Prodrug of a pan-KRas inhibitor

Abstract

The present invention relates to prodrugs of specific compounds that inhibit multiple mutant forms of KRas, i.e., pan-KRas inhibitors. In particular, the present invention relates to prodrugs of these pan-KRas compounds, pharmaceutical compositions containing the prodrugs, and methods of using the same.

Description

Technical Field

[0001] The present invention relates to prodrugs of specific compounds that inhibit multiple mutant forms of KRas, i.e., pan-KRas inhibitors. In particular, the present invention relates to prodrugs of pan-KRas compounds, pharmaceutical compositions containing these prodrugs, and methods of using the same.

Background Art

[0002] Kirsten rat sarcoma 2 virus oncogene homolog (「KRas」) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch cycling between an inactive (GDP-bound) state and an active (GTP-bound) state, and transmits upstream cell signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes including cell proliferation (see, for example, Non-Patent Document 1).

[0003] The role of activated KRas in malignant tumors was observed over 30 years ago (see, for example, Non-Patent Document 2). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and result in constitutive activation of KRas. KRas mutations at codons 12, 13, 61 and other positions in the primary amino acid sequence of KRas are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colorectal / rectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (see, for example, Non-Patent Document 3). Recent publications have also suggested that wild-type KRas inhibition may be a viable therapeutic strategy for treating KRas WT -dependent cancers (see, for example, Non-Patent Document 4).

[0004] The well-known role of KRas in malignant tumors and the discovery of these frequent mutations in KRas in various tumor types have made KRas a very attractive target for the pharmaceutical industry in cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas for treating cancer, KRas inhibitors still have not demonstrated sufficient safety and / or efficacy to obtain regulatory approval (see, for example, Non-Patent Document 5).

[0005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including compounds that disrupt effectors such as guanine nucleotide exchange factors (see, for example, Non-Patent Document 6), as well as recent progress in the covalent targeting of the allosteric pocket of KRas G12C (see, for example, Non-Patent Document 7 and Non-Patent Document 8). Clearly, there remains a continuing interest and effort in developing inhibitors of KRas, particularly inhibitors of the activated KRas mutants.

[0006] A compound having the following formula:

Chemical formula

[0007] Similarly, the formula:

Chemical formula

[0008] In the art, there is a need to develop prodrugs of these and similar compounds that are converted in vivo to these compounds and are thus effective in treating KRas-mediated cancers.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Summary of the Invention

Means for Solving the Problems

[0011] In one aspect, the present invention provides a prodrug of a compound having the following structure:

Chemical Formula

[0012] This compound is described as the species of Example 140 in the specification of PCT International Application No. PCT / US2021 / 010065 (International Publication No. WO 2022 / 132200 Pamphlet).

[0013] In another aspect, the present invention provides a prodrug of a compound having the following structure:

Chemical Formula

[0014] This compound is described as a species of Example 196 in the specification of PCT International Application No. PCT / US2021 / 063722 (International Publication No. WO 2022 / 133038 Pamphlet).

[0015] In one aspect, the provided prodrug has the general structure of formula (I):

Chemical formula

Chemical formula

[0016] In one aspect, R1 is H and R2 is R3-*, R3-O-CH2-*, [Chemical formula] is.

[0017] In another embodiment, R2 is H, and R1 is R3-*, R3-O-CH2-*, [Chemical formula] is.

[0018] In one embodiment, the provided prodrug has the following structure: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] and its pharmaceutically acceptable salts.

[0019] In another embodiment of the present invention, the provided prodrug has the following general structure: [Chemical formula] or has its pharmaceutically acceptable salts (wherein R1 is H, R3-*, R3-O-CH2-*, [Chemical formula] is, A is CH or N; R3 is C1-C 20 alkyl, (C1-C4 alkyl) 0-1 -cycloalkyl, (C1-C4 alkyl) 0-1 -heterocyclyl or (C1-C4 alkyl)0-1 -aryl, and R3 is optionally substituted with C1-C4 alkyl or -O-C1-C4 alkyl; R4 is H or R3; R5 and R6 are independently selected from the group consisting of H and C1-C6 alkyl).

[0020] In one aspect, the compound of formula II is:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] In another aspect of the present invention, the provided prodrug has the following structure:

Chemical formula

Chemical formula

[0022] In one aspect, the compound of formula III is:

Chemical formula

[0023] In another aspect of the present invention, the provided prodrug has the following general structure:

Chemical formula

Chemical formula

[0024] In one aspect, the compound of formula IV is: [Chemical formula] and is selected from the group consisting of the prodrug compound and its pharmaceutically acceptable salts.

[0025] In another aspect of the present invention, a pharmaceutical composition is provided that comprises a therapeutically effective amount of the prodrug compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0026] In yet another aspect of the present invention, a method for inhibiting the activity of cells in a cell that contains wild-type KRas or one or more KRas mutations, such as KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H, is provided. The method comprises contacting the cell with the prodrug of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0027] Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of the prodrug compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0028] Also provided is a method for treating cancer in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of the prodrug compound of the present invention or a pharmaceutical composition thereof, or a pharmaceutically acceptable salt thereof.

[0029] Also provided herein is a method for treating a KRas wild-type, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-related disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of the prodrug compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0030] Also provided herein are prodrug compounds as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in a method of treatment.

[0031] Also provided herein are prodrug compounds as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer.

[0032] Also provided herein are prodrug compounds, or pharmaceutically acceptable salts thereof, for use in inhibiting wild-type KRas or multiple types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0033] Also provided herein are prodrug compounds as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of diseases or disorders associated with wild-type KRas or diseases or disorders associated with KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0034] Also provided herein is the use of the prodrug compounds of the invention as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of cancer.

[0035] Also provided herein is the use of the prodrug compounds of the invention as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for inhibiting the activity of wild-type forms of KRas or mutant forms of KRas including mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0036] 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 the treatment of a disease or disorder associated with wild-type KRas or a disease or disorder associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0037] Also provided herein is a method for the treatment of cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (i.e., a 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 invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] One potential utility of the prodrugs described herein as pan-KRas inhibitors is for the treatment of cancers that develop resistance after long-term treatment with a KRas G12C inhibitor. Accordingly, embodiments of the invention include those in which a patient afflicted with cancer is treated with a prodrug compound described herein where the patient has become unresponsive or has decreased efficacy due to the emergence of resistance-conferring mutations after treatment with a G12C inhibitor.

[0039] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors such as adagrasib (MRTX849) or sotorasib (AMG510) can result in the incorporation of additional mutations that confer resistance to adagrasib. These mutations can confer resistance through a number of mechanisms.

[0040] Mutations that change the mutant cysteine at codon 12 to another amino acid will render current covalent KRas G12C inhibitors ineffective because current inhibitors covalently bind to the mutant cysteine amino acid side chain. Similarly, in patients having one wild-type KRas allele in addition to the KRas G12C mutant allele, mutations of the wild-type codon 12 glycine to another codon will likely allow bypass of signaling in these tumors via the newly mutated protein. The repertoire of codon 12 mutations that can occur by single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, G12C, etc. The repertoire of codon 12 mutations that can occur by single nucleotide base substitutions of the cysteine codon 12 includes, in addition to G12S and G12R, mutations not frequently observed in cancer, such as G12Y, G12F, and G12W.

[0041] Secondary site mutations can also occur at other positions within the KRas G12C mutant gene that confer resistance to KRas G12C inhibitor treatment. These mutations can confer resistance through various mechanisms. The RAS protein is a small GTPase that normally cycles between an active GTP-bound state and an inactive GDP-bound state. GTP is loaded onto the RAS protein via a guanine nucleotide exchange factor (GEF; e.g., SOS1) that is activated by an upstream receptor tyrosine kinase, inducing subsequent interaction with effector proteins that activate RAS-dependent signaling. The RAS protein hydrolyzes GTP to GDP by its intrinsic GTPase activity, which is dramatically enhanced by a GTPase-activating protein (GAP). Mutations at codons 12 and 13 of the RAS protein impair GAP-stimulated GTP hydrolysis, and RAS predominantly assumes the GTP-bound active state. Covalent KRas G12C inhibitors currently in clinical development bind only to GDP-bound KRas G12C. Mutations such as those at codon Q61, which may or may not be present on the same allele as the G12C mutation, can reduce the intrinsic GTPase activity of KRas and shift KRas to a GTP-loaded state that is less susceptible to the effects of covalent inhibition, serving as a mechanism of resistance to KRas G12C inhibitor treatment. Co-mutations such as R68, H95, and Y96 may be present with the KRas G12C mutation and may decrease the binding affinity to the Switch II binding pocket of KRas G12C inhibitors.

[0042] The prodrug compounds of the invention described herein can demonstrate activity against common and rare codon 12 mutations that occur in the KRas protein, which reduce the binding of KRas G12C inhibitors to the KRas protein.

DETAILED DESCRIPTION OF THE INVENTION

[0043] The present invention relates to prodrugs of specific compounds that inhibit multiple mutant forms of KRas, i.e., pan-KRas inhibitors that inhibit wild-type KRas and / or multiple mutant forms of KRas, such as 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 following formula: [Chemical Formula] 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0044] This compound is described as Species of Example 140 in the PCT International Application No. PCT / US2021 / 010065 (International Publication No. WO 2022 / 132200 Pamphlet). The PCT application also describes the method for preparing this compound.

[0045] Similarly, the formula: [Chemical Formula] (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione is described as Species of Example 196 in the PCT International Application No. PCT / US2021 / 063722 (International Publication No. WO 2022 / 133038 Pamphlet). The PCT application also describes the method for preparing this compound.

[0046] The prodrugs of the present invention, pharmaceutical compositions containing a therapeutically effective amount of a compound, and methods of using the same inhibit the activity of wild-type KRas and / or KRas mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H when administered in vivo.

[0047] Definitions 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 this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0048] As used herein, "wild-type KRas" refers to the non-mutated form of the mammalian KRas protein. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "wild-type KRas inhibitor" refers to the compounds of the present invention represented by formulas (I)-(IV) herein or their metabolites. These compounds can negatively regulate or inhibit 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 that is associated with, mediated by, or has wild-type KRas. Non-limiting examples of wild-type KRas-related diseases or disorders are wild-type KRas-related cancers.

[0049] As used herein, "KRas G12A" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by alanine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12 inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or a metabolite thereof. These compounds can negatively regulate or inhibit 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, mediated by, or having a KRas G12A mutation. Non-limiting examples of KRas G12A-related diseases or disorders are KRas G12A-related cancers.

[0050] As used herein, "KRas G12C" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by cysteine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12C inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or a metabolite thereof. These compounds can negatively regulate or inhibit 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, mediated by, or having a KRas G12C mutation. Non-limiting examples of KRas G12C-related diseases or disorders are KRas G12C-related cancers.

