2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,3,5-triazine derivatives as kras g12d inhibitors for the treatment of cancer

Abstract

Compounds are provided which can inhibit KRAS G12D. Also provided are pharmaceutical compositions and medical uses of the same, including the use in treating or preventing conditions such as cancers.

Description

[0001] 2-(3,8-DIAZABICYCLO[3.2.1]OCTAN-3-YL)-1 ,3,5-TRIAZINE DERIVATIVES AS KRAS G12D INHIBITORS FOR THE TREATMENT OF CANCER

[0002] Compounds are provided which can inhibit KRAS G12D. Also provided are pharmaceutical compositions and medical uses of the same, including the use in treating or preventing conditions such as cancers.

[0003] SUMMARY

[0004] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas” or “KRAS”) is a small GTPase and a member of the Ras family of oncogenes. KRAS serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation.

[0005] Aberrant expression of KRAS accounts for up to 20% of all cancers and oncogenic KRAS mutations that stabilize GTP binding and lead to constitutive activation of KRAS and downstream signaling have been reported in 25 -30% of lung adenocarcinomas. KRAS G12D mutation is present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non-small cell lung carcinoma patients, and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8): 818-831. Dataset Version 4).

[0006] The well-known role of KRAS in malignancy and the discovery of these frequent mutations in KRAS in various tumor types made KRAS a highly attractive target of the pharmaceutical industry for cancer therapy. WO 2021 / 041671, WO 2023 / 098425, and WO 2023 / 274324 disclose KRAS G12D inhibitors which are based on a bicyclic (pyrido[4,3-d]pyrimidine) core.

[0007] Clearly there remains a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of activating KRAS mutants, especially KRAS G12D, e.g., for treating KRAS G12D- mediated cancer.

[0008] Accordingly, in a first aspect the present disclosure provides a compound of Formula (0):

[0009] (Formula (0)) or a pharmaceutically acceptable salt thereof, wherein:

[0010] R1is a 6- to 10-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by one or more groups independently selected from =0, 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*2and CH2C(O)ONR*2; or wherein R1is -L3-R1’, wherein R1’ is a 5-membered, monocyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by one or more groups independently selected from =0, CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)OH, C(0)NH2, C(0)0NH2, C(O)R*, C(O)OR*, C(0)NHR*, C(O)NR*2, C(0)0NHR*, and C(O)ONR*2;

[0011] R2is a 5- to 9-membered (e.g. 5- to 8-membered), monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; or a fused, 11- to 14-membered tricyclic group wherein at least one ring is aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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(0)NH2, C(0)NHR*, C(O)NR*2, C(0)0NH2, C(0)0NHR*, C(O)ONR*2, =0, (C2-C3)alkenyl, and (C2-C3)alkynyl;

