2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,5-triazine derivatives as KRAS G12D inhibitors for cancer treatment

Abstract

Compounds capable of inhibiting KRAS G12D are provided. Pharmaceutical compositions and their medical uses are also provided, including for use in treating or preventing conditions such as cancer.

Description

[Technical Field]

[0001] Compounds capable of inhibiting KRAS G12D are provided. Pharmaceutical compositions and their medical uses are also provided, including for use in treating or preventing conditions such as cancer. [Background technology]

[0002] The Carsten rat sarcoma 2 virus oncogene homolog ("KRas" or "KRAS") is a low-molecular-weight GTPase and a member of the Ras family of oncogenes. KRAS functions as a molecular switch cycle between an inactive (GDP-bound) state and an active (GTP-bound) state, transmitting upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cell proliferation.

[0003] Abnormal KRAS expression accounts for up to 20% of all cancers, and oncogenic KRAS mutations, which stabilize GTP binding and lead to constitutive activation of KRAS and downstream signaling, have been reported in 25–30% of lung adenocarcinomas. KRAS G12D mutations are present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal cancer patients, 10.1% of all rectal cancer patients, 4.1% of all non-small cell lung cancer patients, and 1.7% of all small cell lung cancer patients (see, for example, The AACR Project GENIE Consortium, (2017) Cancer Discovery;7;8:818-831.Dataset Version 4).

[0004] The well-known role of KRAS in malignant tumors, and the discovery of these frequent mutations in KRAS across various tumor types, have made KRAS a highly attractive target for the pharmaceutical industry for cancer treatment. International Publication Nos. 2021 / 041671, 2023 / 098425, and 2023 / 274324 disclose KRAS G12D inhibitors based on a bicyclic (pyrido[4,3-d]pyrimidine) core. [Overview of the project] [Problems that the invention aims to solve]

[0005] Clearly, there remains continued interest and effort in developing KRAS inhibitors, particularly those of activated KRAS variants, especially KRAS G12D, for the treatment of KRAS G12D-mediated cancers, for example. [Means for solving the problem]

[0006] Therefore, in a first embodiment, the present disclosure relates to a compound of formula (0): [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 R is a 6-10 member monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and 1 is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2; or R 1 is -L 3 -R 1’ And R 1’ is a 5-membered monocyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R 1’ is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR*2, C(O)ONHR*, and C(O)ONR*2; R 2is a 5- to 9-membered (e.g., 5- to 8-membered) monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom that is N; a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic, and at least one ring comprises at least one ring atom that is N; or a fused 11- to 14-membered tricyclic group, wherein at least one ring is aromatic, and at least one ring comprises at least one ring atom that is N; wherein R 2 may be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2-C3)alkenyl, and (C2-C3)alkynyl; R 3 is a phenyl or naphthalenyl group substituted with OH, and optionally substituted with one or more further groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3)alkenyl, or (C2-C3)alkynyl; or R 3 is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused to a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3)alkenyl, or (C2-C3)alkynyl; or R 3is a condensed 8-10 membered bicyclic group comprising a saturated carbon ring condensed to an aryl ring, where the carbon ring, aryl ring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl; or R 3 This is a fused 8-10 membered bicyclic group comprising a saturated heterocycle fused to an aryl or heteroaryl ring, where the carbocyclic ring, the aryl or heteroaryl ring, or both, may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl; L 1 R is either a bond, or -O-, -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates a bond site to the triazole moiety of the compound of formula (0), and ** indicates R 2 Show the connection point to; L 2is -(C1~C3)alkyl-, C5-heteroaryl optionally substituted with one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, and * is R 3 The bond site is shown, and ** indicates the bond site to the triazole moiety of the compound of formula (0); L 3 is either a bond or -(C1~C3)alkyl-, -O-, -NH- or -N(C1~C3)alkyl; and R 1 , R 2 , and R 3 Among these, each R* is independently selected from (C1-C4)alkyl (e.g., C1-C3)alkyl), (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0007] In embodiments, this disclosure relates to a compound of formula (I): [ka] The present invention provides a compound of formula (0) or a pharmaceutically acceptable salt thereof, wherein in formula (I), R 1is a 6-10 membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R 1 is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR*2, C(O)ONHR*, and C(O)ONR*2; R 2 This includes a 5- to 8-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6-membered monocyclic heteroaryl group containing at least one ring atom that is N; or a condensed 8- to 10-membered bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; Here, R 2 It can be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3) alkenyls, and (C2~C3) alkynyls; R 3 is a phenyl or naphthalenyl group substituted with OH and optionally one or more further groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3) alkenyl, or (C2~C3) alkynyl; or R 3This is a fused 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, heterocycle, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl; L 1 R is -O-, -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates the bond site to the triazole moiety of the compound of formula (I), and ** is R 2 Show the connection point to; L 2 is -(C1~C3)alkyl-, C5-heteroaryl optionally substituted with one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, and * is R 3 The bond site is shown, and ** indicates the bond site to the triazole moiety of the compound of formula (I); and R 1 , R 2 , and R 3Among these, each R* is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0008] Further embodiments provide a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0009] Further embodiments provide a method of treatment comprising administering a therapeutically effective amount of the compounds of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) to a subject in need of treatment. In related embodiments, the Disclosure provides the use of the compounds of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of pharmaceuticals. In further related embodiments, the Disclosure provides the compounds of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy.

[0010] Further embodiments provide a method for treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder involving KRAS G12D, in a subject requiring such treatment, comprising administering an effective amount of the compound of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In related embodiments, the Disclosure provides the use of the compound of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder involving KRAS G12D. In further related embodiments, the Disclosure provides the compound of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder involving KRAS G12D.

[0011] In another aspect, the Disclosure provides a method for treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer) in a subject requiring attention, comprising administering an effective amount of the Compounds of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compounds of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer). In a further related aspect, the Disclosure provides the Compounds of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer).

[0012] In another aspect, the Disclosure provides a method for treating or preventing cancer in a subject where it is needed, comprising administering an effective amount of the Compound of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing cancer. In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing cancer.

[0013] In another embodiment, the Disclosure provides a method for inhibiting KRAS G12D activity, comprising contacting KRAS G12D (e.g., cells containing KRAS G12D) with a compound of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is in vitro or ex vivo. In other embodiments, the method is in vivo. In relevant embodiments, the Disclosure provides an in vitro method for inhibiting KRAS G12D activity in cells, comprising contacting cells with a compound of the Disclosure (e.g., a compound of formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). [Brief explanation of the drawing]

[0014] [Figure 1] The synthesis of compound (1), which is described in more detail in Example 20 of this specification, is shown below. [Figure 2] The synthesis of compound (55), which is described in more detail in Example 21 of this specification, is shown below. [Figure 3] The synthesis of compound (56), which is described in more detail in Example 22 of this specification, is shown below. [Modes for carrying out the invention]

[0015] Herein, specific embodiments of the present disclosure will be described with reference to the description and examples, but it should be understood that such embodiments are for illustrative purposes only and are merely a few examples of many possible specific embodiments that can represent the application of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art in consideration of the interests of the present disclosure and will be deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0016] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but exemplary methods, apparatus and materials are described herein. All technical and patent publications referenced herein are incorporated herein by reference in their entirety.

[0017] The implementation of this disclosure will utilize conventional techniques, such as chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the scope of the art of those skilled in the art, unless otherwise specified. For example, Michael R. Green and Joseph Sambrook, Molecular Cloning (4 thed.,Cold Spring Harbor Laboratory Press 2012);the series Ausubel et al.eds.(2007)Current Protocols in Molecular Biology;the series Methods in Enzymology(Academic Press,Inc.,N.Y.);MacPherson et al.(1991)PCR 1:A Practical Approach(IRL Press at Oxford University Press);MacPherson et al.(1995)PCR 2:A Practical Approach;Harlow and Lane eds.(1999)Antibodies,A Laboratory Manual;Freshney(2005)Culture of Animal Cells:A Manual of Basic Technique,5 thedition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Pat. No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 rd edition (Cold Spring Harbor Laboratory Press (2002)); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press), to which reference is made.

[0018] All numerical specifications (e.g., pH, temperature, time, concentration, molecular weight, including ranges) are approximations that, where appropriate, vary by (+) or (-) in increments of, for example, 0.1 or 1.0. It should be understood that, although not necessarily explicitly stated, the term “approximately” is used before every numerical specification to indicate a conventional level of variability. For example, a numerical specification that is “approximately” given a value may vary by ±10% of that value, or conversely, this variation may be ±5%, ±2%, or ±1% of that value. It should also be understood that, although not necessarily explicitly stated, the reagents described herein are merely illustrative, and their equivalents are known in the art.

[0019] As used herein, the term "room temperature" also means ambient temperature in the range of about 20 to about 25°C, for example, about 20, about 21, about 22, about 23, about 24, or about 25°C.

[0020] As used herein and in the claims, the singular forms “a,” “an,” and “the” include multiple referents unless otherwise clearly indicated by the context. For example, the term “cell” includes multiple cells (including mixtures thereof). Unless otherwise specified or made clear by the context, the term “or” as used herein is understood to be inclusive. The term “including” is used herein to mean “including, but not limited to,” and is used interchangeably with this phrase.

[0021] Where used herein, the terms “comprising” or “comprises” are intended to mean that compositions and methods include the listed elements without excluding other elements. “Essentially consisting of” when used to define compositions and methods means excluding any other elements that are essentially important to the purposes described. Thus, compositions essentially consisting of the elements defined herein will not exclude isolation and purification methods and trace impurities from pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc. “Consists of” means excluding other components, other components beyond trace elements, and substantial method steps for administering the compositions of this disclosure or process steps for producing the compositions or achieving the intended results. Embodiments defined by each of these transitional terms are within the scope of this disclosure. The use of the term “comprising” herein is intended to encompass and disclose corresponding statements in which the term “comprising” is replaced by “consisting essentially of” or “consisting of.”

[0022] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to vertebrates such as mammals. Mammals include, but are not limited to, rodents, livestock, sports animals, pets, and primates, such as mice, rats, rabbits, monkeys, cattle, sheep, pigs, dogs, cats, horses, and humans. In certain embodiments, the mammal is a human.

[0023] "Administering" is defined herein as a means of providing a drug or a composition containing a drug to a target in a manner that brings the drug into contact with (e.g., internally) the body of the target. Such administration may be by any route, including but not limited to oral, transdermal, transmucosal (e.g., by the vagina, rectal, or oral mucosa), injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or intracentral nervous system), or inhalation (e.g., oral or nasal). Administration may also include providing a substance or composition to a portion of the surface of the body of the target, for example, by topical administration to the skin. Pharmaceutical formulations are, of course, administered in a form appropriate to each route of administration.

[0024] Treating or treating a disease includes: (1) preventing the disease, i.e., preventing the development of clinical symptoms of the disease in patients who are susceptible to the disease but have not yet experienced or manifested symptoms of the disease; (2) inhibiting the disease, i.e., stopping or reducing the development of the disease or its clinical symptoms; and / or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0025] The term "affected" refers, when used in conjunction with the term "treatment," to a patient or individual who has been diagnosed with or is susceptible to the disease. A patient may also be referred to as "at risk of developing" the disease due to a family history of the disease or the presence of disease-related genetic mutations. A patient at risk of developing the disease has not yet developed all or some of the characteristic pathological features of the disease.

[0026] An effective dose or therapeutically effective dose is the amount sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, applications, or dosages. Such delivery depends on many variables, including the duration of use of individual dose units, the bioavailability of the therapeutic agent, and the route of administration. However, the specific dose level of the therapeutic agent of this disclosure for any particular subject depends on various factors, including, for example, the activity of the specific compound used, the subject's age, weight, overall health, sex, and diet, administration time, excretion rate, drug combination, severity of the specific disorder being treated, and the form of administration. Therapeutic doses can generally be titrated to optimize safety and efficacy. Typically, dose-response relationships from in vitro and / or in vivo studies can first provide useful guidance on an appropriate dose for patient administration. Generally, it would be desirable to administer an amount of the compound effective in achieving a serum level corresponding to the concentration found to be effective in vitro. Determining these parameters is well within the scope of the art of the art. These considerations, as well as effective formulations and administration procedures, are known in the art and described in standard texts. As used herein in accordance with this definition, the term “therapeutic dose” is a quantity sufficient to treat (e.g., improve) one or more symptoms associated with a condition. The total daily dose may be administered as a single dose or in divided doses and may, at the physician’s discretion, deviate from the typical range shown herein.

[0027] As used herein, the terms “increase” and “rise” are interchangeable and encompass any measurable increase in biological function and / or biological activity and / or concentration. For example, an increase could be at least about 10%, for example at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, for example at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, an increase could be at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the amount or function, or activity or concentration of the control or baseline, for example at least about 20, 25, 50, 100, or more.

[0028] As used herein, the terms “increased expression” and / or “increased activity” of a substance such as KRAS G12D in a sample or cancer or patient typically refer to an increase in the amount of the substance (e.g., KRAS G12D mutant protein), but may also mean an increase in the biological activity of the substance. For example, the increase may be in amounts of about 5%, for example, about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, for example, about 96%, 97%, 98%, 99%, or 100%. Therefore, the increase may be approximately 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, for example, approximately 20, 25, 50, 100 times, or more, compared to the amount (or activity) of a substance such as KRAS G12D in a control sample or multiple control samples, for example, individuals or populations without disease or disorder (e.g., cancer), or in internal controls, as determined by techniques known in the art. If the expression and / or activity of KRAS G12D increases by 1, 2, 3, 4, 5, or more standard deviations compared to the mean (value) or median of KRAS G12D in the control group of the sample, the baseline group of the sample, or retrospective analysis of patient samples, the subject may also be determined to have "increased expression" or "increased activity" of KRAS G12D. As practiced in the art, such control or baseline expression levels can be determined or measured in advance of measurements in the sample or cancer or subject, or can be obtained from a database of such control samples.

[0029] As used herein, the term “pharmaceutically acceptable excipients” encompasses any of the standard pharmaceutically acceptable excipients, such as those listed in, for example, Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co., 2000). Such excipients include carriers such as phosphate-buffered saline and water, and emulsions such as oil / water or water / oil emulsions, as well as various types of wetting agents. Pharmaceutical compositions may also include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like.

[0030] As used herein, the term “alkyl” means a saturated linear or branched functional group essentially consisting of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. Other alkyl groups will be readily apparent to those skilled in the art, given the interests of this disclosure. Terms such as “(C1-C3) alkyl” and “(C1-C6) alkyl” have an equivalent meaning, i.e., a saturated linear or branched functional group essentially consisting of 1-3 (or 1-6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkyl” also applies in the context of other functional groups containing alkyl groups, e.g., “-O(C1-C3) alkyl”. The term “haloalkyl” means an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, and the like. One or more carbon atoms in the alkyl group's skeleton may be substituted (or bonded) by heteroatoms via multiple bonds (e.g., double bonds). For example, a carbon atom of an alkyl group may be bonded to oxygen via a double bond (i.e., substituted with an oxo to provide carbonyl functionality). The presence of such substituents does not prevent the carbon skeleton of the group from being considered alkyl.

[0031] As used herein, the term “alkenyl” means an unsaturated linear or branched functional group consisting essentially of carbon atoms and a corresponding number of hydrogen atoms and containing at least one carbon-carbon double bond. Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (isopropenyl), etc. Other alkenyl groups will be readily apparent to those skilled in the art, given the interests of this disclosure. Terms such as “(C2-C3) alkenyl” and “(C2-C6) alkenyl” have an equivalent meaning, i.e., an unsaturated linear or branched functional group consisting essentially of 2-3 (or 2-6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkenyl” also applies in the context of other functional groups containing alkenyl groups, e.g., “-O(C2-C3) alkenyl.” The term “haloalkenyl” means an alkenyl group substituted with one or more halogens. Where valence is acceptable, one or more carbon atoms in the skeleton of an alkenyl group may be substituted (or bonded to) heteroatoms by multiple bonds (e.g., double bonds); for example, a carbon atom of an alkenyl group may be bonded to oxygen via a double bond (i.e., substituted with an oxo to provide a carbonyl functional group), however such a carbon atom does not participate in the carbon-carbon double bond. The presence of such substituents does not prevent the carbon skeleton of the group from being considered an alkenyl group.

[0032] As used herein, the term “alkynyl” means an unsaturated linear or branched functional group consisting essentially of carbon atoms and a corresponding number of hydrogen atoms and containing at least one carbon-carbon triple bond. Exemplary alkenyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), etc. Other alkynyl groups will be readily apparent to those skilled in the art, given the interests of this disclosure. Terms such as “(C2-C3)alkynyl” and “(C2-C6)alkynyl” have an equivalent meaning, i.e., an unsaturated linear or branched functional group consisting essentially of 2-3 (or 2-6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkynyl” also applies in the context of other functional groups containing alkynyl groups, e.g., “-O(C2-C3)alkynyl”. The term “haloalkynyl” means an alkynyl group substituted with one or more halogens. Where valence is acceptable, one or more carbon atoms in the alkynyl group skeleton may be substituted (or bonded to) heteroatoms by multiple bonds (e.g., double bonds); for example, a carbon atom of an alkynyl group may be bonded to oxygen via a double bond (i.e., substituted with an oxo to provide a carbonyl functional group), provided that such a carbon atom does not participate in a carbon-carbon double or triple bond. The presence of such substituents does not prevent the carbon skeleton of the group from being considered an alkynyl group.

[0033] As used herein, the term “cyclic group” means a saturated, partially or fully unsaturated, or aromatic group having at least 3 to 10 atoms (i.e., ring atoms) that form a ring. Where a cyclic group is defined as having a certain number of members, terms such as “membered,” “membered,” etc., are used to indicate the number of ring atoms in the above cyclic group. For example, a five-membered cyclic group (e.g., a five-membered heterocyclic group) contains five ring atoms. It will be understood that a cyclic group may be part of a larger cyclic system. For example, bicyclo[4.3.0]nonane contains two carboncyclic groups, namely a cyclohexane group and a cyclopentane group, condensed to form a carbocyclic system that constitutes the molecule. The term “cyclic group” is intended to encompass both carboncyclic and heterocyclic groups. The term “carboncyclic” refers to a group having at least 3 to 10 carbon atoms that form a ring. The term "heterocyclic" refers to a group having at least 3 to 10 atoms forming a ring, where at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. Therefore, the term "heterocyclic group" encompasses saturated, unsaturated, and aromatic (i.e., heteroaryl) groups unless the context explicitly indicates otherwise (for example, by specifically requiring "saturated heterocyclic" groups, "unsaturated heterocyclic" groups, or "aromatic heterocyclic" groups), however, "heterocycloalkyl" groups must be saturated, "heterocycloalkenyl" groups must be unsaturated, and "heteroaryl" groups must be aromatic.

[0034] As used herein with respect to cyclic groups, the terms “spiro” or “spirocyclic” indicate that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first and second cyclic groups share only one common atom, i.e., the first and second cyclic groups share only one common ring atom. For example, the spiro[5.5]undecanyl group contains two cyclohexane rings sharing a single carbocyclic atom.

[0035] As used herein with respect to cyclic groups, the term “condensation” means that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have two adjacent atoms in common, i.e., the first and second cyclic groups share two common ring atoms. For example, the bicyclo[4.4.0]decanyl group contains two cyclohexane rings that have two adjacent carbocyclic atoms in common.

[0036] As used herein with respect to cyclic groups, the term “bridged” means that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have more than two adjacent atoms in common, i.e., the first and second cyclic groups share three or more common ring atoms. For example, the bicyclo[3.3.1]nonanyl group contains two cyclohexane rings that have three adjacent carbocyclic atoms in common.

[0037] Within the structural formulas described herein, any ring system (including any spiro, condensed, or bridging ring systems) may be connected to other parts of the molecule via any atom having the appropriate valency. For example, a bicyclic ring may be connected to another part of the molecule via a ring atom (e.g., a second carbon atom or a heteroatom such as N) or a bridgehead (e.g., a third carbon atom). Spiro, condensed, and bridging rings may be fully unsaturated, partially unsaturated, or fully saturated, and one or more of the rings constituting them may have aromatic properties.

[0038] As used herein, the term “cycloalkyl” means a saturated group having at least 3 to 10 carbon atoms (i.e., ring atoms) forming a ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It should be understood that cycloalkyl groups can be monocyclic or polycyclic (e.g., condensed, cross-linked, or spirocyclic). In the case of polycyclic cycloalkyl groups, there may be further rings, e.g., one or more additional rings, all containing 3 to 7 carbon atoms (i.e., ring atoms). An example of a cycloalkyl group having such additional rings is bicyclo[1.1.1]pentanyl. The term “(C3-C7) cycloalkyl” indicates that the cycloalkyl group contains 3 to 7 carbon atoms in the ring portion of the group, which may be monocyclic or polycyclic (e.g., condensed, cross-linked, or spirocyclic), such as cyclopropanyl (having 3 ring carbon atoms) or bicyclo[1.1.1]pentanyl (having 5 ring carbon atoms). One or more ring atoms of a cycloalkyl group may be substituted (i.e., bonded) by a heteroatom via a double bond (e.g., an oxo-substituted cycloalkyl group). The presence of such substituents does not prevent the carbon skeleton of the group from being considered a cycloalkyl group.

[0039] As used herein, the term “cycloalkenyl” means an unsaturated (i.e., partially or completely unsaturated) group having at least 3 to 10 carbon atoms (i.e., ring atoms) forming a ring. The term “cycloalkenyl” is not intended to include cyclic groups having aromatic properties (those considered as aryl groups as defined herein). An example of a cycloalkenyl group is cyclohexenyl. It will be understood that cycloalkenyl groups can be monocyclic or polycyclic (e.g., bridged). In the case of polycyclic cycloalkenyl groups, there are further rings, e.g., one or more additional rings, all containing 3 to 10 carbon atoms (i.e., ring atoms). These additional rings can be saturated or unsaturated. An example of a cycloalkenyl group having such additional rings is bicyclo[2.2.1]hept-5-enyl. The term "(C4-C8) cycloalkenyl" indicates that the cycloalkenyl group contains 4 to 8 carbon atoms in the ring portion of the group, for example, cyclohexynyl (having 6 ring carbon atoms) or bicyclo[2.2.1]hept-5-enyl (having 7 ring carbon atoms). The double bond (or bond) within the cycloalkenyl group is typically between ring carbon atoms (i.e., intraring), but can also be between one ring carbon atom and an adjacent acyclic carbon atom (i.e., extraring).

[0040] As used herein, the term “aryl” means an aromatic group having at least six carbon atoms (i.e., ring atoms) forming a ring. It will be understood that aryl groups can be monocyclic or polycyclic (e.g., condensed). In the case of polycyclic aryl groups, there are further rings, e.g., one or more further rings, all of which contain at least three carbon atoms (i.e., ring atoms). The further rings may also contain one or more heteroatoms, which may be saturated, unsaturated, or aromatic. Polycyclic aryl groups are typically bonded to the rest of the molecule via an aromatic ring and not typically via a ring containing heteroatoms. In embodiments, polycyclic aryl groups do not contain ring heteroatoms. Examples of aryl groups include the phenyl and naphthalenyl groups, as well as the indenyl and indanyl groups. Other aryl groups include, for example, tetrahydroisoquinolinyl, which is bonded to the rest of the molecule via its phenyl ring. (C6~C 10 The term "aryl" indicates that the aryl group contains 6 to 10 carbon atoms in the ring portion of the group, which can be monocyclic or polycyclic (e.g., condensed), and can be, for example, phenyl (which has 6 ring carbon atoms) or indanyl (which has 9 ring carbon atoms).

[0041] As used herein, the term “heterocycloalkyl” means a saturated group having at least 3 to 10 atoms (i.e., ring atoms) forming a ring, where at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. For example, the term “4-10 membered heterocycloalkyl” means a saturated group containing 4 to 10 ring atoms, one or more of which are heterocyclic atoms. Heterocycloalkyl rings may typically have oxo substituents adjacent to the heteroatoms (e.g., 2-oxopyrrolidinyl), but oxygen atoms do not form part of the ring and are excluded from the number of ring atoms. The presence of such substituents does not prevent the ring (or more rings) of the group from being considered a heterocycloalkyl group. Exemplary heterocycloalkyl groups include tetrahydrofuranil, piperidinyl, morpholinyl, and piperazinyl. Any ring sulfur atom may optionally support one or more pendant (i.e., non-ring) oxygen atoms, as seen, for example, in sulforanil groups. In the case of polycyclic heterocyclic groups, there are further rings, e.g., one or more rings, all containing 3 to 7 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. These further rings may be saturated or partially or completely unsaturated (e.g., having aromatic properties). Examples of polycyclic heterocyclic groups include condensed, bridging, and spirocyclic ring systems. When a polycyclic heterocycloalkyl group contains an unsaturated fused ring, the group typically does not bond to the rest of the molecule via its fused ring. Exemplary heterocyclic groups with such further rings include 2-oxaspiro[3.3]heptanyl, tetrahydroisoquinolinyl, 1-azaspiro[3.3]heptane-2-onyl, and 2-azabicyclo[4.1.0]heptanyl. When a heterocycloalkyl group is described as "X~Y member" (where X and Y are integers), this means that the heterocycloalkyl group contains a total number of ring atoms from X to Y. Therefore, for example, a "4- to 7-membered heterocycloalkyl group" contains a total of 4, 5, 6, or 7 ring atoms, such as tetrahydropyranyl (6 ring atoms).

[0042] As used herein, the term “heterocycloalkenyl” means an unsaturated (i.e., partially or completely unsaturated) group having at least 3 to 6 atoms (i.e., ring atoms) forming a ring, where at least 1 to 5 of the ring atoms are carbon, and the remaining at least 1 to 5 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. A heterocycloalkenyl ring may typically have oxo substituents adjacent to the heteroatoms, but oxygen atoms do not form part of the ring and are excluded from the number of ring atoms. An exemplary heterocycloalkenyl group is tetrahydropyridyl. Any ring sulfur atom may optionally support one or more pendant (i.e., acyclic) oxygen atoms. It should be understood that heterocycloalkenyl groups can be monocyclic or polycyclic (e.g., bridging). In the case of polycyclic heterocycloalkenyl groups, there are further rings, e.g., one or more further rings, all containing 3 to 6 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. The aforementioned further rings may be saturated or partially or completely unsaturated (e.g., having aromatic properties). Polycyclic heterocycloalkenyl groups include condensed, bridging, and spirocyclic ring systems. When a polycyclic heterocycloalkenyl group contains an unsaturated fused ring, the group typically does not bond to the rest of the molecule via its fused ring. An exemplary heterocycloalkenyl group having such further rings is tetrahydroindolyl. When a heterocycloalkenyl group is described as "X-Y member," this means that the heterocycloalkenyl group contains a total of X-Y ring atoms. Thus, for example, a "5-8 member heterocycloalkenyl group" contains a total of 5, 6, 7, or 8 ring atoms, such as dihydropyranyl (6 ring atoms).