[0051] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by aspartic acid at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12D inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or a metabolite thereof. These compounds can negatively regulate or inhibit 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 that is related to, mediated by, or has a KRas G12D mutation. Non-limiting examples of KRas G12D-related diseases or disorders are KRas G12D-related cancers.

[0052] As used herein, "KRas G12R" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by arginine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12R inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or a metabolite thereof. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-related disease or disorder" refers to a disease or disorder that is related to, mediated by, or has a KRas G12R mutation. Non-limiting examples of KRas G12R-related diseases or disorders are KRas G12R-related cancers.

[0053] As used herein, "KRas G12S" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by serine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12S inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or a metabolite thereof. These compounds can negatively regulate or inhibit 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 that is related to, mediated by, or has a KRas G12S mutation. Non-limiting examples of KRas G12S-related diseases or disorders are KRas G12S-related cancers.

[0054] As used herein, "KRas G12V" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by valine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are 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 invention represented by formulas (I)-(IV) described herein or a metabolite thereof. These compounds can negatively regulate or inhibit 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 that is related to, mediated by, or has a KRas G12V mutation. Non-limiting examples of KRas G12V-related diseases or disorders are KRas G12V-related cancers.

[0055] As used herein, "KRas G13D" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by aspartic acid at amino acid position 13. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G13D inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or their metabolites. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-related disease or disorder" refers to a disease or disorder that is related to, mediated by, or has a KRas G13D mutation. Non-limiting examples of KRas G13D-related diseases or disorders are KRas G13D-related cancers.

[0056] As used herein, "KRas Q61H" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of glycine by histidine at amino acid position 61. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas Q61H inhibitor" refers to a compound of the invention represented by formulas (I)-(IV) described herein or their metabolites. These compounds can negatively regulate or inhibit 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 that is related to, mediated by, or has a KRas Q61H mutation. Non-limiting examples of KRas Q61H-related diseases or disorders are KRas Q61H-related cancers.

[0057] As used herein, the terms "subject", "individual", or "patient", used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject has experienced and / or presented with 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 a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject has a tumor that is positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). The subject can be a subject having a tumor that is positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, such as the FDA). The subject can be a subject in which the subject's tumor has a wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., the tumor is so identified using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject is suspected of having a cancer associated with wild-type KRas or a 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 having 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).

[0058] As used herein, the term “prodrug” refers to a drug precursor compound that undergoes a conversion in vivo to yield the parent compound or a pharmaceutically acceptable salt, hydrate, or solvate of the parent compound. The conversion can occur by various mechanisms, either metabolic or chemical processes. Consideration of the use of prodrugs is provided by “Prodrugs: Challenges and Rewards, Parts 1 and 2,” Vol. V of the Biotechnology: Pharmaceutical Aspects (Ronald T. Borchardt and C. Russel Middaugh, series editors), ed. 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 preferred prodrugs are those that increase the bioavailability of the parent compound when such a compound is administered to a patient (e.g., by enabling a compound administered orally to be more readily absorbed into the bloodstream), or facilitate delivery of the parent compound to a biological compartment (e.g., the brain or the lymphatic system).

[0059] The prodrug compounds of the present invention may themselves have a prodrug. In that 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 that can provide, either directly or indirectly, the compound of the present invention or its pharmaceutically active metabolite or residue upon administration to a recipient.

[0060] As used herein, the term "metabolite" refers to any substance produced during metabolism, i.e., during digestion or other body chemical processes.

[0061] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient (e.g., a patient suspected of having wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer, a patient having one or more symptoms of wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer, and / or a patient at high risk of developing wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer) has a wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation using a sample from the patient (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample)). The assay may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, an assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0062] The term "regulatory authority" refers to a national agency for approving the medical use of pharmaceuticals with the country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0063] The term "acyl" refers to -C(O)CH3.

[0064] As used herein, the term "alkyl" refers to straight-chain and branched-chain aliphatic groups. For example, as used herein, the terms "C1-C6 alkyl", "C1-C4 alkyl", and "C1-C3 alkyl" refer to straight-chain and branched-chain aliphatic groups having 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0065] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to a C1-C3 alkyl chain or a C1-C4 alkyl chain as defined herein, wherein one or more hydrogens are replaced by halogen. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0066] The "C1-C4 alkylene" group refers to a C1-C4 alkyl group as defined above herein that is disposed between two other chemical groups and serves to connect the chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0067] 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 herein.

[0068] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbons having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, where the cycloalkyl group is optionally further substituted with C1 to C6 alkyl or other groups as defined herein. Examples of cycloalkyl 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]pentanyl.

[0069] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0070] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0071] An “aryl” group is one or more R 8 or R 9 C6-C containing 1-3 aromatic rings, optionally substituted with a group 14 In one embodiment, the aryl group is a C6-C 10 It is an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, where one or two rings of the aryl ring system, respectively, may be saturated or partially saturated, and when the ring system contains two saturated rings, the saturated rings may be fused or spirocyclic. Examples of aryl ring systems containing two saturated rings, where the rings are spirocyclic, include the following ring systems: [ka]

[0072] The "arC1-C6 alkyl" or "arylalkyl" group includes an aryl group covalently bonded to an alkyl group, and each of them can independently be optionally substituted or unsubstituted. Examples of the aralkyl group include, but are not limited to, benzyl, phenethyl, and naphthylmethyl (C6-C 10 ) aryl(C1-C6)alkyl-. Examples of the substituted arC1-C6 alkyl are those in which the alkyl group is substituted with a hydroxyalkyl.

[0073] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, such as 4 to 8 atoms, with one or more atoms selected from the group consisting of N, O, and S. Ring N atoms can be oxidized to N-O, ring S atoms can be oxidized to SO or SO2, and the remaining ring atoms are carbon. Heterocyclyl can be monocyclic, bicyclic, spirocyclic or a bridged ring system. The heterocyclic group can optionally be substituted on the ring nitrogen atom by alkyl, aralkyl, alkylcarbonyl, on sulfur by lower alkyl, and on carbon by lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroindolizinyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1’H,3’H-spiro[cyclopropane-1,2’-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl s, diazaspirononanyl, oxaazabicycloheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, tetrahydro-2H-thiopyran-1-oxide and tetrahydro-2H-thiopyran-1,1-dioxide. Compounds having adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0074] As used herein, the term "heteroaryl" has 3 to 14 ring atoms, preferably 5, 6, 6, 9, or 10 ring atoms, selected from the group consisting of N, O, and S; has 5, 10, or 14 π electrons shared in a cyclic array; and refers to a group having 1 to 3 heteroatoms per ring or 1 to 3 heteroatoms in at least one ring in addition to carbon atoms.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,3,4-oxadiazolyl, 1,4,4-oxadiazolyl, 1,5,4-oxadiazolyl, 1,4,5-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, 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, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,5,4-thiadiazinyl, 1,3,4-thiadiazolyl, 1,4,4-thiadiazolyl, 1,5,4-thiadiazolyl, 1,4,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thieno[2,3-b]thiazole, thieno[2,3-b]oxazole, thieno[2,3-b]imidazole, thiophenyl, triazinyl, 1,3,4-triazolyl, 1,4,4-triazolyl, 1,5,4-triazolyl, 1,4,4-triazolyl, and xanthenyl, and are selected from the group consisting of these."Heteroaryl" also refers to a bicyclic ring system having, in addition to carbon atoms, one to three heteroatoms selected from the group consisting of N, O, and S per ring, where one of the ring systems can be saturated or partially saturated.

[0075] As used herein, an "effective amount" of a compound is 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 may be administered as a single dose or may be administered according to a regimen in which it is effective.

[0076] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to relieve symptoms, or to reduce symptoms in any way, or to stop or reverse the progression of a condition, 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 may be administered as a single dose or may be administered according to a regimen in which it is effective.

[0077] As used herein, treatment means any method by which the symptoms or pathology of a condition, disorder, or disease are alleviated or otherwise beneficially modified. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0078] As used herein, remission of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any alleviation that may result from or be associated with administration of the composition, whether permanent or temporary, persistent or transient.

[0079] Compound In one embodiment of the present invention, a prodrug compound of a compound having the following structure is provided: [Chemical formula] 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0080] This compound is described as a species of Example 140 in the specification of PCT International Application No. PCT / US2021 / 010065 (International Publication No. WO 2022 / 132200 Pamphlet).

[0081] Similarly, for the formula: [Chemical formula] (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorooctahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione is described as a species of Example 196 in the specification of PCT International Application No. PCT / US2021 / 063722 (International Publication No. WO 2022 / 133038 Pamphlet).

[0082] In one aspect, the provided prodrug has the general structure of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein, R1 and R2 are; H, R3-*, R3-O-CH2-*, [Chemical formula] Independently selected from the group consisting of, provided that only one of R1 and R2 can be H; A is CH or N; R3 is C1-C 20 alkyl, (C1-C4 alkyl) 0-1 -cycloalkyl, (C1-C4 alkyl) 0-1 -heterocyclyl or (C1-C4 alkyl) 0-1 -aryl, and R3 is optionally substituted with C1-C4 alkyl or -O-C1-C4 alkyl; R4 is H or R3; R5 and R6 are independently selected from the group consisting of H and C1-C6 alkyl.

[0083] In one embodiment, R1 is H, and R2 is R3-*, R3-O-CH2-*,

Chemical formula

[0084] In another embodiment, R2 is H, and R1 is R3-*, R3-O-CH2-*,

Chemical formula

[0085] In one embodiment, the provided prodrug has the following structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0086] In another aspect of the present invention, the provided prodrug has the following general structure:

Chemical formula

Chemical formula

[0087] In one aspect, the compound of formula II is:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0088] In another aspect of the present invention, the provided prodrug has the following structure:

Chemical formula

Chemical formula

[0089] In one aspect, the compound of formula III is:

Chemical formula

[0090] In another aspect of the present invention, the provided prodrug has the following general structure:

Chemical formula

Chemical formula

[0091] In one embodiment, the compound of formula IV is:

Chemical formula

[0092] In one embodiment, the compounds of formulas (I)-(IV) include bis-hydrochloride, tris-hydrochloride, trifluoroacetate, bis-trifluoroacetate, and tris-trifluoroacetate of the above compounds. The provided prodrug compound or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition.

[0093] Pharmaceutical composition In another aspect, the present invention provides a pharmaceutical composition comprising a prodrug of the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The prodrug compounds of the present invention can be formulated 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, intrathecal, intra-articular, intramedullary, intramuscular, intravitreal, intravenous, intra-arterial, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous, and local administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, the administration can be by the oral route. In some embodiments, the pharmaceutical composition provided is administered to a subject in need of treatment by systemic injection, such as by intravenous injection; or by application to an injection or associated site, such as by direct injection with a syringe or direct application to a site when the site has been surgically exposed; or by local administration.