[0012] R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by one or more additional groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(0)0H, C(O)OR*, C(0)NH2, C(0)NHR*, C(0)NR*2, C(0)0NH2, C(0)0NHR*, C(0)0NR*2, (C2-C3)alkenyl, or (C2-C3)alkynyl; or R3is 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 optionally be substituted by one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(0)0H, C(O)OR*, C(0)NH2, C(0)NHR*, C(0)NR*2, C(0)0NH2, C(0)0NHR*, C(0)0NR*2, NHC(0)R*, (C2-C3)alkenyl, or (C2- C3)alkynyl; or R3is a fused, 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused to an aryl ring, wherein the carbocyclic ring, the aryl ring, or both, may be optionally substituted by one or more groups independently selected from CN, Cl, F, R*, OH, OR*, NH2, NHR*, NR*2, CHO, C(O)R*, C(0)0H, C(O)OR*, C(0)NH2, C(0)NHR*, C(0)NR*2, C(0)0NH2, C(0)0NHR*, C(0)0NR*2, NHC(0)R*, (C2-C3)alkenyl, or (C2-C3)alkynyl; or R3is a fused, 8- to 10-membered bicyclic group comprising a saturated heterocyclic ring fused to an aryl or heteroaryl ring, wherein the carbocyclic ring, the aryl or heteroaryl ring, or both, may be optionally substituted by 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; L1is a bond or is -O-, -(C1-C3)alkyl-, *-O-(C1-C3)alkyl-**, *-(C1-C3)alkyl-O-**, *-C(O)NR’-**, or *- NR’C(O)-**, wherein R’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (0) and ** denotes a point of attachment to R2; L2is -(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’’-**, wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (0); L3is a bond or is -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3) alkyl; and wherein in R1, R2, and R3, 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 may itself be substituted by 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 embodiments, the present disclosure provides a compound of Formula (0) which is a compound of Formula (I): (Formula (I)) or a pharmaceutically acceptable salt thereof, wherein in Formula (I): R1is a 6- to 10-membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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; R2is a 5- to 8-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; or a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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; R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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; or R3is 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 optionally be substituted by 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; L1is -O-, -(C1-C3)alkyl-, *-O-(C1-C3)alkyl-**, *-(C1-C3)alkyl-O-**, *-C(O)NR’-**, or *-NR’C(O)- **, wherein R’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (I) and ** denotes a point of attachment to R2; L2is -(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’’-**, wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (I); and wherein in R1, R2, and R3, 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 by 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. A further aspect provides 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. A further aspect provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a 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 medicament. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy. A further aspect provides a method of treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a 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 medicament for the treatment or prevention of a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated. In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a 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 medicament for the treatment or prevention of a disease or disorder associated with KRAS G12D (e.g., cancer). In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a disease or disorder associated with KRAS G12D (e.g., cancer). In another aspect, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, the disclosure provides the use of a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of cancer. In a further related aspect, the disclosure provides a compound of the disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of cancer. In another aspect, the disclosure provides a method of inhibiting KRAS G12D activity, the method comprising contacting KRAS G12D (e.g., a cell comprising KRAS G12D) with a compound of the present disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is an in vitro or ex vivo method. In other embodiments the method is an in vivo method. In a related aspect, the disclosure provides an in vitro method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell with a compound of the present disclosure (e.g., a compound of Formula (0) or Formula (I) or a pharmaceutically acceptable salt thereof). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 (Fig.1) shows a synthesis of compound (1) as described in further detail herein in Example 20. Figure 2 (Fig.2) shows a synthesis of compound (55) as described in further detail herein in Example 21. Figure 3 (Fig.3) shows a synthesis of compound (56) as described in further detail herein in Example 22. DETAILED DESCRIPTION Although specific embodiments of the present disclosure will now be described with reference to the description and examples, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, recombinant DNA, etc., which are within the skill of the art. See, e.g., Michael R. Green and Joseph Sambrook, Molecular Cloning (4thed., 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, 5thedition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent 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, 3rdedition (Cold Spring Harbor Laboratory Press (2002)); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press). All numerical designations, e.g., pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations which are varied ( + ) or ( - ) by increments of, e.g., 0.1 or 1.0, where appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”, which is used to denote a conventional level of variability. For example, a numerical designation which is “about” a given value may vary by ± 10% of said value; alternatively, the variation may be ± 5%, ± 2%, or ± 1% of the value. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art. As used herein, the term “room temperature” means an ambient temperature in the range of about 20 to about 25 °C, e.g., about 20, about 21, about 22, about 23, about 24 or about 25 °C. As used in the specification and claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”. As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, without excluding other elements. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass, and to disclose, the corresponding statements in which the term “comprising” is replaced by “consisting essentially of” or “consisting of”. A “subject,” “individual”, or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, sport animals, pets, and primates; for example, murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans. In a particular embodiment, the mammal is a human. “Administering” is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being contacted with (e.g., being inside) the subject’s body. Such an administration can be by any route including, without limitation, oral, transdermal, transmucosal, (e.g., by the vagina, rectum, or oral mucosa), by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g., oral or nasal). Administration may also involve providing a substance or composition to a part of the surface of the subject’s body, for example by topical administration to the skin. Pharmaceutical preparations are, of course, given by forms suitable for each administration route. “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; and / or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. The term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with or is predisposed to the disease. A patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease. An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, the severity of the particular disorder being treated, and the form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and / or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with the condition. The total daily dose may be administered in single or divided doses and may, at the physician’s discretion, fall outside of the typical range given herein. As used herein, the terms “increased” and “elevated” are used interchangeably and encompass any measurable increase in a biological function, and / or a biological activity, and / or a concentration. For example, an increase can be by at least about 10%, e.g., at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, an increase can be by at least about 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as at least about 20-fold, 25-fold, 50-fold, 100-fold, or higher, relative to a control or baseline amount or function, or activity, or concentration. 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 refers to an increase in the amount of the substance (e.g., of the KRAS G12D mutant protein), although it may also denote an increase in the biological activity of the substance. For example, an increase can be by an amount of about 5%, e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as about 96%, 97%, 98%, 99%, or 100%. Thus, the increase can be about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, such as about 20-fold, 25-fold, 50-fold, 100-fold, or higher, relative to the amount (or activity) of the substance, such as KRAS G12D, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an "increased expression” or "increased activity" of KRAS G12D if the expression and / or activity of KRAS G12D is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of KRAS G12D in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples. As used herein, the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, for example as described in Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000). Such excipients include carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil / water or water / oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like. As used herein, the term “alkyl” means a saturated linear or branched functional group consisting essentially of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The terms “(C1-C3)alkyl”, “(C1-C6)alkyl”, etc., have equivalent meanings, i.e., a saturated linear or branched functional group consisting essentially of 1 to 3 (or 1 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkyl” also applies in the context of other functional groups which comprise alkyl groups, such as “-O(C1-C3)alkyl-”. The term “haloalkyl” means an alkyl group which is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, etc. One or more carbon atoms in the backbone of the alkyl group may be substituted by (or bonded to) a heteroatom by a multiple bond (e.g., a double bond); for example, a carbon atom of the alkyl group may be bonded to oxygen via a double bond (i.e., substituted by oxo to provide a carbonyl function). The presence of such a substituent does not prevent the carbon backbone of the group being considered as an alkyl group. 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 comprising 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 of skill in the art given the benefit of the present disclosure. The terms “(C2-C3)alkenyl”, “(C2-C6)alkenyl”, etc., have equivalent meanings, i.e., an unsaturated linear or branched functional group consisting essentially of 2 to 3 (or 2 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkenyl” also applies in the context of other functional groups which comprise alkenyl groups, such as “-O(C2- C3)alkenyl-”. The term “haloalkenyl” means an alkenyl group which is substituted by one or more halogens. Where valency permits, one or more carbon atoms in the backbone of the alkenyl group may be substituted by (or bonded to) a heteroatom by a multiple bond (e.g., a double bond); for example, a carbon atom of the alkenyl group may be bonded to oxygen via a double bond (i.e., substituted by oxo to provide a carbonyl function), provided that such carbon atom is not participating in a carbon-carbon double bond. The presence of such a substituent does not prevent the carbon backbone of the group being considered as an alkenyl group. 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 comprising 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 of skill in the art given the benefit of the present disclosure. The terms “(C2-C3)alkynyl”, “(C2-C6)alkynyl”, etc., have equivalent meanings, i.e., an unsaturated linear or branched functional group consisting essentially of 2 to 3 (or 2 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkynyl” also applies in the context of other functional groups which comprise alkynyl groups, such as “-O(C2-C3)alkynyl-”. The term “haloalkynyl” means an alkynyl group which is substituted by one or more halogens. Where valency permits, one or more carbon atoms in the backbone of the alkynyl group may be substituted by (or bonded to) a heteroatom by a multiple bond (e.g., a double bond); for example, a carbon atom of the alkynyl group may be bonded to oxygen via a double bond (i.e., substituted by oxo to provide a carbonyl function), provided that such carbon atom is not participating in a carbon-carbon double or triple bond. The presence of such a substituent does not prevent the carbon backbone of the group being considered as an alkynyl group. 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, the term “members”, “membered” and the like is used to denote the number of ring atoms in said cyclic group. For example, a 5-membered cyclic group (e.g., a 5-membered heterocyclic group) contains 5 ring atoms. It will be appreciated that a cyclic group may be part of a larger cyclic system; for example, bicyclo[4.3.0]nonane comprises two carbocyclic groups, namely a cyclohexane group and a cyclopentane group, which are fused to form the carbocyclic system which makes up the molecule. The term “cyclic group” is intended to encompass both carbocyclic groups as well as heterocyclic groups. The term “carbocyclic” 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 that form a ring, wherein at least 1 to 9 of said ring atoms are carbon and the remaining at least 1 to 9 ring atom(s) (i.e., hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulfur, and oxygen. The term “heterocyclic group” thus encompasses saturated, unsaturated and aromatic (i.e. heteroaryl) groups unless context clearly dictates otherwise (e.g. by specifically requiring a “saturated heterocyclic” group, an “unsaturated heterocyclic” group, or an “aromatic heterocyclic” group), whereas e.g. a “heterocycloalkyl” group must be saturated, a “heterocycloalkenyl” group must be unsaturated, and a “heteroaryl” group must be aromatic. The term “spiro” or “spirocyclic” as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have only one atom in common, i.e., said first and second cyclic groups share only one common ring atom. For example, the spiro[5.5]undecanyl group comprises two cyclohexane rings which have a single carbon ring atom in common. The term “fused” as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have two adjacent atoms in common, i.e., said first and second cyclic groups share two common ring atoms. For example, the bicyclo[4.4.0]decanyl group comprises two cyclohexane rings which have two adjacent carbon ring atoms in common. The term “bridged” as used herein in relation to cyclic groups denotes that a first cyclic group within a multicyclic system is attached to a second cyclic group within said multicyclic system, wherein the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have more than two adjacent atoms in common, i.e., said first and second cyclic groups share three or more common ring atoms. For example, the bicyclo[3.3.1]nonanyl group comprises two cyclohexane rings which have three adjacent carbon ring atoms in common. Within the structural formulae described herein, any ring system (including any spiro, fused, or bridged ring system) may be connected to other parts of a molecule through any atom having suitable valency. For example, a bicyclic ring may be connected to another part of the molecule through a ring atom (e.g., a secondary carbon atom or heteroatom such as N), or a bridgehead (e.g., a tertiary carbon atom). Spiro, fused, and bridged rings may be fully unsaturated, partially unsaturated, or fully saturated, and may have aromatic character in one or more of their constituent rings. As used herein, the term “cycloalkyl” means a saturated group having at least 3 to 10 carbon atoms (i.e., ring atoms) that form a ring. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It will be appreciated that the cycloalkyl group may be monocyclic or multicyclic (e.g., fused, bridged, or spirocyclic). In the case of multicyclic cycloalkyl groups, there are further rings, e.g., 1 or more further rings, all of which contain from 3 to 7 carbon atoms (i.e., ring atoms). Exemplary cycloalkyl groups having such further rings include bicyclo[1.1.1]pentanyl. The term “(C3-C7)cycloalkyl” denotes that the cycloalkyl group contains from 3 to 7 carbon atoms in the ring portion of the group, which may be monocyclic or multicyclic (e.g., fused, bridged, or spirocyclic), for example cyclopropanyl (having 3 ring carbon atoms) or bicyclo[1.1.1]pentanyl (having 5 ring carbon atoms). One or more ring atoms of the cycloalkyl group may be substituted by (i.e., bonded to) a heteroatom by a double bond (e.g., cycloalkyl substituted by oxo). The presence of such a substituent does not prevent the carbon backbone of the group being considered as a cycloalkyl group. As used herein, the term “cycloalkenyl” means an unsaturated (i.e., partially or fully unsaturated) group having at least 3 to 10 carbon atoms (i.e., ring atoms) that form a ring. The term “cycloalkenyl” is not intended to encompass cyclic groups having aromatic character (those being considered as aryl groups as defined herein). Exemplary cycloalkenyl groups include cyclohexenyl. It will be appreciated that the cycloalkenyl group may be monocyclic or multicyclic (e.g., bridged). In the case of multicyclic cycloalkenyl groups, there are further rings, e.g., 1 or more further rings, all of which contain from 3 to 10 carbon atoms (i.e., ring atoms). Those further rings may be saturated or unsaturated. Exemplary cycloalkenyl groups having such further rings include bicyclo[2.2.1]hept-5-enyl. The term “(C4- C8)cycloalkenyl” denotes that the cycloalkenyl group contains from 4 to 8 carbon atoms in the ring portion of the group, for example cyclohexenyl (having 6 ring carbon atoms) or bicyclo[2.2.1]hept-5- enyl (having 7 ring carbon atoms). The double bond (or bonds) within the cycloalkenyl group is / are typically between ring carbon atoms (i.e., endocyclic), although may also be between one ring carbon atom and an adjacent non-ring carbon atom (i.e., exocyclic). As used herein, the term “aryl” means an aromatic group having at least 6 carbon atoms (i.e., ring atoms) that form a ring. It will be appreciated that the aryl group may be monocyclic or multicyclic (e.g., fused). In the case of multicyclic aryl groups, there are further rings, e.g.1 or more further rings, all of which contain at least 3 carbon atoms (i.e., ring atoms). The further rings may also contain one or more heteroatoms and they may be saturated, unsaturated, or aromatic. A multicyclic aryl group is typically attached to the rest of the molecule via an aromatic ring, and typically not via a ring containing a heteroatom. In embodiments, the multicyclic aryl group does not contain any ring heteroatoms. Examples of aryl groups include phenyl and naphthalenyl, as well as indenyl and indanyl groups. Other aryl groups include, for example, tetrahydroisoquinolinyl bonded to the rest of the molecule via its phenyl ring. The term “(C6-C10)aryl” denotes that the aryl group contains from 6 to 10 carbon atoms in the ring portion of the group, which may be monocyclic or multicyclic (e.g., fused), for example phenyl (having 6 ring carbon atoms) or indanyl (having 9 ring carbon atoms). As used herein, the term “heterocycloalkyl” means a saturated group having at least 3 to 10 atoms (i.e., ring atoms) that form a ring, wherein at least 1 to 9 of said ring atoms are carbon and the remaining at least 1 to 9 ring atom(s) (i.e., hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulfur, and oxygen. For example, the term “4- to 10-membered heterocycloalkyl” means a saturated group containing from 4 to 10 ring atoms, of which one or more is a hetero ring atom. Heterocycloalkyl rings may have oxo substituents, typically adjacent to a heteroatom (e.g., 2- oxopyrrolidinyl), but the oxygen atom does not form part of the ring and is excluded from the number of ring atoms. The presence of such a substituent does not prevent the ring (or rings) of the group being considered as a heterocycloalkyl group. Exemplary heterocycloalkyl groups include tetrahydrofuranyl, piperidinyl, morpholinyl and piperazinyl. Any ring sulfur atom may optionally carry one or more pendant (i.e., non-ring) oxygen atoms, as found in, e.g., a sulfolanyl group. In the case of multicyclic heterocyclic groups, there are further rings, e.g., 1 or more further rings, all of which contain from 3 to 7 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. The further rings may be saturated, or partially or fully unsaturated (e.g., having aromatic character). Multicyclic heterocyclic groups include fused, bridged, and spirocyclic ring systems. Where a multicyclic heterocycloalkyl group contains an unsaturated fused ring, the group is typically not bonded to the rest of the molecule via that fused ring. Exemplary heterocyclic groups having such further rings include 2- oxaspiro[3.3]heptanyl, tetrahydroisoquinolinyl, 1-azaspiro[3.3]heptan-2-onyl, and 2- azabicyclo[4.1.0]heptanyl. Where a heterocycloalkyl group is described as being “X- to Y-membered” (where X and Y are integers), this means that the heterocycloalkyl group contains a total number of ring atoms from X to Y. Thus, for example, a “4- to 7-membered heterocycloalkyl group” contains a total of 4, 5, 6, or 7 ring atoms, for example tetrahydropyranyl (6 ring atoms). As used herein, the term “heterocycloalkenyl” means an unsaturated (i.e., partially or fully unsaturated) group having at least 3 to 6 atoms (i.e., ring atoms) that form a ring, wherein at least 1 to 5 of said ring atoms are carbon and the remaining at least 1 to 5 ring atom(s) (i.e., hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulfur, and oxygen. Heterocycloalkenyl rings may have oxo substituents, typically adjacent to a heteroatom, but the oxygen atom does not form part of the ring and is excluded from the number of ring atoms. Exemplary heterocycloalkenyl groups include tetrahydropyridyl. Any ring sulfur atom may optionally carry one or more pendant (i.e., non-ring) oxygen atoms. It will be appreciated that the heterocycloalkenyl group may be monocyclic or multicyclic (e.g., bridged). In the case of multicyclic heterocycloalkenyl groups, there are further rings, e.g., 1 or more further rings, all of which contain from 3 to 6 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. Said further rings may be saturated, or partially or fully unsaturated (e.g., having aromatic character). Multicyclic heterocycloalkenyl groups include fused, bridged, and spirocyclic ring systems. Where a multicyclic heterocycloalkenyl group contains an unsaturated fused ring, the group is typically not bonded to the rest of the molecule via that fused ring. Exemplary heterocycloalkenyl groups having such further rings include tetrahydroindolyl. Where a heterocycloalkenyl group is described as being “X- to Y-membered”, this means that the heterocycloalkenyl group contains a total number of ring atoms from X to Y. Thus, for example, a “5- to 8-membered heterocycloalkenyl group” contains a total of 5, 6, 7, or 8 ring atoms, for example dihydropyranyl (6 ring atoms). As used herein, the term “heteroaryl” means an aromatic (i.e., having aromatic character) group typically containing from 5 to 10 ring atoms, wherein 1 to 9 of said ring atoms are carbon and the remaining 1 to 9 ring atom(s) (i.e., hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulfur, and oxygen. It will be appreciated that the heteroaryl group may be monocyclic or multicyclic (e.g., fused). In the case of multicyclic heteroaryl groups, there are further rings, e.g., 1 or more further rings, all of which contain at least 3 atoms (i.e., ring atoms), which further rings may optionally be aromatic. Examples of heteroaryl groups include monocyclic groups such as pyridyl and 2-oxopyridinyl, as well as multicyclic groups such as indolyl. Where a heteroaryl group is described as being “X- to Y-membered”, this means that the heteroaryl group contains a total number of ring atoms from X to Y. Thus, for example, a “5- to 10-membered heteroaryl group” contains a total of 5, 6, 7, 8, 9, or 10 ring atoms, for example indolyl (9 ring atoms). A heteroaryl group may equivalently be described as a “Cx heteroaryl” group where the number corresponding to subscript x refers to the total number of ring atoms including the heteroatom(s) and carbon atoms in the ring. Thus, for example, a “C5 heteroaryl” group contains a total of 5 ring atoms including any heteroatom(s) provided that at least one heteroatom is present. As used herein, the term “hydrogen” or “H” includes1H and2H (deuterium, “D”). Thus, references to e.g., OH, (C1-C6)alkyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl groups, etc. include such groups which are partly or fully deuterated as well as non-deuterated groups. For example, references to “OH” or “hydroxy” therefore include OD, and references to “C1 alkyl”, “methyl”, “Me”, or “CH3” therefore include e.g., CD3. As used herein, the terms “halo” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to a halogen functional group or to a halogen atom as such. Those of skill in the art will readily be able to ascertain which is intended in the context in which this term is used in the present disclosure. 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 attached via its carbon atom. As used herein, the term “oxo” means a functional group wherein an oxygen atom is connected to the atom bearing this group via a double bond. For example, where a carbon atom carries an oxo group it forms a carbon-oxygen double bond. It will be appreciated that not all atoms within a given structure can be substituted by oxo, and that this will depend on the free valency of the atom to be substituted. As used herein, “-C(O)-” means , “=O” means , “-C(O)NH-” means , “-C(O)NR-” means , “-NHC(O)-” means , and “-NRC(O)-” means . As used herein, “C(O)R*” means , “C(O)OR*” means , “C(O)NR*2” means . The compounds of the present disclosure are described, inter alia, by way of structural formulae. It will be appreciated that these formulae typically show only one form (e.g., resonance form, tautomeric form, etc.) of the compound, whereas certain compounds may exist in more than one such form. This will be readily apparent to the skilled reader. The present disclosure includes all possible tautomers of the compounds characterised by the structural formulae hereinbefore and below, including as single tautomers, or as any mixture of tautomers in any ratio. It will also be appreciated that certain of the present compounds may exist in one or more isomeric (e.g., stereoisomeric) forms. The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc. of the compounds described hereinbefore and below, as well as cis- and trans- forms and conformers of the same. The purification and the separation of isomers may be accomplished by methods described hereinafter, as well as by techniques known in the art. For example, optical isomers of the compounds can be obtained by resolution of the racemic mixture of diastereoisomeric salts thereof (e.g., using an optically active acid or base, or by the formation of covalent diastereomers). A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation, with or without derivatisation, may also be useful, and optically active compounds of the present disclosure can likewise be obtained by chiral syntheses utilizing optically active starting materials. The present disclosure includes all possible stereoisomers of the compounds described herein as single stereoisomers, or as any mixture of said stereoisomers, e.g., (R)- or (S)- isomers, in any ratio. The compounds of the disclosure may exist in the form of free acids or bases, or may exist as addition salts with suitable acids or bases. For example, basic compounds of Formula (0) (e.g. basic compounds of Formula (I)) may be provided as pharmaceutically acceptable acid addition salts with an acid such as HCl. Methods for forming salts are described below and are also known in the art (see, e.g., Berge et al., J Pharm Sci. (1977) 66:1-19). As used herein, the term “pharmaceutically acceptable” when used in connection with salts means a salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. Compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein. The following abbreviations and empirical formulae are used herein: Ac acetyl or acetate (e.g., AcOK = potassium acetate) AcOH acetic acid aq. aqueous atm atmosphere(s) Bn benzyl Boc or BOC tert-butyloxy carbonyl BSA bovine serum albumin cataCXium® 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 number 1651823-59-4 CHAPS 3-((3-cholamidopropl)dimethylammonio)-1-propanesulfonate COSY correlation spectroscopy DavePhos 2-dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-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(diphenylphosphino)propane DTT dithiothreitol EA ethyl acetate ee enantiomeric excess ELSD evaporative light scattering detection eq or equiv equivalent(s) ERK extracellular signal-related kinase ESI-MS electrospray ionization mass spectrometry Et ethyl EtOAc or AcOEt ethyl acetate FBS fetal bovine serum GDP guanosine diphosphate HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HMBC heteronuclear multiple bond coherence HPLC high performance liquid chromatography HSQC heteronuclear single quantum correlation i-PrOH isopropyl alcohol KRAS G12Dhu human KRAS G12D LC liquid chromatography LCMS liquid chromatography / mass spectrometry LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide mCPBA meta-chloroperoxybenzoic acid Me methyl MOM methoxy methyl ether MOMBR bromomethyl methyl ether MS mass spectrometry MW molecular weight NBS N-bromo succinimide NMR nuclear magnetic resonance OTf triflate PDA photodiode array PE petroleum ether PE / EA petroleum ether / ethyl acetate Pd / C palladium on carbon Pd(OAc)2 palladium(II) diacetate PE petroleum ether Ph phenyl p-Tol. para-tolyl ROESY rotational nuclear Overhauser effect spectroscopy RPMI-1640 Roswell Park Memorial Institute 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 hydrogen peroxide UV ultraviolet w (for cell cultures) well; thus e.g., 96w = 96-well WT wild-type Xantphos 9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane); CAS Registry No.161265-03-8 Xantphos Pd G4 (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-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 Compounds In a first aspect the present disclosure provides a compound of Formula (0): (Formula (0)) or a pharmaceutically acceptable salt thereof, wherein: R1is a 6- to 10-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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 wherein R1is -L3-R1’, wherein R1’ is a 5-membered, monocyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1’is optionally substituted by 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; R2is a 5- to 9-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; or a fused, 11- to 14-membered tricyclic group wherein at least one ring is aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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; R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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; or R3is 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 optionally be substituted by 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 R3is a fused, 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused to an aryl ring ,wherein the carbocyclic ring, the aryl ring, or both, may be optionally substituted by 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 R3is a fused, 8- to 10-membered bicyclic group comprising a saturated heterocyclic ring fused to an aryl or heteroaryl ring, wherein the carbocyclic ring, the aryl or heteroaryl ring, or both, may be optionally substituted by 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; L1is a bond or is -O-, -(C1-C3)alkyl-, *-O-(C1-C3)alkyl-**, *-(C1-C3)alkyl-O-**, *-C(O)NR’-**, or *- NR’C(O)-**, wherein R’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (0) and ** denotes a point of attachment to R2; L2is -(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’’-**, wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (0); L3is a bond or is -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3) alkyl; and wherein in R1, R2, and R3, 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 may itself be substituted by 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 embodiments, the compound of Formula (0) is a compound of Formula (I): (Formula I) or a pharmaceutically acceptable salt thereof, wherein in Formula (I): R1is a 6- to 10-membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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; R2is a 5- to 8-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; or a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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; R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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; or R3is 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 optionally be substituted by 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; L1is -O-, -(C1-C3)alkyl-, *-O-(C1-C3)alkyl-**, *-(C1-C3)alkyl-O-**, *-C(O)NR’-**, or *-NR’C(O)- **, wherein R’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (I) and ** denotes a point of attachment to R2; L2is -(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’’-**, wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (I); and wherein in R1, R2, and R3, 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 by 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 compounds of the present disclosure, R1may be -L3-R1’, wherein R1’ is a 5-membered, monocyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1’is optionally substituted by 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, and wherein L3is a bond or is - (C1-C3)alkyl-, -O-, -NH- or -N(C1-C3) alkyl and wherein 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 may itself be substituted by 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 compounds of the present disclosure, R1may be a 6- to 10-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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, wherein 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 may itself be substituted by 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. Where R1is bicyclic, R1may be a bridged bicyclic, fused bicyclic, or spirocyclic group. Thus, R1may be a 6- to 10-membered, bicyclic heterocycloalkyl or heterocycloalkenyl group which is a bridged, fused or spirocyclic group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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*2and CH2C(O)ONR*2, wherein 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 may itself be substituted by 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 compounds of the present disclosure, R1may be a 6- to 10-membered, fused bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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, wherein 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 may itself be substituted by 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 compounds of the present disclosure, R1may be a 6- to 10-membered, spirocyclic bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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, wherein 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 may itself be substituted by 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 compounds of the present disclosure, R1may be a 6- to 10-membered, bridged bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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*2and CH2C(O)ONR*2, wherein 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 may itself be substituted by 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 compounds of the present disclosure, R1may be a 6- to 10-membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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; wherein 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 by 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. R1is a heterocycloalkyl or heterocycloalkenyl group as defined above, i.e., R1is a saturated or unsaturated heterocyclic group; or R1is -L3-R1’, wherein R1’ is a heterocycloalkyl or heterocycloalkenyl group as defined above. Thus, R1is non-aromatic. In embodiments, R1is bound to the triazole moiety of the compound of formula (0) (e.g. the compound of Formula (I)) through a ring atom of R1which is N. In embodiments, R1is selected from:

[0013] wherein each of X1, X2, X3, X4, X5, X6. and X7is independently selected from C(R*’)2, C=O, NR*’, O, and S, and wherein each R*’ is independently selected from H, CN, Cl, F, R*, OR*, NR*2, CHO, C(O)R*, C(O)OR*, C(O)NR*2, and C(O)ONR*2, wherein R* is as defined above. In embodiments of R*’, R* is as defined in accordance with Formula (0). In embodiments of R*’, R* is as defined in accordance with Formula (I). In embodiments each R*’ is independently selected from H, CH2CH3, CH2=CH2, and CH2OCH3. In embodiments, R1is wherein each of X1, X2, X3, X4, X5, and R*’ is as defined above. In embodiments, R1is , wherein X1, X2, X5and R*’ are as defined above. In embodiments, R1is selected from , wherein R*’ is as defined above. In embodiments, . In embodiments, R1is selected from

[0014] In embodiments, R1is selected from In embodiments, R1is selected from

[0015] , . In embodiments, . In embodiments, , wherein X is selected from NH, N(C1-3)alkyl, O, or CH2; v is an integer from 0 to 4; and 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, wherein R* is as defined above. In embodiments of R*’’, R* is as defined in accordance with Formula (0). In embodiments of R*’’, R* is as defined in accordance with 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. In embodiments, , wherein X is selected from NH, N(C1-3)alkyl, O, or CH2; v is an integer from 0 to 4; and 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, wherein R* is as defined above. In embodiments of R*’’, R* is as defined in accordance with Formula (0). In embodiments of R*’’, R* is as defined in accordance with 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. In embodiments, , wherein v is an integer from 0 to 4; and each R*’’ is independently a group R*’’ as defined above. 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. In embodiments, R1is , wherein v is an integer from 0 to 4 and each R*’’ is independently a group R*’’ as defined above. 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. In embodiments, wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, . wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, R1is In embodiments, R1is . In embodiments, R1is . In embodiments, R1is I , each R*’’ is independently a group R*’’ as defined above. In embodiments, . embodiments, R1is is In embodiments, wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, . embodiments, R1is . , .

