-3.60 (m, 3H), 3.54-3.38 (m, 5H), 3.23-2.99 (m, 4H), 2.82-2.60 (m, 5H), 2.39 (br d,J=15.6Hz,1H),2.12-2.07(m,2H),2.02-1.77(m,6H),1.29-1.23(m,3H),1.15-1.11(m,3H); LCMS(ESI,M+1):m / z=716.2. Example 76 Isobutyric acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0233] Step A Isobutyric acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2- (((S,Z)-2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine pyridin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester To a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.0 mg, 1.0 equiv) in DMF (2 mL) was added K 2 CO 3(29.3 mg, 3.5 eq.) and 2-methylpropanoyl chloride (32.3 mg, 5.0 eq.). The reaction was stirred at 50 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [column: waters Xbridge 150×25 mm×5 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 55%-85% B over 9 min] to give the title compound as a yellow solid (10.2 mg, 23% yield); 1H NMR (400MHz, methanol-d4) δ = 7.77-7.69 (m, 1H), 7.42 (dd, J = 2.4, 4.4Hz, 1H), 7.29 (t ,J=9.2Hz,1H),7.15(dd,J=2.4,13.2Hz,1H),6.75-6.48(m,1H),4.23-3.91(m ,5H),3.86-3.76(m,1H),3.69(dd,J=5.2,17.6Hz,1H),3.54-3.38(m,5H),3.2 7-2.97(m,4H),2.87(dtd,J=2.4,7.2,14.0Hz,1H),2.82-2.62(m,3H),2.39(br d,J=15.2Hz,1H),2.16-2.05(m,2H),2.02-1.76(m,6H),1.33(dd,J=3.2,7.2Hz,6H),1.13(dt,J=2.8,7.2Hz,3H); LCMS(ESI,M+1):m / z=730.4. Example 77 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl propanoate

[0234] Step A Propionic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S)- 2-Methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)- 5-Ethyl-6-fluoronaphthalen-2-yl esterTo a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (100 mg, 1.0 equiv) in DMF (1.0 mL) was added K 2 CO 3 (129 mg, 6.0 equiv) and propionyl chloride (57.7 mg, 4.0 equiv). The reaction was stirred at 50 °C for 12 hours. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (4×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [C18, 0.1% NH 3 ·H 2 O conditions] to give the title compound as a white solid (50 mg, 44% yield); 1H NMR (400 MHz, DMSO-d6) δ 10.90-10.61 (m, 1H), 8.65-8.45 (m, 1H), 7.89-7.78 (m, 1H), 7.60-7.50 (m, 1H), 7.42 (t, J = 9.2 Hz, 1H), 7.34-7.15 (m, 1H), 4.90-4.79 (m, 2H), 4.05-3.73 (m, 5H), 3.73-3.59 (m, 1H), 3.56-3.38 (m, 3H) ,3.30-3.21(m,2H),3.21-3.00(m,4H),2.99-2.76(m,3H),2.72-2.54(m,3H),2.34-2.24(m,1H),2.06-1.85(m ,3H),1.84-1.68(m,4H),1.66-1.56(m,1H),1.20-1.12(m,3H),1.11-1.02(m,3H); LCMS(ESI,M+1): m / z=698.4. Example 78 Carbonic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylmethyl ester

[0235] The compound of Example 78 can be prepared by one skilled in the art by methods similar to those described for preparing the compound of Example 30. Example 79 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl piperidine-1-carboxylate

[0236] The compound of Example 79 can be prepared by one skilled in the art by methods similar to those described for preparing the compound of Example 73. Example 80 Cyclopropanecarboxylic acid 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ester

[0237] The compound of Example 80 can be prepared by one skilled in the art by methods similar to those described for preparing the compound of Example 77. Example A Whole blood stability assay

[0238] This example illustrates that exemplary compounds of the invention are cleavage fragments in mouse whole blood.

[0239] Test compounds and stock solutions: stock concentration 10 mM; final concentration 2 μM