[0094] Parenteral administration can be by bolus injection or continuous infusion. Pharmaceutical compositions for injection can be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with an added preservative.

[0095] The pharmaceutical compositions provided can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the formulation can be modified with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as an insoluble derivative, e.g., as an insoluble salt.

[0096] The pharmaceutical composition can be presented in a medical device including, but not limited to, a vial, a pack, or a dispenser device that 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 of a liquid formulation ready for injection. The syringe can be accompanied by instructions for administration.

[0097] The properties 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 biological systems such as cells, cell cultures, tissues, or organisms and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, the compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizing agents and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0098] As used herein, the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the compounds identified above and exhibit minimal or no undesirable toxicological effects. Examples of such salts include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, but are not limited thereto. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly including 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, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilolate, and diphenylacetate, etc.).

[0099] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects in the treated patient. In one embodiment, the dosage of the active compound for all of the above-described conditions (states) ranges from about 0.01 to 300 mg / kg per day, such as 0.1 to 100 mg / kg, and as a further example, is 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will be in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is active by itself, the effective dosage can be estimated as described above using the weight of the derivative, or by other means known to those skilled in the art.

[0100] The pharmaceutical composition comprising the compound of the present invention can be used in the methods of use described herein.

[0101] Methods of Use In yet another aspect, the present invention provides a method for 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 a cell in which inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or Q61H activity is desired with a pharmaceutical composition comprising an effective amount of the prodrug compound of the present invention, a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0102] As used herein, the term "contacting" refers to bringing the specified moieties together in an in vitro or 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, such as a human, having wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutation, and introducing, for example, a prodrug compound provided herein into a sample containing a cell or a purified preparation containing wild-type KRas or a cell or purified preparation containing a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutation.

[0103] 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 negatively regulate 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.

[0104] By negatively regulating 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, the methods described herein are designed to inhibit unwanted cell proliferation, which results in enhanced wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H activity in cells. Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to affect the desired negative regulation 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. The ability of a compound to bind to 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 can be monitored in vitro using well-known methods. In addition, the inhibitory activity of an exemplary compound in cells can be monitored 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 by the amount of phosphorylated ERK.

[0105] In another aspect, there is provided a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a prodrug compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof.

[0106] The compositions and methods provided herein can be used for the treatment of 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 a patient in need thereof, and comprise administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a prodrug compound of formulas (I)-(IV) or a metabolite thereof, a pharmaceutically acceptable salt thereof, or a 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.

[0107] The compositions and methods provided herein can be used for the treatment of a very wide variety of cancers, including tumors such as lung, prostate, breast, brain, skin, cervical, and testicular cancers. 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, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers, and sarcomas. More specifically, these compounds are: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, adenoma, hamartoma, leiomyosarcoma); Genitourinary: 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochronfroma) (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, gliocytoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, meningioma, gliocytoma, sarcoma); Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, sertoli-leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (cancer); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; And adrenal gland: May be used to treat 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.;

[0108] The dosing concentration and route of administration to the patient will vary depending on the cancer being treated. The prodrug compound, its pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-cancer compounds, such as chemotherapy, or used in combination with other treatments, such as radiation or surgical procedures, as an adjuvant before or after surgery.

[0109] Also provided herein are prodrug compounds as defined herein for use in a treatment method, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0110] Also provided herein are prodrug compounds as defined herein for use in the treatment of cancer, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0111] Also provided herein are prodrug compounds, or pharmaceutically acceptable salts thereof, for use in inhibiting wild-type KRas or multiple types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations.

[0112] Also provided herein are prodrug compounds as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of diseases or disorders associated with wild-type KRas or diseases or disorders associated with KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H.

[0113] Also provided herein is the use of the prodrug compounds of the present invention as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of cancer.

[0114] Also provided herein is the use of the prodrug compounds of the present invention as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for inhibiting the activity of wild-type forms of KRas or mutant forms of KRas including mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H.

[0115] Also provided herein is the use of the prodrug compounds of the present invention as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of diseases or disorders associated with wild-type KRas or diseases or disorders associated with KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H.

[0116] Methods for the treatment of cancer in patients in need thereof are also provided herein, the methods comprising (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (i.e., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); (b) administering to the patient a therapeutically effective amount of a prodrug compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0117] One of ordinary skill in the art will recognize that both in vivo and in vitro testing using suitable known and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0118] One of ordinary skill in the art will further recognize that human clinical trials, including first-in-human, dose range, and efficacy testing in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0119] Reaction Schemes and Examples The prodrug compounds of the invention can be prepared using well-known synthetic methods from commercially available reagents and the reaction schemes described herein, and also using other well-known methods similar to those described in, for example, PCT / US2021 / 010065 (WO 2022 / 132200 pamphlet), or using other reagents and conventional methods well known to those of ordinary skill in the art.

[0120] The compounds of the present invention may have one or more chiral centers and can be synthesized as mixtures of stereoisomers, isomers of the same constitution with different arrangements of their atoms in space. The compounds can be used as mixtures, or the individual components / isomers can be separated using conventional methods for the isolation of stereoisomers and enantiomers well-known to those skilled in the art and commercially available reagents, for example, using Chiralpak® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare the individual isomers or enantiomers. Unless otherwise indicated, all chiral forms (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 encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0121] The compounds of the present invention can be in anhydrous, solvated or hydrated forms, and all such forms are included within the scope of the present invention.

[0122] The following examples are intended to illustrate further specific embodiments of the present invention and are not intended to limit the scope of the present invention.

Examples

[0123] Example 1

Chemical formula

[0124] Example 2 [Chemical formula] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-ylpropionate 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 = 9.6 Hz, 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, 6H), 1.88 - 1.70 (m, 4H), 1.69 - 1.61 (m, 1H), 1.30 - 1.20 (m, 1H), 1.16 (dt, J = 1.2, 7.6 Hz, 3H), 0.75 (dt, J = 2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 676.3.

[0125] Example 3 [Chemical Formula] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 isobutyrate 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 = 11.2 Hz, 1H), 4.21 - 4.08 (m, 2H), 4.01 (d, J = 10.4 Hz, 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, 15.2 Hz, 1H), 2.33 (br d, J = 2.0 Hz, 1H), 2.26 - 1.95 (m, 6H), 1.88 - 1.70 (m, 4H), 1.69 - 1.61 (m, 1H), 1.26 (d, J = 7.2 Hz, 7H), 0.75 (dt, J = 2.8, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 690.3.

[0126] Example 4 [Chemical formula] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-ylcyclopropanecarboxylate [Chemical formula] Project A.5 - Ethyl - 6 - fluoro - 4 - (8 - fluoro - 2 - (((2R,7aS) - 2 - fluorooctahydro - 1H - pyrrolidin - 7a - 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 - ylcyclopropanecarboxylate: To a solution of (1R,5R,6R) - 3 - (7 - (8 - ethyl - 7 - fluoro - 3 - hydroxynaphthalen - 1 - yl) - 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorooctahydro - 1H - pyrrolidin - 7a - yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl) - 3 - azabicyclo[3.2.1]octan - 6 - ol (100 mg, 1.0 equivalent) and TEA (49.0 mg, 3.0 equivalents) in DCM (2 mL) was added cyclopropanecarbonyl chloride (25.3 mg, 1.5 equivalents) at - 40 °C. The reaction mixture was stirred at - 40 °C for 3 hours. The mixture was concentrated and purified by preparative HPLC [Water Xbridge 150×25mm×5μm; A: water (NH4HCO3), B: ACN, B%: 58% - 88% in 8 minutes] to give the title compound (66.5 mg, 59% yield) as a white solid. 1H NMR (400 MHz, 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.

[0127] Example 5

Chemical Structure

[0128] Example 6

Chem.

Chem.

[0129] Example 7

Chemical Structure

[0130] Example 8

Chemical Structure

Chemical Structure

[0131] Project B. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 Cs2CO3 (1.5 M, 3.0 equiv) in methoxycyclopentane (15 mL) was added CataCXium A Pd G3 (332 mg, 0.20 equiv). The reaction mixture was stirred at 100 °C for 2 h. The mixture was quenched by adding water and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (2 × 10 mL), dried over Na2SO4, 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.

[0132] Project C. (1R,5R,6R)-3-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[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-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) in DMF (0.5 mL) were added 4 Å 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 mixture was stirred at 40 °C for 12 h. The mixture was filtered and purified by preparative HPLC (column: UniSil 3-100 C18 UItra (150×25 mm×3um); mobile phase: [Water (FA)-ACN]; B%: 26% - 46%, 7 min) to give the title compound (59.9 mg, FA salt) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 9.25 (d, J = 18.0 Hz, 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.

[0133] Example 9

Chemical Structure

Chem.

[0134] Example 10

Chemical Structure

Chem.

[0135] Project B.7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (117 mg, 1.0 equivalent), 2-[3-(ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 g, 1.0 equivalent) and K3PO4 (1.5 M, 534 μL, 3.0 equivalents) in CPME (5 mL) was added with [4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate (17.0 mg, 0.10 equivalent). The reaction mixture was degassed, purged with N2 three times, and stirred at 70 °C under N2 atmosphere for 1 hour. The mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under vacuum, and purified by flash silica gel chromatography (ISCO®; 20.0 g SepaFlash® silica flash column, eluent with 0 - 100% ethyl acetate / petroleum ether gradient @ 50 mL / min) to obtain the title compound (158 mg, yield 64%) as a yellow solid; LCMS (ESI, M+1): m / z = 651.2.

[0136] Process C. (1R,5R,6R)-3-(7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: A solution of 7-[3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl]-8-fluoro-2-[[(2R,8S)-2-fluorotetrahydro-1H-pyrrolidin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.20 g, 1.0 equivalent) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (93.8 mg, 2.4 equivalents) in DMF (14 mL) was added with 4 Å molecular sieves (0.20 g) and DIEA (119 mg, 3.0 equivalents). The reaction mixture was stirred at 40 °C for 12 hours. The mixture was diluted with H2O (14 mL) and extracted with EtOAc (3 × 14 mL).The combined organic layer was dried over Na2SO4, filtered, concentrated under vacuum, and purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 21% - 51%, fractionation) to obtain the title compound (0.13 g, yield 32%) 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, 13.7 Hz, 2H), 4.01 (d, J = 10.6 Hz, 1H), 3.72 (q, J = 7.1 Hz, 3H), 3.11 - 3.01 (m, 3H), 2.83 (br d, J = 6.6 Hz, 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 = 7.1 Hz, 3H), 0.78 - 0.68 (m, 3H); LCMS (ESI, M+1): m / z = 678.2.

[0137] Example 11

Chemical Structure

Chemical Structure

[0138] Example 12

Chem.

Chem.

[0139] Example 13 [Chemical Structure] 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 cyclobutanecarboxylate

Chem.