[0043] As used herein, the term “heteroaryl” typically refers to an aromatic (i.e., aromatic) group containing 5 to 10 ring atoms, where 1 to 9 of the ring atoms are carbon, and the remaining 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. It should be understood that heteroaryl groups can be monocyclic or polycyclic (e.g., condensed). In the case of polycyclic heteroaryl groups, there may be further rings, e.g., one or more further rings, all of which contain at least 3 atoms (i.e., ring atoms), and the further rings may optionally be aromatic. Examples of heteroaryl groups include monocyclic groups such as pyridyl, and polycyclic groups such as 2-oxopyridinyl and indolyl. When a heteroaryl group is described as “X-Y member,” this means that the heteroaryl group contains a total of X to Y ring atoms. Therefore, for example, a "5-10 membered heteroaryl group" contains a total of 5, 6, 7, 8, 9, or 10 ring atoms, such as indolyl (9 ring atoms). A heteroaryl group is "C × It can be equivalently described as a "heteroaryl" group, where the number corresponding to the subscript x refers to the total number of ring atoms, including heteroatoms and carbon atoms in the ring. Therefore, for example, a "C5 heteroaryl" group contains a total of 5 ring atoms, including any heteroatoms, if at least one heteroatom is present.

[0044] As used herein, the terms "hydrogen" or "H" are: 1 H and 2 This includes H (deuterium, "D"). Therefore, references to groups such as OH, (C1-C6) alkyl, (C1-C3) alkyl, (C2-C3) alkenyl, and (C2-C3) alkynyl groups include both partially or completely deuterated and non-deuterated groups. For example, references to "OH" or "hydroxy" include OD, and references to "C1 alkyl," "methyl," "Me," or "CH3" include, for example, CD3.

[0045] As used herein, the terms “halo” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are interchangeable and may refer to a halogen functional group or such halogen atom. Those skilled in the art will readily be able to determine what is intended in the context in which these terms are used in this disclosure.

[0046] As used herein, the term "CN" means a functional group having a carbon atom linked to a nitrogen atom via a triple bond. The CN group is bonded via its carbon atom.

[0047] As used herein, the term "oxo" refers to a functional group in which an oxygen atom is connected to the atom having this group via a double bond. For example, when a carbon atom supports an oxo group, it forms a carbon-oxygen double bond. It will be understood that not all atoms in a given structure can be substituted with an oxo, and this depends on the free valence of the atom being substituted.

[0048] As used herein, "-C(O)-" means [ka] This means that "=O" is [ka] It means that "-C(O)NH-" is [ka] It means that "-C(O)NR-" is [ka] It means that "-NHC(O)-" [ka] This means that "-NRC(O)-" is [ka] This means: When used in this specification, "C(O)R*" means [ka] It means that "C(O)OR*" is [ka] This means that "C(O)NR*2" is [ka] This means that "C(O)ONR*2" is [ka] It means...

[0049] The compounds of this disclosure are described in particular by their structural formulas. These formulas typically show only one form of the compound (e.g., resonance form, tautomer form, etc.), but it will be understood that certain compounds may exist in multiple such forms. This will be readily apparent to the experienced reader. This disclosure includes all possible tautomers of the compounds characterized by the preceding and following structural formulas, either as single tautomers or as any mixture of tautomers in any ratio. It should also be understood that certain compounds may exist in one or more isomeric (e.g., stereoisomer) forms. This disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc., of the compounds described above, as well as their cis and trans forms and conformations. Purification and separation of isomers can be achieved by the methods described below and by techniques known in the art. For example, optical isomers of a compound can be obtained by degrading a racemic mixture of its diastereoisomer salts (e.g., by using optically active acids or bases, or by forming covalent diastereomers). Different processes for separating optical isomers include the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation may also be useful, with or without derivatization, and the optically active compounds of this disclosure can similarly be obtained by chiral synthesis using optically active starting materials. This disclosure includes all possible stereoisomers of the compounds described herein, either as single stereoisomers or in any mixture of the stereoisomers, e.g., (R)- or (S)-isomers, in any proportion.

[0050] The compounds of this disclosure may exist in the form of free acids or bases, or as addition salts with a suitable acid or base. For example, the basic compound of formula (0) (e.g., the basic compound of formula (I)) may be provided as a pharmaceutically acceptable acid addition salt with an acid such as HCl. Methods for forming the salts are described below and are known in the art (see, for example, Berge et al., J Pharm Sci. (1977) 66:1-19).

[0051] As used herein, the term “pharmaceutically acceptable” in relation to salts means salts of the compounds of this disclosure that can be administered without causing any substantially undesirable biological effects or consequently harmful interactions with any other components of a pharmaceutical composition in which they may be included.

[0052] Any reference to a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. Any enumeration of embodiments relating to a variable or aspect herein includes this embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0053] The compositions and methods provided herein can be combined with one or more of the other compositions and methods provided herein.

[0054] The following abbreviations and experimentally based formulas are used herein. Ac: Acetyl or acetate (e.g., AcOK = potassium acetate) Acetic acid (ACOH) aq. Water-based Atm (atm) atmospheric pressure Bn Benzyl Boc or BOC tert-butyloxycarbonyl BSA (Bovine Serum Albumin) cataCXium(registered trademark) A-Pd-G3 Mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)] Palladium(II), [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)] Palladium(II) Methanesulfonate; CAS No. 1651823-59-4 CHAPS 3-((3-colamidopropyl)dimethylammonio)-1-ropanesulfonate COSY Correlation Spectroscopy DavePhos 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl DBA Dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DCM Dichloromethane DIPA (Diisopropylamine) DIPEA or DIEA: Diisopropylethylamine DMEM Dulbecco's Modified Eagle Medium DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) Dppf 1,1'-bis(diphenylphosphino)ferrocene DPPP 1,3-bis(diphenylphosphin)propane DTT (Dithiothreitol) EA ethyl acetate ee Enantiomeric excess ELSD Evaporative Light Scattering Detection eq. or equiv. equivalent ERK extracellular signal-related kinases ESI-MS Electrospray Ionization Mass Spectrometry Et ethyl ethyl acetate (acetate or AcOEt) FBS Fetal Bovine Serum GDP guanosine diphosphate HATU Hexafluorophosphorate azabenzotriazole tetramethyluronium HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid HMBC Heteronuclear Multiple Bond Correlation HPLC (High-Performance Liquid Chromatography) HSQC Heteronuclear Single Quantum Correlation i-PrOH Isopropyl Alcohol KRAS G12Dhu Human KRAS G12D LC (Reset Chromatography) LCMS Liquid Chromatography / Mass Spectrometry LDA Lithium Diisopropylamide LiHMDS (Lithium Bis(Trimethylsilyl)amide) mCPBA (Methachloroperbenzoic acid) Me methyl MOM Methoxymethyl Ether MOMBR Bromomethylmethyl Ether MS mass spectrometry MW molecular weight NBS N-bromosuccinimide NMR nuclear magnetic resonance OTf Triflate PDA Photodiode Array PE (Petroleum Ether) PE / EA Petroleum Ether / Ethyl Acetate Pd / C Palladium Carbon Pd(OAc)2 Palladium(II) Diacetate PE (Petroleum Ether) Ph Phenyl p-Tol. Para-Trill ROESY Rotating Nucleus Overhauser Effect Spectroscopy RPMI-1640 Roswell Park Memorial Laboratory 1640 Medium RT Room temperature; (for LCMS) Retention time SPR Surface Plasmon Resonance TBAB Tetrabutylammonium bromide TBSCl tert-butyldimethylsilyl chloride TCEP Tris(2-carboxyethyl)phosphine TEA (Triethylamine) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TIPS Triisopropylsilane TLC (Thin-Layer Chromatography) TR-FRET Time-Resolved Förster Resonance Energy Transfer UHP urea peroxide UV ultraviolet light w (in the case of cell culture) wells; therefore, for example, 96w = 96 wells WT wild type Xanthophos 9,9-dimethyl-9H-xanthene-4,5-diyl)bis((diphenylphosphan); CAS Registry Number 161265-03-8 XanthophosPd G4 (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthene-4-yl]diphenylphosphine-κP](methanesulfonato-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]-palladium; CAS Registry No. 1621274-19-8 XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; CAS Registry No. 564483-18-7 XPhos PdG3 (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; CAS Registry No. 1445085-55-1

[0055] compound In a first embodiment, the present disclosure relates to a compound of formula (0): [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 R is a 6-10 member monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and 1 is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2; or R 1 is -L 3 -R 1’ And R 1’is a 5-membered monocyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R 1’ is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR*2, C(O)ONHR*, and C(O)ONR*2; R 2 This includes 5-9 member monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl groups containing at least one ring atom that is N or O; 5 or 6 member monocyclic heteroaryl groups containing at least one ring atom that is N; condensed 8-10 member bicyclic groups in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; or condensed 11-14 member tricyclic groups in which at least one ring is aromatic and at least one ring contains at least one ring atom that is N; Here, R 2 It can be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3) alkenyls, and (C2~C3) alkynyls; R 3 is a phenyl or naphthalenyl group substituted with OH and optionally one or more further groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3) alkenyl, or (C2~C3) alkynyl; or R 3is a fused 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, heterocycle, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl; or R 3 is a condensed 8-10 membered bicyclic group comprising a saturated carbon ring condensed to an aryl ring, where the carbon ring, aryl ring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl; or R 3 This is a fused 8-10 membered bicyclic group comprising a saturated heterocycle fused to an aryl or heteroaryl ring, where the carbocyclic ring, the aryl or heteroaryl ring, or both, may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl; L 1 R is either a bond, or -O-, -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates a bond site to the triazole moiety of the compound of formula (0), and ** indicates R 2 Show the connection point to; L 2is -(C1~C3)alkyl-, C5-heteroaryl optionally substituted with one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, and * is R 3 The bond site is shown, and ** indicates the bond site to the triazole moiety of the compound of formula (0); L 3 is either a bond or -(C1~C3)alkyl-, -O-, -NH- or -N(C1~C3)alkyl; and R 1 , R 2 , and R 3 Among these, each R* is independently selected from (C1-C4)alkyl (e.g., C1-C3 alkyl), (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0056] In this embodiment, the compound of formula (0) is the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, in formula (I), R 1is a 6-10 membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R 1 is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR*2, C(O)ONHR*, and C(O)ONR*2; R 2 This includes a 5- to 8-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6-membered monocyclic heteroaryl group containing at least one ring atom that is N; or a condensed 8- to 10-membered bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; Here, R 2 It can be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3) alkenyls, and (C2~C3) alkynyls; R 3 is a phenyl or naphthalenyl group substituted with OH and optionally one or more further groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3) alkenyl, or (C2~C3) alkynyl; or R 3This is a fused 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, heterocycle, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl; L 1 R is -O-, -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates the bond site to the triazole moiety of the compound of formula (I), and ** is R 2 Show the connection point to; L 2 is -(C1~C3)alkyl-, C5-heteroaryl optionally substituted with one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, and * is R 3 The bond site is shown, and ** indicates the bond site to the triazole moiety of the compound of formula (I); and R 1 , R 2 , and R 3Among these, each R* is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0057] In the compounds disclosed herein, R 1 is, -L 3 -R 1’ It could be, R 1’ is a 5-membered monocyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R 1’ L is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR*2, C(O)ONHR*, and C(O)ONR*2. 3 R* is either a bond or -(C1~C3)alkyl-, -O-, -NH- or -N(C1~C3)alkyl, where each R* is independently selected from (C1~C4)alkyl (e.g., C1~C3 alkyl), (C2~C3)alkenyl, (C3~C6)cycloalkyl, (C3~C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1~C3)alkyl, (C2~C3)alkenyl, (C3~C6)cycloalkyl, (C3~C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1~C3)alkyl), (C1~C3)alkyl, (C2~C3)alkenyl, (C2~C3)alkynyl, or O(C1~C3)alkyl.

[0058] In the compounds disclosed herein, R 1R can be a 6-10 member monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, 1 The group is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2, where each R* is independently (C1~C4)alkyl (e.g., (C1~C3)alkyl), (C2~C3)alkyl Selected from kenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0059] R 1 If it is a biring structure, R 1 R can be a bridging bicyclic, condensed bicyclic, or spirocyclic group. Therefore, R 1 R can be a 6-10 membered, bicyclic heterocycloalkyl or heterocycloalkenyl group which is a bridged, condensed, or spirocyclic group containing at least one ring atom which is N, and R 1It is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2, where each R* is independently (C1~C4)alkyl (e.g., (C1~C3)alkyl), (C2~C3)alkenyl, Selected from (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5- or 6-membered monocyclic heteroaryl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, or 5- or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0060] In the compounds disclosed herein, R 1 R can be a 6-10 member fused bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, 1is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2, each R* is independently selected from (C1-C4)alkyl (e.g., (C1-C3)alkyl), (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5- or 6-membered monocyclic heteroaryl, wherein said (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5- or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0061] In the compounds of the present disclosure, R 1 may be a 6 to 10-membered spirocyclic bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N, R 1The group is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2, where each R* is independently (C1~C4)alkyl (e.g., (C1~C3)alkyl), (C2~C3)alkyl Selected from kenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0062] In the compounds disclosed herein, R 1 R can be a 6-10 membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R 1The group is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH2C(O)NHR*, C(O)NR*2, CH2C(O)NR*2, C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2 and CH2C(O)ONR*2, where each R* is independently (C1~C4)alkyl (e.g., (C1~C3)alkyl), (C2~C3)alkyl Selected from kenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0063] In the compounds disclosed herein, R 1 R may be a 6-10 membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, 1 is optionally substituted with one or more groups independently selected from =O, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR*2, C(O)ONHR*, and C(O)ONR*2; Each R* is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein said (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl may itself be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0064] R 1 is a heterocycloalkyl or heterocycloalkenyl group as defined above, that is, R 1 is a saturated or unsaturated heterocyclic group, or R 1 is -L3-R 1’ , and R 1’ is a heterocycloalkyl or heterocycloalkenyl group as defined above. Accordingly, R 1 is non-aromatic.

[0065] In an embodiment, R 1 is bound to the triazole moiety of the compound of formula (0) (e.g., the compound of formula (I)) via a ring atom of R 1 that is N.

[0066] In an embodiment, R 1 is

Chemical Formula

[0067] In this embodiment, R 1 teeth, [ka] And, In the formula, X 1 , X 2 , X 3 , X 4 , X 5 Each of , and R*' is defined as described above.

[0068] In this embodiment, R 1 teeth, [ka] And, In the formula, X 1 , X 2 , X 5 And R*' are as defined above.

[0069] In this embodiment, R 1 teeth, [ka] Selected from the above, where R*' is defined above.

[0070] In this embodiment, R 1 teeth, [ka] That is the case.

[0071] In this embodiment, R 1 teeth, [ka] Selected from, where R*' is as defined above. In the embodiment, R 1 teeth, [ka] That is the case.

[0072] In this embodiment, R 1 teeth, [ka] ( [ka] (including), [ka] ( [ka] (including), [ka] Selected from.

[0073] In this embodiment, R 1 teeth, [ka] ( [ka] (including), [ka] ( [ka] (including), [ka] Selected from.

[0074] In this embodiment, R 1 teeth, [ka] That is the case.

[0075] In this embodiment, R 1 teeth, [ka] That is the case.

[0076] In this embodiment, R 1 teeth, [ka] In the formula, X is NH, N(C 1~3 ) selected from alkyl, O or CH2; v is an integer from 0 to 4; each R*'' is independently selected from H, CN, Cl, F, R*, OH, OR*, NR*2, CHO, C(O)R*, C(O)OR*, C(O)NR*2, and C(O)ONR*2, where R* is as defined above. In embodiments of R*'', R* is as defined according to formula (0). In embodiments of R*'', R* is as defined according to formula (I). In embodiments, v is 1, 2, 3, or 4. In embodiments, v is 1. In embodiments, v is 2. In embodiments, v is 3. In embodiments, v is 4.

[0077] In this embodiment, R 1 teeth, [ka] And X is NH, N(C 1~3) is selected from alkyl, O, or CH2; v is an integer from 0 to 4; each R*'' is independently selected from H, CN, Cl, F, R*, OH, OR*, NR*2, CHO, C(O)R*, C(O)OR*, C(O)NR*2, and C(O)ONR*2, where R* is as defined above. In embodiments of R*'', R* is as defined according to formula (0). In embodiments of R*'', R* is as defined according to formula (I). In embodiments, v is 1, 2, 3, or 4. In embodiments, v is 1. In embodiments, v is 2. In embodiments, v is 3. In embodiments, v is 4.

[0078] In this embodiment, R 1 teeth, [ka] Here, v is an integer from 0 to 4, and each R*'' is independently a base R*'' as defined above. In the embodiment, v is 1, 2, 3, or 4. In the embodiment, v is 1. In the embodiment, v is 2. In the embodiment, v is 3. In the embodiment, v is 4.

[0079] In this embodiment, R 1 teeth, [ka] Here, v is an integer from 0 to 4, and each R*'' is independently a base R*'' as defined above. In the embodiment, v is 1, 2, 3, or 4. In the embodiment, v is 1. In the embodiment, v is 2. In the embodiment, v is 3. In the embodiment, v is 4.

[0080] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0081] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0082] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R1 teeth, [ka] That is the case.

[0083] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0084] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0085] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0086] In this embodiment, R 1 teeth, [ka] In the formula, v is an integer between 0 and 4, and each R*'' is independently a base R*'' as defined above. In the embodiment, v is 1, 2, 3, or 4. In the embodiment, v is 1. In the embodiment, v is 2. In the embodiment, v is 3. In the embodiment, v is 4.

[0087] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0088] In this embodiment, R 1 teeth, [ka] And each R*'' is independently a base R*'' as defined above. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0089] In this embodiment, R 1 teeth, [ka] isn't it.

[0090] In the compounds disclosed herein, R 2This includes 5-9 member monocyclic or bicyclic (e.g., condensed, bridged, or spirocyclic) heterocycloalkyl or heterocycloalkenyl groups containing at least one ring atom that is N or O; 5 or 6 member monocyclic heteroaryl groups containing at least one ring atom that is N; condensed 8-10 member bicyclic groups in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; or condensed 11-14 member tricyclic groups in which at least one ring is aromatic and at least one ring contains at least one ring atom that is N; R 2 R* can be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3)alkenyl, and (C2~C3)alkynyl. In embodiments, R* is as defined according to formula (0). In embodiments, R* is as defined according to formula (I).

[0091] In this embodiment, R 2 This is a condensed 11-14 member tricyclic group in which at least one ring is aromatic and at least one ring atom is nitrogen; R 2 R* can be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3)alkenyl, and (C2~C3)alkynyl. In embodiments, R* is as defined according to formula (0). In embodiments, R* is as defined according to formula (I).

[0092] In this embodiment, R 2 teeth, [ka] That is the case.

[0093] In this embodiment, R 2 This includes a 5-8 member monocyclic or bicyclic (e.g., condensed, bridged, or spirocyclic) heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6 member monocyclic heteroaryl group containing at least one ring atom that is N; or a condensed 8-10 member bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; R 2 R* may be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3)alkenyl, and (C2~C3)alkynyl, where R* is as defined above. In embodiments, R* is as defined according to formula (0). In embodiments, R* is as defined according to formula (I).

[0094] In this embodiment, R 2 teeth, [ka] (In the formula, q and r are independently 0, 1, or 2, and R a and R b Each example is independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3)alkenyl, and (C2~C3)alkinyl, where R* is as defined above, for example, as defined according to formula (0) or as defined according to formula (I); [ka] (In the formula, X 8 , X 9 , X 10 , and X 11 Each of them is independent of C(R k )2, C=O, N(R k ), O, or S, but X 8 , X 9 , X 10 , and X 11 At least one of them is N(R k ) [ka] (In the formula, X 12 , X 13 , and X 14 Each of them is independent of C(R k )2, C=O, N(R k ), O, or S are selected, X 15 and X 16 Each is independently selected from C and N, except X 12 , X 13 , and X 14 At least one of them is N(R k ) and / or X 15 and X 16 At least one of them is N); [ka] (In the formula, X 17 , X 18 , X 19 , X 20 , and X 21 Each of them is independent of C(R k )2, C=O, N(R k ), selected from O or S, however X 17 , X 18 , X 19 , X 20 , and X 21 At least one of them is N(R k ), O, or S); [ka] (In the formula, Y1 , Y 2 , Y 3 , and Y 4 These are N, O, S, and NR, respectively, and are independent of each other. k , or CR k And, however, Y 1 , Y 2 , Y 3 , and Y 4 At least one of them is N or NR k It is; [ka] (In the formula, Y 5 , Y 6 and Y 7 These are N, O, S, and NR, respectively, and are independent of each other. k , or CR k Y 8 and Y 9 Each of them is independently N or C, except Y 5 , Y 6 and Y 7 At least one of them is N, or NR k and / or Y 8 and Y 9 At least one of them is N); and [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of these is independently N, O, S, or CR. k And, however, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 (At least one of them is N) Selected from; Each R kR* is independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyls, and (C2-C3) alkynyls, where R* is as defined above. In embodiments, R* is as defined according to formula (0). In embodiments, R* is as defined according to formula (I).

[0095] In this embodiment, R 2 teeth, [ka] And here, q, r, R a , and R b This is as defined above.

[0096] In this embodiment, R 2 teeth, [ka] And here, q, r, R a , and R b This is as defined above.

[0097] In this embodiment, R 2 teeth, [ka] (Here, R k (As defined above).

[0098] In this embodiment, R 2 teeth, [ka] (In the formula, R b (and r are as defined above), [ka] (for example [ka] ), [ka] (for example [ka] ), [ka] Selected from.

[0099] In this embodiment, R 2 teeth, [ka] (In the formula, R b (and r are as defined above), [ka] (In the formula, R k (As defined above), [ka] (In the formula, Rb and r are as defined above.) Selected from.

[0100] In this embodiment, R 2 teeth, [ka] (In the formula, R b (and r are as defined above), [ka] (In the formula, R* is as defined above) (For example) [ka] ), [ka] (R* is as defined above) (For example) [ka] ), [ka] Selected from.

[0101] In this embodiment, R 2 teeth, [ka] (for example [ka] ) or [ka] (for example, [ka] )

[0102] In this embodiment, R 2 teeth, [ka] That is the case.

[0103] In this embodiment, R 2 teeth, [ka] And R b This is as defined above.

[0104] In this embodiment, R 2 teeth [ka] And each R b They are independent and as defined above.

[0105] In this embodiment, R 2 teeth, [ka] And R b This is as defined above.

[0106] In this embodiment, R b It is either F or Cl.

[0107] In this embodiment, R 2 teeth, [ka] That is the case.

[0108] In this embodiment, R 2 teeth, [ka] That is the case.

[0109] In this embodiment, R 2 teeth, [ka] That is the case.

[0110] In this embodiment, R 2 teeth, [ka] That is the case.

[0111] In the compounds disclosed herein, L 1R is either a bond, or -O-, -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates a bond site to the triazole moiety of the compound of formula (0) (e.g., the compound of formula (I)), and ** is R 2 This indicates the connection point to L. 1 However, if it is a (C2~C3) alkyl, *-O(C2~C3 alkyl)-** or *-(C2~C3 alkyl)O-**, the C2 or C3 alkyl can be linear or branched, for example, -CH(CH3)-, *-OCH(CH3)-**, or *-CH(CH3)O-**.

[0112] In this embodiment, L 1 R is -O-, -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates the bond site to the triazole moiety of the compound of formula (0) (e.g., the compound of formula (I)), and ** is R 2 This indicates the connection point to [the specified location].

[0113] In this embodiment, L 1 R is -O-, -(C2~C3)alkyl-, *-O-(C2~C3)alkyl-**, *-(C2~C3)alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C1~C3)alkyl, * indicates the bond site to the triazole moiety of the compound of formula (0) (e.g., the compound of formula (I)), and ** is R 2 This indicates the connection point to [the specified location].

[0114] In this embodiment, L 1 These are -O-, -CH2CH2-, *-OCH2-**, *-CH2O-**, *-OCH(CH3)-**, or *-CH(CH3)O-**.

[0115] In this embodiment, L 1 These are -O-, -CH2CH2-, *-OCH2-**, or *-CH2O-**.

[0116] In this embodiment, L 1 It is -O- or *-OCH2-**.

[0117] In this embodiment, L 1 These are -O-, -CH2CH2-, *-OCH2-**, *-OCH(CH3)-**, or *-CH2O-**.

[0118] In this embodiment, L 1 These are -O-, *-OCH(CH3)-**, or *-OCH2-**.

[0119] In this embodiment, L 1 It is -O- or *-OCH(CH3)-**.

[0120] In this embodiment, L 1 This is either *-OCH(CH3)-** or *-OCH2-**.

[0121] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] In the formula, q, r, R a , R b , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , Y 1 , Y 2 , Y 3, Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 This is as defined above.

[0122] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] (for example [ka] ), [ka] (for example, [ka] ), [ka] That is the case.

[0123] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] (In the formula, R k (As defined above), [ka] That is the case.

[0124] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] (In the formula, R* is as defined above) (For example) [ka] ), [ka] (In the formula, R* is as defined above) (For example) [ka] ), [ka] That is the case.

[0125] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] (In the formula, R k (As defined above).

[0126] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] (R* is as defined above) (For example) [ka] ), [ka] (R* is defined as above) (For example) [ka] ) is. In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] (for example [ka] ), [ka] (for example [ka] )

[0127] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] In the formula, q, r, R a and R b This is as defined above.

[0128] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] And R b This is as defined above.

[0129] In this embodiment, L 1 and R 2 They are based together [ka] It forms, in the formula, q, r, R a and R b This is as defined above.

[0130] In this embodiment, L 1 and R 2 They are based together [ka] Forms R b This is as defined above.

[0131] In this embodiment, L 1 is *-OCH2-**, and R 2 teeth, [ka] That is the case.

[0132] In this embodiment, L 1 and R 2 They are based together [ka] It forms.