[0016] In embodiments, wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, , wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, . embodiments, . In embodiments, R1is wherein v is an integer from 0 to 4 and each R*’’ is independently a group R*’’ as defined above. 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. In embodiments, wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, In embodiments, wherein each R*’’ is independently a group R*’’ as defined above. In embodiments, I n embodiments, R is not: In the compounds of the present disclosure, R2is a 5- to 9-membered, monocyclic or bicyclic (e.g. fused, bridged or spirocyclic) heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; or a fused, 11- to 14-membered tricyclic group wherein at least one ring is aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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 in accordance with Formula (0). In embodiments, R* is as defined in accordance with Formula (I). In embodiments, R2is a fused, 11- to 14-membered tricyclic group wherein at least one ring is aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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 in accordance with Formula (0). In embodiments, R* is as defined in accordance with Formula (I). In embodiments, . In embodiments, R2is a 5- to 8-membered, monocyclic or bicyclic (e.g. fused, bridged, or spirocyclic) heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; or a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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, wherein R* is as defined above. In embodiments, R* is as defined in accordance with Formula (0). In embodiments, R* is as defined in accordance with Formula (I). In embodiments, R2is selected from: , wherein q and r are each independently 0, 1, or 2, and each instance of Raand Rbis 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, wherein R* is as defined above, e.g. as defined in accordance with Formula (0) or as defined in accordance with Formula (I).; , wherein X8, X9, X10, and X11are each independently selected from C(Rk)2, C=O, N(Rk), O, or S, provided that at least one of X8, X9, X10, and X11is N(Rk); , wherein X12, X13, and X14are each independently selected from C(Rk)2, C=O, N(Rk), O, or S and X15and X16are each independently selected from C and N, provided that at least one of X12, X13, and X14is N(Rk) and / or at least one of X15and X16is N; , wherein X17, X18, X19, X20, and X21are each independently selected from C(Rk)2, C=O, N(Rk), O or S, provided that at least one of X17, X18, X19, X20, and X21is N(Rk), O, or S; , wherein Y1, Y2, Y3, and Y4are each independently N, O, S, NRk, or CRk, provided that at least one of Y1, Y2, Y3, and Y4is N or NRk; , wherein Y5, Y6and Y7are each independently N, O, S, NRk, or CRk, and Y8and Y9are each independently N or C, provided that at least one of Y5, Y6, and Y7is N or NRkand / or at least one of Y8and Y9is N; , wherein Z1, Z2, Z3, Z4and Z5are each independently N, O, S or CRk, provided that at least one of Z1, Z2, Z3, Z4and Z5is N; wherein each Rkis 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 wherein R* is as defined above. In embodiments, R* is as defined in accordance with Formula (0). In embodiments, R* is as defined in accordance with Formula (I). In embodiments, , wherein q, r, Ra, and Rbare as defined above. In embodiments, , wherein q, r, Ra, and Rbare as defined above. In embodiments, (wherein Rkis as defined above). In embodiments, R2is selected from:

[0017] In embodiments, R2is selected from:

[0018] In embodiments, .

[0019] ly as defined above. In embodiments, , wherein Rbis as defined above. In embodiments, Rbis F or Cl.

[0020]

[0021] In the compounds of the present disclosure, L1is a bond or is -O-, -(Ci-C3)alkyl-, *-O-(Ci-C3)alkyl- **, *-(Ci-C3)alkyl-O-**, *-C(O)NR’-**, or *-NR’C(O)-**, wherein R’ is H, OH, CN, Cl, F, or (Ci- C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of formula (0) (e.g. a compound of Formula (I)) and ** denotes a point of attachment to R2. Where L1is (C2-C3) alkyl, *-O(C2-C3 alkyl)-** or *-(C2-C3 alkyl)O-** the C2 or C3 alkyl group may be linear or branched, e.g. - CH(CH3)-, *-OCH(CH3)-**, or *-CH(CH3)O-**.

[0022] In embodiments, L1is -O-, -(Ci-C3)alkyl-, *-O-(Ci-C3)alkyl-**, *-(Ci-C3)alkyl-O-**, *-C(O)NR’-**, or *-NR’C(O)-**, wherein R’ is H, OH, CN, Cl, F, or (Ci-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (0) (e.g. a compound of Formula (I)) and ** denotes a point of attachment to R2.

[0023] In embodiments, L1is -O-, -(C2-C3)alkyl-, *-O-(C2-C3)alkyl-**, *-(C2-C3)alkyl-O-**, *-C(O)NR’-**, or *-NR’C(O)-**, wherein R’ is H, OH, CN, Cl, F, or (Ci-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (0) (e.g. a compound of Formula (I)) and ** denotes a point of attachment to R2.

[0024] In embodiments, L1is -O-, -CH2CH2-, *-OCH2-**, *-CH2O-**, *-OCH(CH3)-**, or *-CH(CH3)O-**.

[0025] In embodiments, L1is -O-, -CH2CH2-, *-OCH2-**, or *-CH2O-**.

[0026] In embodiments, L1is -O- or *-OCH2-**.

[0027] In embodiments, L1is -O-, -CH2CH2-, *-OCH2-**, *-OCH(CH3)-** or *-CH2O-**.

[0028] In embodiments, L1is -O-, *-OCH(CH3)-** or *-OCH2-**.

[0029] In embodiments, L1is -O- or *-OCH(CH3)-**. In embodiments, L1is *-OCH(CH3)-** or *-OCH2-**.

[0030] I , ein Rkis as defined above). In embodiments, (wherein R* is as defined above) (e.g. defined above. In embodiments, , wherein Rbis as defined above. In embodiments, L1and R2together form a group or , wherein q, r, Ra, and Rbare as defined above. In embodiments, L1and R2together form a group , wherein Rbis as defined above.

[0031] In embodiments, (wherein Rkis as defined above).

[0032] each independently selected from C(Rk)2, C=O, N(Rk), O, or S, provided that at least one of X8, X9, X10, and X11is N(Rk); wherein each Rkis 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 wherein 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 may itself be substituted by 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 embodiments, , wherein X8, X9, X10, and X11are each independently selected from C(Rk)2, C=O, N(Rk), O, or S, provided that at least one of X8, X9, X10, and X11is N(Rk); wherein each Rkis 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 wherein 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 by 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 embodiments, , wherein each Rkis 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 wherein each R* is independently selected from (Ci-C3)alkyl, (C2-C3)alkenyl, (C3- Ce)cycloalkyl, and (C3-Ce)cycloalkenyl, wherein said (Ci-C3)alkyl, (C2-C3)alkenyl, (C3- Ce)cycloalkyl, or (C3-Ce)cycloalkenyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, NH2, NH((Ci-C3)alkyl), (Ci-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or O(Ci-C3) alkyl.

[0033] C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-Ce)cycloalkenyl, wherein said (Ci-C3)alkyl, (C2- C3)alkenyl, (C3-Ce)cycloalkyl, or (C3-Ce)cycloalkenyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, NH2, NH((Ci-C3)alkyl), (Ci-C3)alkyl, (C2-C3)alkenyl,

[0034] (C2-C3)alkynyl, or O(Ci-C3) alkyl)), e.g.

[0035] In the compounds of the present disclosure, R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)); or R3is 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 optionally be substituted by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)); or R3is a fused, 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused to an aryl ring, wherein the carbocyclic ring, the aryl ring, or both, may be optionally substituted by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)); or R3is a fused, 8- to 10-membered bicyclic group comprising a saturated heterocyclic ring fused to an aryl or heteroaryl ring, wherein the carbocyclic ring, the aryl or heteroaryl ring, or both, may be optionally substituted by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)); or R3is 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 optionally be substituted by 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, R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, R3is 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 optionally be substituted by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, R3is selected from wherein m is 1 or 2 and n is 0, 1, or 2; and each Rcand Rdis independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)alkynyl, provided that at least one Rcis OH; , wherein s is 1, 2, or 3, and wherein when s is 1, Rgis OH, and when s is 2 or 3, at least one Rgis OH and each remaining Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl; and , wherein Y10is S, O, or NR’’’ wherein 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, with the proviso that when t is zero, u is nonzero, and that when u is zero, t is nonzero; and each Rhand Riis 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, and (C2-C3)alkynyl, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, R3is a naphthalenyl group which is substituted by OH and optionally by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, wherein when m is 1, Rcis OH, and when m is 2, at least one Rcis OH and the other Rcis independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)alkynyl.

[0036] In embodiments, R3is selected from

[0037] In embodiments, R3is selected from , wherein Rdis as defined above. In embodiments, each Rdis independently selected from F, Cl, C≡CH, and CH2CH3. In embodiments, R3is selected from

[0038] In embodiments, R3is a phenyl group which is substituted by OH and optionally by 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, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, R3is , wherein s is 1, 2, or 3, and wherein when s is 1, Rgis OH, and when s is 2 or 3 at least one Rgis OH and each remaining Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl. In embodiments, , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1- C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl. In embodiments, , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2- C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2- C3)alkenyl, or (C2-C3)alkynyl. In embodiments, , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2- C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2- C3)alkenyl, or (C2-C3)alkynyl.

[0039] In embodiments, , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments, , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3- C6)cycloalkyl may itself be substituted by 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 Rgis OH. F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3- C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments, , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2- C3)alkenyl, or (C2-C3)alkynyl. , (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1- C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl. In embodiments, , wherein Rgis F or Cl.