[0240] Test compound and control working solution preparation: Intermediate solution: Dilute 5 μL of compound stock solution (10 mM in dimethyl sulfoxide (DMSO)) with 45 μL of DMSO (intermediate solution concentration: 1 mM, 100% DMSO) Propantheline bromide (control) intermediate solution: dilute 5 μL of propantheline bromide stock solution (10 mM in ultrapure water) with 45 μL of ultrapure water (intermediate solution concentration: 1 mM) Working solution 1: 20 μL of the test compound intermediate solution (1 mM) was mixed with 180 μL of 45% ACN / H 2 O (working solution concentration: 100 μM, 40.5% ACN, 10% DMSO) dilution Working solution 2: 20 μL of control intermediate solution (1 mM) was mixed with 180 μL of 45% ACN / H2 O (working solution concentration: 100 μM, 40.5% ACN, 10% DMSO) dilution Species / Matrix: CD-1 mouse blood Number of individuals: n>3 males Anticoagulant used: EDTA-K2 method Fresh blood was collected on the day of the experiment and pre-warmed in a 37°C water bath. • Using the Apricot automated workstation, add 98 μL / well of blank blood to all 96-well reaction plates (blank, T0, T10, T30, T60, and T120). • The Apricot automated workstation adds 2 μL / well of working solution (100 μM) to all reaction plates (T0, T10, T30, T60 and T120) except the blank. • Incubate all reaction plates containing the mixture of compound and blood at 37°C in a water bath. • Incubate the reaction plate at 37°C and start the timer. At the end of the incubation, mix 100 μL of water with 100 μL of spiked blood sample, then add 800 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in ACN) to precipitate proteins. Mix thoroughly. • Seal each plate and shake for 20 minutes. After shaking, each plate was centrifuged at 4000 rpm and 4°C for 20 minutes. After centrifugation, transfer 150 μL of supernatant from each reaction plate to its corresponding bioassay plate using an Apricot automated workstation. • Each bioassay plate was subjected to LC-MS / MS analysis. Data analysis Calculate the % remaining of the test compound after incubation in the blood using the following equation: % Remaining = 100x (PAR at designated incubation time / PAR at T0 time) Where PAR is the peak area ratio of the analyte to the internal standard (IS) The designated incubation time points are T0 (0 min), Tn (n = 0, 10, 30, 60 and 120 min) Table 1 Mouse whole blood stability Formation of the parent compound was observed for those examples with short half-lives. Example B Plasma stability assay

[0241] This example illustrates that exemplary compounds of the invention are cleaved fragments in human plasma.

[0242] Test compounds and stock solutions: stock concentration 10 mM; final concentration 2 μM

[0243] Test compound and control working solution preparation: - Test compound intermediate solution: 10 μL of compound stock solution (10 mM in dimethyl sulfoxide (DMSO)) was diluted with 90 μL of DMSO (intermediate solution concentration: 1 mM, 100% DMSO). - Control intermediate solution: 10 μL of the control stock solution (10 mM in dimethyl sulfoxide (DMSO)) was diluted with 90 μL of DMSO (intermediate solution concentration: 1 mM, 100% DMSO). Species / Matrix: Human plasma Number of individuals: 3 males and 3 females Anticoagulants used: Heparin method • Prior to the experiment, the pooled frozen plasma was thawed in a water bath at 37° C. The plasma was centrifuged at 4000 rpm for 5 minutes to remove clots, if any. • Using the Apricot automated workstation, add 98 μL / well of blank plasma to all 96-well reaction plates (blank, T0, T10, T30, T60, and T120). • The Apricot automated workstation adds 2 μL / well of working solution (100 μM) to all reaction plates (T0, T10, T30, T60 and T120) except the blank. • Incubate all reaction plates containing mixtures of compound and plasma at 37°C in a water bath. • Incubate the reaction plate at 37°C and start the timer. - At the end of the incubation, add 500 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in ACN) to precipitate proteins. Mix thoroughly. • Seal each plate and shake for 20 minutes. After shaking, centrifuge each plate at 4000 rpm and 4°C for 20 minutes After centrifugation, 50 μL of supernatant was transferred into 100 μL of HPLC water using an Apricot automated workstation. Each bioassay plate was sealed and shaken for 10 minutes prior to LC-MS / MS analysis Data analysis Calculate the % remaining of the test compound after incubation in the blood using the following equation: % Remaining = 100x (PAR at designated incubation time / PAR at T0 time) Where PAR is the peak area ratio of the analyte to the internal standard (IS) The designated incubation time points are T0 (0 min), Tn (n = 0, 10, 30, 60 and 120 min) Table 2 Human plasma stability Formation of the parent compound was observed for those examples with short half-lives.

[0244] Although the invention has been described in conjunction with specific embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention which generally follow the principles of the invention and which involve departures from the invention which come within the known or customary practice of the art to which the invention pertains and which are applicable to the basic characteristics as set forth above and which appear within the scope of the appended claims.

Claims

1. A prodrug of a compound having the following structure: or a pharmaceutically acceptable salt thereof.

2. The prodrug compound or salt of claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof, in R1 and R2 are independently selected from the group consisting of: H, R3-*, R3-O-CH2-*, Provided that only one of R1 and R2 may be H; A is CH or N; R3 is C1-C 20 Alkyl, (C1-C4 alkyl) 0-1 -Cycloalkyl, (C1-C4 alkyl) 0-1 -Heterocyclic group or (C1-C4 alkyl) 0-1 -aryl, wherein R3 is optionally substituted by C1-C4 alkyl or -O-C1-C4 alkyl; R4 is H or R3; and R5 and R6 are independently selected from the group consisting of H and C1-C6 alkyl.