[0133] In this embodiment, L 1 is -O-, R 2 teeth, [ka] In the formula, q, r, R a , R b , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Z1 , Z 2 , Z 3 , Z 4 , and Z 5 This is as defined above.

[0134] In this embodiment, L 1 is -O-, R 2 teeth, [ka] That is the case.

[0135] In some embodiments, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (for example [ka] ), [ka] (for example [ka] ), [ka] That is the case.

[0136] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (In the formula, R k (As defined above), [ka] That is the case.

[0137] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (In the formula, R* is as defined above) (For example) [ka] ), [ka] (In the formula, R* is as defined above) (For example, [ka] ), [ka] That is the case.

[0138] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (In the formula, R k (As defined above).

[0139] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (In the formula, R* is as defined above) (For example, [ka] ), or [ka] (In the formula, R* is as defined above) (For example, [ka] )

[0140] In some embodiments, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (for example [ka] ), or [ka] (for example [ka] )

[0141] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] And in the formula, X 8 , X 9 , X 10 , and X 11 Each of them is independent of C(R k )2, C=O, N(R k ), O, or S, but X 8 , X 9 , X 10 , and X 11 At least one of them is N(R k ) and; each R kR* is independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, and (C2-C3) alkynyl, and each R* is independently selected from (C1-C4) alkyl (e.g., C1-C3) alkyl), (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3- Selected from C6) cycloalkenyls and 5- or 6-membered monocyclic heteroaryls, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl or 5- or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl.

[0142] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] And in the formula, X 8 , X 9 , X 10 , and X 11 Each of them is independent of C(R k )2, C=O, N(R k ), O, or S, but X 8 , X 9 , X 10 , and X 11 At least one of them is N(R k ) and; each R kThe following are independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3) alkenyl, and (C2~C3) alkynyl, and each R* is independently selected from (C1~C3) alkyl, (C2~C3) alkenyl, (C3~C6) cyclo Selected from lucyl and (C3-C6) cycloalkenyl, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, or (C3-C6) cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl.

[0143] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] And in the formula, each R k The following are independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3) alkenyl, and (C2~C3) alkynyl, and each R* is independently selected from (C1~C3) alkyl, (C2~C3) alkenyl, (C3~C6) cyclo Selected from lucyl and (C3-C6) cycloalkenyl, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, or (C3-C6) cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl.

[0144] In this embodiment, L 1 This is *-OCH(CH3)-**, and R 2 teeth, [ka] (for example [ka] ), [ka] (for example [ka] ), or [ka] (wherein R* is selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl), for example. [ka] That is the case.

[0145] In the compounds disclosed herein, R 3R is a phenyl or naphthalenyl group substituted with OH and optionally with one or more additional groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I); or R 3 is a fused 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, heterocycle, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)); or R 3 R is a condensed 8-10 membered bicyclic group comprising a saturated carbon ring condensed to an aryl ring, where the carbon ring, aryl ring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)); or R 3is a fused 8-10 membered bicyclic group comprising a saturated heterocycle fused to an aryl or heteroaryl ring, where the carbocyclic ring, aryl or heteroaryl ring, or both, may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, NHC(O)R*, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)).

[0146] In this embodiment, R 3 R is a phenyl or naphthalenyl group substituted with OH and optionally with one or more additional groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I); or R 3 This is a fused 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, heterocycle, or both can be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0147] In this embodiment, R 3R* is a phenyl or naphthalenyl group substituted with OH and optionally with one or more additional groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)).

[0148] In this embodiment, R 3 is a fused 8-10 membered bicyclic group comprising a saturated carbocyclic ring fused to a heterocyclic ring, where the carbocyclic ring, heterocyclic ring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)).

[0149] In this embodiment, R 3 teeth, [ka] (wherein m is 1 or 2, and n is 0, 1, or 2; each R c and R d The elements are independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, and (C2-C3) alkynyl, wherein at least one Rc is OH. [ka] (In the formula, s is 1, 2, or 3, and when s is 1, R g If is OH and s is 2 or 3, then at least one R g OH is, and each of the remaining Rg is independently F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl); and [ka] (In the formula, Y 10 R is S, O, or NR''', where R''' is H, OH, CN, Cl, F, or (C1-C3) alkyl; t is 0, 1, 2, or 3, and u is 0, 1, or 2, except when t is zero, u is not zero, and when u is zero, t is not zero; each R h and R i R* is independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyls, and (C2-C3) alkynyls, where R* is as defined above (e.g., according to formula (0) or formula (I)). Selected from.

[0150] In this embodiment, R 3 R* is a naphthalenyl group substituted with OH and optionally with one or more additional groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)).

[0151] In this embodiment, R3 teeth, [ka] And in the formula, when m is 1, R c OH is OH, and if m is 2, then at least one R c is OH, and the other Rc is independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, and (C2-C3) alkynyl.

[0152] In this embodiment, R 3 teeth, [ka] Selected from, in the formula, R c This is as defined above.

[0153] In this embodiment, R 3 teeth, [ka] Selected from, in the formula, R c , R d , and n are as defined above.

[0154] In this embodiment, R 3 teeth, [ka] Selected from, in the formula, R c , R d , and m are as defined above.

[0155] In this embodiment, R 3 teeth, [ka] Selected from, in the formula, R d This is as defined above.

[0156] Control mechanism, each Rd These are independently selected from F, Cl, C≡CH, and CH2CH3.

[0157] In this embodiment, R 3 teeth, [ka] Selected from.

[0158] In this embodiment, R 3 teeth, [ka] Selected from.

[0159] In this embodiment, R 3 R* is a phenyl group substituted with OH and optionally with one or more further groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl, where R* is as defined above (e.g., according to formula (0) or according to formula (I)).

[0160] In this embodiment, R 3 teeth, [ka] The formula is such that s is 1, 2, or 3, and when s is 1, Rg is OH, and when s is 2 or 3, at least one Rg is OH, and each remaining Rg is independently F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0161] In this embodiment, R 3 teeth, [ka] And in the formula, each R g The group is independently F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0162] In this embodiment, R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0163] In this embodiment, R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0164] In this embodiment, R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0165] In this embodiment, R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0166] In this embodiment, R 3 teeth, [ka] In the formula, each Rg is independently F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl, provided that at least one R g It is OH.

[0167] In this embodiment, R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0168] In this embodiment, R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0169] In this embodiment, R 3 teeth, [ka] And in the formula, Rg It is either F or Cl.

[0170] In this embodiment, R 3 teeth, [ka] And in the formula, R g It is either F or Cl.

[0171] In this embodiment, R 3 teeth, [ka] That is the case.

[0172] In this embodiment, R 3 teeth, [ka] That is the case.

[0173] In this embodiment, R 3 This is a fused 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, heterocycle, or both can be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0174] In this embodiment, R 3is a fused bicyclic group comprising a 6-membered saturated carbon ring fused to a 5-membered heteroring, where the carbon ring, heteroring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl. In embodiments, the heteroring contains at least one heteroatom which is S. In embodiments, R 3 teeth, [ka] And in the formula, Y 10 R is S, O, or NR''', where R''' is H, OH, CN, Cl, F, or (C1-C3) alkyl; t is 0, 1, 2, or 3, and u is 0, 1, or 2, except when t is zero, u is not zero, and when u is zero, t is not zero; each R h and R i R* is independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyls, and (C2-C3) alkynyls, where R* is as defined above (e.g., according to formula (0) or formula (I)). In embodiments, each R h and R i These are independently selected from F, Cl, CN, OH, NH2, (C1-C3) alkyl, (C2-C3) alkenyl, and (C2-C3) alkynyl.

[0175] In this embodiment, R 3 teeth, [ka] And in the formula, R h , R it and u are as defined above.

[0176] In a particular embodiment, R 3 teeth, [ka] And in the formula, R h , R i t and u are as defined above.

[0177] In this embodiment, R 3 teeth, [ka] And in the formula, R h , R i , and u are as defined above.

[0178] In a particular embodiment, R 3 teeth, [ka] And in the formula, R h and R i This is as defined above.

[0179] In this embodiment, R 3 teeth, [ka] And in the formula, R h , R i , and u are as defined above.

[0180] In a particular embodiment, R 3 teeth, [ka] And in the formula, R h and R i This is as defined above.

[0181] In this embodiment, R 3 teeth, [ka] And in the formula, R h , R i , and u are as defined above.

[0182] In a particular embodiment, R 3 teeth, [ka] In the formula, R h and R i This is as defined above.

[0183] In a more specific embodiment, R 3 teeth, [ka] In a more specific embodiment, R 3 teeth, [ka] That is the case.

[0184] In this embodiment, R 3 This is a fused bicyclic formula comprising a 6-membered saturated heterocycle fused to a 5-membered heteroaryl ring, where the saturated heterocycle, the heteroaryl ring, or both may be optionally substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, or (C2-C3) alkynyl. In embodiments, the saturated heterocycle comprises at least one heteroatom that is N. In embodiments, the heteroaryl ring comprises at least one heteroatom that is N.

[0185] In this embodiment, R 3 teeth, [ka] And in the formula, t is 0, 1, 2, or 3, and u is 0, 1, or 2, except when t is zero, u is not zero, and when u is zero, t is not zero; and each R h and R i R* is independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyls, and (C2-C3) alkynyls, where R* is as defined above (e.g., according to formula (0) or formula (I)). In embodiments, each R h and R i These are independently selected from F, Cl, CN, OH, NH2, (C1-C3) alkyl, (C2-C3) alkenyl, and (C2-C3) alkynyl.

[0186] In the compounds disclosed herein, L 2 is -(C1~C3)alkyl-, C5-heteroaryl optionally substituted with one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, where R'' is H, OH, CN, Cl, F, or (C1~C3)alkyl, and * is R 3 The bond site is shown, and ** indicates the bond site to the triazole moiety of the compound of formula (0) (e.g., the compound of formula (I)).

[0187] In this embodiment, L 2is a C5-heteroaryl compound containing at least one ring atom that is N and optionally substituted with -(C1~C3)alkyl-, one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is as defined above.

[0188] In this embodiment, L 2 is a C5-heteroaryl compound containing at least two ring atoms that are N and optionally substituted with -(C1~C3)alkyl-, one or more R'', *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**, where R'' is as defined above.

[0189] In this embodiment, L 2 is -(C1~C3)alkyl-, *-O-(C1~C3)alkyl-**, *-(C1~C3)alkyl-O-**, -(C2~C3)alkenyl-, -(C2~C3)alkynyl-, *-(C1~C3)alkyl-NR''-**, *-NR''(C1~C3)alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C1~C3)alkyl-**, or *-(C1~C3)alkyl-NR''-**; or L 2is pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, or 2,4-diazafuran, any of which may be optionally substituted with one or more R'', where R'' is as defined above.

[0190] In this embodiment, L 2 -CH2CH2-, -CH=CH-, -C≡C-, *-CH2O-**, *-OCH2-**, *-CH2NH-**, *-NHCH2-**, *-N(CH3)C(O)-**, *-C(O)N(CH3)-**, *-NHC(O)-**, *-C(O)NH-**, [ka] That is the case.

[0191] In this embodiment, L 2 -CH2CH2, -C≡C-, [ka] That is the case.

[0192] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (II): [ka] (In the formula, R*', L 1 , L 2 , R 2 , R c , R d (where n and m are as defined above) is obtained.

[0193] In the embodiment of formula (II), R 1teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0194] In the embodiment of formula (II), R 1 teeth, [ka] Therefore, the compound of formula (IIa): [ka] (In the formula, L 1 , L 2 , R 2 , R c , R d (where n and m are as defined above) is obtained.

[0195] In the embodiment of formula (II), R 1 teeth, [ka] Therefore, the compound of formula (IIb): [ka] (In the formula, L 1 , L 2 , R 2 , R c , R d (where n and m are as defined above) is obtained.

[0196] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (III): [ka] (In the formula, R*', L 1 , L 2 , R 2 , R c , R d (where n is as defined above) is obtained.

[0197] In the embodiment of formula (III), R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0198] In the embodiment of formula (III), R 1 teeth, [ka] Therefore, the compound of formula (IIIa): [ka] (In the formula, L 1 , L 2 , R 2 , R c , R d (and n are as defined above) are obtained.

[0199] In the embodiment of formula (III), R 1 teeth, [ka] Therefore, equation (IIIb): [ka] (In the formula, L 1 , L 2 , R 2 , R c , R d (and n are as defined above) are obtained.

[0200] In embodiments of formula (III) including formulas (IIIa) and (IIIb), R 3 teeth, [ka] And in the formula, R d This is as defined above.

[0201] In embodiments of formula (III) including formulas (IIIa) and (IIIb), R 3 teeth, [ka] That is the case.

[0202] In embodiments of formula (III) including formulas (IIIa) and (IIIb), R 3 teeth, [ka] That is the case.

[0203] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (IV): [ka] (In the formula, R*', L1 , L 2 , R 2 , and s are as defined above, and each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g (where is OH) is obtained.

[0204] In the embodiment of formula (IV), R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0205] In the embodiment of formula (IV), R 1 teeth, [ka] Therefore, equation (IVa): [ka] (In the formula, L 1 , L 2 , R 2 , R g And s are as defined above) and this is obtained.

[0206] In the embodiment of formula (IV), R 1 teeth, [ka] Therefore, equation (IVb): [ka] (In the formula, L 1 , L 2 , R 2 , R g And s are as defined above) and this is obtained.

[0207] In embodiments of formula (IV) including formulas (IVa) and (IVb), R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0208] In embodiments of formula (IV) including formulas (IVa) and (IVb), R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0209] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (V): [ka] (In the formula, L 1 , L 2 , and R 2 As defined above, each R g The obtained is independently F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl, provided that at least one Rg is OH.

[0210] In the embodiment of formula (V), R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0211] In the embodiment of formula (V), R 1 teeth, [ka] Therefore, the compound of formula (Va): [ka] (In the formula, L 1 , L 2 , and R 2 As defined above, each R gR is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g (where is OH) is obtained.

[0212] In the embodiment of formula (V), R 1 teeth, [ka] Therefore, the compound of formula (Vb): [ka] (In the formula, L 1 , L 2 , and R 2 As defined above, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g (where is OH) is obtained.

[0213] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] And in the formula, R gis F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0214] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0215] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0216] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0217] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] And in the formula, R g It is either F or Cl.

[0218] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] And in the formula, R g It is either F or Cl.

[0219] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] That is the case.

[0220] In embodiments of formula (V) including formulas (Va) and (Vb), R 3 teeth, [ka] That is the case.

[0221] In this embodiment, R 1 teeth, [ka] And R 2 teeth, [ka] Therefore, the compound of formula (VI): [ka] (In the formula, R*', L 1 , L 2 , R 3 q, r, R a and R b (As defined above) is obtained.

[0222] In the embodiment of formula (VI), R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0223] In the embodiment of formula (VI), R 1 teeth, [ka] Therefore, the compound of formula (VIa): [ka] (In the formula, L 1 , L 2 , R 3 q, r, R a and R b (As defined above) is obtained.

[0224] In the embodiment of formula (VI), R 1 teeth, [ka] Therefore, the compound of formula (VIb): [ka] (In the formula, L 1 , L 2 , R 3 q, r, R a and R b (As defined above) is obtained.

[0225] In this embodiment, R 1 teeth, [ka] And R 2 teeth, [ka] Therefore, the compound of formula (VI.I): [ka] (In the formula, R*'', L 1 , L 2 , R 3 X, q, r, v, R a and R b (As defined above) is obtained.

[0226] In the embodiment of equation (VI.I), X is O, and therefore R 1 teeth, [ka] In this embodiment, X is O and v is 2. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0227] In the embodiment of formula VI.I, R 1 teeth, [ka] Therefore, the compound of formula (VI.Ia): [ka] (In the formula, L 1 , L 2 , R 3 q, r, R a and R b (As defined above) is obtained.

[0228] In the embodiment of formula VI.I, R 1 teeth, [ka] Therefore, the compound of formula (VI.Ib): [ka] (In the formula, L 1 , L 2 , R 3 q, r, R a and R b (As defined above) is obtained.

[0229] In this embodiment, R 1 teeth, [ka] And R 2 teeth, [ka] Therefore, the compound of formula (VII): [ka] (In the formula, R*', L 1 , L 2 , R 3 and R b (As defined above) is obtained.

[0230] In the embodiment of formula (VII), R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0231] In the embodiment of formula (VII), R 1 teeth, [ka] Therefore, the compound of formula (VIIa): [ka] (In the formula, L 1 , L 2 , R 3 and R b (As defined above) is obtained.

[0232] In the embodiment of formula (VII), R 1 teeth, [ka] Therefore, the compound of formula (VIIb): [ka] (In the formula, L 1 , L 2 , R 3 and R b (As defined above) is obtained.

[0233] In this embodiment, R 1 teeth, [ka] And R 2 teeth, [ka] Therefore, the compound of formula (VII.I): [ka] (In the formula, R*'', L 1 , L 2 , R 3 , X, v and R b (As defined above) is obtained.

[0234] In the embodiment of equation (VII.I), X is O, and therefore R 1 teeth, [ka] In this embodiment, X is O and v is 2. In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] In this embodiment, R 1 teeth, [ka] That is the case.

[0235] In the embodiment of formula VII.I, R 1 teeth, [ka] Therefore, the compound of formula (VII.Ia): [ka] (In the formula, L 1 , L 2 , R 3 and R b (As defined above) is obtained.

[0236] In the embodiment of formula VII.I, R 1 teeth, [ka] Therefore, the compound of formula (VII.Ib): [ka] (In the formula, L 1 , L 2 , R 3 and R b (As defined above) is obtained.

[0237] In embodiments of formula VI (including formulas (VIa) and (VIb)), formula VI.I (including formulas (VI.Ia) and (VI.Ib)), formula (VII) (including formulas (VIIa) and (VIIb)), and formula (VII.I) (including formulas (VII.Ia) and (VII.Ib)), R 2 teeth, [ka] In embodiments of formula VI (including formulas (VIa) and (VIb)), formula VI.I (including formulas (VI.Ia) and (VI.Ib)), formula VII (including formulas (VIIa) and (VIIb)), and formula VII.I (including formulas (VII.Ia) and (VII.Ib)), R 2 teeth, [ka] That is the case.

[0238] In this embodiment, R 2 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (VIII): [ka] (In the formula, L 1 , L 2 , R 1 , Ra, R b , R c , R d (where n, m, q, and r are as defined above) is obtained.

[0239] In the embodiment of formula (VIII), R 2 teeth, [ka] And in the formula, R b This is as defined above.

[0240] In the embodiment of formula (VIII), R 3 teeth, [ka] And in the formula, R d And n are as defined above.

[0241] In this embodiment, R 2 teeth, [ka] And R 3 teeth, [ka] And thus the compound of formula (IX): [ka] (In the formula, L 1 , L 2 , R 1 , R b , R d (and n are as defined above) are obtained.

[0242] In embodiments of formulas (VIII) and (IX), R 2 teeth, [ka] In the embodiments of formulas (VIII) and (IX), R 2 teeth, [ka] That is the case.

[0243] In embodiments of formulas (VIII) and (IX), R 3 teeth, [ka] And in the formula, R d This is as defined above.

[0244] In embodiments of formulas (VIII) and (IX), R 3 teeth, [ka] That is the case.

[0245] In embodiments of formulas (VIII) and (IX), R 3 teeth, [ka] Selected from.

[0246] In embodiments of formulas (VIII) and (IX), R 3 teeth, [ka] And in the formula, R d As defined above, R 2 teeth, [ka] That is the case.

[0247] In embodiments of formulas (VIII) and (IX), R 2 teeth, [ka] And R 3 teeth, [ka] And R d This is as defined above.

[0248] In embodiments of formulas (VIII) and (IX), R 3 teeth, [ka] And R 2 teeth, [ka] That is the case.

[0249] In embodiments of formulas (VIII) and (IX), R 3 teeth, [ka] And R 2 teeth, [ka] That is the case.

[0250] In this embodiment, R 2 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (X): [ka] (In the formula, R 1 , L 1 , L 2 , R a , R b q, r, and s are as defined above, and each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g (where is OH) is obtained.

[0251] In the embodiment of equation (X), R 2 teeth, [ka] And R b This is defined as described above.

[0252] In the embodiment of equation (X), R 3 teeth, [ka] And in the formula, each R gR is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0253] In this embodiment, R 2 teeth, [ka] And R 3 teeth, [ka] And thus the compound of formula (XI): [ka] (In the formula, R 1 , L 1 , L 2 , and R b As defined above, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g (where is OH) is obtained.

[0254] In embodiments of equations (X) and (XI), R 2 teeth, [ka] That is the case.

[0255] In embodiments of equations (X) and (XI), R 2 teeth, [ka] That is the case.

[0256] In embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0257] In embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl.

[0258] In embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, each R gR is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0259] In embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g It is OH.

[0260] In embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g OH is R 2 teeth, [ka] That is the case.

[0261] In embodiments of equations (X) and (XI), R 3 teeth [ka] And in the formula, R g is F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl, R 2 teeth, [ka] That is the case.

[0262] In embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided that at least one R g OH is R 2 teeth, [ka] In the embodiments of equations (X) and (XI), R 3 teeth, [ka] And in the formula, each R g R is independently F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or (C3-C6) cycloalkyl, where the (C3-C6) cycloalkyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, (C1-C3) alkyl, (C2-C3) alkenyl, or (C2-C3) alkynyl, 2 teeth, [ka] That is the case.

[0263] In embodiments of formulas (VIII), (IX), (X), and (XI), R 1 teeth, [ka] That is the case.

[0264] In embodiments of formulas (VIII), (IX), (X), and (XI), R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] Therefore, in further embodiments, compounds of formulas (XII) to (XVIII) are provided, where L 1 , L 2 , R a , R b , R c , R d , R g n, m, q, r, and s are as defined above: [ka] [ka] [ka] [ka]

[0265] In embodiments of equations (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R 1 teeth, [ka] That is the case.

[0266] In embodiments of equations (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R 2 teeth, [ka] And in the formula, R b This is as defined above.

[0267] In embodiments of equations (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R 1 teeth, [ka] And R 2 teeth, [ka] And in the formula, R b This is as defined above.

[0268] In this embodiment, the compound of formula (XIX): [ka] Provided, in the formula, L 2 , R b , R dAnd n are as defined above.

[0269] In this embodiment, the compound of formula (XX): [ka] Provided, in the formula, L 2 , R b , R c , R d And n are as defined above.

[0270] In this embodiment, the compound of formula (XXI): [ka] Provided, in the formula, R g , L 2 and R b This is as defined above.

[0271] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (XXII): [ka] (In the formula, R*', L 1 , L 2 , R 2 , R h , R i t, u and Y 10 (As defined above) is obtained.

[0272] In this embodiment, R 1 teeth, [ka] And R3 teeth, [ka] Therefore, the compound of formula (XXII.I): [ka] (In the formula, R*'', L 1 , L 2 X, R 2 , R h , R i t, u, v and Y 10 (As defined above) is obtained.

[0273] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (XXIII): [ka] (In the formula, R*', L 1 , L 2 , R 2 , R h , R i (where t and u are as defined above) is obtained.

[0274] In this embodiment, R 1 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (XXIII.I): [ka] (wherein R*'', L 1 , L 2 , X, R 2 , R h , R i , t, u and v are as defined above) is obtained.

[0275] In an embodiment of formula (XXIII) and formula (XXIII.I), R 3 is

Chemical Formula

[0276] In an embodiment, R 1 is

Chemical Formula

Chemical Formula

Chemical Formula

[0277] In an embodiment, R 1 is

Chemical Formula

Chemical Formula

[0278] In embodiments of formula (XXIV) and formula (XXIV.I), R 3 teeth, [ka] And R h , R i And u are as defined above.

[0279] In embodiments of formula (XXIV) and formula (XXIV.I), R 3 teeth, [ka] And R h and R i This is as defined above.

[0280] In certain embodiments of formulas (XXIV) and (XXIV.I), R 3 teeth, [ka] And R h and R i This is as defined above.

[0281] In certain embodiments of formulas (XXIV) and (XXIV.I), R 3 teeth, [ka] And R h and R i This is as defined above.

[0282] In more specific embodiments of formulas (XXIV) and (XXIV.I), R 3 teeth, [ka] That is the case.

[0283] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 This includes 5-9 membered (e.g., 5-8 membered) monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl groups containing at least one ring atom that is N or O; 5 or 6 membered monocyclic heteroaryl groups containing at least one ring atom that is N; and condensed 8-10 membered bicyclic groups in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; R 2 R* may be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3) alkenyl, and (C2~C3) alkynyl; each R* may be independently substituted with one or more groups selected from (C1~C4) alkyl (e.g., C1~C3) alkyl), (C2~C3) alkenyl, (C3~C6) cycloalkyl Selected from (C3-C6) cycloalkenyl and 5- or 6-membered monocyclic heteroaryl, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl or 5- or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl.

[0284] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 R is a 5- to 8-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6-membered monocyclic heteroaryl group containing at least one ring atom that is N; or a condensed 8- to 10-membered bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; R 2 R* may be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3)alkenyl, and (C2~C3)alkynyl; each R* may be independently substituted with one or more groups selected from (C1~C3)alkyl, (C2~C3)alkenyl, (C3~C 6) Selected from cycloalkyl and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0285] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 R is a 5- to 9-membered monocyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N or O, and 2It can be substituted with one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2~C3) alkenyls, and (C2~C3) alkynyls. In embodiments, each R* is independently selected from (C1-C4) alkyl (e.g., C1-C3) alkyl), (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl, or 5 or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl. In the embodiment, each R* is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl.

[0286] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 teeth, [ka] And in the formula, X 8 , X 9 , X 10 , and X 11 Each of them is independent of C(Rk )2, C=O, N(R k ), O, or S, but X 8 , X 9 , X 10 , and X 11 At least one of them is N(R k ) and; each R k R* is independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3) alkenyl, and (C2-C3) alkynyl, and each R* is independently selected from (C1-C4) alkyl (e.g., C1-C3) alkyl), (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3- Selected from C6) cycloalkenyls and 5- or 6-membered monocyclic heteroaryls, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl or 5- or 6-membered monocyclic heteroaryl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl.