[0040] , In embodiments, R3is 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 optionally be substituted by 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, R3is a fused bicyclic group comprising a 6-membered saturated carbocyclic ring fused to a 5-membered heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both, may optionally be substituted by 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 heterocyclic ring comprises at least one heteroatom which is S. In embodiments, R3is , wherein Y10is S, O, or NR’’’ wherein 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, with the proviso that when t is zero, u is nonzero, and that when u is zero, t is nonzero; and each Rhand Riis 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, and (C2-C3)alkynyl, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, each Rhand Riis independently selected from F, Cl, CN, OH, NH2, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2- C3)alkynyl. , wherein Rh, Ri, t, and u are as defined above. In particular embodiments, , wherein Rh, Ri, t, and u are as defined above. , wherein Rh, Ri, and u are as defined above. or In particular embodiments, R3is , , or , wherein Rhand Riare as defined above. , wherein Rh, Ri, and u are as defined above. or In more particular embodiments, . more particular embodiments, . In embodiments, R3is a fused bicyclic group comprising a 6-membered saturated heterocyclic ring fused to a 5-membered heteroaryl ring, wherein the saturated heterocyclic ring, the heteroaryl ring, or both, may optionally be substituted by 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 heterocyclic ring comprises at least one heteroatom which is N. In embodiments, the heteroaryl ring comprises at least one heteroatom which is N. In embodiments, , wherein t is 0, 1, 2, or 3 and u is 0, 1, or 2, with the proviso that when t is zero, u is nonzero, and that when u is zero, t is nonzero; and each Rhand Riis 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, and (C2-C3)alkynyl, wherein R* is as defined above (e.g. in accordance with Formula (0) or in accordance with Formula (I)). In embodiments, each Rhand Riis independently selected from F, Cl, CN, OH, NH2, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)alkynyl. In the compounds of the present disclosure, L2is –(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’’-**, wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (0) (e.g. a compound of Formula (I)). In embodiments, L2is –(C1-C3)alkyl-, C5-heteroaryl optionally substituted with one or more R’’ and containing at least one ring atom which is N, *-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’’-**, wherein R’’ is as defined above. In embodiments, L2is –(C1-C3)alkyl-, C5-heteroaryl optionally substituted with one or more R’’ and containing at least two ring atoms which are N, *-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’’-**, wherein R’’ is as defined above. In embodiments, L2is –(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 L2is 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’’, wherein R’’ is as defined above. In embodiments L2is -CH2CH2-, -CH=CH-, -C≡C-, *-CH2O-**, *-OCH2-**, *-CH2NH-**, *-NHCH2-**, *-N(CH3)C(O)-**, *-C(O)N(CH3)-**, *-NHC(O)-**, *-C(O)NH-**,

[0041] I In embodiments, , thereby providing a compound of Formula (II):

[0042] (Formula (II)) Wherein R*’, L1, L2, R2, Rc, Rd, n, and m are as defined above. . In embodiments of Formula ( thereby providing a compound of Formula (IIa):

[0043] (Formula (IIa)) wherein L1, L2, R2, Rc, Rd, n, and m are as defined above. In embodiments of Formula ( , thereby providing a compound of Formula (IIb): (Formula (IIb)) wherein L1, L2, R2, Rc, Rd, n, and m are as defined above. In embodiments, R1 , thereby providing a compound of Formula (III): (Formula (III)) wherein R*’, L1, L2, R2, Rc, Rd, and n are as defined above.

[0044] . In embodiments of Formula thereby providing a compound of Formula (IIIa): (Formula (IIIa)) wherein L1, L2, R2, Rc, Rd, and n are as defined above. In embodiments of Formula , thereby providing a compound of Formula (IIIb): (Formula (IIIb)) wherein L1, L2, R2, Rc, Rd, and n are as defined above. In embodiments of Formula (III), including Formula (IIIa) and Formula (IIIb), R3is defined above. In embodiments of Formula (III), including Formula (IIIa) and Formula (IIIb), R3is or In embodiments of Formula (III), including Formula (IIIa) and Formula (IIIb), R3is In embodiments, , thereby providing a compound of Formula (IV): (Formula (IV)) wherein R*’, L1, L2, R2, and s are as defined above, and wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3- C6)cycloalkyl may itself be substituted by 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 Rgis OH. . In embodiments of Formula thereby providing a compound of Formula (IVa): (Formula (IVa)) wherein L1, L2, R2, Rg, and s are as defined above. In embodiments of Formula thereby providing a compound of Formula (IVb): (Formula (IVb)) wherein L1, L2, R2, Rg, and s are as defined above. In embodiments of Formula (IV), including Formula (IVa) and Formula (IVb), R3is is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl. In embodiments of Formula (IV), including Formula (IVa) and Formula (IVb), R3is , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2- C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl. In embodiments, , thereby providing a compound of Formula (V):

[0045] (Formula (V)) wherein L1, L2, and R2are as defined above, and wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. . In embodiments of Formula ( thereby providing a compound of Formula (Va):

[0046] (Formula (Va)) wherein L1, L2, and R2are as defined above, and wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula ( thereby providing a compound of Formula (Vb): (Formula (Vb)) wherein L1, L2, and R2are as defined above, and wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2- C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl. In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is , , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2- C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl. In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is , wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2- C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl. In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is , wherein Rgis F or Cl. In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is In embodiments of Formula (V), including Formula (Va) and Formula (Vb), R3is . In embodiments of Formula (V), including Formula is . In embodiments, , thereby providing a compound of Formula (VI): (Formula (VI)) wherein R*’, L1, L2, R3, q, r, Ra, and Rbare as defined above. . In embodiments of Formula ( thereby providing a compound of Formula (VIa): (Formula (VIa)) wherein L1, L2, R3, q, r, Ra, and Rbare as defined above. (Formula (VIb)) wherein L1, L2, R3, q, r, Ra, and Rbare as defined above. In embodiments, , thereby providing a compound of Formula (VI.I): (Formula (VI.I)) wherein R*’’, L1, L2, R3, X, q, r, v, Ra, and Rbare as defined above.

[0047] In embodiments of Formula (VI.I), X is O and thus . embodiments, X is O and v is 2. In embodiments, . embodiments, R1is In embodiments of Formula thereby providing a compound of Formula (VI.Ia):

[0048] (Formula (VI.Ia)) wherein L1, L2, R3, q, r, Ra, and Rbare as defined above. In embodiments of Formula thereby providing a compound of Formula (VI.Ib): (Formula (VI.Ib)) wherein L1, L2, R3, q, r, Ra, and Rbare as defined above. In embodiments, , thereby providing a compound of Formula (VII): (Formula (VII)) wherein R*’, L1, L2, R3, and Rbare as defined above. . In embodiments of Formula thereby providing a compound of Formula (VIIa): (Formula (VIIa)) wherein L1, L2, R3, and Rbare as defined above. In embodiments of Formula thereby providing a compound of Formula (VIIb):

[0049] (Formula (VIIb)) wherein L1, L2, R3, and Rbare as defined above. In embodiments, , thereby providing a compound of Formula (VII.I): (Formula (VII.I)) wherein R*’’, L1, L2, R3, X, v, and Rbare as defined above. In embodiments of Formula (VII.I), X is O and thus . embodiments,

[0050] . In embodiments of Formula thereby providing a compound of Formula (VII.Ia): (Formula (VII.Ia)) wherein L1, L2, R3, and Rbare as defined above. In embodiments of Formula thereby providing a compound of Formula (VII.Ib): (Formula (VII.Ib)) wherein L1, L2, R3, and Rbare as defined above. In embodiments of Formula VI (including Formula (VIa) and Formula (VIb)) and Formula VI.I (including Formula (VI.Ia) and Formula (VI.Ib)) and Formula (VII) (including Formula (VIIa) and Formula (VIIb)) and Formula (VII.I) (including Formula (VII.Ia) and Formula (VII.Ib)), R2is . In embodiments of Formula VI (including Formula (VIa) and Formula (VIb)) and Formula VI.I (including Formula (VI.Ia) and Formula (VI.Ib)) and Formula VII (including Formula (VIIa) and Formula (VIIb)) and Formula VII.I (including Formula (VII.Ia) and Formula (VII.Ib)), R2 (Formula (VIII)) wherein L1, L2, R1, Ra, Rb, Rc, Rd, n, m, q, and r are as defined above. In embodiments of Formula , wherein Rdand n are as defined above. (Formula (IX)) wherein L1, L2, R1, Rb, Rd, and n are as defined above. In embodiments of Formula (VIII) and Formula embodiments of Formula (VIII) and Formula In embodiments of Formula (VIII) and Formula (IX), R3is defined above.

[0051] In embodiments of Formula (VIII) and Formula (IX), R3is , r . In embodiments of Formula (VIII) and Formula (IX), R3is selected from In embodiments of Formula (VIII) and Formula (IX), R2is is defined above. In embodiments of Formula (VIII) and Formula (IX), R3is

[0052] In embodiments of Formula (VIII) and Formula (IX), R3is

[0053] compound of Formula (X):

[0054] (Formula (X)) wherein R1, L1, L2, Ra, Rb, q, r, and s are as defined above, and wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3- C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula ( , wherein Rbis as defined above. In embodiments of Formula ( , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3- C6)cycloalkyl may itself be substituted by 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 Rgis OH.

[0055] (Formula (XI)) wherein R1, L1, L2, and Rbare as defined above, and wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula (X) and Formula ( In embodiments of Formula (X) and Formula ( In embodiments of Formula (X) and Formula ( wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3- C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula (X) and Formula ( Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl. In embodiments of Formula (X) and Formula (XI), R3 , , , , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3- C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula (X) and Formula (XI), R3 , , , , , , y , y , (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 Rgis OH. In embodiments of Formula (X) and Formula ( ,wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3- C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, provided In embodiments of Formula (X) and Formula ( ,wherein Rgis F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3- C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, . In embodiments of Formula (X) and Formula (XI), R3is , , wherein each Rgis independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3- C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by 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 embodiments of Formula (X) and Formula (XI),

[0056] independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl, . In embodiments of Formulas (

[0057] In embodiments of Formulas (VIII), (IX), (X) and (XI), R1is . In embodiments, R*’ is H and thus . Thus in further embodiments there are provided compounds of Formulas (XII) – (XVIII), wherein L1, L2, Ra, Rb, Rc, Rd, Rg, n, m, q, r, and s are as defined above: (Formula (XII))

[0058] (Formula (XIV))

[0059] (Formula (XVI))

[0060] . In embodiments of Formula (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R2is In embodiments of Formula (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R1is , wherein Rbis as defined above. In embodiments, there are provided compounds of Formula (XIX): (Formula (XIX)) wherein L2, Rb, Rd, and n are as defined above. In embodiments, there are provided compounds of Formula (XX):

[0061] (Formula (XX)) wherein L2, Rb, Rc, Rd, and n are as defined above. In embodiments, there are provided compounds of Formula (XXI): wherein Rg, L2, and Rbare as defined above. In embodiments, , thereby providing a compound of Formula (XXII): (Formula (XXII)) wherein R*’, L1, L2, R2, Rh, Ri, t, u, and Y10are as defined above. In embodiments, , thereby providing a compound of Formula (XXII.I):

[0062] (Formula (XXII.I)) wherein R*’’, L1, L2, X, R2, Rh, Ri, t, u, v, and Y10are as defined above. In embodiments, , thereby providing a compound of Formula (XXIII):

[0063] (Formula (XXIII)) wherein R*’, L1, L2, R2, Rh, Ri, t, and u are as defined above. In embodiments, , thereby providing a compound of Formula (XXIII.I):

[0064] (Formula (XXIII.I)) wherein R*’’, L1, L2, X, R2, Rh, Ri, t, u, and v are as defined above. In embodiments of Formula (XXIII) and Formula (XXIII.I), R3is

[0065] (Formula (XXIV)) wherein R*’, L1, L2, R2, Rh, Ri, and u are as defined above. In embodiments, thereby providing a compound of Formula (XXIV.I):

[0066] (Formula (XXIV.I)) wherein R*’’, L1, L2, X, R2, Rh, Ri, t, u, and v are as defined above. In embodiments of Formula (XXIV) and Formula ( , wherein Rh, Ri, and u are as defined above.