[0140] Example 14

Chemical Structure

Chem.

[0141] Engineering 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 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (60.1 mg, 2.0 equivalents), KOAc (34.9 mg, 3.0 equivalents) and cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (17.3 mg, 0.2 equivalent) in dioxane (1 mL) was degassed and purged with N2 three times. This mixture was stirred at 100 °C for 3 hours under a N2 atmosphere. 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 obtain 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 = 9.6 Hz, 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, 7.6 Hz, 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).

[0142] Engineering C.7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: A solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (105 mg, 1.0 equivalent) 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 equivalents) in methoxycyclopentane (1 mL) was added with cataCXium® A Pd G3 (34.9 mg, 0.2 equivalent) and Cs2CO3 (1.5 M, 3.0 equivalents). The aqueous solution was degassed and purged three times with N2. The mixture was stirred at 80 °C for 3 hours under a N2 atmosphere. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse-phase HPLC (0.1% FA conditions) to obtain the title compound (76.0 mg, 34% yield) as a black solid; LCMS (ESI, M+1): m / z = 677.2.

[0143] Project D. (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-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-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-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60.0 mg, 1.0 equiv) and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (16.9 mg, 1.5 equiv) in DMF (0.5 mL) was added DIEA (34.4 mg, 3.0 equiv). The reaction mixture was stirred at 50 °C for 14 h.This mixture was filtered and purified by reverse-phase HPLC (column: Water Xbridge 150×25 mm×5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 62% - 92%, 9 min) to obtain the title compound (8.80 mg, yield 14%) as a white solid; 1H NMR (400 MHz, CD3OD) δ = 9.29 - 9.18 (m, 1H), 7.84 - 7.72 (m, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.37 - 7.18 (m, 2H), 5.69 - 5.59 (m, 1H), 5.43 - 5.20 (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, 19.1 Hz, 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, 6H), 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, 7.6 Hz, 1H), 1.40 (br d, J = 14.4 Hz, 1H), 0.86 - 0.75 (m, 3H); LCMS (ESI, M+1): m / z = 704.5.

[0144] Example 15

Chemical Structure

Chemical Structure

[0145] Example 16 [Chem.] (1R,5R,6R)-3-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol [Chem.] Step A. 2-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (500 mg, 1.0 equiv) in CH3CN (10 mL) were added DIEA (408 mg, 2.0 equiv) and (bromomethyl)benzene (540 mg, 2.0 equiv). The reaction mixture was stirred at 25 °C for 12 h. The mixture was quenched by the addition of water (10 mL) and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4, concentrated, and purified by column chromatography to afford the title compound (600 mg) as a white solid; LCMS (ESI, M+1): m / z = 407.3.

[0146] Project B.7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equivalent) and 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (194 mg, 0.90 equivalent) in CMPE (5 mL) were added K3PO4 (1.5 M, 0.3 mL, 1.0 equivalent) and CataCXium A Pd G3 (3.58 mg, 0.01 equivalent). The reaction mixture was stirred at 80 °C for 12 h under a N2 atmosphere. The mixture was quenched by adding water (10 mL) and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4, and concentrated to give the crude product as a brown oil, which was used in the next step without further purification; LCMS (ESI, M+1): m / z = 683.4.

[0147] Process C. (1R,5R,6R)-3-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 7-(3-(benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) in DMF (1 mL) were added 4 Å MS (20.0 mg), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (29.8 mg, 1.6 equiv) and DIPEA (36.2 mg, 2.0 equiv). The reaction mixture was stirred at 40 °C for 12 h. 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, 3.4 Hz, 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, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 710.3.

[0148] Example 17 [Chemical formula] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-ylcyclopentanecarboxylate [Chemical formula] Project A.5 - Ethyl - 6 - fluoro - 4-(8 - fluoro - 2 - (((2R,7aS)-2 - fluorooctahydro - 1H - pyrrolidin - 7a - 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)cyclopentanecarboxylate: A mixture of (1R,5R,6R)-3-(7-(8 - ethyl - 7 - fluoro - 3 - hydroxynaphthalen - 1 - yl)-8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)-3 - azabicyclo[3.2.1]octan - 6 - ol (100 mg, 1.0 equivalent) and TEA (49.0 mg, 3.0 equivalents) in DCM (1.0 mL) was added with cyclopentanecarbonyl chloride (21.4 mg, 1.0 equivalent) at once 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 × 2 mL).The combined organic layer was dried over Na2SO4, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 28% - 58%, 10 min) to obtain the title compound (27.0 mg, yield 22.8%) as a white solid; SFC: ee>95%, column: Chiralpak AS-3 50×4.6mm I.D., 3um mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% - 40% B in A; 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 = 12.4 Hz, 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); 13C NMR (400 MHz, methanol-d4) δ = -116.78, -139.04, -173.73; LCMS (ESI, M+1): m / z = 716.2.

[0149] Example 18

Chemical Structure

Chem.

[0150] Example 19 [Chemical Structure] tert-Butyl (5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 [Chemical Structure] Engineering A. tert-butyl (5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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: (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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), Boc2 (38.7 mg, 2.2 equivalents), TEA (24.5 mg, 3.0 equivalents) and K2CO3 (11.1 mg, 1.0 equivalent) in DMF (0.5 mL) solution was added 1,4,7,10,13,16-hexaoxacyclooctadecane (21.3 mg, 1.0 equivalent). The reaction was stirred at 25 °C for 17.5 hours. The mixture was filtered and purified by preparative HPLC [Water Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: ACN; B%: 62% - 92% in 8 minutes] to obtain 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.

[0151] Example 20 [Chemistry] ((5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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)methyldimethylcarbamate [Chemistry] Step A. Chloromethyldimethylcarbamate: Dimethylamine (2 M, 6.49 mL, 0.6 equiv) was slowly added to a solution of chloromethyl carbonochloridate (2.79 g, 1.0 equiv) and DIEA (8.39 g, 3.0 equiv) in THF (10 mL) at -60 °C. The reaction mixture was stirred at -60 °C for 0.5 h. The mixture was quenched by adding water (30 mL) at 0 °C and extracted with ethyl acetate (4 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 50 / 1 - 10 / 1] to give 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).

[0152] Project B. ((5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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)methyldimethylcarbamate: A mixture of (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (60.0 mg, 1.0 eq) and K2CO3 (40.2 mg, 3.0 eq) in DMF (1.0 mL) was added with chloromethyldimethylcarbamate (14.7 mg, 1.10 eq). The reaction mixture was stirred at 20 °C for 12 h. The mixture was filtered and purified by preparative HPLC [Water Xbridge C18 150×50 mm×10 μm; A: water (NH4HCO3), B: ACN; B%: 55% - 58% in 9 min] to give the title compound (38.0 mg, 53% yield) as a white solid; 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 = 7.6 Hz, 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.

[0153] Example 21 [Chem.] 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-ylcyclohexanecarboxylate [Chem.] Project A.5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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)cyclohexanecarboxylate: 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-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (100 mg, 1.0 equiv) and TEA (49.0 mg, 3.0 equiv) in DCM (1.0 mL) was added cyclohexanecarbonyl chloride (23.7 mg, 1.0 equiv) at -40 °C in one portion 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 × 2 mL).The combined organic layer was dried over Na2SO4, concentrated, and purified by preparative HPLC {column: Phenomenex luna C18 150×25mm×10um; mobile phase [water (FA)-ACN]; B%: 28% - 58%, 10 min} to obtain the title compound (14.5 mg, yield 11.9%) as a white solid; SFC: ee>95%, column: Chiralpak AS-3 50 ×4.6mm I.D., 3μm; mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); gradient elution: 5% - 40% B in A; 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), 3.50 - 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, 2H), 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); 19F NMR (400 MHz, methanol-d4) δ = -116.74, -139.20, -173.84; LCMS (ESI, M+1): m / z = 730.4.

[0154] Example 22 [Chemical formula] 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)ethyldimethylcarbamate

Chem.

[0155] Project B.1 - ((5-Ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)ethyldimethylcarbamate: 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 equivalent) and 1-chloroethyldimethylcarbamate (206 mg, 1.0 equivalent) in acetonitrile (5 mL) was added K2CO3 (563 mg, 3.0 equivalents). The reaction mixture was stirred at 25 °C for 16 h. The mixture was quenched by adding water (5 mL), extracted with EA (3 × 5 mL), dried over Na2SO4, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 15 / 1 - 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).

[0156] Engineering C.1 - ((5 - ethyl - 6 - fluoro - 4 - (8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy) - 4 - (2,2,2 - trifluoroethoxy)pyrido[4,3 - d]pyrimidin - 7 - yl)naphthalen - 2 - yl)oxy)ethyldimethylcarbamate: 7 - chloro - 8 - fluoro - 2 - (((2R,7aS) - 2 - fluorotetrahydro - 1H - pyrrolidin - 7a(5H) - yl)methoxy) - 4 - (2,2,2 - trifluoroethoxy)pyrido[4,3 - d]pyrimidine (230 mg, 1.0 equivalent), 1 - ((5 - ethyl - 6 - fluoro - 4 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)naphthalen - 2 - yl)oxy)ethyldimethylcarbamate (282 mg, 1.2 equivalents), CataCXium A Pd G3 (38.0 mg, 0.1 equivalent) and Cs2CO3 (1.5 M in water, 0.6 mL) in methoxycyclopentane (3 mL) were degassed and purged with N2 three times. The reaction mixture was stirred at 80 °C for 4.5 h under a N2 atmosphere. The mixture was quenched by adding water, extracted with EtOAc, dried over Na2SO4, concentrated and purified by reverse - phase flash [water (0.1% FA) / acetonitrile] to give the title compound (200 mg, 52% yield) as a yellow oil; 1 1H NMR (400 MHz, DMSO - d6) δ = 9.21 (s, 1H), 7.90 (dd, J = 6.0, 8.8 Hz, 1H), 7.69 (dd, J = 2.8, 7.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.23 (dd, J = 2.4, 4.8 Hz, 1H), 6.64 - 6.54 (m, 1H), 5.35 - 5.19 (m, 1H), 4.30 - 4.15 (dd, J = 2.8, 8.0 Hz, 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, 5.2 Hz, 3H), 0.71 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M + 1): m / z = 608.3。

[0157] Project D.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)ethyldimethylcarbamate: To a solution of (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (18.0 mg, 2.0 eq), DIEA (27.4 mg, 3.0 eq) and 4 Å 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-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)oxy)ethyldimethylcarbamate (50 mg, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 h.This mixture was filtered, and the filtrate was purified by preparative HPLC [column: Water Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: ACN; B%: 58% - 88% in 8 minutes] to obtain the title compound (15.9 mg, yield 29%) as a white solid; SFC: >99% ee, column: (S,S)Whelk-O1 50×4.6 mm I.D., 3.5 μm, mobile phase: 40% EtOH (0.05% DEA) in CO2, flow rate: 3 mL / min, detector: 220 nm, tR1: 1.552 min, tR2: 1.988; 1H NMR (400 MHz, DMSO-d6) δ = 9.37 - 9.24 (d, J = 3.2, 1H), 7.88 (dd, J = 6.4, 9.0 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.45 (dt, J = 2.4, 9.6 Hz, 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, 19.6 Hz, 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, 5.2 Hz, 3H), 1.29 - 1.20 (m, 1H), 0.73 (dt, J = 3.4, 7.3 Hz, 3H); LCMS (ESI, M+1): m / z = 735.4.