[0287] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 teeth, [ka] And in the formula, X 8 , X 9 , X 10 , and X 11 Each of them is independent of C(R k )2, C=O, N(R k ), O, or S, but X 8 , X 9 , X 10 , and X 11At least one of them is N(R k ) and; each R k The following are independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3) alkenyl, and (C2~C3) alkynyl, and each R* is independently selected from (C1~C3) alkyl, (C2~C3) alkenyl, (C3~C6) cyclo Selected from lucyl and (C3-C6) cycloalkenyl, where the (C1-C3) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, or (C3-C6) cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3) alkyl), (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or O(C1-C3) alkyl.

[0288] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 teeth, [ka] And in the formula, each R kis independently selected from H, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH2, C(O)NHR*, C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2~C3)alkenyl, and (C2~C3)alkynyl, each R* is independently selected from (C1~C3)alkyl, (C2~C3)alkenyl, (C3~C6)cycloalkyl, and (C3~C6)cycloalkenyl, wherein said (C1~C3)alkyl, (C2~C3)alkenyl, (C3~C6)cycloalkyl, or (C3~C6)cycloalkenyl may itself be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1~C3)alkyl), (C1~C3)alkyl, (C2~C3)alkenyl, (C2~C3)alkynyl, or O(C1~C3)alkyl.

[0289] In an embodiment, R 2 is

Chemical Structure

Chemical Structure

Chemical Structure

[0290] In an embodiment, R 2 is

Chemical Structure

[0291] In this embodiment, R 1 teeth, [ka] And R 2 teeth, [ka] Therefore, the compound of formula (XXVII): [ka] (In the formula, R*'', L 1 , L 2 , R 3 , X, and R k (As defined above) is obtained.

[0292] In this embodiment, R 1 teeth, [ka] And R 2 teeth, [ka] And R 3 teeth, [ka] Therefore, the compound of formula (XXVIII): [ka] (In the formula, R*'', L 1 , L 2 X, R h , R i , R k (where t, u, and v are as defined above) is obtained.

[0293] In an embodiment of formula (XXVIII), R 3 teeth, [ka] (for example [ka] ) is. In a particular embodiment of formula (XXVIII), R 3 teeth, [ka] (for example [ka] In a more specific embodiment of equation (XXVIII), R 3 teeth, [ka] That is the case.

[0294] In embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), (XXIV.I), (XXVII), and (XXVIII), R 2 teeth, [ka] (for example, [ka] ), [ka] (for example [ka] ) and R 2 teeth, [ka] (wherein R* is selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl), for example. [ka] is, or R 2 teeth, [ka] (wherein R* is selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl itself may be substituted with one or more groups independently selected from F, Cl, CN, OH, NH2, NH((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(C1-C3)alkyl), for example. [ka] That is the case.

[0295] Embodiments of formulas (XXII), (XXIII), (XXIV), (XXV), and (XXVI) are shown in R 1 teeth, [ka] In this embodiment, R*' is H, and therefore R 1 teeth, [ka] That is the case.

[0296] Embodiments of formulas (XXII), (XXIII), (XXIV), (XXV), and (XXVI) are shown in R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] That is the case.

[0297] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] That is the case.

[0298] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] That is the case.

[0299] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] In embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 teeth, [ka] That is the case.

[0300] In this embodiment, the compound of formula (0) or formula (I) is [ka] isn't it.

[0301] In this embodiment, the compound of formula (0) or formula (I) is [ka] isn't it.

[0302] In the embodiment, the compound is selected from the group consisting of the compounds in Table 1 below and their stereoisomers (including enantiomers and their diastereomers, as well as mixtures of their stereoisomers such as mixtures of enantiomers or mixtures of diastereomers of the compounds in Table 1), where "#" indicates the compound number:

[0303] [Table 1]

[0304] [Table 2]

[0305] [Table 3]

[0306] [Table 4]

[0307] [Table 5]

[0308] [Table 6]

[0309] Table 7

[0310] Table 8

[0311] Table 9

[0312] Table 10

[0313] Table 11

[0314] Table 12

[0315] Table 13

[0316] Table 14

[0317] Table 15

[0318] Table 16

[0319] Table 17

[0320] Table 18

[0321] Table 19

[0322] Table 20

[0323] Table 21

[0324] Table 22

[0325] Table 23

[0326] Table 24

[0327] Table 25

[0328] Table 26

[0329] Table 27

[0330] [Table 28]

[0331] [Table 29]

[0332] [Table 30]

[0333] In embodiments, the compounds of the present disclosure are characterized according to their binding and / or inhibitory activity to KRAS G12D when measured according to assays described in the following examples, for example.

[0334] In embodiments, when the compounds of this disclosure are measured according to an SPR assay, such as in the following examples, their dissociation constant K is given to KRAS G12D. D It is characterized according to the following.

[0335] In this embodiment, the compound has a K content of ≤10 μM with respect to KRAS G12D. D The compound has the following characteristics: In the embodiment, the compound has a K content of less than about 5 μM, less than about 1 μM, less than about 0.5 μM, less than about 0.4 μM, less than about 0.3 μM, less than about 0.2 μM, or less than about 0.1 μM. D In embodiments, the compound has a K content of less than about 50 nM with respect to KRAS G12D, for example, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. D It holds.

[0336] In embodiments, the compounds of this disclosure are characterized according to their binding and / or inhibitory activity to GDP-bound KRAS G12D when measured according to assays described in the following examples, for example.

[0337] In embodiments, the compound has an IC for binding of GDP-bound KRAS G12D with an IC of less than about 50 nM, for example, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. 50 In embodiments, the compound has an IC50 for GDP-bound KRAS G12D binding of less than about 2 nM, for example less than about 1.5 nM, less than about 1.25 nM, less than about 1 nM, less than about 0.75 nM, or less than about 0.5 nM.

[0338] In the embodiments, the compound has a higher affinity for KRAS G12D than for wild-type (WT) KRAS. Therefore, in the embodiments, when measured according to SPR, for example, when measured according to the SPR assay described in the following examples, the compound has a higher affinity for KRAS G12D than for WT KRAS. D In this embodiment, the compound has at least 5 times the selectivity for binding to KRAS G12D in preference to WT KRAS (for example, K D (WT KRAS) vs K D When defined by the ratio of (KRAS G12D), for example, when measured according to the SPR assay described in the following examples. In the embodiments, the compound has at least about 10, 15, 20, 25, or 30 times selectivity to KRAS G12D compared to WT KRAS (for example, K D (WT KRAS) vs K D (As defined by the ratio of KRASG 12D, for example, when measured according to the SPR assay described in the following examples). In the examples, the compounds show a significant improvement in cellular capacity compared to compounds known in the art.

[0339] In embodiments, the compound induces multi-mutant RAS cell inhibition while preserving WT KRAS, NRAS, and HRAS; therefore, the compound acts as a pan-KRAS inhibitor that not only preserves other RAS isoforms but also preserves wild-type KRAS while exhibiting multi-mutant KRAS inhibition. This has the beneficial effect of significantly expanding the patient population by approximately three times compared to compounds known in the art. In embodiments, the compound exhibits cell inhibition of KRAS mutant G12D and at least one of KRAS mutants G12A, G12C, G12V, Q61H, G13D, or other KRAS mutants, or combinations thereof, while preserving WT KRAS (e.g., cell inhibition of KRAS G12D and combinations of at least two, at least three, at least four, or at least five of them, e.g., cell inhibition of KRAS G12D and combinations of any two, any three, any four, or any five of them). In embodiments, the compound exhibits cellular inhibition of at least one of the KRAS mutants G12D and KRAS mutants G12A, G12C, G12V, Q61H, and G13D, or a combination thereof, while preserving WT KRAS (e.g., cellular inhibition of KRAS G12D and any combination of at least two, at least three, at least four, or all five thereof, e.g., cellular inhibition of any two, any three, any four, or all five combinations thereof). In embodiments, the compound exhibits cellular inhibition of each of the KRAS mutants G12D, G12A, G12C, G12V, Q61H, and G13D while preserving WT KRAS.

[0340] In embodiments, the compounds of the present disclosure are characterized according to their cellular inhibition of KRAS cell lines, as measured by inhibition of KRAS-mediated phosphorylation of ERK, as described in the following examples, for example. In embodiments, the compounds are characterized by IC for inhibition of ERK phosphorylation in WT KRAS cell lines greater than approximately 10 μM. 50IC for inhibition of ERK phosphorylation of KRAS variant G12D and at least one of KRAS variants G12A, G12C, G12V, Q61H, or G13D, or any combination thereof, at concentrations of less than approximately 500 nM, for example, less than approximately 250 nM, less than approximately 100 nM, less than approximately 500 nM, less than approximately 250 nM, less than approximately 250 nM, less than approximately 250 nM, less than approximately 10 50 This indicates.

[0341] In the embodiments, the compounds exhibit increased permeability and / or improved oral bioavailability compared to compounds known in the art.

[0342] Pharmaceutical composition In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (0) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0343] In the embodiment, the pharmaceutical composition comprises a compound of formula (0) or a pharmaceutically acceptable salt thereof.

[0344] In the embodiment, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0345] In the embodiments, the pharmaceutical composition comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IIa) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

[0346] In the embodiments, the pharmaceutical composition comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IIIb) or a pharmaceutically acceptable salt thereof.

[0347] In the embodiments, the pharmaceutical composition comprises a compound of formula (IV) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (Iva) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IVb) or a pharmaceutically acceptable salt thereof.

[0348] In the embodiments, the pharmaceutical composition comprises a compound of formula (V) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (Va) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (Vb) or a pharmaceutically acceptable salt thereof.

[0349] In the embodiments, the pharmaceutical composition comprises a compound of formula (VI) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (Via) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VIb) or a pharmaceutically acceptable salt thereof.

[0350] In the embodiments, the pharmaceutical composition comprises a compound of formula (VI.I) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VI.Ia) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VI.Ib) or a pharmaceutically acceptable salt thereof.

[0351] In the embodiments, the pharmaceutical composition comprises a compound of formula (VII) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VIIa) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VIIb) or a pharmaceutically acceptable salt thereof.

[0352] In the embodiments, the pharmaceutical composition comprises a compound of formula (VII.I) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VII.Ia) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (VII.Ib) or a pharmaceutically acceptable salt thereof.

[0353] In the embodiment, the pharmaceutical composition comprises a compound of formula (VIII) or a pharmaceutically acceptable salt thereof.

[0354] In the embodiment, the pharmaceutical composition comprises a compound of formula (IX) or a pharmaceutically acceptable salt thereof.

[0355] In the embodiment, the pharmaceutical composition comprises a compound of formula (X) or a pharmaceutically acceptable salt thereof.

[0356] In the embodiment, the pharmaceutical composition comprises a compound of formula (XI) or a pharmaceutically acceptable salt thereof.

[0357] In the embodiment, the pharmaceutical composition comprises a compound of formula (XII) or a pharmaceutically acceptable salt thereof.

[0358] In the embodiment, the pharmaceutical composition comprises a compound of formula (XIII) or a pharmaceutically acceptable salt thereof.

[0359] In the embodiment, the pharmaceutical composition comprises a compound of formula (XIV) or a pharmaceutically acceptable salt thereof.

[0360] In the embodiment, the pharmaceutical composition comprises a compound of formula (XV) or a pharmaceutically acceptable salt thereof.

[0361] In the embodiment, the pharmaceutical composition comprises a compound of formula (XVI) or a pharmaceutically acceptable salt thereof.

[0362] In the embodiment, the pharmaceutical composition comprises a compound of formula (XVII) or a pharmaceutically acceptable salt thereof.

[0363] In the embodiment, the pharmaceutical composition comprises a compound of formula (XVIII) or a pharmaceutically acceptable salt thereof.

[0364] In the embodiment, the pharmaceutical composition comprises a compound of formula (XIX) or a pharmaceutically acceptable salt thereof.

[0365] In the embodiment, the pharmaceutical composition comprises a compound of formula (XX) or a pharmaceutically acceptable salt thereof.

[0366] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXI) or a pharmaceutically acceptable salt thereof.

[0367] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXII) or a pharmaceutically acceptable salt thereof.

[0368] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXII.I) or a pharmaceutically acceptable salt thereof.

[0369] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXIII) or a pharmaceutically acceptable salt thereof.

[0370] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXIII.I) or a pharmaceutically acceptable salt thereof.

[0371] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXIV) or a pharmaceutically acceptable salt thereof.

[0372] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXIV.I) or a pharmaceutically acceptable salt thereof.

[0373] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXV) or a pharmaceutically acceptable salt thereof.

[0374] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXVI) or a pharmaceutically acceptable salt thereof.

[0375] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXVII) or a pharmaceutically acceptable salt thereof.

[0376] In the embodiment, the pharmaceutical composition comprises a compound of formula (XXVIII) or a pharmaceutically acceptable salt thereof.

[0377] The pharmaceutical compositions disclosed herein can be formulated for administration in solid or liquid form, for example, using conventional carriers or excipients. The compositions can be adapted, for example, using techniques known in the art, for oral administration (e.g., as a solution, suspension, tablet, or capsule), parenteral administration (e.g., as a solution, dispersion, suspension, or emulsion, or as a dry powder for reconstitution), or topical application (e.g., as a cream, ointment, patch, or spray applied to the skin).

[0378] In embodiments, the compounds have good permeability and oral bioavailability (e.g., improved permeability and / or improved oral bioavailability compared to compounds known in the art). These properties are particularly beneficial because they completely reduce or avoid the need to use lipid / liposomal formulations for administering the compounds. Accordingly, in embodiments, the pharmaceutical compositions disclosed herein are not formulated as lipid formulations or liposomal formulations.

[0379] Medical use The compounds disclosed herein act as inhibitors of KRAS G12D and are useful in treating KRAS G12D-related disorders and conditions. In particular, the compounds disclosed herein are useful in treating cancer, especially KRAS G12D-related cancers.

[0380] In this embodiment, the Disclosure provides a therapeutic method comprising administering a therapeutically effective amount of the Compounds of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) to a subject in need of treatment. In a related embodiment, the Disclosure provides the use of the Compounds of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of pharmaceuticals. In a further related embodiment, the Disclosure provides the Compounds of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) for use in therapy.

[0381] The compounds of this disclosure are useful for treating or preventing diseases or disorders in which KRAS G12D is known to play a role; diseases or disorders associated with increased KRAS G12D activity; and diseases or disorders in which inhibition or antagonism of KRAS G12D activity is beneficial.

[0382] In one embodiment, the Disclosure provides a method for treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder involving KRAS G12D, in a subject requiring attention, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) to the subject. In a related embodiment, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder involving KRAS G12D. In further relevant embodiments, the Disclosure provides compounds of the Disclosure (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof, or compounds of formula (0) or pharmaceutically acceptable salts thereof) for use in the treatment or prevention of diseases or disorders mediated by or involving KRAS G12D.

[0383] In another embodiment, the Disclosure provides a method for treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer such as KRAS G12D-associated cancer) in a subject requiring treatment, comprising administering an effective amount of the Compounds of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) to the subject. In a related embodiment, the Disclosure provides the use of the Compounds of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer such as KRAS G12D-associated cancer). In further relevant embodiments, the Disclosure provides compounds of the Disclosure (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof, or compounds of formula (0) or pharmaceutically acceptable salts thereof) for use in the treatment or prevention of diseases or disorders associated with KRAS G12D (e.g., cancers such as KRAS G12D-associated cancers).

[0384] In another aspect, the Disclosure provides a method for treating or preventing cancer in a subject where it is needed, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing cancer. In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the Compound of Formula (0) or a pharmaceutically acceptable salt thereof) for use in treating or preventing cancer (e.g., KRAS G12D-associated cancer).

[0385] In the embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., partially or completely), reduces evasion of growth inhibition, reduces or inhibits the growth of cancerous or precancerous cells, suppresses the proliferation of cancerous or precancerous cells, and / or reduces the survival of cancerous or precancerous cells.

[0386] In the embodiment, the cancer is a KRAS G12D-associated cancer. In the embodiment, the cancer is characterized by increased KRAS G12D expression. In the embodiment, the cancer has elevated KRAS G12D activity. In the embodiment, one or more cancer cells express KRAS G12D.

[0387] In some embodiments, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In other embodiments, the cancer is a leukemia (e.g., chronic lymphocytic leukemia, CLL; acute myeloid leukemia, AML; or chronic myeloid leukemia, CML).

[0388] In one embodiment, the cancer is a primary tumor. In another embodiment, the cancer is a secondary tumor (e.g., a metastatic tumor).

[0389] In the embodiment, cancer is selected from colorectal cancer (CRC) (e.g., rectal cancer), small intestine cancer, lung cancer (e.g., non-small cell lung cancer, NSCLC; small cell lung cancer; lung adenocarcinoma; or lung squamous cell carcinoma), pancreatic cancer (e.g., adenocarcinoma), breast cancer (e.g., ductal carcinoma or mammary gland adenocarcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, ovarian cancer, brain tumor (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer, bile duct cancer (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

[0390] In this embodiment, the cancer is selected from colorectal cancer (CRC) (e.g., rectal cancer), lung cancer (e.g., non-small cell lung cancer, NSCLC; small cell lung cancer; lung adenocarcinoma; or lung squamous cell carcinoma), and pancreatic cancer (e.g., adenocarcinoma).

[0391] In another embodiment, the Disclosure provides a method for inhibiting KRAS G12D activity, comprising contacting KRAS G12D (e.g., cells containing KRAS G12D) with a compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (0) or a pharmaceutically acceptable salt thereof). In embodiments, the method is in vitro or ex vivo. In other embodiments, the method is in vivo. In relevant embodiments, the Disclosure provides an in vitro method for inhibiting KRAS G12D activity in cells, comprising contacting cells with a compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (0) or a pharmaceutically acceptable salt thereof).

[0392] The compounds of this disclosure (e.g., compounds of formula (I) or formula (0)) and pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions that optionally contain one or more pharmaceutically acceptable excipients.

[0393] It will be understood that various aspects of the methods and treatments of the present disclosure can be achieved by administering an effective amount of the compound of the present disclosure (e.g., the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the compound of formula (0) or a pharmaceutically acceptable salt thereof) to a subject in the form of a pharmaceutical composition which may optionally contain one or more pharmaceutically acceptable excipients as described herein.

[0394] The compounds disclosed herein may be used alone (for example, as monotherapy) or in combination with one or more cancer treatments.

[0395] While generally disclosed herein, non-limiting embodiments are provided below to further illustrate this disclosure. [Examples]

[0396] The preparation of exemplary compounds described herein is described below. Other compounds within the scope of this disclosure may be prepared in accordance with the art known to those skilled in the art, using methods and procedures similar to those described in detail below.

[0397] Example 1: General synthesis scheme The compounds described herein were produced using several synthetic protocols. These synthetic protocols share common crossovers and can be used as alternatives in the synthesis of the compounds described herein.

[0398] Scheme 1 The following scheme, Scheme 1, illustrates an exemplary method for preparing a compound in accordance with the present disclosure and examples.

[0399] 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane is reacted with UHP to obtain (92-21). (92-21) is reacted with PhN(OTf)2 and K2CO3 to obtain (92-22). (92-22) is bonded with ethynyltriisopropylsilane in the presence of a palladium catalyst to obtain intermediate 2. Intermediate 2 is bonded with intermediate 1 in the presence of a palladium catalyst to obtain intermediate (92-3). The triple bond of (92-3) is reduced by adding hydrogen and Pd(OH)2 / C to obtain (92-4), and the BOC protecting group of (92-4) is removed to obtain (92-0). [ka] [ka]

[0400] Scheme 2 The following scheme, Scheme 2, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples.

[0401] 4-bromo-5-chloronaphthalen-2-ol is reacted with MOMBr to obtain (94-1). (94-1) is bonded with ethynyltriisopropylsilane in the presence of a palladium catalyst to obtain intermediate 5. Intermediate 5 is bonded with intermediate 1 in the presence of a palladium catalyst to obtain intermediate (94-3), and the BOC protecting group of (94-3) is removed to obtain (94-0). [ka]

[0402] Scheme 3 The following scheme, Scheme 3, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples.

[0403] Intermediate 7 is obtained by bonding (96-5) with ethynyltriisopropylsilane in the presence of a palladium catalyst. Intermediate 7 is bonded with intermediate 1 in the presence of a palladium catalyst to obtain intermediate (96-2). The BOC protecting group of (96-2) is removed to obtain (96-0). [ka]

[0404] Scheme 4 The following scheme, Scheme 4, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples.

[0405] Commercially available 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate is bonded with CO in the presence of a palladium catalyst to obtain intermediate (107-1). (107-1) is reacted with oxalyl chloride and ammonium hydroxide to obtain intermediate 8. Intermediate 8 is bonded with intermediate 1 in the presence of a palladium catalyst to obtain (107-3). The TIPS protecting group of (107-3) is removed to obtain (107-4). The BOC protecting group of (96-2) is removed to obtain (107-0). [ka] [ka]

[0406] Scheme 5 The following scheme, Scheme 5, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples.

[0407] (91-1) is bonded with (96-5) in the presence of a palladium catalyst to obtain (97-21). The double bond of (97-21) is reduced by adding hydrogen and Pd(OH)2 / C to obtain (97-22). The BOC protecting group of (97-22) is removed to obtain (97-0). [ka]

[0408] Scheme 6 The following scheme, Scheme 6, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples.

[0409] Commercially available 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate is bonded with (91-1) in the presence of a palladium catalyst to obtain intermediate (21-40). The double bond of (21-40) is reduced with Zn and AcOH to obtain (21-51). The BOC protecting group of (21-51) is removed to obtain (21-19). The TIPS protecting group of (21-19) is removed to obtain (21-0). [ka]

[0410] Scheme 7 The following scheme, Scheme 7, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples.

[0411] The BOC protecting group of (92-24) is removed to obtain (85-0). [ka]

[0412] Examples 2-45: Synthesis Examples Examples 2–45 describe the synthetic protocols used to arrive at the exemplary compounds disclosed herein. Further compounds of this disclosure can be similarly synthesized, as will be understood by those skilled in the art.

[0413] In the following synthesis protocols, the notations R and S (or R* and S*) are used to indicate the stereochemistry at a particular chiral center, and therefore, unless otherwise specified, the use of the indices R, R, R*, or R* in the following specific examples should not be understood to refer to substituents R or R* as defined with respect to the Markush formulas provided in the prior disclosure.

[0414] Table 2 below lists the compounds synthesized in the following synthesis examples, identified according to the relevant example number, and (where appropriate) the compound numbers assigned to such compounds in Table 1:

[0415] [Table 31]

[0416] [Table 32]

[0417] [Table 33]

[0418] [Table 34]

[0419] [Table 35]

[0420] [Table 36]

[0421] [Table 37]

[0422] [Table 38]

[0423] [Table 39]

[0424] [Table 40]

[0425] [Table 41]

[0426] [Table 42]

[0427] [Table 43]

[0428] [Table 44]

[0429] Experimental Techniques Unless otherwise specified, the following analytical techniques were used in Examples 2-45 below.

[0430] 400MHz liquid-state NMR experiments were performed using a 5mm PI HR-BBO400S1-BBF / H / D-5.0-Z SP probe (Bruker BioSpin AG, Switzerland) with a 400MHz (9.4 Tesla) AVANCE NEO 400MHz ( 1 In the case of H, 400MHz, 13 The data was recorded at 100MHz (in the case of C).

[0431] 300MHz liquid-state NMR experiments were performed using a 5mm PABBO BB-1H / D Z-GRD probe (Bruker BioSpin AG, Switzerland) on a 300MHz (7.04 Tesla) AVANCE III HD 300MHz ( 1 In the case of H, 300MHz, 13 Recorded at 75MHz (in the case of C).

[0432] All experiments (1D) used to describe the resonance assignment procedure and the structure of the product 1 H, 2D 1 H- 1 H-COSY, 2D 1 H- 1 H-ROESY, 2D 1 H- 13 C-HSQC, 2D 1 H- 13 C-HMBC) was recorded at 300k. The 1H chemical shift is recorded in ppm as s (single line), d (double line), t (triple line), q (quadruple line), dd (double line), m (multiple lines), or br s (broad single line). The chemical shift value (8) is shown in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.

[0433] LC-MS chromatography analysis was recorded using the following instrument: Agilent 1260 (UV: Acquity PDA, MS: QDa, ELSD).

[0434] The instruments were tested using Ascentis Express C18 (100 × 4.6 mm). All of them were tested with the following eluent combinations: water / 0.1% FA and acetonitrile / 0.1% FA as ionization modes, and positive electrospray ES+, with UV detection set to 220 and 254 nm.

[0435] Temperatures are expressed in degrees Celsius (°C). The reagents used in the following examples may be obtained from commercially available sources, or prepared from commercially available starting materials as described herein, or by methods known in the art. The progress of the reactions described herein may be monitored as appropriate by LC or TLC, and the reaction time and temperature may be adjusted accordingly, as will be readily understood by those skilled in the art.

[0436] Preparation of intermediates The intermediate was prepared for use in Examples 2 to 22 below, according to the following method.

[0437] Intermediate 1: tert-butyl3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Step 1: To a stirred solution of cyanuric chloride (10.00 g, 54.2 mmol, 1.0 equivalent) and DIEA (10.51 g, 81.3 mmol, 1.5 equivalent) in DCM (250 mL), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.21 g, 43.4 mmol, 0.8 equivalent) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (250 mL). The resulting mixture was extracted with DCM (3 × 250 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography eluting with PE / siRNA (30:1) to obtain tert-butyl(1R,5S)-3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8 carboxylate (13.70 g, yield 63%) as a white solid.

[0438] Step 2: tert-butyl3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of tert-butyl(1R,5S)-3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8 carboxylate (5.00 g, 13.9 mmol, 1.0 equivalent) and Cs2CO3 (27.13 g, 83.3 mmol, 3 equivalents) in MeCN (200 mL), [(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methanol (6.63 g, 41.6 mmol, 1.5 equivalents) was gradually added at 25°C under a nitrogen atmosphere. The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ELISA (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography eluted with PE / siRNA (5:1) to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.30 g, yield 79%) as a white solid.