[0067] above. In particular embodiments of Formula (XXIV) and Formula ( , , wherein Rhand Riare as defined above. In particular embodiments of Formula (XXIV) and Formula ( , , wherein Rhand Riare as defined above. In more particular embodiments of Formula (XXIV) and Formula (XXIV.I), R3is . In embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (XXIV) and Formula (XXIV.I), R2is a 5- to 9-membered (e.g. 5- to 8-membered), monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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; and wherein 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 may itself be substituted by 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 embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (XXIV) and Formula (XXIV.I), R2is a 5- to 8-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; or a fused, 8- to 10- membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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; and wherein 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 by 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 embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (XXIV) and Formula (XXIV.I), R2is a 5- to 9-membered monocyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O, and wherein R2may be substituted by 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, 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 may itself be substituted by 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 embodiments, 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 by 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 embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (XXIV) and Formula , wherein X8, X9, X10, and X11are each independently selected from C(Rk)2, C=O, N(Rk), O, or S, provided that at least one of X8, X9, X10, and X11is N(Rk); wherein each Rkis 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 wherein 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 may itself be substituted by 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 embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (XXIV) and Formula , wherein X8, X9, X10, and X11are each independently selected from C(Rk)2, C=O, N(Rk), O, or S, provided that at least one of X8, X9, X10, and X11is N(Rk); wherein each Rkis 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 wherein 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 by 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 embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (XXIV) and Formula (XXIV.I), R2is , wherein each Rkis 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 wherein 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 by 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 embodiments, R2is , thereby providing a compound of Formula (XXV): (Formula (XXV)) wherein L1, L2, R1, Ra, Rb, Rh, Ri, q and r, t, u, and Y10are as defined above. thereby providing a compound of Formula (XXVI): (Formula (XXVI)) Wherein L1, L2, R1, Ra, Rb, Rh, Ri, q and r, t, and u are as defined above. In embodiments, thereby providing a compound of Formula (XXVII):

[0068] (Formula (XXVII)) wherein R*’’, L1, L2, R3, X, v, and Rkare as defined above. (Formula (XXVIII)) wherein R*’’, L1, L2, X, Rh, Ri, Rk, t, u and v are as defined above. . In embodiments of Formula (XXII), Formula (XXII.I), Formula (XXIII), Formula (XXIII.I), Formula (wherein R* is 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 by 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) (wherein R* is 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 by 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 embodiments of Formula (XXII), (XXIII), (XXIV), (XXV), and (XXVI), R1is . , .

[0069] . . , . , . , , ,

[0070] Formula (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI) , (XXVII) and (XXVIII), R1is . In embodiments of Formula (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI) , (XXVII) and (XXVIII), In embodiments of Formula (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI) , (XXVII) and (XXVIII), ( XXIII.I), (XXIV.I), (XXV), (XXVI) , (XXVII) and (XXVIII), R is . In embodiments of Formula (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI) , (XXVII) and (XXVIII), R1

[0071] . In embodiments, the compound of Formula (0) or Formula (I) is not: . In embodiments, the compound of Formula (0) or Formula (I) is not:

[0072] . In embodiments, the compound is selected from the group consisting of the compounds in Table 1 below and their stereoisomers (including enantiomers and diastereomers thereof, and mixtures of stereoisomers thereof, such as mixtures of enantiomers or mixtures of diastereomers of the compounds of Table 1) wherein “ ” denotes “Compound number”:

[0073] Table 1

[0074] In embodiments, the compounds of the disclosure are characterised according to their binding and / or inhibitory activity against KRAS G12D, e.g., as measured according to the assays described in the examples below. In embodiments, the compounds of the disclosure are characterised according to their dissociation constants KD in relation to KRAS G12D, e.g. when measured according to SPR, such as when measured according to an SPR assay as described in the examples below. In embodiments the compounds have a KD of ≤10 μM with respect to KRAS G12D. In embodiments, the compounds have a KD 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. In embodiments, the compounds have a KD of less than about 50 nM , e.g. 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 with respect to KRAS G12D. In embodiments, the compounds of the disclosure are characterised according to their binding and / or inhibitory activity against GDP-bound KRAS G12D, e.g., as measured according to the assays described in the examples below. In embodiments, the compounds have an IC50 for binding GDP-bound KRAS G12D of less than about 50 nM, e.g. 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. In embodiments, the compounds have an IC50 for binding GDP-bound KRAS G12D of less than about 2 nM, e.g. 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. In embodiments the compounds have greater affinity for KRAS G12D than for wild-type (WT) KRAS. Thus, in embodiments the compounds have a higher KD with respect to WT KRAS than with respect to KRAS G12D, e.g., when measured according to SPR, such as when measured according to an SPR assay as described in the examples below. In embodiments, the compound has at least 5-fold selectivity for binding to KRAS G12D in preference to WT KRAS (e.g., as defined by the ratio of KD (WT KRAS) to KD (KRAS G12D), e.g., when measured according to SPR, such as when measured according to an SPR assay as described in the examples below). In embodiments, the compound has at least about 10- fold, 15-fold, 20-fold, 25-fold, or 30-fold selectivity for KRAS G12D over WT KRAS (e.g., as defined by the ratio of KD (WT KRAS) to KD (KRAS G12D), e.g., when measured according to SPR, such as when measured according to an SPR assay as described in the examples below). In embodiments, the compounds show significant improvements in cellular potency as compared to compounds known in the art. In embodiments, the compounds have multi-mutant RAS cellular inhibition whilst sparing WT KRAS, NRAS and HRAS; thus, the compounds act as pan-KRAS inhibitors which not only spare other RAS isoforms but also spare wild-type KRAS while exhibiting multi-mutant KRAS inhibition. This has the beneficial effect of significantly expanding the patient population by approximately three-fold as compared to compounds known in the art. In embodiments, the compounds exhibit cellular inhibition of KRAS mutant G12D and at least one of KRAS mutants G12A, G12C, G12V, Q61H, G13D, or other KRAS mutants, or a combination thereof (e.g. cellular inhibition of a combination of KRAS G12D and at least two, at least three, at least four, or at least five thereof, such as a combination of KRAS G12D and any two, any three, any four, or any five thereof), whilst sparing WT KRAS. In embodiments, the compounds exhibit cellular inhibition of KRAS mutant G12D and at least one of KRAS mutants G12A, G12C, G12V, Q61H, G13D, or a combination thereof (e.g. cellular inhibition of a combination of KRAS G12D and at least two, at least three, at least four, or all five thereof, such as a combination of any two, any three, any four, or all five thereof), whilst sparing WT KRAS. In embodiments, the compounds exhibit cellular inhibition of each of KRAS mutants G12D, G12A, G12C, G12V, Q61H, and G13D, whilst sparing WT KRAS. In embodiments, the compounds of the disclosure are characterised according to their cellular inhibition of KRAS cell lines, e.g., as measured by inhibition of KRAS mediated phosphorylation of ERK as described in the examples below. In embodiments, the compounds exhibit IC50 for inhibition of ERK phosphorylation for WT KRAS cell lines of greater than about 10 µM, and inhibition of ERK phosphorylation for KRAS mutant G12D and optionally at least one of KRAS mutants G12A, G12C, G12V, Q61H, or G13D, or a combination thereof (e.g. inhibition of ERK phosphorylation of a combination of KRAS G12D and at least two, at least three, at least four, or all five thereof, such as a combination of KRAS G12D and any two, any three, any four, or all five thereof), of less than about 500 nM, e.g., less than about 250 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, or less than about 1 nM. In embodiments, the compounds exhibit increased permeability and / or improved oral bioavailability compared to compounds known in the art. Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein (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) and at least one pharmaceutically acceptable excipient or carrier. In embodiments, the pharmaceutical composition comprises a compound of Formula (0) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IIa) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IIb) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (III) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IIIa) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IIIb) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IV) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (Iva) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IVb) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (V) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (Va) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (Vb) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VI) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (Via) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VIb) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VI.I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VI.Ia) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VI.Ib) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VIIa) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VIIb) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VII.I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VII.Ia) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VII.Ib) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (VIII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (IX) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (X) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XI) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XIII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XIV) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XV) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XVI) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XVII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XVIII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XIX) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XX) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXI) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXII.I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXIII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXIII.I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXIV) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXIV.I) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXV) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXVI) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXVII) or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises a compound of Formula (XXVIII) or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions disclosed herein may be formulated for administration in solid or liquid form, e.g., using conventional carriers or excipients. Compositions may be adapted for, e.g., 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 to be applied to the skin) using techniques known in the art. In embodiments, the compounds have good permeability and oral bioavailability (e.g. improved permeability and / or improved oral bioavailability as compared to compounds known in the art). These properties are particularly beneficial as they reduce or avoid altogether the need to employ lipid / liposome formulations for dosing of the compounds. Thus, in embodiments, the pharmaceutical compositions disclosed herein are not formulated as lipid formulations or as liposome formulations. Medical uses Compounds of the present disclosure act as inhibitors of KRAS G12D, which gives them utility in the treatment of KRAS G12D-associated disorders and conditions. In particular, compounds of the disclosure are useful in the treatment of cancers, especially KRAS G12D-associated cancers. Viewed from this aspect, the disclosure provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of 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 a related aspect, the disclosure provides the use of 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 the manufacture of a medicament. In a further related aspect, the disclosure provides 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) for use in therapy. Compounds of the present disclosure are useful in 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. In one aspect, the present disclosure provides a method of treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated, in a subject in need thereof, the method comprising administering to the subject an effective amount of 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 a related aspect, the disclosure provides the use of 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 the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated. In a further related aspect, the disclosure provides 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) for use in the treatment or prevention of a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated. In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder associated with KRAS G12D (e.g., cancer, such as a KRAS G12D-associated cancer) in a subject in need thereof, the method comprising administering to the subject an effective amount of 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 a related aspect, the disclosure provides the use of 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 the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with KRAS G12D (e.g., cancer, such as a KRAS G12D-associated cancer). In a further related aspect, the disclosure provides 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) for use in the treatment or prevention of a disease or disorder associated with KRAS G12D (e.g., cancer, such as a KRAS G12D-associated cancer). In another aspect, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of 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 a related aspect, the disclosure provides the use of 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 the manufacture of a medicament for the treatment or prevention of cancer. In a further related aspect, the disclosure provides 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) for use in the treatment or prevention of cancer (e.g., a KRAS G12D-associated cancer). In embodiments, the compound reduces angiogenesis, reduces, or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., in part or completely), reduces evasion of growth suppression, reduces, or inhibits growth of cancerous or pre-cancerous cells, supresses proliferation of cancerous or pre-cancerous cells, and / or reduces the survival of cancerous or pre-cancerous cells. In embodiments, the cancer is a KRAS G12D-associated cancer. In embodiments, the cancer is characterized by increased KRAS G12D expression. In embodiments, the cancer has elevated KRAS G12D activity. In embodiments, one or more cancer cells express KRAS G12D. In embodiments, the cancer is a solid tumour (e.g., a melanoma, carcinoma, or blastoma). In other embodiments, the cancer is leukaemia (e.g., chronic lymphocytic leukaemia, CLL; acute myelogenous leukaemia, AML; or chronic myelogenous leukaemia, CML). In embodiments, the cancer is a primary tumour. In other embodiments, the cancer is a secondary tumour (e.g., a metastatic tumour). In embodiments, the cancer is selected from colorectal cancer (CRC) (e.g., rectal cancer), small bowel 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 breast carcinoma or breast adenocarcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, ovarian cancer, brain cancer (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. In embodiments, 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). In another aspect, the disclosure provides a method of inhibiting KRAS G12D activity, the method comprising contacting KRAS G12D (e.g., a cell comprising KRAS G12D) with a compound of the present 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 an in vitro or ex vivo method. In other embodiments the method is an in vivo method. In a related aspect, the disclosure provides an in vitro method of inhibiting KRAS G12D activity in a cell, the method comprising contacting the cell with a compound of the present 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). Compounds of the present disclosure (e.g., compounds of Formula (I), or compounds of Formula (0)) and the pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions, which may optionally comprise one or more pharmaceutically acceptable excipients. It will be appreciated that the methods and treatments of the various aspects of this disclosure may be effected by administering to a subject an effective amount of 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 the form of a pharmaceutical composition, which may optionally comprise one or more pharmaceutically acceptable excipients, as described herein. The compounds disclosed herein may be used alone (e.g., as a monotherapy) or in combination with one or more cancer therapies. Having been generally disclosed herein, the following non-limiting examples are provided to further illustrate this disclosure. EXAMPLES The preparation of exemplary compounds according to the present disclosure is described below. Other compounds within the scope of the disclosure may be made according to analogous methods and procedures to those described in detail below, in accordance with techniques known to those of skill in the art. Example 1: General synthetic schemes A number of synthetic protocols were used to produce the compounds described herein. These synthetic protocols have common intersections and can be used alternatively for synthesis of the compounds described herein. Scheme 1 The following scheme, Scheme 1, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane is reacted with UHP to provide (92-21). (92-21) is reacted with PhN(OTf)2 and K2CO3 to provide (92- 22). (92-22) is coupled with ethynyltriisopropylsilane in the presence of palladium catalyst to provide Intermediate 2. Intermediate 2 is coupled with Intermediate 1 in the presence of palladium catalyst to provide Intermediate (92-3). The triple bond of (92-3) is reduced by adding hydrogen and Pd(OH)2 / C to provide (92-4), and the BOC protecting group of (92-4) is removed to provide (92-0).