[0158] Example 23 [Chemical Structure] (1R,5R,6R)-3-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol [Chemical Structure] Step A. 2-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (500 mg, 1.0 equiv) in CH3CN (5.0 mL) were added DIEA (408 mg, 2.0 equiv) and ((chloromethoxy)methyl)benzene (495 mg, 2.0 equiv). The reaction mixture was stirred at 25 °C for 12 h. The mixture was quenched by adding water and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (2 × 5 mL), dried over Na2SO4, concentrated, and purified by column chromatography to give the title compound (560 mg, 81% yield) as a colorless liquid.

[0159] Step B. 7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equiv) in CMPE (10 mL) were added K3PO4 (1.5 M, 0.3 mL, 1.0 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and APhos Pd G3 (2.59 mg, 0.01 equiv). The reaction mixture was stirred at 70 °C under N2 atmosphere for 12 h. The mixture was quenched by adding water and concentrated to remove the organic solvent. The mixture was extracted with EtOAc (3 × 3 mL), dried over Na2SO4, concentrated to give the crude product as a brown oil; LCMS (ESI, M+1): m / z = 713.4.

[0160] Process C. (1R,5R,6R)-3-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[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-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) in DMF (1.0 mL) were added 4 Å 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 mixture was stirred at 40 °C for 12 h. The mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 27% - 57%, 9 min and column: Water Xbridge 150×25 mm×5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 68% - 98%, 9 min) to give the title compound (26.8 mg, 25% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 9.43 - 9.16 (m, 1H), 7.96 - 7.83 (m, 1H), 7.71 (d, J = 2.8 Hz, 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.

[0161] Example 24

Chem.

Chem.

[0162] Example 25 [Chemical Structure] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 decanoate [Chemical Structure] Project A.5 - Ethyl - 6 - fluoro - 4-(8 - fluoro - 2 - (((2R,7aS)-2 - fluorotetrahydro - 1H - pyrrolidin - 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 decanoate: 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 - pyrrolidin - 7a(5H)-yl)methoxy)pyrido[4,3 - d]pyrimidin - 4 - yl)-3 - azabicyclo[3.2.1]octan - 6 - ol (3.00 g, 1.0 equivalent) and TEA (1.47 g, 3.0 equivalents) in dichloromethane (30 mL) was added decanoyl chloride (1.11 g, 1.2 equivalents). The reaction mixture was stirred at 0 °C for 2 hours and at 20 °C for 10 hours. The mixture was quenched by adding water (20 mL) and extracted with dichloromethane (4 × 30 mL).The combined organic layer was 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% in 15 min] to obtain the title compound (2.28 g, yield 61%) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 9.39 - 9.22 (m, 1H), 8.02 - 7.98 (m, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.53 - 7.49 (m, 1H), 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 = 10.0 Hz, 1H), 3.72 (br t, J = 12.0 Hz, 1H), 3.33 - 3.27 (m, 1H), 3.15 - 2.97 (m, 3H), 2.87 - 2.76 (m, 1H), 2.60 (br t, J = 7.2 Hz, 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.

[0163] Example 26

Chemical Structure

Chemical Structure

[0164] Example 27 [Chemical Structure] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl acetate [Chemical formula] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl acetate: A solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 with Ac2O (48.9 mg, 3.1 eq) at -40 °C. The reaction mixture was stirred at -40 °C for 3.5 h. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (2 × 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% in 10 min] to obtain 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, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 690.3.

[0165] Example 28 [Chemical Structure] (R)-7-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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

Chem.

[0166] Example 29 [Chemical formula] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl propionate [Chemical formula] Project A. 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl propionate: A solution of (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 dropwise with propionic anhydride (22.1 mg, 1.0 eq) in THF (0.5 mL) at -40 °C. The reaction mixture was stirred at -40 °C for 1 h and at 25 °C for 15 h. 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% in 10 min] to obtain the title compound (44.0 mg, yield 35%) 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 = 17.6 Hz, 1H), 3.61 - 3.33 (m, 7H), 3.28 - 2.97 (m, 4H), 2.65 (dq, J = 2.0, 7.6 Hz, 3H), 2.46 - 1.80 (m, 10H), 1.25 (dt, J = 2.0, 7.6 Hz, 3H), 1.12 (dt, J = 2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 704.5.

[0167] Example 30 [Chemical formula] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylmethyl carbonate

Chemical formula

[0168] Example 31 [Chemical formula] (R)-7-(7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 [Chemical formula] Step A. 8-Ethyl-7-fluoro-3-hydroxy-8,8a-dihydronaphthalen-1-yl trifluoromethanesulfonate: 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (5.0 g, 1.0 equivalent) was added portionwise to HCl·MeOH (4M, 50.0 mL) at 0 °C. 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 diluted with H2O (100 mL) and extracted with ethyl acetate (4 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (4.4 g, 99% yield, crude) as a red oil.

[0169] 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 equivalent) and DIPEA (2.28 g, 3.0 equivalents) in dichloromethane (20 mL) was added chloromethoxyethane (833 mg, 1.5 equivalents) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. The mixture was diluted with H2O (60 mL) and extracted with dichloromethane (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 20 / 1] to give the title compound (2.2 g, 94% yield) as a pale yellow oil; 11H NMR (400 MHz, CDCl3) δ = 7.59 (dd, J = 5.6, 9.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.26 - 7.21 (m, 1H), 5.29 (s, 2H), 3.74 (q, J = 7.2 Hz, 2H), 3.20 (dq, J = 2.8, 7.2 Hz, 2H), 1.21 (dt, J = 5.2, 7.2 Hz, 6H).

[0170] Procedure C. 7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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) were added Cs2CO3 (2.53 g, 2.5 equiv) and 4 Å molecular sieves (50 mg). Xantphos Pd G4 (298 mg, 0.1 equiv) was added under N2 atmosphere and the reaction mixture was stirred at 90 °C for 14 h. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (4 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by reverse phase flash [water (FA, 0.1%) / acetonitrile = 1 / 1] to afford the title compound (346 mg, yield 19%) as a brown gum; LCMS (ESI, M+1): m / z = 569.4.

[0171] Project D.7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (340 mg, 1.0 equiv) in DMF (5 mL) was added sodium ethylsulfanyl (176 mg, 3.5 equiv). The mixture was stirred at 60 °C for 2 h. The mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound (330 mg, crude) as a brown oil; LCMS (ESI, M+1): m / z = 555.2.

[0172] Engineering E.7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate: 7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (300 mg, 1.0 equiv), DIEA (209 mg, 3.0 equiv) in THF (7 mL) solution was added with DMAP (6.61 mg, 0.1 equiv) and 4-methylbenzenesulfonyl chloride (155 mg, 1.5 equiv) at 0 °C. The reaction mixture was stirred at 20 °C for 1.5 h. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (4 × 20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography [Al2O3, ethyl acetate] to obtain the title compound (270 mg, yield 67%) as a brown rubber; LCMS (ESI, M+1): m / z = 709.2.

[0173] Engineering F. (R)-7-(7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2,4-dione: To a solution of 7-(3-(Ethoxymethoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (150 mg, 1.0 eq) and (R)-1,3,7-triazaspiro[4.5]decan-2,4-dione (64.4 mg, 1.8 eq) in DMF (2 mL) were added DIEA (54.7 mg, 2.0 eq) and 4 Å molecular sieves (20 mg). The reaction mixture was stirred at 40 °C for 14 h. The mixture was filtered and purified by reverse phase flash [water (FA, 0.1%) / acetonitrile = 2 / 3] and preparative HPLC [column: Water Xbridge 150×25 mm×5 μm; mobile phase: water (NH4HCO3)-ACN; B%: 54% - 84% in 8 min] to give the title compound (34.3 mg, 22% yield) as a white solid; 1 H NMR (400 MHz, 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), 2.10 - 1.67 (m, 10H), 1.19 - 1.11 (m, 3H), 1.06 (dt, J = 2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 706.5.

[0174] Example 32 [Chemical formula] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylcyclopropanecarboxylate

Chem.

[0175] Example 33 [Chemical Structure] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl butyrate [Chemical formula] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl butyrate: 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-hexahydropyrrolidin-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) was added with butanoyl chloride (24.7 mg, 1.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 8 h. The mixture was quenched by adding H2O (5 mL) at 0 °C and extracted with DCM (3 × 5 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative HPLC [Water Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN; B%: 60% - 90%, gradient] and [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN; B%: 53% - 83%, 8 min] to obtain the title compound (6.70 mg, yield 6.0%) as a peach-colored solid; 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), 2.66 - 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.

[0176] Example 34

Chem.

Chem.

[0177] Example 35

Chemical Structure

Chem.

[0178] Example 36 [Chemistry] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylethyl carbonate [Chemistry] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl ethyl carbonate: Diethyl dicarbonate (12.5 mg, 1.00 equivalent) was added to a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equivalent) and TEA (15.6 mg, 2.00 equivalents) in THF (1 mL) at 0 °C. The reaction mixture 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), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Xbridge Prep OBD C18 150 mm × 30 mm × 5 μm column (eluent: 30% - 60% CH3CN and H2O containing 0.05% TFA)). The collected fractions were neutralized with saturated NaHCO3 (5 mL) and extracted with ethyl acetate (3 × 3 mL).The combined organic layer was washed with brine (2 × 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (5.00 mg, yield 8.5%) 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。

[0179] Example 37 [Chemical formula] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylazetidine-1-carboxylate [Chemical formula] Project A: 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylazetidine-1-carboxylate: A mixture of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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) was added (4-nitrophenyl) carbonochloridate (31.1 mg, 1.0 eq) at -10 °C under N2. 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 × 2 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 23% - 53%, 10 min) to give the title compound (7.15 mg, yield 6.32%) as a white solid. SFC: ee = 18.7%, column: Chiralcel OD-3 50x4.6mm I.D., 3um, mobile phase: phase A for CO2, phase B for 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 = 2.0 Hz, 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 s, 1H), 2.87 (br s, 1H), 2.84 - 2.78 (m, 2H), 2.34 - 2.24 (m, 3H), 2.07 (m, 1H), 2.00 - 1.89 (m, 4H), 1.83 - 1.69 (m, 6H), 1.07 (m, 3H); F NMR (400 MHz, DMSO-d6) δ = -117.30, -172.08; LCMS (ESI, M+1): m / z = 744.5。

[0180] Example 38 [Chemical Structure] (5R)-7-(7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 [Chemical Structure] Process A. 8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl trifluoromethanesulfonate: To a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (10.0 g, 1.0 eq) in ACN (50 mL) was added HCl·dioxane (4 M, 50 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and dissolved in water (20 mL). The residue was adjusted to pH = 10 at 0 °C using 10% aqueous NaOH 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) as a yellow solid.