[0439] Intermediate 2: ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane [ka] Step 1: 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol A solution of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.00 g, 11.1 mmol, 1.0 equivalent) and UHP (4.17 g, 44.4 mmol, 4.0 equivalent) in MeOH (40 mL) was stirred at 40°C for 6 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (6:1) to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (2.00 g, yield 74%) as a pale yellow oil. ESI-MS m / z = 249.10 [MH] - Calculated MW: 250.01

[0440] Step 2: 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (1.00 g, 3.99 mmol, 1.0 equivalent), K2CO3 (1.10 g, 7.99 mmol, 2.0 equivalent), and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.71 g, 4.79 mmol, 1.2 equivalents) in THF (10 mL) was stirred at 40°C for 5 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (1.50 g, yield 98%) as a pale yellow oil. ESI-MS m / z = 381.00 [MH] - Calculated MW: 382.05

[0441] Step 3: ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (1.00 g, 2.61 mmol, 1.0 equivalent), CuI (50.0 mg, 0.26 mmol, 0.1 equivalent), ethinyltriisopropylsilane (0.57 g, 3.13 mmol, 1.2 equivalents), and Pd(PPh3)2Cl2 (90.0 mg, 0.13 mmol, 0.05 equivalents) in DMF (10 mL) was stirred at 80°C for 5 hours under an argon atmosphere. The resulting mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Â(8:1) to obtain ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane (800.0 mg, yield 74%) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.82(dd,J=9.0,6.0Hz,1H),7.61(d,J=2.7Hz,1H),7.47(d,J=2.7Hz,1H),7.42(t,J=9.3Hz,1H),5. 31(s,2H),3.64(qd,J=7.3,3.0Hz,2H),3.42(s,3H),1.26(m,J=7.3,3.0Hz,3H),1.2-1.11(m,21H).

[0442] Intermediate 3: 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline [ka] Step 1: 6,8-dibromo-3-fluoroquinoline-5-amine A stirred solution of 3-fluoroquinoline-5-amine (2.00 g, 12.3 mmol, 1.0 equivalent) in DMF (30 mL) was to be added dropwise by adding a solution of NBS (4.50 g, 25.2 mmol, 2.0 equivalent) in DMF (10 mL) under a nitrogen atmosphere at -15°C. The resulting mixture was stirred under a nitrogen atmosphere at -15°C for 1 hour. The reaction was quenched by adding water at -15°C. The precipitated solid was collected by filtration and washed with water. This yielded 6,8-dibromo-3-fluoroquinoline-5-amine (4.00 g, 95% yield) as a yellow solid. ESI-MS m / z=318.9[M+H] + Calculated MW: 317.9

[0443] Step 2: 5-Bromo-8-fluoro-[1,2,3]oxadiazolo4,5-f]quinoline A mixture of 6,8-dibromo-3-fluoroquinoline-5-amine (4.00 g, 12.6 mmol, 1.0 equivalent) and NaNO2 (1.62 g, 23.4 mmol, 2.5 equivalents) in CH3COOH (50 mL) was mixed with propanoic acid (50 mL) at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / ELISA (1:1) to obtain 5-bromo-8-fluoro-[1,2,3]oxadiazolo[4,5-f]quinoline (2.20 g, yield 64%) as a yellow solid. ESI-MS m / z=267.9[M+H] + Calculated MW: 266.9

[0444] Step 3: 8-Bromo-3-fluoroquinoline-6-ol To a stirred solution of 5-bromo-8-fluoro-[1,2,3]oxadiazolo-4,5-f]quinoline (2.20 g, 8.20 mmol, 1.0 equivalent) in EtOH (50 mL) and THF (50 mL), NaBH4 (776.2 mg, 20.5 mmol, 2.5 equivalents) was added at 0°C. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water at 0°C. The mixture was acidified to pH 7 with 1 M HCl (aqueous solution). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / ethyl acetate (1:1) to obtain 8-bromo-3-fluoroquinoline-6-ol (1.23 g, yield 53.2%) as a brown solid. ESI-MS m / z=242.0[M+H] + Calculated MW: 241.0 1 H NMR(300MHz,DMSO-d6)δ 10.69(s,1H),8.77(d,J=2.7Hz,1H),8.14(dd,J=9.9,2.8Hz,1H),7.68(d,J=2.8Hz,1H),7.22(d,J=2.5Hz,1H).

[0445] Step 4: 8-Bromo-3-fluoro-6-(methoxymethoxy)quinolone To a stirred solution of 8-bromo-3-fluoroquinoline-6-ol (500.0 mg, 2.06 mmol, 1.0 equivalent) and DIEA (533.9 mg, 4.13 mmol, 2.0 equivalent) in DCM (10 mL), bromo(methoxy)methane (309.7 mg, 2.47 mmol, 1.2 equivalents) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. The reaction product was diluted with water at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / Â 2:1) to obtain 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline (433.0 mg, yield 73%) as a brown solid. ESI-MS m / z=286.0[M+H] + Calculated MW: 285.0 1 ¹H NMR (400MHz, chloroform-d)δ: 8.70 (d, J=2.7Hz, 1H), 7.71 (d, J=2.6Hz, 1H), 7.62 (dd, J=8.8, 2.7Hz, 1H), 7.23 (d, J=2.6Hz, 1H), 5.22 (s, 2H), 3.45 (s, 3H).

[0446] Intermediate 4: 3-Fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethinyl)quinolone [ka] Step 1: 3-Fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethinyl)quinolone 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline (300.0 mg, 1.04 mmol, 1.0 equivalent), ethinyltriisopropylsilane (1.34 g, 7.34 mmol, 7.0 equivalents), CuI (39.9 mg, 0.21 mmol, 0.2 equivalents), Pd(PPh3)2Cl2 (73.6 mg, 0.10 mmol, 0.1 equivalents), DIEA (406.5 mg, 3.14 mmol, 3.0 equivalents), and DMF (15 mL) were added to a 40 mL vial at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under an argon atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filtered cake was washed with ethyl acetate. The reaction product was diluted with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium 2 SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / Â1 4:1) to obtain 3-fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethinyl)quinolone (322.0 mg, yield 79%) as a black oil. ESI-MS m / z=388.2[M+H] + Calculated MW: 387.2 1H NMR(400MHz,chloroform-d)δ 8.73(d,J=2.8Hz,1H),7.67-7.56(m,2H),7.28(d,J=2.7Hz,1H),5.28(s,2H),3.51(s,3H),1.21-1.18(m,21H).

[0447] Intermediate 5: ((8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane [ka] Step 1: 1-Bromo-8-chloro-3-(methoxymethoxy)naphthalene To a stirred solution of 4-bromo-5-chloronaphthalen-2-ol (2.00 g, 7.76 mmol, 1.0 equivalent) and DIEA (2.01 g, 15.5 mmol, 2.0 equivalent) in DCM (20 mL), bromo(methoxy)methane (1.94 g, 15.5 mmol, 2.0 equivalent) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. The reaction was quenched by adding water at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (4:1) to obtain 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (2.16 g, 93% yield) as a reddish solid. 1 ¹H NMR (300 MHz, chloroform-d) δ: 7.70-7.62 (m, 2H), 7.50 (dd, J=7.5, 1.3 Hz, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.34-7.24 (m, 1H), 5.27 (s, 2H), 3.51 (s, 3H).

[0448] Step 2: ((8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethinyl)triisopropylsilane Ethinyltriisopropylsilane (3.02 g, 16.5 mmol, 5.0 equivalents) was added to a stirred mixture of 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (1.00 g, 3.31 mmol, 1.0 equivalent), CuI (130.0 mg, 0.66 mmol, 0.2 equivalents), Pd(PPh3)2Cl2 (230.0 mg, 0.33 mmol, 0.1 equivalent), and DIEA (1.29 g, 9.94 mmol, 3.0 equivalents) in DMF (20 mL) under an argon atmosphere at room temperature. The resulting mixture was stirred under an argon atmosphere at 100 °C for 16 hours. The resulting mixture was extracted with Â. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / Â1 3:1) to obtain ((8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (1.30 g, yield 97%) as a black liquid. 1 H NMR(300MHz,DMSO-d6)δ 7.87(dd,J=8.1,1.5Hz,1H),7.63(d,J=2.6Hz,1H),7.56-7.39(m,3H),5.35(s,2H),3.43(s,3H),1.13(d,J=2.8Hz,21H).

[0449] Intermediate 6: 6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinoline [ka] Step 1: 6,8-Dibromoquinoline-5-amine To a stirred solution of 5-aminoquinoline (5.00 g, 34.7 mmol, 1.0 equivalent) in DMF (30 mL), NBS (12.34 g, 69.4 mmol, 2.0 equivalents) (dissolved in 30 mL of DMF) was added dropwise at -10°C. The resulting mixture was stirred at -10°C for 1 hour. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / ethyl acetate (3:1) to obtain 6,8-dibromoquinoline-5-amine (9.00 g, 81%) as a brown solid. ESI-MS m / z = 300.8 [M + H] + Calculated MW: 299.9. 1 H NMR(400MHz,DMSO-d6)δ 8.94(dd,J=4.2,1.5Hz,1H),8.74(dd,J=8.6,1.6Hz,1H),8.04(s,1H),7.56(dd,J=8.6,4.1Hz,1H),6.35(s,2H).

[0450] Step 2: 5-Bromo-[1,2,3]oxadiazolo[4,5-f]quinoline To a stirred mixture of 6,8-dibromoquinoline-5-amine (8.80 g, 29.1 mmol, 1.0 equivalent) in AcOH (60 mL) and propanoic acid (20 mL), NaNO2 (3.02 g, 43.7 mmol, 1.5 equivalent) was gradually added at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / ethyl acetate (4:1) to obtain 5-bromo-[1,2,3]oxadiazolo[4,5-f]quinoline (7.20 g, 96% yield) as a brown solid. ESI-MS m / z=249.8[M+H] + Calculated MW: 249.0

[0451] Step 3: 8-Bromoquinoline-6-ol To a stirred mixture of 5-bromo-[1,2,3]oxadiazolo-4,5-f]quinoline (7.00 g, 27.9 mmol, 1.0 equivalent) in EtOH (40 mL) and THF (40 mL), NaBH4 (2.44 g, 64.5 mmol, 2.3 equivalents) was gradually added at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 4 hours. The resulting mixture was diluted with water. The mixture was neutralized to pH 7 with 1 M HCl (aqueous solution) and extracted with HCl. The combined organic layers were washed with brine. After filtration, the filtrate was concentrated under reduced pressure. This yielded 8-bromoquinoline-6-ol (6.20 g, yield 44%) as a brown solid. The crude product mixture was used directly in the next step without further purification. ESI-MS m / z = 223.8 [M + H] + Calculated value MW: 223.0

[0452] Step 4: 8-Bromo-6-(methoxymethoxy)quinoline To a stirred mixture of 8-bromoquinoline-6-ol (6.10 g, 27.2 mmol, 1.0 equivalent) and DIEA (7.04 g, 54.5 mmol, 2.0 equivalent) in DCM (50 mL), methane and bromo(methoxy)methane (4.42 g, 35.4 mmol, 1.3 equivalents) were added dropwise at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 25°C for 1.5 hours. The resulting mixture was quenched with water and extracted with DCM. The combined organic layer was concentrated under reduced pressure to obtain 8-bromo-6-(methoxymethoxy)quinoline (3.20 g, yield 43%) as a brown oil. ESI-MS m / z = 205.0 [M + H] + Calculated MW: 204.1. 1 H NMR(400MHz,DMSO-d6)δ 8.88(dd,J=4.2,1.6Hz,1H),8.34(dd,J=8.4,1.7Hz,1H),7.91(d,J=2.6Hz,1H),7.58(m,2H),5.37(s,2H),3.45(s,3H).

[0453] Step 5: 6-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]quinoline To a stirred mixture of 8-bromo-6-(methoxymethoxy)quinoline (1.60 g, 5.9 mmol, 1.0 equivalent) and ethinyltriisopropylsilane (5.44 g, 29.8 mmol, 5.0 equivalents) in DMF (15 mL), DIEA (2.31 g, 17.9 mmol, 3.0 equivalents), CuI (14.2 mg, 0.07 mmol, 0.2 equivalents) and Pd(PPh3)2Cl2 (418.9 mg, 0.59 mmol, 0.1 equivalents) were added. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, diluted with water (50 mL), and filtered. The filtered cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / Â5:1) to obtain 6-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]quinoline (1.60 g, yield 72%) as a green solid. ESI-MS m / z = 370.2 [M + H] + Calculated MW: 369.2

[0454] Intermediate 7: ((3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl)ethynyl)triisopropylsilane [ka] Step 1: ((3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl)ethynyl)triisopropylsilane To a stirred mixture of 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene (420.0 mg, 1.37 mmol, 1.0 equivalent), DIPA (1.39 g, 13.7 mmol, 10 equivalents), and ethinyltriisopropylsilane (300.7 mg, 1.64 mmol, 1.2 equivalents) in DMF (10 mL), CuI (26.1 mg, 0.13 mmol, 0.1 equivalent) and Pd(PPh3)2Cl2 (48.2 mg, 0.06 mmol, 0.05 equivalents) were added under a nitrogen atmosphere at 25°C. The resulting mixture was stirred under a nitrogen atmosphere at 60°C for 2 hours. The mixture was cooled to 30°C. The resulting mixture was diluted with water (10 mL) and then extracted with Â. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / Â10:1) to obtain {2-[3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl]ethynyl}triisopropylsilane (459.1 mg, yield 78%) as a yellow solid. Calculated MW: 406.2. 1 1H NMR (400 MHz, chloroform-d) δ: 6.97 (d, J=3.2 Hz, 1 H), 6.95 (d, J=3.4 Hz, 1 H), 5.04 (d, J=3.2 Hz, 2 H), 3.39 (s, J=1.0 Hz, 3 H), 1.44-1.38 (m, 1 H), 1.25-1.14 (m, 6 H), 1.11-1.01 (m, 21 H).

[0455] Intermediate 8: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamide [ka] Step 1: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthoic acid A mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yltrifluoromethanesulfonate (5.00 g, 9.53 mmol, 1.0 equivalent), Et3N (2.84 g, 28.05 mmol, 3.0 equivalent), and butyl[(3R,5S,7s)-adamantan-1-yl][(1s,3R,5S,7s)-adamantan-1-yl]phosphan{2'-amino-[1,1'-biphenyl]-2-yl}palladium illium methanesulfonate (3.41 g, 4.67 mmol, 0.5 equivalent) in DMSO:H2O (100 ml:10 ml) was stirred at 80°C for 16 hours under a carbon monoxide (20 atm) atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with Âr (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxylic acid (1.50 g, 22%) as a brown oil. ESI-MS m / z=431.30[M+H] + Calculated MW: 430.20

[0456] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamide To a mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxylic acid (1.50 g, 3.48 mmol, 1.0 equivalent) and DMF (127.3 mg, 1.742 mmol, 0.5 equivalent) in DCM, (COCl)2 (663.2 mg, 5.22 mmol, 1.5 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for a further 1 hour. The resulting mixture was concentrated under vacuum. THF (10 mL) was added to the above mixture at 0°C, followed by NH3.H2O (5 mL, 128.40 mmol, 36.8 equivalents) at 0°C. The resulting mixture was stirred at 0°C for a further 1 hour. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 30 minutes; detector, UV 254 nm, to obtain 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxamide (540.0 mg, yield 34%) as a dark red solid. ESI-MS m / z=430.17[M+H] + Calculated MW: 429.21 1 H NMR(400MHz,DMSO-d6)δ 8.03-7.92(m,2H),7.58(d,J=2.6Hz,1H),7.50(t,J=8.9Hz,1H),7.23(d,J= 2.6Hz,1H),7.01(s,1H),5.33(s,2H),3.43(s,3H),1.13(d,J=4.8Hz,21H).

[0457] Intermediate 9: ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane [ka] Step 1: 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol A solution of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.00 g, 11.1 mmol, 1.0 equivalent) and UHP (4.17 g, 44.4 mmol, 4.0 equivalent) in MeOH (40 mL) was stirred at 40°C for 6 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (6:1) to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (2.00 g, yield 74%) as a pale yellow oil. ESI-MS m / z = 249.10 [MH] - Calculated MW: 250.10

[0458] Step 2: 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (1.00 g, 3.99 mmol, 1.0 equivalent), K2CO3 (1.10 g, 7.99 mmol, 2.0 equivalent), and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.71 g, 4.79 mmol, 1.2 equivalents) in THF (10 mL) was stirred at 40°C for 5 hours under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (1.50 g, yield 98%) as a pale yellow oil. ESI-MS m / z=381.00[MH] - Calculated MW: 382.05

[0459] Step 3: ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (1.00 g, 2.61 mmol, 1.0 equivalent), CuI (50.0 mg, 0.26 mmol, 0.1 equivalent), and Pd(PPh3)2Cl2 (90.0 mg, 0.13 mmol, 0.05 equivalent) in DMF (10 mL) was stirred at 80°C for 5 hours under an argon atmosphere. The resulting mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / ethyl acetate (8:1) to obtain ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane (800.0 mg, yield 74%) as a pale yellow oil. Calculated MW: 414.24 1 H NMR(400MHz,DMSO-d6)δ 7.82(dd,J=9.0,6.0Hz,1H),7.61(d,J=2.7Hz,1H),7.47(d,J=2.7Hz,1H),7.42(t,J=9.3Hz,1H),5. 31(s,2H),3.64(qd,J=7.3,3.0Hz,2H),3.42(s,3H),1.26(m,J=7.3,3.0Hz,3H),1.2-1.11(m,21H).

[0460] Intermediate 10: (7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methanol [ka] Step 1: 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol A solution of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.00 g, 11.1 mmol, 1.0 equivalent) and UHP (4.17 g, 44.4 mmol, 4.0 equivalent) in MeOH (40 mL) was stirred at 40°C for 6 hours under an argon atmosphere. The resulting mixture was cooled to 20°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (6:1) to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (2.00 g, 74%) as a pale yellow oil. ESI-MS m / z = 249.10 [MH] - Calculated MW: 250.01

[0461] Step 2: 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (1.00 g, 3.99 mmol, 1.0 equivalent), K2CO3 (1.10 g, 7.99 mmol, 2.0 equivalents), and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.71 g, 4.79 mmol, 1.2 equivalents) in 10 mL of THF was stirred at 40°C for 5 hours under an argon atmosphere. The resulting mixture was cooled to 20°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yltrifluoromethanesulfonate (1.50 g, 98%) as a pale yellow oil. ESI-MS m / z = 381.00 [MH] - Calculated MW: 382.05

[0462] Intermediate 11: 5-bromo-7-(methoxymethoxy)quinoline [ka] Step 1: To a stirred mixture of 5-bromo-7-methoxyquinoline (1.00 g, 4.20 mmol, 1.0 equivalent) in toluene (10 mL), AlCl3 (1.68 g, 12.6 mmol, 3.0 equivalent) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The reaction was quenched with water at 0°C. The aqueous layer was extracted with CHCl3 / I-PrOH(3 / 1). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 5-bromoquinoline-7-ol (600.0 mg, yield 64%) as an orange solid. ESI-MS m / z = 224.0 / 226.0 [M+H] + Calculated MW: 223.1 / 225.1. 1 H NMR(300MHz,DMSO-d6)δ 10.58(s,1H),8.81(dd,J=4.3,1.6Hz,1H),8.33(ddd,J=8.5,1.7,0.9Hz,1H),7.54(d,J=2.3Hz,1H),7.45-7.41(m,1H),7.30(dd,J=2.3,0.9Hz,1H).

[0463] Step 2: Bromo(methoxy)methane (1.45 g, 11.6 mmol, 2.6 equivalents) was added dropwise to a stirred mixture of 5-bromoquinoline-7-ol (440.0 mg, 4.46 mmol, 1.0 equivalent) and DIEA (1.73 g, 13.4 mmol, 3.0 equivalents) in DCM (20 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours. The reaction product was poured into ice / water, and the resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography eluted with DCM / MeOH (100% ~ 10:1). The pure fraction was concentrated to obtain 5-bromo-7-(methoxymethoxy)quinolone (410.0 mg, yield 99%) as a yellow solid. ESI-MS m / z = 268.0 / 270.0 [M+H] +Calculated MW: 267.1 / 269.1. 1 H NMR(300MHz,DMSO-d6)δ 8.91(dd,J=4.3,1.6Hz,1H),8.42(ddd,J=8.5,1.6,0.8Hz,1H),7.76(d,J=2.4Hz,1H),7.64-7.51(m,2H),5.41(s,2H),3.44(s,3H).

[0464] Intermediate 12: 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene [ka] Step 1: (3-bromo-5-chlorophenoxy)(tert-butyl)dimethylsilane To a stirred mixture of 3-bromo-5-chlorophenol (20.00 g, 96.4 mmol, 1.0 equivalent) and imidazole (32.82 g, 482.0 mmol, 5.0 equivalents) in DCM (400 mL), TBSCl (21.80 g, 144.6 mmol, 1.5 equivalents) was gradually added at 0°C under an argon atmosphere. The resulting mixture was stirred at 20°C for 2 hours under an argon atmosphere. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain 3-bromo-5-chlorophenoxy(tert-butyl)dimethylsilane (27.00 g, yield 87%) as a yellow oil. Calculated MW: 320.0

[0465] Step 2: 2-Bromo-6-chloro-4-hydroxybenzaldehyde To a stirred solution of (3-bromo-5-chlorophenoxy)(tert-butyl)dimethylsilane (18.00 g, 55.9 mmol, 1.0 equivalent) in THF (200 mL), LDA (56 mL, 111.9 mmol, 2.0 equivalents, 2 M in THF) was added dropwise at -78°C under an argon atmosphere. The resulting mixture was stirred at -65°C for 1 hour under an argon atmosphere. DMF (20.45 g, 279.8 mmol, 5.0 equivalents) was added dropwise to the above mixture over 1 hour at -78°C. The resulting mixture was stirred for a further 2 hours at -65°C. The mixture was warmed to 0°C. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (200 mL) at 0°C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with RINKAN (3 × 300 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product, 2-bromo-6-chloro-4-hydroxybenzaldehyde, was used directly in the next step without further purification. 1 H NMR(400MHz,CD3OD-d4)δ 10.2(s,1H),7.10(s,1H),6.92(s,1H).

[0466] Step 3: 2-Bromo-6-chloro-4-(methoxymethoxy)benzaldehyde To a stirred mixture of 2-bromo-6-chloro-4-hydroxybenzaldehyde (22.00 g, 93.4 mmol, 1.0 equivalent) and DIEA (36.23 g, 280.3 mmol, 3.0 equivalents) in DCM, MOM-Cl (12.42 g, 186.8 mmol, 2.0 equivalents) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at 0°C for 2 hours under an argon atmosphere. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1) to obtain 2-bromo-6-chloro-4-(methoxymethoxy)benzaldehyde (18.00 g, yield 69%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 9.98(s,1H),7.24(s,1H),7.10(s,1H),5.16(s,2H),3.20(s,3H).

[0467] Step 4: (Z / E)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(propa-1-en-1-yl)benzene To a stirred mixture of ethyltriphenylphosphanium bromide (39.85 g, 107.3 mmol, 1.5 equivalents) in 300 mL of THF at 0°C, potassium tert-butoxide (107.3 mL, 107.3 mmol, 1.5 equivalents, 1 M in THF) was added under an argon atmosphere. The resulting mixture was stirred at 0°C for 1 hour under an argon atmosphere. To the above mixture, 2-bromo-6-chloro-4-(methoxymethoxy)benzaldehyde (20.00 g, 71.5 mmol, 1.0 equivalent) in 100 mL of THF was added dropwise over 30 minutes at 0°C. The resulting mixture was stirred for a further 1 hour at 20°C. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with siRNA (3 × 400 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / Â(6:1) to obtain (Z / E)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(propa-1-en-1-yl)benzene (15.00 g, yield 72%) as a colorless oil. Calculated MW: 290.0

[0468] Step 5: 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene Under an argon atmosphere, a mixture of diethylzinc (21.18 g, 171.4 mmol, 10 equivalents) and TFA (19.55 g, 171.4 mmol, 10 equivalents) in DCM (200 mL) was stirred at -40°C. The resulting mixture was stirred under an argon atmosphere at -40°C for 1 hour. Diiodomethane (45.93 g, 171.4 mmol, 10 equivalents) was added dropwise to the above mixture at -40°C for 10 minutes. The resulting mixture was stirred for a further 1 hour at -40°C. (E / Z)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(propa-1-en-1-yl)benzene (5.00 g, 17.1 mmol, 1.0 equivalent) was added dropwise to the above mixture at -40°C for 10 minutes. The resulting mixture was stirred for a further 20 hours at 20°C. The mixture was cooled to 0°C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 100% over 2 hours; detector, UV 254 nm, to obtain 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene (1.00 g, yield 19%) as a colorless oil. Calculated MW: 304. 1 H NMR(400MHz,CDCl3)δ 7.25(s,1H),7.01(s,1H),5.11(s,2H),3.50(s,3H),1.37-1.31(m,1H),1.28-1.25(m,3H),1.04-1.01(m,1H),0.98-0.86(m,2H).

[0469] Intermediate 13: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-amine [ka] Step 1: N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1,1-diphenylmethaneimine To a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate (6.00 g, 11.0 mmol, 1.0 equivalent), Pd2(dba)3CHCl3 (1.16 g, 1.10 mmol, 0.1 equivalent), and Cs2CO3 (7.31 g, 22.4 mmol, 2.0 equivalent), diphenylmethaneimine (4.06 g, 22.4 mmol, 2.0 equivalent) in toluene (100 mL) was added at room temperature under an argon atmosphere. The resulting mixture was stirred at 110 °C for 2 hours under an argon atmosphere. The resulting reaction mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Â(5:1) to obtain N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1,1-diphenylmethaneimine (3.55 g, yield 56%) as a black oil. ESI-MS m / z=566.3[M+H] + Calculated MW: 565.3

[0470] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-amine To a stirred mixture of N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1,1-diphenylmethaneimine (3.55 g, 6.27 mmol, 1.0 equivalent) in THF (20 mL), HCl (4 mL, 1 M) was added dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature under an air atmosphere for 30 minutes. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse-phase flash under the following conditions (column: Xselect CSH Prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 70 mL / min; gradient: 60%B~100%B, 100%B over 30 mins; wavelength: 220 / 254 nm; RT1 (min): 10.88) to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-amine (1.65 g, yield 66%) as a black oil. ESI-MS m / z=402.2[M+H] + Calculated MW: 401.2. 1 H NMR(400MHz,DMSO-d6)δ 7.75(dd,J=9.2,6.1Hz,1H),7.32(t,J=8.9Hz,1H),6.77(d,J=2.5Hz,1H),6.56( S,2H),6.53(d,J=2.4Hz,1H),5.23(s,2H),3.42(s,3H),1.12(d,J=3.9Hz,21H).