[0075] Scheme 2 The following scheme, Scheme 2, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. 4-bromo-5-chloronaphthalen-2-ol is reacted with MOMBr to provide (94-1). (94-1) is coupled with ethynyltriisopropylsilane in the presence of palladium catalyst to provide Intermediate 5. Intermediate 5 is coupled with Intermediate 1 in the presence of palladium catalyst to provide Intermediate (94-3), and the BOC protecting group of (94-3) is removed to provide (94-0). Scheme 3 The following scheme, Scheme 3, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. (96-5) is coupled with ethynyltriisopropylsilane in the presence of palladium catalyst to provide Intermediate 7. Intermediate 7 is coupled with Intermediate 1 in the presence of palladium catalyst to provide Intermediate (96-2). The BOC protecting group of (96-2) is removed to provide (96-0). Scheme 4 The following scheme, Scheme 4, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. Commercial product 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate is coupled with CO in the presence of palladium catalyst to provide Intermediate (107-1). (107-1) is reacted with oxalyl chloride and ammonium hydroxide to provide Intermediate 8. Intermediate 8 is coupled with Intermediate 1 in the presence of palladium catalyst to provide (107-3). The TIPS protecting group of (107-3) is removed to provide (107-4). The BOC protecting group of (96-2) is removed to provide (107-0).

[0076] Scheme 5 The following scheme, Scheme 5, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. (91-1) is coupled with (96-5) in the presence of palladium catalyst to provide (97-21). The double bond of (97-21) is reduced by adding hydrogen and Pd(OH)2 / C to provide (97-22). The BOC protecting group of (97-22) is removed to provide (97-0).

[0077] Scheme 6 The following scheme, Scheme 6, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. Commercial product 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate is coupled with (91-1) in the presence of palladium catalyst to provide Intermediate (21-40). The double bond of (21-40) is reduced by Zn and AcOH to provide (21-51). The BOC protecting group of (21-51) is removed to provide (21-19). The TIPS protecting group of

[0078] Scheme 7 The following scheme, Scheme 7, illustrates an exemplary way of preparing compounds in accordance with the present disclosure and examples. The BOC protecting group of (92-24) is removed to provide (85-0). Examples 2 - 45: Synthetic examples Examples 2 to 45 describe synthetic protocols which were employed in order to arrive at illustrative compounds disclosed herein. As would be understood by the skilled person, further compounds of the disclosure may be synthesized analogously. In the synthetic protocols which follow, R and S (or R* and S*) notation is employed to indicate the stereochemistry at particular chiral centres; thus, unless expressly stated otherwise, the use of the index R, R, R*, or R* in the specific examples below should not be understood as referring to a substituent group R or R* as defined in relation to the Markush formulae provided in the preceding disclosure. Table 2 below lists the compounds synthesized in the following synthetic examples, identified according to the relevant Example No. as well as (where appropriate) the compound numbers allocated to such compounds in Table 1:

[0079] Table 2

[0080] Experimental techniques The following analytical techniques were employed in Examples 2-45 below, unless otherwise specified. 400 MHz Liquid-state NMR experiments were recorded on 400 MHz(9.4 Tesla) AVANCE NEO 400MHz (400 MHz for1H，100 MHz for13C) using a 5mm PI HR-BBO400S1-BBF / H / D-5.0-Z SP probe (Bruker BioSpin AG, Switzerland). 300 MHz Liquid-state NMR experiments were recorded on 300 MHz(7.04 Tesla) AVANCE III HD 300MHz (300 MHz for1H，75 MHz for13C) using a 5mm PABBO BB-1H / D Z-GRD probe (Bruker BioSpin AG, Switzerland). All the experiments used for the resonance assignment procedure and the elucidation of the products structure (1D1H, 2D1H-1H-COSY, 2D1H-1H-ROESY, 2D1H-13C-HSQC, 2D1H-13C-HMBC) were recorded at 300k. 1H chemical shifts are reported in ppm as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet), or br s (broad singlet). Chemical shift values (8) are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard. LCMS chromatography analysis were recorded using the following apparatus: Agilent 1260 (UV: Acquity PDA MS: QDa, ELSD) The apparatus was tested using a Ascentis Express C18 (100*4.6mm). All of them used a combination of the following eluents: Water / 0.1%FA and Acetonitrile / 0.1%FA and a positive electrospray ES+ as ionization mode, The UV detection was set up at 220 and 254 nm. Temperatures are given in degrees Celsius (°C). The reactants used in the examples below may be obtained from commercial sources or they may be prepared from commercially available starting materials as described herein or by methods known in the art. The progress of the reactions described herein were followed as appropriate by LC or TLC, and as the skilled person will readily realise, reaction times and temperatures may be adjusted accordingly. Preparation of Intermediates Intermediates were prepared for use in Examples 2-22 below according to the following methods. Intermediate 1: tert-Butyl 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: To a stirred solution of cyanuric chloride (10.00 g, 54.2 mmol, 1.0 equiv) and DIEA (10.51 g, 81.3 mmol, 1.5 equiv) in DCM (250 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (9.21 g, 43.4 mmol, 0.8 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 20 °C under nitrogen atmosphere. The resulting mixture was diluted with water (250 mL). The resulting mixture was extracted with DCM (3 x 250 mL). The combined organic layers were washed with brine (3x200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography, eluting with PE / EtOAc (30:1) to afford 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, 63% yield) as a white solid. Step 2: tert-Butyl 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 1,3,5-triazin-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 equiv) and Cs2CO3 (27.13 g, 83.3 mmol, 3 equiv) in MeCN (200 mL) was added [(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methanol (6.63 g, 41.6 mmol, 1.5 equiv) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 25 °C under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3x200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to afford tert-butyl (1R,5S)-3-(4- {[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5.30 g, 79% yield) as a white solid. Intermediate 2: ((8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl)ethynyl)triisopropylsilane -3-(methoxymethoxy) naphthalen-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 equiv) and UHP (4.17 g, 44.4 mmol, 4.0 equiv) in MeOH (40 mL) was stirred for 6 h at 40oC under nitrogen atmosphere. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (6:1) to afford 8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-ol (2.00 g, 74% yield) as a light yellow oil. ESI-MS m / z =249.10 [M- H]-; Calculated MW: 250.01 8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl trifluoromethanesulfonate A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (1.00 g, 3.99 mmol, 1.0 equiv), K2CO3 (1.10 g, 7.99 mmol, 2.0 equiv) and 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonylmethanesulfonamide (1.71g, 4.79mmol, 1.2equiv) in THF (10 mL) was stirred for 5h at 40oC under nitrogen atmosphere. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to afford 8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.50g, 98% yield) as a light yellow oil. ESI-MS m / z = 381.00 [M-H]-; Calculated MW: 382.05 ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.00 g, 2.61 mmol, 1.0 equiv), CuI (50.0 mg, 0.26 mmol, 0.1 equiv), ethynyltriisopropylsilane(0.57 g, 3.13 mmol, 1.2 equiv) and Pd(PPh3)2Cl2 (90.0 mg, 0.13 mmol, 0.05 equiv) in DMF (10 mL) was stirred for 5h at 80oC under argon atmosphere. The resulting mixture was cooled down to room temperature and diluted with EtOAc. 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, eluting with PE / EtOAc (8:1) to afford ((8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (800.0 mg, 74% yield) as a light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.82 (dd, J = 9.0, 6.0 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.42 (t, J = 9.3 Hz, 1H), 5.31 (s, 2H), 3.64 (qd, J = 7.3, 3.0 Hz, 2H), 3.42 (s, 3H), 1.26 (m, J = 7.3, 3.0 Hz, 3H), 1.2-1.11 (m, 21H). Intermediate 3: 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline Step 1: 6, 8-Dibromo-3-fluoroquinolin-5-amine To a stirred solution of 3-fluoroquinolin-5-amine (2.00 g, 12.3 mmol, 1.0 equiv) in DMF (30 mL) was added a solution of NBS (4.50 g, 25.2 mmol, 2.0 equiv) in DMF (10 ml) dropwise at -15oC under nitrogen atmosphere. The resulting mixture was stirred for 1h at -15oC under nitrogen atmosphere. The reaction was quenched by the addition of water at -15oC. The precipitated solids were collected by filtration and washed with water. This resulted in 6, 8-dibromo- 3-fluoroquinolin-5-amine (4.00 g, 95% yield) as a yellow solid. ESI-MS m / z = 318.9 [M+H]+; Calculated MW: 317.9