[0181] Process 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-hydroxynaphthalen-1-yl trifluoromethanesulfonate (5.00 g, 1.0 eq) and 3,4-dihydro-2H-pyran (2.49 g, 2.0 eq) in DCM (50 mL) was added TsOH (127 mg, 0.05 eq). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated and purified by column chromatography [petroleum ether / ethyl acetate = 1 / 0 - 50 / 1] to give the title compound (5.00 g, two-step yield: 74%) as a yellow oil; 1 H NMR (400 MHz, methanol-d4) 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).

[0182] Engineering C.7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine: A mixture of 8-ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.00 g, 1.0 equivalent) and 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (916 mg, 1.2 equivalents) in toluene (10 mL) was added with Cs2CO3 (1.54 g, 2.0 equivalents), Xantphos (342 mg, 0.25 equivalent) and Pd2(dba)3 (352 mg, 0.15 equivalent) under N2 atmosphere. The reaction mixture was stirred at 110 °C for 12 h under N2 atmosphere. The reaction mixture was quenched with H2O (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 condition] to obtain the title compound (1.00 g, 60% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 595.3.

[0183] Engineering D. 7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equiv) in DMAc (10 mL) was added NaH (484 mg, purity 60%, 8.0 equiv) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. Then, 7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (900 mg, 1.0 equiv) was added to this mixture. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was quenched by adding H2O (50 mL) and extracted with EtOAc (3 × 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.

[0184] Engineering E.7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate: 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-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (500 mg, 1.0 equiv) and 4-methylbenzene-1-sulfonyl chloride (246 mg, 1.5 equiv) in DCM (5 mL) were added DIEA (334 mg, 3.0 equiv) and DMAP (10.5 mg, 0.1 equiv). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with H2O (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.

[0185] Engineering F. (5R)-7-(7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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: 7-(8-Ethyl-7-fluoro-3-((tetrahydro-2H-pyran-2-yl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (200 mg, 1.0 equivalent) and DIEA (52.8 mg, 1.5 equivalents) in DMF (1.0 mL) solution was added (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (92.1 mg, 2.0 equivalents). The reaction mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated and purified by preparative HPLC [Water Xbridge C18 150×50mm×10μm; A: water (NH4HCO3), B: ACN, B%: 64% - 94% in 10 minutes] [Water Xbridge C18 150×25mm×5μm; A: water (NH4HCO3), B: ACN, B%: 58% - 88% in 10 minutes] to obtain the title compound (20.4 mg, yield 10%) as a white solid; 1 H NMR (400 MHz, methanol-d4) 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), 3.73 - 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.

[0186] Example 39 [Chemistry] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivalate [Chemistry] Project A. 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl pivalate: A solution of (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 dropwise with pivaloyl chloride (19.0 mg, 1.0 eq) at -40 °C under N2 atmosphere. The reaction mixture was stirred at -40 °C for 2 h. The mixture was quenched with anhydrous methanol (1 mL) at -40 °C and stirred for 10 min. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 3 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by preparative HPLC [column: PPhenomenex C18 75 × 30 mm × 3 μm; mobile phase: water (FA)-ACN; B%: 25% - 55% in 7 min] to obtain the title compound (64 mg, yield 55%) 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, 17.6 Hz, 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 = 2.0 Hz, 9H), 1.13 (dt, J = 2.4, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 732.5.

[0187] Example 40 [Chemical Structure] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl isopropyl carbonate [Chemical formula] Project A. 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl isopropyl carbonate: A solution of (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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) was added with isopropyl carbonochloridate (18.9 mg, 0.50 equiv) at -68 °C. The reaction mixture was stirred at -68 °C for 30 min. The mixture was quenched with NH4Cl (5 mL) at 25 °C, diluted with water (5 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Xtimate C18 150×40 mm×10um; mobile phase: [water(NH3)-ACN]; B%: 30%~60%, 7 min)) to obtain the title compound (22.4 mg, yield 9.6%) as a white solid; 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, 8.8 Hz, 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, 12.5 Hz, 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 = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 734.3.

[0188] Example 41 [Chemical formula] (R)-7-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 [Chemical formula] Project A. (R)-7-(7-(3-(Benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2,4-dione: A mixture of 7-(3-(benzyloxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-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]decan-2,4-dione (27.4 mg, 1.5 equiv) in DMF (1 mL) was added with DIEA (83.7 mg, 6.0 equiv) and 4 Å molecular sieves (10 mg). The reaction mixture was stirred at 60 °C for 12 h. 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 obtain the title compound (41.0 mg, yield 47%) 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 = 9.2 Hz, 1H), 5.44 - 5.23 (m, 1H), 5.17 (s, 2H), 4.28 - 3.92 (m, 5H), 3.65 (br dd, J = 4.4, 17.6 Hz, 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.

[0189] Example 42 [Chemical formula] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylcyclopentanecarboxylate

Chem.

[0190] Example 43

Chemical formula

Chemical formula

[0191] Example 44 [Chemical Structure] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl hexanoate [Chemical formula] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl hexanoate: 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-hexahydropyrrolidin-8-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1,3,9-triazaspiro[4.5]decan-2,4-dione (100 mg, 1.0 equivalent) and TEA (46.9 mg, 3.0 equivalents) in DCM (2 mL) was added with hexanoyl chloride (31.2 mg, 1.5 equivalents) at 0 °C. The reaction mixture was stirred at 0 °C for 6 h. The mixture was quenched by adding H2O (5 mL) at 0 °C and extracted with DCM (3 × 5 mL).The combined organic layer was dried over Na2SO4, concentrated, and purified by preparative HPLC [Water Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: ACN; B%: 70% - 100%, gradient] and [Waters Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: ACN; B%: 65% - 95%, 8 min] to obtain the title compound (4.89 mg, yield 4.0%) as an off-white solid; 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.

[0192] Example 45

Chemical Structure

Chemical Structure

[0193] Example 46 [Chemical Structure] tert-Butyl (4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl) carbonate

Chem.

[0194] Example 47

Chem.

Chem.

[0195] Example 48

Chemical Structure

Chem.

[0196] Example 49

Chemical Structure

Chem.

[0197] Project B.7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine: A mixture of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (600 mg, 1.0 equiv) and 3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (1.02 g, 1.2 equiv) in dioxane (5 mL) was added with Xantphos Pd G4 (179 mg, 0.1 equiv) and Cs2CO3 (1.82 g, 3.0 equiv). The reaction mixture was stirred at 90 °C for 12 h under a N2 atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase flash [C18, 0.1% formic acid condition] to obtain the title compound (160 mg, yield 13%) as a yellow oil; LCMS (ESI, M+1): m / z = 631.5.

[0198] Engineering C.7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol: To a mixture of NaH (20.1 mg, purity 60%, 2.0 equiv) in DMAC (2 mL) was slowly added EtSH (87.2 mg, 5.5 equiv) at 0 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 10 minutes. 7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 hour. The mixture was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound (220 mg, crude) as a yellow solid.

[0199] Project D.7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate: To a solution of 7-(3-((benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (200 mg, 1.0 equivalent) and DIEA (126 mg, 3.0 equivalents) in dichloromethane (2 mL) were added DMAP (3.96 mg, 0.1 equivalent) and 4-methylbenzenesulfonyl chloride (92.7 mg, 1.5 equivalents) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2 × 5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound (80.0 mg, crude) as a yellow oil.

[0200] Engineering E. (R)-7-(7-(3-((Benzyloxy)methoxy)-8-ethyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2,4-dione: A solution of 4-methylbenzenesulfonate (70 mg, 1.0 equivalent) and (R)-1,3,7-triazaspiro[4.5]decan-2,4-dione (30.7 mg, 2.0 equivalents) in DMF (0.5 mL) was added with DIEA (23.5 mg, 2.0 equivalents) and 4 Å molecular sieves (10 mg). The reaction mixture was stirred at 40 °C for 12 hours. The mixture was filtered and purified by reverse-phase flash [C18, 0.1% formic acid condition] and preparative HPLC [column: Water Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: (ACN), B%: 65% - 95% in 8 minutes] to obtain the title compound (18.4 mg, yield 26%); 1 H NMR (400 MHz, CD3OD) δ = 7.62 (dd, J = 6.0, 8.8 Hz, 1H), 7.38 - 7.08 (m, 8H), 5.41 (d, J = 4.0 Hz, 2H), 5.35 - 5.16 (m, 1H), 4.75 (d, J = 3.2 Hz, 2H), 4.27 - 3.87 (m, 5H), 3.65 (br d, J = 17.6 Hz, 1H), 3.48 (br d, J = 9.6 Hz, 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, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 768.5。

[0201] Example 50 [Chemical Structure Diagram] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl octanoate [Chemical formula] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl octanoate: A solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equivalent) and TEA (15.6 mg, 2.0 equivalents) in THF (2 mL) was added with octanoyl chloride (25.1 mg, 2.0 equivalents) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (3 mL) at 25 °C and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (Xbridge Prep OBD C18 150 mm × 30 mm × 5 μm column (eluent: 30% - 60% CH3CN and H2O containing 0.05% TFA)).The collected fraction was neutralized with an aqueous solution of NaHCO3 (2 M, 2 mL), extracted with ethyl acetate (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (4.02 mg, yield 6.8%) 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 = 7.2 Hz, 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 = 7.2 Hz, 5H); LCMS (ESI, M+1): m / z = 774.2.

[0202] Example 51

Chemical Structure

Chemical Structure

[0203] Example 52 [Chemistry] ((4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl)oxy)methyldimethylcarbamate [Chemistry] Step A. Chloromethyldimethylcarbamate: Dimethylamine (2 M, 6.49 mL, 0.60 equiv) was slowly added to a solution of chloromethyl carbonochloridate (2.79 g, 1.0 equiv) and DIEA (8.39 g, 3.0 equiv) in THF (10 mL) at -60 °C. The reaction mixture was stirred at -60 °C for 0.5 h. The mixture was quenched with water (30 mL) at 0 °C and extracted with ethyl acetate (4 × 30 mL). The combined organic layers were 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 afford 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).