[0471] Intermediate 14: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol [ka] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (2-bromoethinyl)triisopropylsilane (29.33 g, 112.2 mmol, 1.0 equivalent) was added at 0°C to a mixture of 7-fluoronaphthalene-1,3-diol (20.00 g, 112.3 mmol, 1.0 equivalent), [RuCl2(Binap)2]dichloro[(R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl]ruthenium(II) (8.92 g, 11.2 mmol, 0.1 equivalent), and AcOK (22.03 g, 224.5 mmol, 2.0 equivalent) in toluene. The resulting mixture was stirred at 110°C for a further 2 hours. The mixture was cooled to 20°C. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with ELISA (3 × 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Âti to obtain 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1,3-diol (40.00 g, yield 91%) as a dark yellow oil. ESI-MS m / z=359.2[M+H] + Calculated MW: 358.2

[0472] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol To a stirred mixture of 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1,3-diol (50.00 g, 139.4 mmol, 1.0 equivalent) and DIEA (54.07 g, 418.3 mmol, 3.0 equivalents) in DCM (500 mL), bromomethoxymethane (26.14 g, 209.2 mmol, 1.5 equivalents) was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at 20°C for 1 hour under an argon atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Â1 to obtain 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-ol) (30.00 g, yield 54%) as a brown oil. ESI-MS m / z=403.0[M+H] + Calculated MW: 402.0

[0473] Intermediate 15: 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene [ka] Step 1: (3E)-4-(2,3-difluorophenyl)buta-3-enoic acid To a stirred mixture of 2,3-difluorobenzaldehyde (50.00 g, 351.8 mmol, 1.0 equivalent) and 3-(bromotriphenyl-λ-5-phosphanyl)propanoic acid (160.70 g, 387.0 mmol, 1.1 equivalent) in THF (500 mL), t-BuOK (703.7 mL, 703.7 mmol, 2.0 equivalents, 1 M in THF) was added dropwise at -70°C under a nitrogen atmosphere. The resulting mixture was stirred at -70°C for 1 hour under a nitrogen atmosphere. The mixture was then heated to 20°C and stirred at 20°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (500 mL) and concentrated under reduced pressure. The resulting mixture was filtered, and the filtrate was acidified to pH 2 with HCl (1 M aqueous solution). The resulting mixture was extracted with Âr (3 × 500 mL). The combined organic layers were washed with water (500 × 2 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / Âi (10:1~2:1). The pure fraction was concentrated under reduced pressure to obtain (3E)-4-(2,3-difluorophenyl)buta-3-enoic acid (52.00 g, yield 75%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform) δ 7.10-6.98 (m, 3H), 6.44 (d, J=11.5, 1.7 Hz, 1H), 5.82 (td, J=11.6, 7.2 Hz, 1H), 2.43 (dd, J=7.3 Hz, 2H).

[0474] Step 2: 4-(2,3-difluorophenyl)butanoic acid To a stirred solution of (3E)-4-(2,3-difluorophenyl)buta-3-enoic acid (52.00 g, 262.4 mmol, 1.0 equivalent) in 1.5 L of siRNA, 10% Pd / C (11.17 g, 104.9 mmol, 0.4 equivalents) was added under a nitrogen atmosphere at 20°C. The resulting mixture was stirred under a hydrogen atmosphere at 20°C for 2 hours. The resulting mixture was filtered, and the filter cake was washed with siRNA (3 × 200 mL). The filtrate was concentrated under reduced pressure to obtain 4-(2,3-difluorophenyl)butanoic acid (50.00 g, yield 95%) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 7.32-7.08(m,3H),2.74-2.63(m,2H),2.25(t,J=7.3Hz,2H),1.81(m,2H).

[0475] Steps 3-4: 5,6-difluoro-3,4-dihydro-2H-naphthalene-1-one To a stirred solution of 4-(2,3-difluorophenyl)butanoic acid (50.00 g, 249.7 mmol, 1.0 equivalent) and DMF (912.8 mg, 12.4 mmol, 0.05 equivalent) in DCM (1 L), oxalyl chloride (63.40 g, 499.5 mmol, 2.0 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 0.5 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to obtain a residue (50.00 g, yellow solid). To a stirred solution of the residue (50.00 g, yellow solid) in DCM (1 L), AlCl3 (50.31 g, 377.3 mmol, 1.5 equivalent) was added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 40°C for 1 hour under a nitrogen atmosphere. The reaction was quenched by adding water / ice (1 L) at 0°C. The resulting mixture was extracted with DCM (3 × 500 mL). The combined organic layer was washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / siRNA (100:1~2:1). The pure fraction was concentrated under reduced pressure to obtain 5,6-difluoro-3,4-dihydro-2H-naphthalen-1-one (43.00 g, 95% yield in 2 steps) as a yellow oil. ESI-MS m / z = 183.1 [M + H] + Calculated value MW: 182.0

[0476] Steps 5-6: 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridine-2(1H)-one To a stirred solution of 5,6-difluoro-3,4-dihydro-2H-naphthalen-1-one (41.00 g, 225.0 mmol, 1.0 equivalent) and HBr / AcOH (2.0 mL, 22.5 mmol, 0.1 equivalent, 33%) in AcOH (900 mL), Br2 (11.5 mL, 225.0 mmol, 1.0 equivalent) in AcOH (50 mL) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with DCM (500 mL). The resulting mixture was washed with water (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue. LiBr (23.75 g, 273.4 mmol, 1.7 equivalents) and Li2CO3 (20.21 g, 273.5 mmol, 1.7 equivalents) were added to a stirred solution of the residue in DMF (1 L) under a nitrogen atmosphere at 20°C. The resulting mixture was stirred under a nitrogen atmosphere at 160°C for 1 hour. The mixture was cooled to 20°C. The resulting mixture was diluted with siRNA (2 L). The resulting mixture was washed with water (3 × 1 L). The combined organic layers were washed with brine (3 × 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / siRNA (100:1~10:1), and the pure fraction was concentrated under reduced pressure to obtain 5,6-difluoronaphthalen-1-ol (26.00 g, 64% yield in 2 steps) as a brown solid. ESI-MS m / z=179.1[MH] - Calculated MW: 180.0. 1 H NMR(400MHz,DMSO-d6)δ 10.59(s,1H),8.06-7.95(m,1H),7.54-7.41(m,3H),7.01-6.91(m,1H).

[0477] Step 7: 5,6-Difluoronaphthalene-1-yltrifluoromethanesulfonate To a stirred mixture of 5,6-difluoronaphthalen-1-ol (26.00 g, 144.3 mmol, 1.0 equivalent) in DCM (300 mL), DIEA (46.63 g, 360.8 mmol, 2.5 equivalents) and Tf2O (52.93 g, 187.6 mmol, 1.3 equivalents) were added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / Â(20:1~5:1), and the pure fraction was concentrated under reduced pressure to obtain 5,6-difluoronaphthalene-1-yltrifluoromethanesulfonate (36.00 g, yield 80%) as a yellow oil. ESI-MS m / z=310.9[MH] - Calculated MW: 311.9. 1 H NMR(400MHz,DMSO-d6)δ 8.20(d,J=7.3Hz,1H),8.01-7.70(m,4H).

[0478] Step 8: N-(5,6-difluoronaphthalene-1-yl)-1,1-diphenylmethaneimine To a stirred mixture of 5,6-difluoronaphthalene-1-yltrifluoromethanesulfonate (36.00 g, 115.3 mmol, 1.0 equivalent) and α-phenyl-benzenemethaneimine (62.69 g, 345.9 mmol, 3.0 equivalents) in toluene (500 mL), Pd2(dba)3 (10.56 g, 11.5 mmol, 0.1 equivalent), xanthophos (13.34 g, 23.1 mmol, 0.2 equivalents) and Cs2CO3 (112.71 g, 345.9 mmol, 3.0 equivalents) were added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 12 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with RINKAN (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / siRNA (100:1~5:1), and the pure fraction was concentrated under reduced pressure to obtain N-(5,6-difluoronaphthalen-1-yl)-1,1-diphenylmethaneimine (34.00 g, yield 86%) as a yellow solid. ESI-MS m / z = 344.0 [M + H] + Calculated value MW: 343.1

[0479] Step 9: 5,6-Difluoronaphthalene-1-amine N-(5,6-difluoronaphthalen-1-yl)-1,1-diphenylmethaneimine (34.00 g, 99.0 mmol, 1.0 equivalent) in 4 M HCl (g) in MeOH (500 mL) was stirred under an air atmosphere at 10°C for 4 hours. The resulting mixture was concentrated under vacuum. The residue was neutralized to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with alkylammonium phosphate (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / alkylammonium phosphate (50:1~3:1). The pure fraction was concentrated under reduced pressure to obtain 5,6-difluoronaphthalen-1-amine (16.00 g, 90% yield) as a yellow solid. ESI-MS m / z=180.0[M+H] + Calculated MW: 179.0

[0480] Step 10: 2,4-dibromo-5,6-difluoronaphthalene-1-amine A stirred solution of 5,6-difluoronaphthalene-1-amine (16.00 g, 89.3 mmol, 1.0 equivalent) in AcOH (550 mL) was to be added dropwise at 0°C under a nitrogen atmosphere by adding a solution of Br2 (31.11 g, 194.7 mmol, 2.2 equivalents) in AcOH (550 mL). The resulting mixture was stirred at 70°C for 1 hour under a nitrogen atmosphere. The mixture was cooled to 20°C. The precipitated solid was collected by filtration and washed with AcOH (550 mL). The residue was diluted with 15% NaOH aqueous solution (200 mL). The resulting mixture was stirred at 20°C for 20 minutes under an air atmosphere. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The resulting mixture was concentrated under vacuum to obtain 2,4-dibromo-5,6-difluoronaphthalene-1-amine (25.00 g, 83% yield) as an off-white solid. ESI-MS m / z = 337.9 [M + H] + Calculated MW: 336.9

[0481] Step 11: 5-bromo-6,7-difluoronaphtho[1,2-d][1,2,3]oxadiazole To a stirred solution of 2,4-dibromo-5,6-difluoronaphthalene-1-amine (25.00 g, 74.1 mmol, 1.0 equivalent) in AcOH (450 mL), propanoic acid (41.66 g, 562.3 mmol, 7.5 equivalents) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 0.5 hours under a nitrogen atmosphere. NaNO2 (7.68 g, 111.3 mmol, 1.5 equivalents) was added to the above mixture at 0°C. The resulting mixture was stirred for a further 1 hour at 20°C. The precipitated solid was collected by filtration and washed with water (3 × 200 mL). The residue was concentrated under vacuum to obtain 5-bromo-6,7-difluoronaphtho[1,2-d][1,2,3]oxadiazole (17.40 g, yield 82%) as a yellow solid. ESI-MS m / z=284.9[M+H]+ Calculated MW: 283.9

[0482] Step 12: 4-bromo-5,6-difluoronaphthalene-2-ol To a stirred solution of 5-bromo-6,7-difluoronaphtho[1,2-d][1,2,3]oxadiazole (17.40 g, 61.0 mmol, 1.0 equivalent) in THF (70 mL) and EtOH (210 mL), NaBH4 (5.38 g, 142.2 mmol, 2.3 equivalents) was added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 0.5 hours under a nitrogen atmosphere. The reaction was quenched by adding water (70 mL) at 20°C. The resulting mixture was extracted with SiO2 (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / siRNA (20:1~3:1), and the pure fraction was concentrated under reduced pressure to obtain 4-bromo-5,6-difluoronaphthalene-2-ol (8.90 g, yield 56%) as a yellow solid. ESI-MS m / z=256.9[M+H] + Calculated MW: 257.9

[0483] Step 13: 8-Bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene Bromomethoxymethane (7.56 g, 60.4 mmol, 1.7 equivalents) was added dropwise to a stirred solution of 4-bromo-5,6-difluoronaphthalen-2-ol (8.90 g, 34.3 mmol, 1.0 equivalent) and DIEA (11.10 g, 85.8 mmol, 2.5 equivalents) in DCM (100 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 0.5 hours. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (20:1~5:1). The pure fraction was concentrated under reduced pressure to obtain 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene (8.90 g, yield 85%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.89-7.56(m,4H),5.36(s,2H),3.45(s,3H).

[0484] Preparation of compounds Example 2: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] Step 1: tert-butyl3-(4,6-dichloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of 2,4,6-trichloro-1,3,5-triazine (5.00 g, 27.1 mmol, 1.0 equivalent) in DCM (50 mL), DIEA (3.50 g, 27.1 mmol, 1.0 equivalent) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.76 g, 27.1 mmol, 1.0 equivalent) were added at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in RINKAN (100 mL) and washed with water (50 mL). The resulting mixture was concentrated under vacuum to obtain tert-butyl 3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, yield 82%) as an off-white solid. ESI-MS m / z=360.15[M+H] + Calculated MW: 359.09.

[0485] Step 2: tert-butyl3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 22.2 mmol, 1.0 equivalent), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (3.54 g, 22.2 mmol, 1.0 equivalent), DCM (60 mL), and DIEA (2.87 g, 22.2 mmol, 1.0 equivalent) were stirred in a solution. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with DCM:MeOH (10:1) to obtain tert-butyl3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.00 g, yield 93%) as a white solid. ESI-MS m / z=483.45[M+H] + Calculated MW: 482.22. 1 H NMR(300MHz,chloroform-d)δ 5.41-5.13(m,1H),4.53-4.41(m,2H),4.41-4.20(m,2H),4.20-4.02(m,2H),3.23(dd,J=29.3,13.5H z,5H),3.04-2.90(m,1H),2.35-2.03(m,3H),1.92(d,J=17.3Hz,5H),1.73-1.56(m,2H),1.50(s,9H).

[0486] Step 3: tert-butyl3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.20g, 4.63mmol, 1.0 equivalent), 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yltrifluoro A mixture of methanesulfonate (2.48 g, 4.63 mmol, 1.0 equivalent), Pd2(dba)3 (850.0 mg, 0.93 mmol, 0.2 equivalents), P(p-Tol)3 (710.0 mg, 2.32 mmol, 0.5 equivalents), DIEA (3.00 g, 23.2 mmol, 5.0 equivalents), HCOOH (320.0 mg, 6.95 mmol, 1.5 equivalents), TBAB (2.24 g, 6.95 mmol, 1.5 equivalents), and DMF (15 mL) was stirred. The resulting mixture was stirred at 120°C for 1.5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. Water (50 mL) was added to the resulting mixture and extracted with RINKAN (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / Â5=1:2) to obtain tert-butyl3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3g, yield 33%) as a yellow solid. ESI-MS m / z=859.45[M+H] + Calculated MW: 858.47.

[0487] Step 4: tert-butyl3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.30 g, 1.51 mmol, 1.0 equivalent), Zn (990.0 mg, 15.1 mmol, 10 equivalents), and AcOH (15 mL) were stirred together. The resulting mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with Â(3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH10:1) to obtain tert-butyl3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, yield 76%) as a yellow oil. ESI-MS m / z=861.35[M+H] + Calculated MW: 860.48.

[0488] Step 5: 4-(2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol To a 40 mL vial, tert-butyl 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.16 mmol, 1.0 equivalent), dioxane (2 mL), and HCl (gas) were added dropwise to dioxane (6 mL). The resulting mixture was stirred under a nitrogen atmosphere at 25°C for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain 4-(2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (740.0 mg, yield 88%) as a yellow solid. ESI-MS m / z = 717.50 [M + H] + Calculated MW: 716.40.

[0489] Step 6: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-ethynyl-6-fluoronaphthalene-2-ol 4-(2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (730.0 mg, 1.02 mmol, 1.0 equivalent), CsF (7.73 g, 50.9 mmol, 50 equivalents), and DMF (15 mL) were mixed in a stirring solution. The resulting mixture was stirred at 25°C for 1 hour under a nitrogen atmosphere. Water (20 mL) was added to the resulting mixture and extracted with Â(3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 5:1) to obtain a crude product (150 mg) as an off-white solid. The crude product was subjected to preparative HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 30%B to 57%B over 7 min; wavelength: 254 nm / 220 nm The compound was re-purified by (nm;RT1(min):6.8) to obtain 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-ethynyl-6-fluoronaphthalene-2-ol (41.7 mg, yield 7%, LCMS purity: 95.6% at 254 nm, 96.2% at 220 nm) as a white solid. ESI-MS m / z=561.25[M+H] + Calculated MW: 560.27. 1H NMR(400MHz,DMSO-d6)δ 9.75(s,1H),7.83(dd,J=9.1,6.1Hz,1H),7.39(t,J=8.9Hz,1H),7.07(d,J=2.6Hz,1H),7.01(d,J=2.6Hz,1H),5.25(d, J=54.4Hz,1H),4.63(d,J=1.2Hz,1H),4.28(d,J=12.4Hz,1H),4.19(d,J=12.5Hz,1H),4.00(t,J=10.6Hz,1H),3.94-3.7 8(m,3H),3.50-3.39(m,2H),3.12-3.02(m,2H),3.03-2.85(m,5H),2.84-2.74(m,1H),2.45-2.36(m,1H),2.10-2.04(m, 1H),2.03-1.97(m,1H),1.97-1.87(m,1H),1.86-1.79(m,1H),1.78-1.67(m,2H),1.65-1.54(m,2H),1.54-1.38(m,2H). 19 F NMR(377MHz,DMSO-d6)δ -110.33,-172.13(d,J=4.3Hz).

[0490] Example 3: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)oxy)methyl)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of [7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]methanol (258.8 mg, 0.62 mmol, 1.0 equivalent) in THF (5 mL), NaH (74.5 mg, 3.10 mmol, 5.0 equivalents) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 30 minutes under a nitrogen atmosphere. To the above mixture, tert-butyl(1R,5S)-3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300.0 mg, 0.62 mmol, 1 equivalent) was added at 20°C. The resulting mixture was stirred for a further 2 hours at 20°C. The reaction was quenched by adding water (10 mL) at 0°C. The resulting mixture was extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1~5:1), and the pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (420.0 mg, 78%) as a yellow solid. ESI-MS m / z=863.4[M+H] + Calculated MW: 862.5

[0491] Step 2: Tert-butyl(1R,5S)-3-(4-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of tert-butyl(1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.46 mmol, 1.0 equivalent) in DMF (10 mL), CsF (704.0 mg, 4.63 mmol, 10 equivalents) was added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1~5:1), and the pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280.0 mg, crude product) as an off-white solid. ESI-MS m / z=707.2[M+H] + Calculated MW: 706.3

[0492] Step 3: 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene A solution of tert-butyl(1R,5S)-3-(4-{[(2R,7S)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]methoxy}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.14 mmol, 1.0 equivalent) in HCOOH (2 mL) was stirred at 20°C for 4 hours under a nitrogen atmosphere. The residue was purified by reverse combi-flash chromatography under the following conditions: YMC-Actus Triart C18 ExRS column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 39%B to 59%B over 8 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 6.08. The pure fraction was concentrated and then freeze-dried to obtain 4-{[(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)oxy]methyl}5-ethynyl-6-fluoronaphthalene-2-ol (14.1 mg, yield 17%, 97.3% at 254 nm; 96.8% at 220 nm) as a white solid. ESI-MS m / z=563.2[M+H] + Calculated MW: 562.3 1H NMR(400MHz,DMSO-d6)δ 7.90(dd,J=9.2,6.1Hz,1H),7.44(t,J=9.0Hz,1H),7.34(d,J=2.6Hz,1H),7.23(d,J=2.6Hz,1H),6.07 (q,J=13.1Hz,2H),5.24(d,J=54.3Hz,1H),4.60(d,J=1.1Hz,1H),4.30-4.14(m,2H),4.05-3.84(m,2H) ,3.43(s,3H),3.04(s,2H),3.01-2.90(m,3H),2.80(q,J=8.5Hz,1H),2.06(d,J=3.7Hz,1H),1.98(s,1 H),1.90(d,J=15.3Hz,1H),1.82(s,1H),1.74(dd,J=13.1,7.9Hz,2H),1.61(s,2H),1.53-1.36(m,2H).

[0493] Example 4: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-chloronaphthalene-2-ol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Dioxane / water (24 mL, 5:1) contains tert-butyl(1R,5S)-3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 4.14 mmol, To a stirred solution of 1.0 equivalent of 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (960.0 mg, 6.21 mmol, 1.5 equivalents), Pd(DtBPF)Cl2 (270.0 mg, 0.41 mmol, 0.1 equivalent) and K2CO3 (1.72 g, 12.4 mmol, 3.0 equivalents) were gradually added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / ethyl acetate (1:9). The pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.98 g, yield 83%) as a yellow solid. ESI-MS m / z=475.5[M+H] + Calculated MW: 474.3

[0494] Step 2: Tert-butyl(1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphthalene-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Dioxane (10 mL) contains tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900.0 mg, 1.89 mmol, 1.0 equivalent) and 1-bromo-8-chloro-3-(methoxymethyl) To a stirred solution of toxy)naphthalene (629.0 mg, 2.08 mmol, 1.1 equivalents), 1,2,2,6,6-pentamethylpiperidine (883.4 mg, 5.68 mmol, 3.0 equivalents), tris(2-methylphenyl)phosphan (115.4 mg, 0.37 mmol, 0.2 equivalents), and Pd(OAc)2 (42.58 mg, 0.190 mmol, 0.1 equivalents) were gradually added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Â(1:3). The pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphthalene-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720.0 mg, yield 54.61%) as a brown solid. ESI-MS m / z=695.4[M+H] + Calculated MW: 694.3

[0495] Step 3: Tert-butyl(1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of tert-butyl(1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphthalene-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500.0 mg, 0.71 mmol, 1.0 equivalent) in DCM (100 mL), Pt / C (841.8 mg, 4.31 mmol, 6.0 equivalent) was added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 4 hours under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse combi-flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (0.1% FA), gradient 70%–80% over 10 minutes; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, yield 30%) as a yellow solid. ESI-MS m / z=697.2[M+H] + Calculated MW: 696.3

[0496] Step 4: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-chloronaphthalene-2-ol To a stirred solution of tert-butyl(1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, 0.21 mmol, 1.0 equivalent) in MeCN (1.5 mL), HCl (gas) (0.3 mL) in dioxane was added at 20°C under an air atmosphere. The resulting mixture was stirred at 20°C under an air atmosphere for 1 hour. The resulting mixture was purified by preparative HPLC under the following conditions: (Column: Kinetex EVO C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 35%B to 41%B over 10 minutes; Wavelength: 254 nm / 220 nm; RT1 (min): 9.6). The pure fraction was freeze-dried to obtain 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-chloronaphthalene-2-ol (13.6 mg, yield 11%) as a white solid. ESI-MS m / z=553.2[M+H] + Calculated MW: 552.2. 1 H NMR(400MHz,DMSO-d6)δ 9.91(s,1H),7.67(d,1H),7.43-7.23(m,2H),7.12-6.96(m,2H),5.24(d,J=54.3 Hz,1H),4.25(dd,J=37.1,12.5Hz,2H),4.03-3.81(m,2H),3.81-3.66(m,2H),3.4 4(s,2H),3.13-3.02(m,2H),3.02-2.83(m,5H),2.83-2.71(m,1H),2.09-1.97(m, 2H),1.95-1.78(m,2H),1.78-1.64(m,2H),1.64-1.55(m,2H),1.48-1.34(m,2H).

[0497] Example 5: 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethynyl]-5-ethyl-6-fluoronaphthalene-2-ol [ka] Step 1: 4-[2-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethynyl]-5-ethyl-6-fluoronaphthalene-2-ol To a stirred solution of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethynyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120.0 mg, 0.17 mmol, 1.0 equivalent) in dioxane (2 mL), HCl (gas) (3 mL) in dioxane was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL). The residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD column 30*150 mm, 5 m; Mobile phase A: Water (0.1% FA), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 2%B~2%B at 1 min, 2%B~7%B at 1.5 min, 7%~30%B at 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.73. This yielded 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethynyl)-5-ethyl-6-fluoronaphthalene-2-ol (70.1 mg, yield 73%) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.27-8.15(m,2H),7.75(dd,J=9.1,5.9Hz,1H),7.49(d,J=2.6Hz,1H),7.44-7.34(m,2 H),5.27(d,J=54Hz,1H),4.44-4.22(m,2H),4.13-3.95(m,2H),3.77-3.48(m,5H),3.0 9-3.07(m,3H),3.02-2.98(m,1H),2.87-2.79(m,1H),2.12-2.10(m,1H),2.03-2.01(m ,1H),2.00-1.92(m,1H),1.89-1.68(m,5H),1.56-1.54(m,2H),1.32(t,J=7.3Hz,3H).

[0498] Example 6: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol [ka] Steps 1-2: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol To a stirred solution of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-(2-{3-chloro-5-hydroxy-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl}ethynyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350.0 mg, 0.53 mmol, 1.0 equivalent) in MeOH (6 mL), Pd(OH)2 / C (150.4 mg, 1.07 mmol, 2.0 equivalent) was added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 3 hours under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-(2-{3-chloro-5-hydroxy-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl}ethyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300.0 mg, yield 85%) as a brown solid.

[0499] To a stirred mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-(2-{3-chloro-5-hydroxy-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl}ethyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.28 mmol, 1.0 equivalent) in MeCN (2 mL), HCl (gas) (2 mL, 4 M) in dioxane was added under a nitrogen atmosphere at 20°C. The resulting mixture was stirred under an air atmosphere at 20°C for 0.5 hours. The mixture was concentrated to obtain the crude product (200.0 mg), which was then subjected to preparative HPLC under the following conditions: (Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 42%B to 57%B over 8 mins; Wavelength: 254 nm / 220 nm) The solution was purified by (nm;RT1(min):8.38). The pure fraction was freeze-dried to obtain 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol (40.0 mg, yield 21%, purity 96.3% (254 nm); 96.1% (220 nm)) as a white solid. ESI-MS m / z=557.3[M+H] + Calculated MW: 556.2 1H NMR(400MHz,DMSO-d6)δ 9.58(s,1H),6.59(dd,J=23.3,2.5Hz,2H),5.24(d,J=54.4Hz 1H),4.25(dd,J=45.1,12.5Hz,2H),4.07-3.79(m,2H),3.43(s,2H),3.17-3.01(m,4H),3.00-2.91(m,3H),2.85-2.72(m,3H),2.15- 1.87(m,3H),1.85-1.66(m,3H),1.65-1.55(m,2H),1.49-1.36(m,2H),1.31-1.24(m,1H),1.22(d,J=5.8Hz,3H),0.92-0.67(m,3H).