3. The compound of claim 2, wherein R1 is H and R2 is selected from the group consisting of: <h2 style=";text-align:left;direction:ltr">R3-*, R3-O-CH2-*,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 4. The compound of claim 2, wherein R2 is H and R1 is selected from the group consisting of: <h2 style=";text-align:left;direction:ltr">R3-*, R3-O-CH2-*,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 5. The prodrug compound or salt of claim 2, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

6. The prodrug compound or salt of claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: <h2 style=";text-align:left;direction:ltr">R3-*, R3-O-CH2-*,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A is CH or N; R3 is C1-C 20 Alkyl, (C1-C4 alkyl) 0-1 -Cycloalkyl, (C1-C4 alkyl) 0-1 -Heterocyclic group or (C1-C4 alkyl) 0-1 -aryl, wherein R3 is optionally substituted by C1-C4 alkyl or -O-C1-C4 alkyl; R4 is H or R3; and R5 and R6 are independently selected from the group consisting of H and C1-C6 alkyl.

7. The compound or salt of claim 6, wherein A is CH.

8. The compound or salt of claim 6, wherein R4 is R3.

9. The compound or salt of claim 6, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

10. The prodrug compound or salt of claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: <h2 style=";text-align:left;direction:ltr">R3-*, R3-O-CH2-*,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A is CH or N; R3 is C1-C 20 Alkyl, (C1-C4 alkyl) 0-1 -Cycloalkyl, (C1-C4 alkyl) 0-1 -Heterocyclic group or (C1-C4 alkyl) 0-1 -aryl, wherein R3 is optionally substituted by C1-C4 alkyl or -O-C1-C4 alkyl; R4 is H or R3; and R5 and R6 are independently selected from the group consisting of H and C1-C6 alkyl.

11. The compound or salt of claim 10, wherein A is CH.

12. The compound or salt of claim 10, wherein R4 is R3.

13. The compound or salt of claim 10, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

14. The prodrug compound or salt of claim 1, wherein the compound has the following structure: or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: <h2 style=";text-align:left;direction:ltr">R3-*, R3-O-CH2-*,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A is CH or N; R3 is C1-C 20 Alkyl, (C1-C4 alkyl) 0-1 -Cycloalkyl, (C1-C4 alkyl) 0-1 -Heterocyclic group or (C1-C4 alkyl) 0-1 -aryl, wherein R3 is optionally substituted by C1-C4 alkyl or -O-C1-C4 alkyl; R4 is H or R3; and R5 and R6 are independently selected from the group consisting of H and C1-C6 alkyl.

15. The compound or salt of claim 14, wherein A is CH.

16. The compound or salt of claim 14, wherein R4 is R3.

17. The compound or salt of claim 14, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. A method for inhibiting the activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H in a cell, the method comprising contacting the cell in which the KRas activity is desired to be inhibited with an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

20. A method for treating cancer, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 18, to a patient suffering from cancer.

21. The method of claim 20, wherein the therapeutically effective amount of the compound is about 0.01 to 100 mg / kg / day.

22. The method of claim 21, wherein the therapeutically effective amount of the compound is about 0.1 to 50 mg / kg / day.

23. The method of claim 20, wherein the cancer is selected from the group consisting of: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary Tract: Kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (endometrial carcinoma (serous =The following are some of the following: malignant tumors: ovarian (epidermal, ovarian, genital, ovarian, ureteral), cervical (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma.

24. The method of claim 23, wherein the cancer is a KRas G12A-associated cancer.

25. The method of claim 23, wherein the cancer is a KRas G12C-associated cancer.

26. The method of claim 23, wherein the cancer is a KRas G12D-associated cancer.

27. The method of claim 23, wherein the cancer is a KRas G12R-associated cancer.

28. The method of claim 23, wherein the cancer is a KRas G12S-associated cancer.

29. The method of claim 23, wherein the cancer is a KRas G12V-associated cancer.

30. The method of claim 23, wherein the cancer is a KRas G13D-associated cancer.

31. The method of claim 23, wherein the cancer is a KRas Q61H-associated cancer.

32. The method of claim 23, wherein the cancer is a KRas G12A-associated cancer.

33. The method of claim 23, wherein the cancer is associated with at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

34. The method of any one of claims 20-33, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

35. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutations; and (b) administering to the patient a therapeutically effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18.

36. The method of any one of claims 19-35, wherein the administration is via a route selected from the group consisting of: Parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and local administration.

37. The method of claim 36, wherein the route of administration is oral.

38. The method of claim 36, wherein the administration is intravenous injection.

39. The method of claim 36, wherein the route of administration is intramuscular injection.

40. The method of claim 36, wherein the route of administration utilizes a delivery device.

41. The method of claim 36, wherein administering is performed in a hospital setting.

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