[0204] Project B. ((4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl)oxy)methyldimethylcarbamate: A mixture of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 K2CO3 (128 mg, 3.0 equiv) in DMF (1.0 mL) was added with chloromethyldimethylcarbamate (33.9 mg, 0.80 equiv). The reaction mixture was stirred at 20 °C for 12 h. 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 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 15% - 45% in 10 min].The product was further purified by SFC [DAICEL CHIRALPAK AS 250 mm × 30 mm, 10 μm; A: [ACN, B: EtOH (0.1% NH3H2O), B%: 30% - 30% in 3.8 min] and preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 16% - 46% in 10 min] to obtain the title compound (3.44 mg, yield 1.5%, 0.18 HCOOH) as a white solid; 1H NMR (400 MHz, 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.

[0205] Example 53

Chemical Structure

Chemical Structure

[0206] Example 54

Chem.

Chem.

[0207] Example 55

Chem.

Chem.

[0208] Example 56 [Chemical Structure] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 4-methylpiperidine-1-carboxylate [Chemical Structure] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 4-methylpiperidine-1-carboxylate: A solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equivalent) and TEA (31.2 mg, 2.0 equivalents) in DCM (3.0 mL) was added with 4-nitrophenyl carbonochloridate (31.1 mg, 1.0 equivalent) at -10 °C. The mixture was stirred at -10 °C for 30 minutes, and then 4-methylpiperidine (15.3 mg, 1.0 equivalent) 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 layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 27% - 57% in 10 min] and [Water Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: ACN]; B%: 63% - 93% in 10 min] to obtain the title compound (11.1 mg, yield 9.1%) as a white solid; 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 - 3.66 (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.

[0209] Example 57

Chemical Structure

Chemical Structure

[0210] Example 58

Chemical Structure

Chemical Structure

[0211] Example 59 [Chemical formula] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl (S)-3-methylpiperidine-1-carboxylate [Chemical formula] Project A: 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl (S)-3-methylpiperidine-1-carboxylate: A solution of (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 with (4-nitrophenyl) carbonochloridate (31.1 mg, 1.0 eq) at -10 °C. 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 150×25mm×10um; mobile phase: [water (FA)-ACN]; gradient: 27% - 57% B in 10 minutes) to obtain the title compound (30.0 mg, yield 23.2%, 0.2HCOOH) as a white solid. 1H NMR (400 MHz, 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.

[0212] Example 60

Chem.

Chem.

[0213] Example 61

Chemical Structure

Chem.

[0214] Example 62

Chem.

Chem.

[0215] Example 63 [Chemistry] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 [Chemistry] Project A. 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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: To a solution of (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 eq) in DMF (100 mL) were added K2CO3 (3.41 g, 8.0 eq) and adamantan-1-carbonyl chloride (3.07 g, 5.0 eq). The reaction mixture was stirred at 40 °C for 18 h. The mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Water Xbridge Prep OBD C18 150×40 mm×10 μm; A: water (NH4HCO3), B: ACN; B%: 65% - 95% in 15 min] to give the title compound (395 mg, 15% yield) as an off-white solid; 1H NMR (400 MHz, 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 - 5.13 (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 = 7.1 Hz, 3H); LCMS (ESI, M+1): m / z = 810.4.

[0216] Example 64 [Chemistry] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl cyclobutanecarboxylate [Chemistry] Project A. 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylcyclobutanecarboxylate: To a solution of (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 K2CO3 (128 mg, 3.0 eq). The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated, and purified by preparative HPLC [column: Water Xbridge 150 × 25 mm × 5 μm; mobile phase: water (ammonia hydroxide v / v, B: ACN); gradient: 56% - 86% B in 9 min] to give the title compound (26.0 mg, yield 11%) as an off-white solid; 1H NMR (400 MHz, 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 = 9.2 Hz, 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 = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 730.4.

[0217] Example 65 [Chemical Structure] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl bis(2-methoxyethyl)carbamate

Chem.

[0218] Example 66

Chem.

Chem.

[0219] Example 67 [Chemical formula] 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylbicyclo[2.1.1]hexane-1-carboxylate [Chemical formula] Project A. 4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylbicyclo[2.1.1]hexane-1-carboxylate: To a solution of bicyclo[2.1.1]hexane-1-carboxylic acid (38.9 mg, 2.0 eq) in DCM (0.5 mL) were added isobutyl carbonochloridate (37.9 mg, 1.8 eq) and TEA (78.1 mg, 5.0 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h, and (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-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 mixture was stirred at 25 °C for 24 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL).The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Water Xbridge 150×25 mm×5 μm; mobile phase: water (ammonium bicarbonate v / v)-ACN; gradient: 63% - 93% B in 9 minutes] to obtain the title compound (9.34 mg, yield 7.4%) 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 (br d, J = 17.2 Hz, 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.

[0220] Example 68

Chemical Structure

Chemical Structure

[0221] Example 69 [Chemical Formula] 4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 2,2-diethylbutanoate [Chemical Formula] Project A. 2,4,6-Trichlorobenzoic acid 2,2-diethylbutanoic anhydride: To a solution of 2,2-diethylbutanoic acid (70.0 mg, 1.0 equiv) in DCM (2 mL) were added TEA (98.2 mg, 2.0 equiv) and 2,4,6-trichlorobenzoyl chloride (118 mg, 1.0 equiv). The reaction mixture was stirred at 30 °C for 12 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 TLC [SiO2, petroleum ether / ethyl acetate = 50 / 1] to give the title compound (166 mg, 49% yield) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.54 (s, 2H), 1.62 - 1.55 (m, 6H), 0.76 (t, J = 7.6 Hz, 9H).

[0222] Engineering B.4-(4-((R)-2,4-Dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl 2,2-diethylbutanoate: To a solution of 2,4,6-trichlorobenzoic acid 2,2-diethylbutanoic anhydride (120 mg, 1.0 eq) in toluene (6 mL) were added DMAP (83.4 mg, 2.0 eq) and (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 eq). The reaction mixture was stirred at 90 °C for 12 h. The mixture was diluted with water (15 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: Water Xbridge 150 × 25 mm × 5 μm; mobile phase: water (NH4HCO3)-ACN; gradient: 70% - 100% B in 9 min] and SFC [column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: CO2-EtOH (0.1% NH3·H2O); B%: 50%, isocratic elution mode] to give the title compound (6.30 mg, yield 2.3%) as an off-white solid; 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 - 5.17 (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 = 7.2 Hz, 9H); LCMS (ESI, M+1): m / z = 774.5.

[0223] Example 70

Chem.

Chem.

[0224] Project B. (S,Z)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine: A solution of tert-butyl (S,Z)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8.00 g, 1.0 equivalent) in HCl·MeOH (4 M, 30 mL, 6.5 equivalents) 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.

[0225] Engineering C. (S,Z)-7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (6.00 g, 1.0 equivalent) and 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (8.92 g, 1.3 equivalents) in dioxane (100 mL) was added Cs2CO3 (17.5 g, 3.0 equivalents). The mixture was degassed and purged three times with N2. 1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (872 mg, 0.05 equivalent) was added to the mixture. The reaction was degassed and purged three times with nitrogen. 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.

[0226] Project D. (S,Z)-7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol: To a solution of (S,Z)-7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (5.00 g, 1.0 equiv) in DMAC (30.0 mL) was added NaSEt (2.23 g, 3.0 equiv). The reaction mixture was stirred at 60 °C for 1 hour. The mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 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 afford the title compound (4.50 g, 86% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 553.1.

[0227] Project E. (R)-7-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2,4-dione: To a solution of (S,Z)-7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (6.00 g, 1.0 equiv) in DMSO (60 mL) were added TEA (3.30 g, 3.0 equiv) and PyBOP (8.48 g, 1.5 equiv). The reaction mixture was stirred at 25 °C for 0.5 h. Then (R)-1,3,7-triazaspiro[4.5]decan-2,4-dione (2.76 g, 1.5 equiv) was added to the mixture. The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 2 / 1~0 / 1] to give the title compound (7.2 g, 90% yield) as a red solid; LCMS (ESI, M+1): m / z = 704.3.

[0228] Project F. (R)-7-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-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: TFA (7.68 g, 49.1 equivalents) was added to a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-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 equivalent) in DCM (5 mL). The reaction mixture was stirred at 15 °C for 0.1 h. The mixture was diluted with DCM (10 mL) and quenched with TEA to pH = 8 at -40 °C. The mixture was diluted with water (20 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Water Xbridge Prep OBD C18 150 × 40 mm × 10 um; mobile phase: [water (NH4HCO 3)-ACN];勾配: Purified with 35% - 65% B in 12 minutes to obtain the title compound (175 mg, yield 19%) as a red solid; LCMS (ESI, M+1): m / z = 660.3.

[0229] Project G.4-(4-((R)-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-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: To a solution of (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-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) were added K2CO3 (125 mg, 15 equiv) and (3r,5r,7r)-adamantan-1-carbonyl chloride (307 mg, 10 equiv). The reaction mixture was stirred at 50 °C for 5 h. 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 in 10 min] to give the title compound (18.2 mg, yield 16%, 0.24 HCOOH) as an off-white solid; 11H NMR (400 MHz, methanol-d4) δ = 7.79 - 7.73 (m, 1H), 7.41 (t, J = 2.4 Hz, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.12 (dd, J = 2.0, 7.6 Hz, 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。

[0230] Example 71

Chemical Structure

[0231] Example 72

Chemical Structure

[0232] Example 73

Chem.

Chem.

[0233] Example 74

Chem.

Chem.

[0234] Example 75

Chem.

[0235] Example 76 [Chem.] 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl isobutyrate [Chem.] Project A. 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-yl isobutyrate: To a solution of CAN-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2,4-dione (40.0 mg, 1.0 equiv) in DMF (2 mL) were added K2CO3 (29.3 mg, 3.5 equiv) and 2-methylpropanoyl chloride (32.3 mg, 5.0 equiv). The reaction mixture was stirred at 50 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL).The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Water Xbridge 150×25 mm×5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 55% - 85% B in 9 min] to obtain the title compound (10.2 mg, yield 23%) as a yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 7.77 - 7.69 (m, 1H), 7.42 (dd, J = 2.4, 4.4 Hz, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.15 (dd, J = 2.4, 13.2 Hz, 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, 17.6 Hz, 1H), 3.54 - 3.38 (m, 5H), 3.27 - 2.97 (m, 4H), 2.87 (dtd, J = 2.4, 7.2, 14.0 Hz, 1H), 2.82 - 2.62 (m, 3H), 2.39 (br d, J = 15.2 Hz, 1H), 2.16 - 2.05 (m, 2H), 2.02 - 1.76 (m, 6H), 1.33 (dd, J = 3.2, 7.2 Hz, 6H), 1.13 (dt, J = 2.8, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 730.4.

[0236] Example 77

Chemical Structure

Chemical Structure

[0237] Example 78 [Chemical formula] 4-(4-(CAN-2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((S)-2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ylmethyl carbonate The compound of Example 78 can be prepared by one of ordinary skill in the art by a method similar to that described for the preparation of the compound of Example 30.