[0500] Example 7: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2-methylcyclopropyl]phenol [ka] Step 1: {2-[3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl]ethynyl}triisopropylsilane To a stirred mixture of 1-bromo-3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]benzene (1.00 g, 3.27 mmol, 1.0 equivalent) and ethynyltris(propan-2-yl)silane (1.19 g, 6.54 mmol, 2.0 equivalents) in DMF (10 mL), DIEA (1.27 g, 9.81 mmol, 3.0 equivalents), Pd(PPh3)2Cl2 (229.6 mg, 0.32 mmol, 0.1 equivalent), and CuI (124.6 mg, 0.65 mmol, 0.2 equivalents) were added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with siRNA (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse combi-flash chromatography under the following conditions: column, C18; mobile phase, A: FA in water (0.1%), B: MeCN, 60% to 100% gradient over 20 minutes; detector, UV 254 nm. The pure fraction was concentrated under vacuum to obtain {2-[3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl]ethynyl}triisopropylsilane (1.16 g, yield 87%) as a brown solid. ESI-MS m / z = no Ms signal; calculated MW: 406.2

[0501] Step 2: Tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1S,2S)-2-methylcyclopropyl]phenyl]ethynyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.57g, 3.24 mmol, 1.2 equivalents) and {2-[3-chloro-5-( To a stirred mixture of methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl]ethynyl}triisopropylsilane (1.16 g, 2.85 mmol, 1.0 equivalent), CuI (108.5 mg, 0.57 mmol, 0.2 equivalents) and Pd(PPh3)4 (329.3 mg, 0.28 mmol, 0.1 equivalents) were added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 0.5 hours under a nitrogen atmosphere. CsF (1.30 g, 8.55 mmol, 3.0 equivalents) was added to the above mixture at 0°C. The resulting mixture was stirred further at 40°C for 16 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with RINKAN (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / siRNA (50:1~2:1), and the pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1S,2S)-2-methylcyclopropyl]phenyl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.20 g, yield 66%) as a brown solid. ESI-MS m / z=697.3[M+H] + Calculated MW: 696.3

[0502] Step 3: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2-methylcyclopropyl]phenol To a stirred mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1S,2S)-2-methylcyclopropyl]phenyl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.28 mmol, 1.0 equivalent) in MeCN (1 mL), HCl (gas) (1 mL, 4 M) in dioxane was added at 20°C under an air atmosphere. The resulting mixture was stirred at 20°C under an air atmosphere for 0.5 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse combi-flash chromatography under the following conditions: Column: Xbridge phenyl OBD column, 19*150 mm, 5 m; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 40%B to 55%B over 8 mins; Wavelength: 254 nm / 220 nm; RT1 (min): 6.9. The pure fraction was concentrated under vacuum to obtain 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2-methylcyclopropyl]phenol (28.0 mg, yield 17%, purity 95.7% (254 nm), 95.5% (220 nm)) as a white solid. ESI-MS m / z=553.2[M+H]+;Calculated value MW:552.2 1H NMR(300MHz,DMSO-d6)δ 6.94(d,J=2.5Hz,1H),6.89(d,J=2.5Hz,1H),5.26(d,J=54.4Hz,1H),4.23(t,J=1 2.4Hz,2H),4.10-3.88(m,2H),3.50-3.44(m,3H),3.10-2.96(m,5H),2.81(q,J=9 .0,8.3Hz,1H),2.10(d,J=4.8Hz,1H),2.03-1.90(m,2H),1.88-1.70(m,3H),1.64 (s,2H),1.53-1.38(m,3H),1.28(d,J=5.9Hz,3H),1.08(s,1H),0.92-0.75(m,2H).

[0503] Example 8: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-ethyl-6-fluoronaphthalene-2-ol [ka] Step 1: Tert-butyl 3-(4-((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate DMF (8 mL) contains {2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethinyl}triisopropylsilane (800.0 mg, 1.92 mmol, 1.0 equivalent), tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate (1.11 g, 2.31 mmol, 1.2 equivalents), CuI (73.4 mg, 0.38 mmol, 0.2 equivalents), and Pd(PPh3)2Cl2 (135.4 mg, 0.19 mmol, 0.1 equivalents) were stirred together, and CsF (1.46 g, 9.64 mmol, 5.0 equivalents) was gradually added at 0°C under an argon atmosphere. The resulting mixture was stirred at 0°C for 0.5 hours under an argon atmosphere. The resulting mixture was stirred at 40°C for 5 hours under an argon atmosphere. The resulting mixture was cooled to room temperature and diluted with SiO2. The resulting mixture was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (1:1) to obtain tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethynyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800.0 mg, yield 59%) as a yellowish-brown oil. ESI-MS m / z=705.45[M+H] + Calculated MW: 704.35. 1H NMR(400MHz,DMSO-d6)δ 7.88(dd,J=9.1,5.9Hz,1H),7.74(d,J=2.7Hz,1H),7.70(d,J=2.7Hz,1H),7.48(t,J=9.3Hz,1H),5.36( s,2H),4.48-4.34(m,2H),4.26(s,2H),4.09(t,J=10.9Hz,1H),4.01(t,J=10.1Hz,1H),3.58(d,J=8.1H z,2H),3.43(s,3H),3.28-3.20(m,1H),3.18-2.92(m,5H),2.83(d,J=7.2Hz,1H),2.10(s,1H),2.03(s, 1H),1.98(d,J=10.2Hz,1H),1.88-1.70(m,4H),1.56(d,J=9.4Hz,2H),1.44(s,9H),1.35-1.31(m,3H).

[0504] Step 2: Tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.56 mmol, 1.0 equivalent) and Pd(OH)2 / C (400.0 mg, 2.84 mmol, 5.0 equivalents) in MeOH (20 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered, and the filtered cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. This yielded tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300.0 mg, yield 75%) as a pale yellow solid. ESI-MS m / z = 709.35 [M + H] + Calculated MW: 708.38 1 H NMR(400MHz,DMSO-d6)δ 7.74(dd,J=9.0,6.2Hz,1H),7.39-7.29(m,2H),7.18(d,J=2.7Hz,1H),5.26(s,2H),4.44(d,J=12.8Hz,1H),4.37(d,J= 12.9Hz,1H),4.21(s,2H),4.07-3.99(m,1H),3.97-3.87(m,1H),3.54(dd,J=9.3,6.3Hz,2H),3.39(s,3H),3.28-3.18(m ,2H),3.09-2.96(m,6H),2.88(t,J=7.9Hz,2H),2.81(q,J=8.7Hz,1H),2.06(d,J=3.1Hz,1H),2.00-1.96(m,1H),1.96- 1.89(m,1H),1.82(d,J=7.2Hz,3H),1.76-1.68(m,2H),1.53-1.45(m,2H),1.43(d,J=2.5Hz,9H),1.24(t,J=7.4Hz,3H).

[0505] Step 3: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethyl)-5-ethyl-6-fluoronaphthalene-2-ol To a stirred solution of tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280.0 mg, 0.39 mmol, 1.0 equivalent) in dioxane (2 mL), HCl (gas) (9 mL) in dioxane was added dropwise at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature under an argon atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 5%B to 20%B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.35) to obtain 4-[2-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-ethyl-6-fluoronaphthalene-2-ol (33.0 mg, yield 15%) as a pale yellow solid. ESI-MS m / z=565.25[M+H] + Calculated MW: 564.30 1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.24-8.18(m,1H),7.61(dd,J=9.0,6.2Hz,1H),7.25(t,J=9.4Hz,1H),7.02(t,J= 2.3Hz,2H),5.25(d,J=54.3Hz,1H),4.35(d,J=12.7Hz,1H),4.25(d,J=12.9Hz,1H),4.12-3.17(m,3H),3.55-3.53(m,2 H),3.50-3.42(m,1H),3.25-3.18(m,2H),3.13-2.94(m,5H),2.91-2.75(m,3H),2.08-2.06(m,1H),2.00-1.98(m,1H), 1.97-1.88(m,1H),1.87-1.78(m,1H),1.78-1.70(m,2H),1.67-1.65(m,2H),1.49-1.46(m,2H),1.23(t,J=7.3Hz,3H).

[0506] Example 9: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethinyl)-5-chloronaphthalene-2-ol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethinyl)triisopropylsilane (300.0 mg, 0.74 mmol, 1.0 equivalent), tert-butyl 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (431.4 mg, 0.89 mmol, 1.2 equivalents), CuI (28.3 mg, 0.14 mmol, 0.2 equivalents), Pd(PPh3)4 (86.0 mg, 0.07 mmol, 0.1 equivalent), and DMF (10 mL) were added to a 40 mL vial at 0°C. The resulting mixture was stirred at 0°C for 30 minutes under an argon atmosphere. CsF (565.3 mg, 3.72 mmol, 5.0 equivalents) was added to the mixture at 0°C under an argon atmosphere. The resulting mixture was stirred at 40°C for 16 hours under an argon atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The reaction product was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10:1) to obtain tert-butyl(1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (425.0 mg, yield 82%) as a black solid. ESI-MS m / z=693.3[M+H] + Calculated MW: 692.3

[0507] Step 2: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethinyl)-5-chloronaphthalene-2-ol To a stirred solution of tert-butyl(1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthalene-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250.0 mg, 0.36 mmol, 1.0 equivalent) in MeCN (6 mL), HCl (gas) in dioxane (6 mL) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was subjected to preparative HPLC (column: XBridge Prep Phenyl) under the following conditions. Purified by OBD column 19*250mm, 5m; mobile phase A: 10 mmol / L NH4HCO3 + 0.05% NH3H2O, mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 5%B~5%B at 1 min, 5%B~31%B at 2 min, 31%~50%B at 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.32) and 4-((4-((1R,5S)-3,8- Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethinyl)-5-chloronaphthalene-2-ol (31.0 mg, yield 15%, 96.5% (254 nm), 96.7% (220 nm)) was obtained as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ 7.59(t,J=3.1Hz,1H),7.47(d,J=8.2Hz,1H),7.31-7.27(m,1H),7.22-7.15(m,2H),5.29(d,J=53.4Hz,1H),4.43-4.40(m,2H),4.19-4.0 2(m,2H),3.60(s,2H),3.34-3.19(m,3H),3.13-2.99(m,3H),2.31-2.16(m,2H),2.08-2.06(m,1H),1.93-1.91(m,3H),1.80-1.60(m,4H).

[0508] Example 10: 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethynyl)-5-chloro-4-((1S,2S)-2-methylcyclopropyl)phenol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-((3-chloro-5-(methoxymethoxy)-2-((1S,2S)-2-methylcyclopropyl)phenyl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred mixture of {2-[3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl]ethynyl}triisopropylsilane (460.0 mg, 1.13 mmol, 1.0 equivalent) and tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (654.9 mg, 1.35 mmol, 1.2 equivalents) in DMF (10 mL), CuI (21.5 mg, 0.11 mmol, 0.1 equivalent) and Pd(PPh3)4 (65.2 mg, 0.05 mmol, 0.05 equivalent) were added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. CsF (858.2 mg, 5.65 mmol, 5.0 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred for a further 2 hours at 40°C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / siRNA 3:1) to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1R*,2S*)-2-methylcyclopropyl]phenyl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (55 mg, yield 30.50%) as a pale yellow solid. ESI-MS m / z=697.3[M+H] + Calculated MW: 696.3

[0509] Step 2: 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)ethynyl)-5-chloro-4-((1S,2S)-2-methylcyclopropyl)phenol 70.0 mg, 0.10 mmol, 1.0 equivalent of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1R*,2S*)-2-methylcyclopropyl]phenyl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and HCl (gas) in dioxane were added at 0°C to a 40 mL vial. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was subjected to preparative HPLC under the following conditions: (Column: XBridge Prep Phenyl OBD column 19*250mm, 5m; Mobile phase A: 10 mmol / L NH4HCO3 + 0.05% NH3H2O; Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5%B~5%B at 1 min, 5%B~38%B at 2 min, 38%~55%B at 10 min; Wavelength: 254 nm / 220 nm) Purified by ESI-MS m / z=553.2 nm;RT1(min):9.23, 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethynyl]-5-chloro-4-[(1R*,2S*)-2-methylcyclopropyl]phenol (18.0 mg, yield 32%, purity 98.8% (254 nm); purity 98.9% (220 nm)) was obtained as an off-white solid. ESI-MS m / z=553.2. [M+H] + Calculated MW: 552.2. 1H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),6.92(dd,J=23.3,2.6Hz,2H),5.26(d,J=54.3Hz,1H),4.24 (t,J=14.1Hz,2H),4.12-3.91(m,2H),3.50(s,2H),3.12-2.97(m,5H),2.8 6-2.77(m,1H),2.16-1.89(m,3H),1.88-1.70(m,3H),1.65(s,2H),1.53- 1.41(m,3H),1.28(d,J=5.9Hz,3H),1.15-1.01(m,1H),0.91-0.76(m,2H).

[0510] Example 11: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2-methylcyclopropyl]phenol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(E)-2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]ethenyl]-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate DIEA (1.18 g, 9.17 mmol, 4.0 equivalents) was added to a stirred mixture of tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-ethenyl-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.31 g, 2.75 mmol, 1.2 equivalents) and rel-1-bromo-3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]benzene (700.3 mg, 2.29 mmol, 1.0 equivalent) in DMF (8 mL) at room temperature under a nitrogen atmosphere. To the above mixture, Pd2(dba)3 (209.8 mg, 0.23 mmol, 0.1 equivalent) and P(p-tol)3 (139.5 mg, 0.46 mmol, 0.2 equivalent) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for a further 2 hours. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with siRNA / PE (2:1) to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-[(E)-2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]ethenyl]-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.30 g, yield 81%) as a pale yellow solid. ESI-MS m / z=699.3[M+H] + Calculated MW: 698.3

[0511] Step 2: Tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]ethyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-[(E)-2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]ethenyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300.0 mg, 0.43 mmol, 1.0 equivalent) in 10 mL of ethyl phosphate, Pd(OH)2 / C (300.0 mg, 2.14 mmol, 5.0 equivalent) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred further at room temperature under a hydrogen atmosphere for 30 minutes. The resulting mixture was filtered, and the filter cake was washed with ethyl phosphate. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC(siRNA) to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220.0 mg, yield 73%) as a white solid. ESI-MS m / z=701.3[M+H] + Calculated value MW: 700.4

[0512] Step 3: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2-methylcyclopropyl]phenol To a stirred mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210.0 mg, 0.30 mmol, 1.0 equivalent) in dioxane (2 mL), HCl (gas) (4 M in dioxane) (6 mL) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred further at 0°C for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column 30*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 0%B to 27%B in 10 mins; wavelength: 254 nm / 220 nm; RT1 (min): 7.08 / 8.49). This yielded 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2-methylcyclopropyl]phenol (37.0 mg, yield 22%, purity 96.0% (254 nm); purity 96.8% (220 nm)) as a white solid. ESI-MS m / z=557.3[M+H] + Calculated MW: 556.3 1H NMR(400MHz,DMSO-d6)δ 9.55(s,1H),8.16(d,J=15.0Hz,1H),6.62(d,J=2.5Hz,2H),5.25(d,J=56.0Hz,1H) ,4.60-4.25(m,2H),4.21-3.98(m,3H),3.80-3.70(m,2H),3.20-3.17(m,3H),3.15- 3.05(m,5H),2.99-2.97(m,1H),2.84-2.81(m,2H),2.07-2.04(m,1H),1.99-1.96( m,1H),1.89-1.62(m,5H),1.53-1.51(m,1H),1.31-1.21(m,4H),0.87-0.70(m,3H).

[0513] Example 12: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxamide [ka] Step 1: 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxylic acid To a stirred solution of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 4.14 mmol, 1.0 equivalent) and DIEA (2.68 g, 20.7 mmol, 5.0 equivalents) in dioxane (20 mL) and water (2 mL), Pd(OAc)2 (139.45 mg, 0.62 mmol, 0.15 equivalents) and DPPP (256.19 mg, 0.62 mmol, 0.15 equivalents) were gradually added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 16 hours under a carbon monoxide atmosphere. The mixture was cooled to 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (1:0~5:1), and the pure fraction was concentrated to obtain 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-carboxylic acid (450.0 mg, yield 22%) as an off-white solid. ESI-MS m / z=493.3[M+H] + Calculated MW: 492.2

[0514] Step 2: Tert-butyl(1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)carbamoyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-carboxylic acid (200.0 mg, 0.41 mmol, 1.0 equivalent) and TEA (164.4 mg, 1.62 mmol, 4.0 equivalents) in DCM (5 mL), (COCl)2 (103.1 mg, 0.81 mmol, 2.0 equivalents) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 30 minutes under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. A solution of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-amine (163.1 mg, 0.41 mmol, 1.0 equivalent) and TEA (123.3 mg, 1.22 mmol, 3.0 equivalents) in DCM (2 mL) at 0°C was added dropwise to the above mixture in DCM (2 mL) at 20°C. The resulting mixture was stirred further at 20°C for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1~1:1), and the pure fraction was concentrated under vacuum to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yl]carbamoyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, yield 20%) as a brown solid. ESI-MS m / z=876.4[M+H] + Calculated MW: 875.5

[0515] Step 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxamide To a stirred solution of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yl]carbamoyl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.08 mmol, 1.0 equivalent) in MeCN (1 mL), HCl (gas) (0.2 mL, 4 M) in dioxane was added under a nitrogen atmosphere at 20°C. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0516] To the above mixture, DMF (1 mL) and CsF (124.5 mg, 0.80 mmol, 10 equivalents) were added at 20°C. The resulting mixture was stirred at 50°C for a further 1 hour. The mixture was cooled to 20°C. The resulting mixture was filtered, and the filter cake was washed with DMF (2 × 0.5 mL). The filtrate was concentrated under reduced pressure. The crude product (40.0 mg) was subjected to preparative HPLC under the following conditions: (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 30%B to 45%B in 10 mins; Wavelength: 254 nm / 220 nm) The solution was purified by (nm;RT1(min):8.18). The pure fraction was concentrated and then freeze-dried to obtain 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-N-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-1,3,5-triazine-2-carboxamide (7.2 mg, yield 16%, 96.38%@254 nm, 95.99%(220 nm)) as a yellow solid. ESI-MS m / z=576.35[M+H] + Calculated MW: 575.25. 1H NMR(400MHz,DMSO-d6)δ 11.00(s,1H),10.64-9.33(m,1H),7.82(dd,J=9.2,6.0Hz,1H),7.58(d,J=2.5Hz,1H) ,7.36(t,J=9.0Hz,1H),7.10(d,J=2.5Hz,1H),5.43-4.71(m,1H),4.59-4.39(m,2H),4 .20(d,J=12.5Hz,1H),4.01(dt,J=42.2,10.6Hz,2H),3.43(s,3H),3.08-2.91(m,5H), 2.76(td,J=8.8,5.7Hz,1H),2.20-1.89(m,3H),1.88-1.69(m,3H),1.63-1.41(m,4H).

[0517] Example 13: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)methoxy)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.00 g, 8.28 mmol, 1.0 equivalent) and TEA (2.51 g, 24.84 mmol, 3.0 equivalents), Dppf (914.9 mg, 1.65 mmol, 0.2 equivalents) and Pd(OAc)2 (185.9 mg, 0.82 mmol, 0.1 equivalents) were added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 16 hours under a carbon monoxide atmosphere. The mixture was cooled to 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / siRNA (4:1~3:1). The pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.80 g, yield 33%) as a red solid. ESI-MS m / z=507.25[M+H] + Calculated MW: 506.3

[0518] Step 2: Tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 3.55 mmol, 1.0 equivalent) and CaCl2 (1.38 g, 12.4 mmol, 3.5 equivalents) in THF / MeOH (2:1, 30 mL), NaBH4 (336.1 mg, 8.88 mmol, 2.5 equivalents) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 16 hours under a nitrogen atmosphere. The reaction was quenched with water at 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (1:10~1:7). The pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, yield 56%) as a white solid. ESI-MS m / z=479.25[M+H] + Calculated MW: 478.3

[0519] Step 3: Tert-butyl(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate DIAD (507.1 mg, 2.51 mmol, 3.0 equivalents) was added dropwise to a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-ol (403.8 mg, 1.01 mmol, 1.2 equivalents) and PPh3 (679.6 mg, 2.59 mmol, 3.1 equivalents) in THF (10 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 hours. To the above mixture, tert-butyl(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.84 mmol, 1.0 equivalent) was added at 20°C. The resulting mixture was stirred for a further 16 hours at 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water (0.1% FA), gradient from 60% to 70% over 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, yield 35%) as a yellow solid. ESI-MS m / z=863.3[M+H] + Calculated MW: 862.5.

[0520] Steps 4-5: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)methoxy)-5-ethynyl-6-fluoronaphthalene-2-ol To a stirred solution of tert-butyl(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.23 mmol, 1.0 equivalent) in DMF (2 mL), CsF (351.9 mg, 2.32 mmol, 10 equivalents) was added at 20°C under an air atmosphere. The resulting mixture was stirred at 20°C under an air atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (2 × 10 mL). The filtrate was concentrated under vacuum to obtain tert-butyl(1R,5S)-3-(4-(((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, crude product) as a brown oil. To a stirred solution of tert-butyl(1R,5S)-3-(4-(((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, crude product) in DCM (0.5 mL), FA (2 mL) was added at 20°C under an air atmosphere. The resulting mixture was stirred at 20°C under an air atmosphere for 2 hours. The resulting mixture was purified by preparative HPLC under the following conditions: (Column: Xbridge phenyl OBD column, 19*150 mm, 5 m; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH3H2O; Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 27%B~42%B over 10 mins; Wavelength: 254 nm / 220 nm; RT1 (min): 9.4).The pure fraction was freeze-dried to obtain 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)methoxy)-5-ethynyl-6-fluoronaphthalene-2-ol (23.4 mg, yield 14%) as a white solid. ESI-MS m / z=563.15[M+H] + Calculated MW: 562.3. 1 H NMR(400MHz,DMSO-d6)δ 7.73(dd,J=9.1,5.7Hz,1H),7.35(t,J=9.1Hz,1H),6.79(d,J=2.1Hz,1H),6.64(d,J=2.2Hz,1H),5.2 9-5.10(m,1H),5.06(s,2H),4.35(s,1H),4.19(d,J=12.6Hz,1H),4.05(d,J=12.5Hz,1H),4.00-3.84( m,2H),3.48-3.44(m,1H),3.32-3.25(m,1H),3.06-2.89(m,4H),2.86-2.70(m,2H),2.04-1.92(m,2H) ,1.91-1.74(m,2H),1.74-1.64(m,2H),1.64-1.49(m,2H),1.43(t,J=10.5Hz,1H),1.33-1.21(m,1H).

[0521] Example 14: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] Step 1: tert-butyl(1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A solution of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.07 mmol, 1.0 equivalent) in NH3 / MeOH (7M, 15 mL) was stirred at 50°C for 4 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The resulting mixture was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.20 g, crude product) as a white solid. ESI-MS m / z=464.2[M+H] + Calculated MW: 463.3

[0522] Step 2: ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphthalene-1-yl)ethynyl)triisopropylsilane To a stirred solution of [7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]methanol (200.0 mg, 0.48 mmol, 1.0 equivalent) and PPh3 (151.1 mg, 0.58 mmol, 1.2 equivalents) in DCM (2 mL), CBr4 (191.0 mg, 0.58 mmol, 1.2 equivalents) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1.5 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Â, and the pure fraction was concentrated under reduced pressure to obtain ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (220.0 mg, yield 96%) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) δ 7.70 (dd, J=9.0, 5.8Hz, 1H), 7.36 (s, 2H), 7.29-7.23 (m, 1H), 5.67 (s, 2H), 5.27 (s, 2H), 3.51 (s, 3H), 1.30-1.17 (m, 21H).

[0523] Step 3: tert-butyl(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methyl)amino)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of tert-butyl(1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.43 mmol, 1.0 equivalent) in DMF (10 mL), NaH (51.8 mg, 1.29 mmol, 3.0 equivalents, 60%) was gradually added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere. ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (208.2 mg, 0.43 mmol, 1.0 equivalent) was added to the above mixture at 20°C. The resulting mixture was stirred for a further 2 hours at 50°C. The mixture was cooled to 20°C. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / Âti, and the pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methyl)amino)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210.0 mg, yield 56%) as an off-white solid. ESI-MS m / z=862.5[M+H] + Calculated MW: 861.5

[0524] Step 4: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthalene-2-ol To a stirred solution of tert-butyl(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methyl)amino)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.23 mmol, 1.0 equivalent) in DMF (5 mL), CsF (352.3 mg, 2.32 mmol, 10 equivalents) was added at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C under a nitrogen atmosphere for 16 hours. The resulting mixture was filtered, and the filter cake was washed with DMF (3 × 2 mL). The filtrate was concentrated under reduced pressure. HCOOH (3 mL) was added to the above mixture at 20°C. The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 16 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30*150 mm, 5 m; mobile phase A: 10 mmol NH4HCO3 + 0.05% NH3H2O; mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 28%B~48%B over 8 mins; wavelength: 254 / 220 nm; RT1 (min): 9.37). The pure fraction was concentrated and then freeze-dried to obtain 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthalene-2-ol (15.4 mg, yield 12%) as a white solid. ESI-MS m / z=562.30[M+H] + Calculated MW: 561.3. 1H NMR(400MHz,DMSO-d6)δ 9.84(s,1H),7.85(ddd,J=8.8,6.2,1.8Hz,1H),7.54(dt,J=48.7,6.2Hz,1H),7.40(td,J=9.0,1.9Hz,1H),7.21-6.99(m,2H),5.4 5-5.01(m,3H),4.86(d,J=1.3Hz,1H),4.33-3.68(m,4H),3.43(s,1H),3.25-3.18(m,1H),3.12-2.52(m,7H),2.14-1.33(m,10H).