[0238] Example 79

Chemical formula

[0239] Example 80

Chemical formula

[0240] Example A Whole blood stability assay This example shows that the exemplary compound of the invention is cleaved in mouse whole blood.

[0241] Test compound and stock solution: Stock concentration 10 mM; final concentration 2 μM

[0242] Preparation of test compound and control working solutions: · Intermediate solution: 5 μL of the compound stock solution (10 mM in dimethyl sulfoxide (DMSO)) was diluted with 45 μL of DMSO (intermediate solution concentration: 1 mM, 100% DMSO) · Propantheline bromide (control) intermediate solution: 5 μL of the propantheline stock solution (10 mM in ultrapure water) was diluted 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 diluted with 180 μL of 45% ACN / H2O (working solution concentration: 100 μM, 40.5% ACN, 10% DMSO) · Working solution 2: 20 μL of the control intermediate solution (1 mM) was diluted with 180 μL of 45% ACN / H2O (working solution concentration: 100 μM, 40.5% ACN, 10% DMSO) 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 at 37 °C in a water bath. · Using an Apricot automated workstation, 98 μL / well of blank blood was added to all 96-well reaction plates (blank, T0, T10, T30, T60, and T120). · Using an Apricot automated workstation, 2 μL / well of the working solution (100 μM) was added to all reaction plates except the blank (T0, T10, T30, T60, and T120). · All reaction plates containing the mixture of the compound and blood were incubated at 37 °C in a water bath. · Incubate the reaction plate at 37 °C and start the timer. · At the end of 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 the protein. 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, transfer 150 μL of the supernatant from each reaction plate to its corresponding bioanalysis plate using an Apricot automated workstation. · Subject each bioanalysis plate to LC-MS / MS analysis. Data Analysis · Calculate the percentage of the test compound remaining in blood after incubation using the following formula: · Percentage remaining = 100 × (PAR at the specified incubation time / PAR at T0 time) · Where PAR is the peak area ratio of the analyte to the internal standard (IS). · The specified incubation time points are T0 (0 minutes), Tn (n = 0, 10, 30, 60, and 120 minutes).

[0243]

Table 1

[0244]

Table 2

[0245] The formation of the parent compound was observed for those with a short half-life.

[0246] Example B Plasma Stability Assay This example shows that the exemplary compounds of the present invention are cleaved in human plasma.

[0247] Test compound and stock solution: Stock concentration 10 mM; final concentration 2 μM

[0248] Preparation of test compound and control working solutions: · Test compound intermediate solution: 10 μL of the 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 Anticoagulant used: Heparin Method · Pooled frozen plasma was thawed in a 37°C water bath before the experiment. The plasma was centrifuged at 4000 rpm for 5 minutes and any clots were removed. · Using an Apricot automated workstation, 98 μL / well of blank plasma was added to all 96-well reaction plates. (Blank, T0, T10, T30, T60 and T120) · Using an Apricot automated workstation, 2 μL / well of the working solution (100 μM) was added to all reaction plates except the blank. (T0, T10, T30, T60 and T120) · All reaction plates containing the mixture of compound and plasma were incubated at 37°C in a water bath. · The reaction plates were incubated at 37°C and the timer was started. · At the end of the incubation, 500 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labeltalol in ACN) was added to precipitate the protein. It was mixed thoroughly. · Each plate was sealed and shaken for 20 minutes. · After shaking, each plate was centrifuged at 4000 rpm and 4°C for 20 minutes. · After centrifugation, 50 μL of the supernatant was transferred to 100 μL of HPLC water using an Apricot automated workstation. · Each bioanalytical plate was sealed and shaken for 10 minutes prior to LC-MS / MS analysis Data analysis · The percentage of the test compound remaining after incubation in blood was calculated using the following formula: · Percentage remaining = 100 × (PAR at the specified incubation time / PAR at T0 time) · Where PAR is the peak area ratio of the analyte to the internal standard (IS). · The specified incubation time points are T0 (0 minutes), Tn (n = 0, 10, 30, 60, and 120 minutes).

[0249]

Table 3

[0250]

Table 4

[0251] The formation of the parent compound was observed for those with a short half-life.

[0252] Although the invention has been described in connection with its specific embodiments, it is further amendable, and this application is such that any variation, use, or adaptation of the invention generally follows the principles of the invention and falls within the scope of known or customary practice within the technical field to which the invention pertains and includes departures from the present disclosure that may be applied to the essential features shown hereinabove and is as described hereinafter within the scope of the appended claims.

Claims

1. The following structure: 【Chemistry 1】 A prodrug compound of the compound indicated by or a pharmaceutically acceptable salt thereof.

2. The following structure: 【Chemistry 2】 [In the formula, R １ and R ２ teeth; H、R ３ -*、R ３ -O-CH ２ -*、 【Transformation 3】 Independently selected from the group consisting of, however, R １ and R ２ Only one of them can be H; A is either CH or N; R ３ is C １ to C ２０ alkyl, (C １ to C ４ alkyl) ０－１ -cycloalkyl, (C １ to C ４ alkyl) ０－１ -heterocyclyl or (C １ to C ４ alkyl) ０－１ -aryl, and R ３ is C １ to C ４ alkyl or -O-C １ to C ４ alkyl, optionally substituted; R ４ is H or R ３ ; R ５ and R ６ H and C １ ~C ６ [Independently selected from the group consisting of alkyl groups] The prodrug compound according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the compound represented by or a pharmaceutically acceptable salt thereof.

3. R １ H is R ２ but: R ３ -*、R ３ -O-CH ２ -*、 【Chemistry 4】 A prodrug compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

4. R ２ H is R １ but: R ３ -*、R ３ -O-CH ２ -*、 【Transformation 5】 A prodrug compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

5. The following: 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 and its pharmaceutically acceptable salts A prodrug compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

6. The following structure: 【Chemistry 11】 [In the formula, R １ teeth, R ３ -*、R ３ -O-CH ２ -*、 【Chemistry 12】 Selected from the group consisting of; A is either CH or N; R ３ C １ ~C ２０ Alkyl, (C １ ~C ４ Alkyl) ０－１ -Cycloalkyl, (C １ ~C ４ Alkyl) ０－１ - Heterocyclyl or (C １ ~C ４ Alkyl) ０－１ - It is aryl, R ３ C １ ~C ４ Alkyl or -O-C １ ~C ４ Optionally substituted with alkyl; R ４ is H or R ３ And; R ５ and R ６ H and C １ ~C ６ [Independently selected from the group consisting of alkyl groups] The prodrug compound according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the compound represented by or a pharmaceutically acceptable salt thereof.

7. A is CH, the prodrug compound according to claim 6 or a pharmaceutically acceptable salt thereof.

8. R ４ R ３ The prodrug compound according to claim 6 or a pharmaceutically acceptable salt thereof.

9. The following: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 and its pharmaceutically acceptable salts A prodrug compound according to claim 6 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

10. The following structure: 【Chemistry 21】 [In the formula, R １ teeth, R ３ -*、R ３ -O-CH ２ -*、 【Chemistry 22】 Selected from the group consisting of; A is either CH or N; R ３ is C １ to C ２０ alkyl, (C １ to C ４ alkyl) ０－１ -cycloalkyl, (C １ to C ４ alkyl) ０－１ -heterocyclyl or (C １ to C ４ alkyl) ０－１ -aryl, and R ３ is C １ to C ４ alkyl or -O-C １ to C ４ alkyl, optionally substituted; R ４ is H or R ３ And; R ５ and R ６ H and C １ ~C ６ [Independently selected from the group consisting of alkyl groups] The prodrug compound according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the compound represented by or a pharmaceutically acceptable salt thereof.

11. A is CH, the prodrug compound according to claim 10 or a pharmaceutically acceptable salt thereof.

12. R ４ is R ３ The prodrug compound according to claim 10 or a pharmaceutically acceptable salt thereof.

13. The following: 【Chemistry 23】 and its pharmaceutically acceptable salts A prodrug compound according to claim 10 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

14. The following structure: 【Chemistry 24】 [In the formula, R １ teeth, R ３ -*、R ３ -O-CH ２ -*、 【Chemistry 25】 Selected from the group consisting of; A is either CH or N; R ３ C １ ~C ２０ Alkyl, (C １ ~C ４ Alkyl) ０－１ -Cycloalkyl, (C １ ~C ４ Alkyl) ０－１ - Heterocyclyl or (C １ ~C ４ Alkyl) ０－１ - It is aryl, R ３ C １ ~C ４ Alkyl or -O-C １ ~C ４ Optionally substituted with alkyl; R ４ is H or R ３ And; R ５ and R ６ H and C １ ~C ６ [Independently selected from the group consisting of alkyl groups] The prodrug compound according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the compound represented by or a pharmaceutically acceptable salt thereof.

15. A is CH, the prodrug compound according to claim 14 or a pharmaceutically acceptable salt thereof.

16. R ４ R ３ The prodrug compound according to claim 14 or a pharmaceutically acceptable salt thereof.

17. The following: 【Chemistry 26】 and its pharmaceutically acceptable salts A prodrug compound according to claim 14 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

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

19. The pharmaceutical composition according to claim 18 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 cells.

20. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of a prodrug compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

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

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

23. The aforementioned cancers include: cardiac sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, 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), testes (seminocarcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampulla carcinoma, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (retinocellular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrosis exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glial cell tumor, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glial cell tumor, sarcoma); Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer) A pharmaceutical composition according to claim 20, selected from the group consisting of: granulosa-encapsular cell tumors, Sertoli-Leydig cell tumors, undifferentiated germ cell tumors, malignant teratomas; vulvas (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

24. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G12A-related cancer.

25. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G12C-related cancer.

26. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G12D-related cancer.

27. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G12R-related cancer.

28. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G12S-related cancer.

29. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G12V-related cancer.

30. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas G13D-related cancer.

31. The pharmaceutical composition according to claim 23, wherein the cancer is a KRas Q61H-related cancer.

32. The pharmaceutical composition according to claim 23, wherein the cancer is related to at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

33. The pharmaceutical composition according to claim 20, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

34. The pharmaceutical composition according to claim 18 for treating cancer determined to be associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutations.

35. The pharmaceutical composition according to claim 20, administered via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasacral, intrathecal, intramuscular, intravitreous, intravenous, intra-arterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

36. The pharmaceutical composition according to claim 35, wherein the route of administration is orally.

37. The pharmaceutical composition according to claim 35, wherein the administration is by intravenous injection.

38. The pharmaceutical composition according to claim 35, wherein the administration route is intramuscular injection.

39. The pharmaceutical composition according to claim 35, wherein the administration route utilizes a delivery device.

40. The pharmaceutical composition according to claim 35, wherein the administration is carried out in a hospital setting.

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