[0525] Example 15: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthamide [ka] Step 1: tert-butyl3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamide)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Dioxane contains 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethinyl]naphthalene-1-carboxamide (190.0 mg, 0.44 mmol, 1.0 equivalent) and tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (426.5 mg, 0.88 mmol, 2.0 equivalent), Cs2CO3 (288.1 mg, 0.88 mmol, 2.0 equivalent), XPhos (126.4 mg, 0.26 mmol, 0.6 equivalent), and XPhos Pd A mixture of G3 (112.2 mg, 0.13 mmol, 0.3 equivalents) was stirred at 80°C for 16 hours under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% over 40 minutes; detector, UV 254 nm to obtain tert-butyl 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamide)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 65%) as a reddish solid. ESI-MS m / z=876.56[M+H] + Calculated MW: 875.46

[0526] Step 2: tert-butyl3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamide)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of tert-butyl 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamide)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.22 mmol, 1.0 equivalent) and CsF (173.3 mg, 1.1 mmol, 5.0 equivalent) in DMF was stirred at room temperature for 0.5 hours under a nitrogen atmosphere. The resulting mixture was extracted with Â. The combined organic layer was washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamide)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160.0 mg, yield 65%) as a reddish solid. ESI-MS m / z=720.31;[M+H] + Calculated MW: 719.32

[0527] Step 3: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthamide A mixture of tert-butyl 3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamide)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160.0 mg, 0.15 mmol, 1.0 equivalent) and HCl (gas) (5 mL) in dioxane was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (NH4HCO3 / MeCN / H2O) to obtain N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthamide (36.3 mg, yield 40%) as a pale yellow solid. ESI-MS m / z=576.24;[M+H] + Calculated MW: 575.25 1 H NMR(400MHz,DMSO-d6)δ 10.88-10.83(m,1H),10.01(s,1H),7.91-7.85(m,1H),7.51-7.42(m,1H),7.23( s,1H),6.90(s,1H),5.21(d,J=54.2Hz,1H),4.55(s,1H),4.00-3.93(m,1H),3.81 -3.52(m,2H),3.25(s,1H),3.07-2.85(m,3H),2.83-2.61(m,3H),2.27-2.23(m, 1H),2.08-1.74(m,5H),1.74-1.58(m,3H),1.55-1.14(m,3H),0.80-0.75(m,1H).

[0528] Example 16: 4-(1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-1H-imidazole-4-yl)-5-ethynyl-6-fluoronaphthalene-2-ol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-(4-iodoimidazole-1-yl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.07 mmol, 1.0 equivalent) and Cs2CO3 (2.02 g, 6.21 mmol, 3.0 equivalents) in DMF (20 mL), 4-iodo-1H-imidazole (601.4 mg, 3.10 mmol, 1.5 equivalents) was gradually added at 25°C. The resulting mixture was stirred under a nitrogen atmosphere at 100°C for 16 hours. The mixture was cooled to 20°C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1), and the pure fraction was concentrated to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-(4-iodoimidazole-1-yl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (860.0 mg, yield 65%) as a brown solid. [ESI-MS m / z=641.1 M+H] + Calculated MW: 640.1

[0529] Step 2: Tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yl]imidazole-1-yl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolidine-7a-yl]methoxy}-6-(4-iodoimidazole-1-yl)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500.0 mg, 0.78 mmol, 1.0 equivalent) and {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in water (2 mL) and dioxane (10 mL). To a stirred mixture of (600.1 mg, 1.17 mmol, 1.5 equivalents) K2CO3 (323.6 mg, 2.34 mmol, 3.0 equivalents) and butyl[(3R,5S,7s)-adamantan-1-yl][(1s,3R,5S,7s)-adamantan-1-yl]phosphan{2'-amino-[1,1'-biphenyl]-2-yl}palladium illium methanesulfonate (113.7 mg, 0.16 mmol, 0.2 equivalents) were gradually added at 20°C. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to 20°C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with dimethyl phosphate (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / siRNA (1:1), and the pure fraction was concentrated to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yl]imidazole-1-yl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (285.0 mg, yield 41%) as a yellow solid. ESI-MS m / z = 899.4 [M + H] + Calculated MW: 898.4

[0530] Step 3: Tert-butyl(1R,5S)-3-(4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-1H-imidazole-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethinyl]naphthalene-1-yl]imidazole-1-yl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (285.0 mg, 0.32 mmol, 1.0 equivalent) in DMF (5 mL), CsF (481.4 mg, 3.17 mmol, 10 equivalents) was gradually added at 20°C. The resulting mixture was stirred at 20°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. ESI-MS m / z=743.3[M+H] + Calculated MW: 742.3

[0531] Step 4: 4-[1-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)imidazole-4-yl]-5-ethynyl-6-fluoronaphthalene-2-ol; formic acid To a mixture of tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{4-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl]imidazole-1-yl}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280.0 mg, 0.38 mmol, 1.0 equivalent) in MeCN (4 mL), HCl (gas) (4 mL, 4 M) in dioxane was added, and the resulting mixture was stirred at 20°C for 2 hours under a nitrogen atmosphere. The mixture was concentrated to obtain the product (280.0 mg, crude product), which was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 36%B to 56%B in 10 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 6.4). The pure fraction was freeze-dried to obtain 4-[1-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazine-2-yl)imidazole-4-yl]-5-ethinyl-6-fluoronaphthalene-2-ol (47.0 mg, yield 21%) as a yellow solid. ESI-MS m / z=599.2[M+H] + Calculated MW: 598.2. 1 H NMR(400MHz,DMSO-d6)δ 8.63(s,1H),8.24(s,1H),7.90(t,J=10.4,0.0Hz,2H),7.48-7.08(m,3H) ,5.28(d,J=54.1Hz,1H),4.56(d,J=13.0Hz,1H),4.38(d,J=12.3Hz,1H),4 .24(s,1H),4.10(dt,J=43.5,10.2Hz,2H),3.75(s,2H)3.05(d,J=30.1Hz, 3H),2.83(s,1H),2.20-1.83(m,3H),1.81(d,J=31.8Hz,5H),1.61(s,2H).

[0532] Example 17: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1,3,5-triazine-2-yl)oxy)methyl)-5,6-difluoronaphthalene-2-ol [ka] Step 1: Tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]methoxy}-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of [7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl]methanol (252.7 mg, 0.99 mmol, 1.2 equivalents) in THF (5 mL), LiHMDS (0.76 mL, 0.99 mmol, 1.2 equivalents, 1.3 M in THF) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. To the above mixture, tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-chloro-1,3,5-triazine-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.20 mmol, 1.0 equivalent) was added at 0°C. The resulting mixture was stirred for a further 2 hours at 20°C. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with siRNA (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (10:1), and the pure fraction was concentrated under reduced pressure to obtain tert-butyl(1R,5S)-3-(4-{[(2R,7aS)-2-fluorohexahydropyrrolidine-7a-yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl]methoxy}-1,3,5-triazine-2-yl)-3,8-diaza...

Claims

1. Compound of formula (0): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, R １ is a 6- to 10-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N, and R １ is =O, CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)OH, C(O)NH ２ , C(O)ONH ２ , C(O)R*, C(O)OR*, OC(O)R*, C(O)NHR*, CH ２ C(O)NHR*, C(O)NR* ２ , CH ２ C(O)NR* ２ , C(O)ONHR*, CH ２ C(O)ONHR*, C(O)ONR* ２ and CH ２ C(O)ONR* ２ which is optionally substituted with one or more groups independently selected from; or R １ is -L ３ -R １’ , and R １’ is a 5-membered monocyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N, and R １’ is =O, CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)OH, C(O)NH ２ , C(O)ONH ２ , C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR* ２ , C(O)ONHR*, and C(O)ONR* ２ which is optionally substituted with one or more groups independently selected from; R ２ This includes a 5- to 9-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6-membered monocyclic heteroaryl group containing at least one ring atom that is N; a condensed 8- to 10-membered bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; or a condensed 11- to 14-membered tricyclic group in which at least one ring is aromatic and at least one ring contains at least one ring atom that is N; Here, R ２ are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , = O, ( C ２ ~C ３ ) alkenyl, and (C ２ ~C ３ ) may be substituted with one or more groups independently selected from the alkynyl group; R ３ OH, and optionally CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ ) A phenyl or naphthalenyl group substituted with one or more additional groups independently selected from the alkynyl group; or R ３ This is a condensed 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, the heterocycle, or both are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , NHC(O)R*, (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ ) may be optionally substituted with one or more groups independently selected from the alkynyl group; or R ３ This is a condensed 8-10 membered bicyclic group containing a saturated carbon ring condensed to an aryl ring, where the carbon ring, the aryl ring, or both are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , NHC(O)R*, (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ ) may be optionally substituted with one or more groups independently selected from the alkynyl group; or R ３ This is a fused 8-10 membered bicyclic group comprising a saturated heterocycle fused to an aryl or heteroaryl ring, where the carbon ring, aryl or heteroaryl ring, or both are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , NHC(O)R*, (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ ) may be optionally substituted with one or more groups independently selected from the alkynyl group; L １ is a bond, or -O-, -(C １ ~C ３ )alkyl-, *-O-(C １ ~C ３ )alkyl-**, *-(C １ ~C ３ )alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, R' is H, OH, CN, Cl, F, or (C １ ~C ３ )alkyl, * represents the point of attachment to the triazole moiety of the compound of formula (0), ** represents the point of attachment to R ２ ; L ２ is -(C １ ~C ３ )alkyl-, C ５ -heteroaryl optionally substituted with one or more R'', *-O-(C １ ~C ３ )alkyl-**, *-(C １ ~C ３ )alkyl-O-**, -(C ２ ~C ３ )alkenyl-, -(C ２ ~C ３ )alkynyl-, *-(C １ ~C ３ )alkyl-NR''-**, *-NR''(C １ ~C ３ )alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C １ ~C ３ )alkyl-**, or *-(C １ ~C ３ )alkyl-NR''-**, wherein R'' is H, OH, CN, Cl, F, or (C １ ~C ３ )alkyl, * indicates the point of attachment to R ３ and ** indicates the point of attachment to the triazole moiety of the compound of formula (0); L ３ is a combination, or -(C １ ~C ３ ) alkyl-, -O-, -NH- or -N(C １ ~C ３ ) is alkyl; and R １ , R ２ , and R ３ In the middle, each R* is independent, (C １ ~C ４ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ３ ~C ６ ) Cycloalkyl, (C ３ ~C ６ ) Selected from cycloalkenyls and 5 or 6-membered monocyclic heteroaryls, where the (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ３ ~C ６ ) Cycloalkyl, (C ３ ~C ６ ) Cycloalkenyls or 5- or 6-membered monocyclic heteroaryls themselves are F, Cl, CN, OH, NH ２ NH((C １ ~C ３ )alkyl), (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ２ ~C ３ ) Alkinyl, or O(C １ ~C ３ (It may be substituted with one or more groups independently selected from alkyl groups.)

2. The aforementioned compound is a compound of formula (I): 【Chemistry 2】 (In formula (I): R １ is a 6-10 membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom which is N, and R １ =O, CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)OH, C(O)NH ２ , C(O)ONH ２ , C(O)R*, C(O)OR*, C(O)NHR*, C(O)NR* ２ , C(O)ONHR*, and C(O)ONR* ２ It is optionally replaced by one or more elements independently selected from; R ２ This includes a 5- to 8-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6-membered monocyclic heteroaryl group containing at least one ring atom that is N; or a condensed 8- to 10-membered bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; Here, R ２ are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ , C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , = O, ( C ２ ~C ３ ) Alkenyl, and (C ２ ~C ３ ) may be substituted with one or more groups independently selected from the alkynyl group; R ３ OH, and optionally CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ , C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ ) A phenyl or naphthalenyl group substituted with one or more additional groups independently selected from the alkynyl group; or R ３ This is a condensed 8-10 membered bicyclic group containing a saturated carbon ring fused to a heterocycle, where the carbon ring, the heterocycle, or both are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ , C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ ) may be optionally substituted with one or more groups independently selected from the alkynyl group; L １ is -O-, -(C １ ~C ３ ) alkyl-, *-O-(C １ ~C ３ ) Alkyl-**, *-(C １ ~C ３ ) alkyl-O-**, *-C(O)NR'-**, or *-NR'C(O)-**, where R' is H, OH, CN, Cl, F, or (C １ ~C ３ ) is alkyl, * indicates the bond site to the triazole moiety of the compound of formula (I), and ** indicates R ２ It shows the connection point to; L ２ is, -(C １ ~C ３ ) C optionally substituted with alkyl- or one or more R'' ５ -heteroaryl, *-O-(C １ ~C ３ ) Alkyl-**, *-(C １ ~C ３ ) Alkyl-O-**,-(C ２ ~C ３ ) Alkenil-,-(C ２ ~C ３ ) Alkinyl-, *-(C １ ~C ３ ) alkyl-NR''-**, *-NR''(C １ ~C ３ )alkyl-**, *-C(O)NR''-**, *-NR''C(O)-**, *-NR''-(C １ ~C ３ ) Alkyl-**, or *-(C １ ~C ３ ) alkyl-NR''-**, where R'' is H, OH, CN, Cl, F, or (C １ ~C ３ ) is alkyl, and * is R ３ The binding site is shown, and ** indicates the binding site to the triazole moiety of the compound of formula (I); and R １ , R ２ , and R ３ In the middle, each R* is independent, (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ３ ~C ６ ) cycloalkyl and (C ３ ~C ６ ) Selected from cycloalkenyl, where (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ３ ~C ６ ) Cycloalkyl, or (C ３ ~C ６ ) Cycloalkenyl itself is F, Cl, CN, OH, NH ２ NH((C １ ~C ３ )alkyl), (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ２ ~C ３ ) Alkinyl, or O(C １ ~C ３ (It may be substituted with one or more groups independently selected from alkyl.) The compound or pharmaceutically acceptable salt described in claim 1.

3. R １ but, 【Transformation 3】 The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

4. R １ but, 【Chemistry 4】 The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

5. R ３ but, 【Transformation 5】 (wherein m is 1 or 2, and n is 0, 1, or 2; each R ｃ and R ｄ These are independently F, Cl, CN, OH, (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenyl, and (C ２ ~C ３ ) Selected from alkinyl, but with at least one R ｃ (is OH); 【Transformation 6】 (In the formula, s is 1, 2, or 3, and when s is 1, R ｇ If is OH and s is 2 or 3, then at least one R ｇ OH is OH, and each of the remaining R ｇ These are independently F, Cl, CN, OH, (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ２ ~C ３ ) Alkinyl, or (C ３ ~C ６ ) is a cycloalkyl, where the above (C ３ ~C ６ ) The cycloalkyl itself is F, Cl, CN, OH, (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, or (C ２ ~C ３ (which may be substituted with one or more groups independently selected from the alkynyl group); and 【Transformation 7】 (In the formula, Y １０ is S, O, or NR''', where R''' is H, OH, CN, Cl, F, or (C １ ~C ３ ) is alkyl; t is 0, 1, 2, or 3, and u is 0, 1, or 2, provided that if t is zero, u is not zero, and if u is zero, t is not zero; each R ｈ and R ｉ These are independently CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ , C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , (C ２ ~C ３ ) Alkenyl, and (C ２ ~C ３ ) Selected from alkynyl, where R* is as defined in claim 1 or claim 2. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from among.

6. R ３ but, 【Transformation 8】 (In the formula, R ｃ , R ｄ , R ｇ , R ｈ , R ｉ (where n and u are as defined in claim 5) A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from among.

7. R ３ but, 【Chemistry 9】 (In the formula, R ｄ , R ｇ and R ｉ (This is as defined in claim 5.) A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from among.

8. L ２ but, -CH ２ CH ２ -, -C≡C-, *-CH ２ O-**, *-OCH ２ -**, *-C(O)-NH-**, *-CH ２ NH-**, *-N(CH ３ )C(O)-**, *-NHC(O)-**, and 【Chemistry 10】 Selected from, * and ** are as defined in claim 1 or claim 2, the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

9. R ２ but, 【Chemistry 11】 (In the formula, q and r are independently 0, 1, or 2, and R ａ and R ｂ Each example independently includes CN, Cl, F, R*, OH, OR*, and NH. ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ , C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , = O, ( C ２ ~C ３ ) alkenyl, and (C ２ ~C ３ ) selected from alkynyl, where R* is as defined in claim 1 or claim 2); 【Chemistry 12】 (In the formula, X ８ , X ９ , X １０ , and X １１ Each of them is independent of C(R) ｋ ) ２ , C=O, N(R ｋ ), selected from O, or S, however X ８ , X ９ , X １０ , and X １１ At least one of them is N(R) ｋ ) is ); 【Chemistry 13】 (In the formula, X １２ , X １３ , and X １４ Each of them is independent of C(R) ｋ ) ２ , C=O, N(R ｋ ), selected from O or S, X １５ and X １６ Each is independently selected from C and N, except X １２ , X １３ , and X １４ At least one of them is N(R) ｋ ) and / or X １５ and X １６ (At least one of them is N); 【Chemistry 14】 (In the formula, X １７ , X １８ , X １９ , X ２０ , and X ２１ Each of them is independent of C(R) ｋ ) ２ , C=O, N(R ｋ ), selected from O, or S, however X １７ , X １８ , X １９ , X ２０ , and X ２１ At least one of them is N(R) ｋ ), O, or S); 【Chemistry 15】 (In the formula, Y １ , Y ２ , Y ３ , and Y ４ These are N, O, S, and NR, respectively, independently. ｋ , or CR ｋ And, however, Y １ , Y ２ , Y ３ , and Y ４ At least one of them is N or NR ｋ (is); 【Chemistry 16】 (In the formula, Y ５ , Y ６ , and Y ７ These are N, O, S, and NR, respectively, independently. ｋ , or CR ｋ Y ８ and Y ９ Each is independently N or C, except Y ５ , Y ６ , and Y ７ At least one of them is N or NR ｋ and / or Y ８ and Y ９ (At least one of them is N); and 【Chemistry 17】 (In the formula, Z １ Z ２ Z ３ Z ４ , and Z ５ Each is independently N, O, S, or CR ｋ And, however, Z １ Z ２ Z ３ Z ４ , and Z ５ (At least one of them is N) Selected from; Each R ｋ These are independently H, CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ , C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , (C ２ ~C ３ ) alkenyl, and (C ２ ~C ３ A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, selected from alkynyl, where R* is as defined in claim 1 or claim 2.

10. R ２ but, [Chemistry 18] (In the formula, R ｂ (and r are as defined in claim 9), 【Chemistry 19】 (In the formula, R ｋ (As defined in claim 9) (For example, 【Chemistry 20】 teeth, 【Chemistry 21】 (It is) 【Chemistry 22】 A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from among.

11. R ２ but, 【Chemistry 23】 The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. R ２ but, 【Chemistry 24】 And R ｋ However, the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, as defined in claim 9.

13. R ２ but, 【Chemistry 25】 The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

14. L １ is -O-, *-OCH(CH ３ )-**, or *-O-CH ２ - A compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, which is -**.

15. The compound is a compound of formula (III), formula (IV), formula (XXII), or formula (XXII.I): 【Chemistry 26】 【Chemistry 27】 (In the formula, In each of equations (III), (IV), and (XXII), L １ L is as defined in claim 1, claim 2, or claim 14. ２ is as defined in claim 1, claim 2, or claim 8, where R*' is H, CN, Cl, F, R*, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ Selected from, where R* is as defined in claim 1 or claim 2; R ２ This is as defined in any one of claims 9 to 13; In equation (III), R ｃ , R ｄ n and m are as defined in claim 5; In equation (IV), R ｇ and s are as defined in claim 5; In equation (XXII), R ｈ , R ｉ , t, u and Y １０ This is as defined in claim 5; In equation (XXII.I), L １ L is as defined in claim 1, claim 2, or claim 14; ２ This is as defined in claim 1, claim 2, or claim 8; R ２ R is defined as any one of claims 9 to 13; ｈ , R ｉ , t, u and Y １０ X is as defined in claim 5; X is NH, N(C １～３ ) Alkyl, O, or CH ２ Selected from; v is an integer from 0 to 4; each R*'' is independently H, CN, Cl, F, R*, OH, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ , selected from, where R* is as defined in claim 1 or claim 2. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

16. The compound is a compound of formula (VI) or formula (VI.I): 【Chemistry 28】 (In the formula, in formula (VI), L １ L is as defined in claim 1, claim 2, or claim 14; ２ is as defined in claim 1, claim 2, or claim 8; R*' is H, CN, Cl, F, R*, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ Selected from, where R* is as defined in claim 1 or claim 2; R ３ L is defined in any one of claims 5 to 7; in formula (VI.I), L １ L is as defined in claim 1, claim 2, or claim 10; ２ is as defined in claim 1, claim 2, or claim 8; X is NH, N(C １～３ ) Alkyl, O, or CH ２ Selected from; v is an integer between 0 and 4; each R*'' is independently H, CN, Cl, F, R*, OH, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ Selected from, where R* is as defined in claim 1 or claim 2; R ３ (This is as defined in any one of claims 5 to 7.) The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

17. The compound is a compound of formula (XXIII.I) or formula (XXIV.I). 【Chemistry 29】 (In the formulas, in each of formulas (XXIII.I) and (XXIV.I), L １ L is as defined in claim 1, claim 2, or claim 14; ２ This is as defined in claim 1, claim 2, or claim 8; R ｈ , R ｉ ,t and u are as defined in claim 5; X is NH, N(C １～３ ) Alkyl, O, or CH ２ Selected from; v is an integer from 0 to 4; each R*'' is independently H, CN, Cl, F, R*, OH, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ Selected from, where R* is as defined in claim 1 or claim 2; R ２ (This is as defined in any one of claims 9 to 13.) The compound or pharmaceutically acceptable salt according to claim 1 or claim 2.

18. R ２ is a 5- to 9-membered monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group containing at least one ring atom that is N or O; a 5 or 6-membered monocyclic heteroaryl group containing at least one ring atom that is N; a condensed 8- to 10-membered bicyclic group in which one or both rings are aromatic and at least one ring contains at least one ring atom that is N; R ２ are CN, Cl, F, R*, OH, OR*, NH ２ , NHR*, NR* ２ , CHO, C(O)R*, C(O)OH, C(O)OR*, C(O)NH ２ , C(O)NHR*, C(O)NR* ２ C(O)ONH ２ , C(O)ONHR*, C(O)ONR* ２ , = O, ( C ２ ~C ３ ) alkenyl, and (C ２ ~C ３ ) may be substituted with one or more groups independently selected from the alkynyl group; each R* may independently be (C １ ~C ４ ) Alkyl (e.g., C １ ~C ３ )alkyl), (C ２ ~C ３ ) Alkenil, (C ３ ~C ６ ) Cycloalkyl, (C ３ ~C ６ ) Selected from cycloalkenyls and 5 or 6-membered monocyclic heteroaryls, where (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ３ ~C ６ ) Cycloalkyl, (C ３ ~C ６ ) Cycloalkenyls or 5- or 6-membered monocyclic heteroaryls themselves are F, Cl, CN, OH, NH ２ NH((C １ ~C ３ )alkyl), (C １ ~C ３ ) alkyl, (C ２ ~C ３ ) Alkenil, (C ２ ~C ３ ) Alkinyl, or O(C １ ~C ３ A compound of formula (XXII) or formula (XXII.I) according to claim 15, or a compound of formula (XXIII.I) or formula (XXIV.I) according to claim 17, or a pharmaceutically acceptable salt thereof, which may be substituted with one or more groups independently selected from alkyl groups.

19. R ２ but, 【Transformation 30】 And in the formula, X ８ , X ９ , X １０ and X １１ However, the compound according to claim 18 or a pharmaceutically acceptable salt thereof, as defined in claim 9.

20. R ２ However, the compound according to claim 18 or 19 or a pharmaceutically acceptable salt thereof, as defined in claim 12 or claim 13.

21. The compound is a compound of formula (VII), formula (X), or formula (XXV): 【Chemistry 31】 (In the formula, In each of equations (VIII), (X), and (XXV), L １ L is as defined in claim 1, claim 2, or claim 14. ２ This is as defined in claim 1, claim 2, or claim 8, and R １ This is as defined in claim 1, claim 2, or claim 3, and R ａ , R ｂ q and r are as defined in claim 9; In equation (VIII), R ｃ , R ｄ n and m are as defined in claim 5; In equation (X), R ｇ and s are as defined in claim 5; In equation (XXV), R ｈ , R ｉ , t, u and Y １０ (This is as defined in claim 5.) The compound or pharmaceutically acceptable salt according to claim 1 or claim 2.

22. The compound is a compound of formula (XXVII) or formula (XXVIII): 【Chemistry 32】 (In the formula, In equation (XXVII), L １ L is as defined in claim 1, claim 2, or claim 14; ２ This is as defined in claim 1, claim 2, or claim 8; R ｋ X is as defined in claim 9; X is NH, N(C １～３ ) Alkyl, O, or CH ２ Selected from; v is an integer between 0 and 4; each R*'' is independently H, CN, Cl, F, R*, OH, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ Selected from, where R* is as defined in claim 1 or claim 2; R ３ This is as defined in any one of claims 5 to 7; In equation (XXVIII), L １ L is as defined in claim 1, claim 2, or claim 14; ２ This is as defined in claim 1, claim 2, or claim 8; R ｋ X is as defined in claim 9; X is NH, N(C １～３ ) Alkyl, O, or CH ２ Selected from; v is an integer from 0 to 4; each R*'' is independently H, CN, Cl, F, R*, OH, OR*, NR* ２ , CHO, C(O)R*, C(O)OR*, C(O)NR* ２ , and C(O)ONR* ２ Selected from, where R* is as defined in claim 1 or claim 2; where R ｈ , R ｉ (t and u are as defined in claim 5) The compound or pharmaceutically acceptable salt according to claim 1 or claim 2.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

24. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23, for use in treatment.

25. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23, for use in the treatment or prevention of cancer.

26. The compound for use according to claim 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is a KRAS G12D-related cancer.

27. The compound for use according to claim 25 or 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the cancer is selected from colorectal cancer, lung cancer, and pancreatic cancer.

28. A therapeutic method comprising administering to a target subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described in any one of claims 1 to 22, or a pharmaceutical composition described in claim 23.

29. A method for treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is involved, in a subject requiring treatment, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

30. A method for treating or preventing a disease or disorder related to KRAS G12D in a subject requiring treatment, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

31. A method for treating or preventing the disease or disorder according to claim 30, wherein the disease or disorder is cancer.

32. A method for treating or preventing cancer in a subject requiring treatment, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 22, or a pharmaceutical composition according to claim 23.

33. A method for inhibiting KRAS G12D activity, comprising contacting KRAS G12D with a compound or pharmaceutically acceptable salt described in any one of claims 1 to 22, or with the pharmaceutical composition described in claim 23.

34. The method according to claim 31 or 32, wherein the cancer is a KRAS G12D-related cancer.

35. The method according to any one of claims 31, 32, or 34, wherein the cancer is selected from colorectal cancer, lung cancer, and pancreatic cancer.

Images