[0081] Step 2: 5-Bromo-8-fluoro-[1,2,3]oxadiazolo[4,5-f]quinoline To a mixture of 6,8-dibromo-3-fluoroquinolin-5-amine (4.00 g, 12.6 mmol, 1.0 equiv) and NaNO2 (1.62 g, 23.4 mmol, 2.5 equiv) in CH3COOH (50 mL) were added propanoic acid (50 mL) at 0oC. The resulting mixture was stirred for 1 h at 0oC under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford 5-bromo-8-fluoro-[1,2,3]oxadiazolo[4,5-f]quinoline (2.20 g, 64% yield) as a yellow solid. ESI-MS m / z = 267.9 [M+H]+; Calculated MW: 266.9 Step 3: 8-Bromo-3-fluoroquinolin-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 equiv) in EtOH (50 mL) and THF (50 mL) was added NaBH4 (776.2 mg, 20.5 mmol, 2.5 equiv) at 0oC. The resulting mixture was stirred for 1h at 0oC under nitrogen atmosphere. The resulting mixture was diluted with water at 0oC. The mixture was acidified to pH 7 with 1M HCl (aq.). The resulting mixture was extracted with EtOAc. 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 / EtOAc (1:1) to afford 8- bromo-3-fluoroquinolin-6-ol (1.23 g, 53.2% yield) as a brown solid. ESI-MS m / z = 242.0 [M+H]+; Calculated MW: 241.01H NMR (300 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.77 (d, J = 2.7 Hz, 1H), 8.14 (dd, J = 9.9, 2.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H). Step 4: 8-Bromo-3-fluoro-6-(methoxymethoxy)quinolone To a stirred solution of 8-bromo-3-fluoroquinolin-6-ol (500.0 mg, 2.06 mmol, 1.0 equiv) and DIEA (533.9 mg, 4.13 mmol, 2.0 equiv) in DCM (10 mL) was added bromo(methoxy)methane (309.7 mg, 2.47 mmol, 1.2 equiv) dropwise at 0oC under argon atmosphere. The resulting mixture was stirred for 2 h at room temperature under argon atmosphere. The reaction was diluted with water at 0oC. 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 Prep-TLC (PE / EtOAc 2:1) to afford 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline (433.0 mg, 73% yield) as a brown solid. ESI-MS m / z = 286.0 [M+H]+; Calculated MW: 285.01H NMR (400 MHz, Chloroform-d) δ 8.70 (d, J = 2.7 Hz, 1H), 7.71 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 8.8, 2.7 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 5.22 (s, 2H), 3.45 (s, 3H). Intermediate 4: 3-Fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinolone Step 1: 3-Fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinolone Into a 40 mL vial were added 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline (300.0 mg, 1.04 mmol, 1.0 equiv), ethynyltriisopropylsilane (1.34 g, 7.34 mmol, 7.0 equiv), CuI (39.9 mg, 0.21 mmol, 0.2 equiv), Pd(PPh3)2Cl2(73.6 mg, 0.10 mmol, 0.1 equiv), DIEA (406.5 mg, 3.14 mmol, 3.0 equiv) and DMF (15 mL) at room temperature. The resulting mixture was stirred for 2h at 100oC under argon atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The reaction was diluted with water at room temperature. The resulting mixture was extracted with EtOAc. 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 Prep-TLC (PE / EtOAc 4:1) to afford 3-fluoro-6- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinolone (322.0 mg, 79% yield) as a black oil. ESI-MS m / z = 388.2 [M+H]+; Calculated MW: 387.21H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 2.8 Hz, 1H), 7.67 – 7.56 (m, 2H), 7.28 (d, J = 2.7 Hz, 1H), 5.28 (s, 2H), 3.51 (s, 3H), 1.21-1.18 (m, 21H). Intermediate 5: ((8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane 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 equiv) and DIEA (2.01 g, 15.5 mmol, 2.0 equiv) in DCM (20 mL) was added bromo(methoxy)methane (1.94 g, 15.5 mmol, 2.0 equiv) dropwise at 0oC under argon atmosphere. The resulting mixture was stirred for 2h at room temperature under argon atmosphere. The reaction was quenched by the addition of water at 0oC. 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, eluting with PE / EtOAc (4:1) to afford 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (2.16 g, 93% yield) as a reddish solid.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). Step 2: ((8-Chloro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane To a stirred mixture of 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (1.00 g, 3.31 mmol, 1.0 equiv), CuI (130.0 mg, 0.66 mmol, 0.2 equiv), Pd(PPh3)2Cl2 (230.0 mg, 0.33 mmol, 0.1 equiv) and DIEA (1.29 g, 9.94 mmol, 3.0 equiv) in DMF (20 mL) was added ethynyltriisopropylsilane (3.02 g, 16.5 mmol, 5.0 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 16h at 100oC under argon atmosphere. The resulting mixture was extracted with EtOAc. 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 Prep-TLC (PE / EtOAc 3:1) to afford ((8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (1.30 g, 97% yield) as a black liquid.1H NMR (300 MHz, DMSO-d6) δ 7.87 (dd, J = 8.1, 1.5 Hz, 1H), 7.63 (d, J = 2.6 Hz, 1H), 7.56 – 7.39 (m, 3H), 5.35 (s, 2H), 3.43 (s, 3H), 1.13 (d, J = 2.8 Hz, 21H). Intermediate 6: 6-(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinoline 0095 Step 1: 6, 8-Dibromoquinolin-5-amine To a stirred solution of 5-aminoquinoline (5.00 g, 34.7 mmol, 1.0 equiv) in DMF (30 mL) was added NBS (12.34 g, 69.4 mmol, 2.0 equiv) (dissolved in 30 mL DMF) dropwise at -10 °C. The resulting mixture was stirred for 1h at -10 °C. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water 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 / EtOAc (3:1) to afford 6,8-dibromoquinolin-5-amine (9.00 g, 81%) as a brown solid. ESI-MS m / z = 300.8 [M+H]+; Calculated MW: 299.9.1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 4.2, 1.5 Hz, 1H), 8.74 (dd, J = 8.6, 1.6 Hz, 1H), 8.04 (s, 1H), 7.56 (dd, J = 8.6, 4.1 Hz, 1H), 6.35 (s, 2H). Step 2: 5-Bromo-[1,2,3]oxadiazolo[4,5-f]quinoline To a stirred mixture of 6,8-dibromoquinolin-5-amine (8.80 g, 29.1 mmol, 1.0 equiv) in AcOH (60 mL) and propanoic acid (20 mL) was added NaNO2 (3.02 g, 43.7 mmol, 1.5 equiv) in portions at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1) to afford 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 Step 3: 8-Bromoquinolin-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 equiv) in EtOH (40 mL) and THF (40 mL) was added NaBH4 (2.44 g, 64.5 mmol, 2.3 equiv) in portions at 0°C. The resulting mixture was stirred for 4 h at 0 °C under nitrogen atmosphere. The resulting mixture was diluted with water. The mixture was neutralized to pH 7 with 1M HCl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 8-bromoquinolin-6-ol (6.20 g, 44% yield) as a brown solid. The crude product mixture was used in the next step directly without further purification. ESI-MS m / z = 223.8 [M+H]+; Calculated MW: 223.0 Step 4: 8-Bromo-6-(methoxymethoxy)quinoline To a stirred mixture of 8-bromoquinolin-6-ol (6.10 g, 27.2 mmol, 1.0 equiv) and DIEA (7.04 g, 54.5 mmol, 2.0 equiv) in DCM (50 mL) was added methane, bromo(methoxy)methane (4.42 g, 35.4 mmol, 1.3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1.5 h at 25oC under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with DCM. The combined organic layers were concentrated under reduced pressure to afford 8-bromo-6- (methoxymethoxy)quinoline (3.20 g, 43% yield) as a brown oil. ESI-MS m / z = 205.0 [M+H]+; Calculated MW: 204.1.1H NMR (400 MHz, DMSO-d6) δ 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.34 (dd, J = 8.4, 1.7 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.58 (m, 2H), 5.37 (s, 2H), 3.45 (s, 3H). 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 equiv) and ethynyltriisopropylsilane (5.44 g, 29.8 mmol, 5.0 equiv) in DMF (15 mL) were added DIEA (2.31 g, 17.9 mmol, 3.0 equiv), CuI (14.2 mg, 0.07 mmol, 0.2 equiv) and Pd(PPh3)2Cl2 (418.9 mg, 0.59 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was cooled down to room temperature, diluted with water (50 mL), and filtered. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc 5:1) to afford 6-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]quinoline (1.60 g, 72% yield) as a green solid. ESI-MS m / z = 370.2 [M+H]+; Calculated MW: 369.2 Intermediate 7: ((3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl)ethynyl)triisopropylsilane 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 equiv), DIPA (1.39 g, 13.7 mmol, 10 equiv) and ethynyltriisopropylsilane (300.7 mg, 1.64 mmol, 1.2 equiv) in DMF (10 mL) were added CuI (26.1 mg, 0.13 mmol, 0.1 equiv) and Pd(PPh3)2Cl2 (48.2 mg, 0.06 mmol, 0.05 equiv) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to 30 °C. The resulting mixture was diluted with water (10 mL) then extracted with EtOAc. 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 Prep-TLC (PE / EtOAc 10:1) to afford {2-[3-chloro-5-(methoxymethoxy)-2-(2- methylcyclopropyl)phenyl]ethynyl}triisopropylsilane (459.1 mg, 78% yield) as a yellow solid. Calculated MW: 406.2.1HNMR (400 MHz, Chloroform-d) δ 6.97 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 3.4 Hz, 1H), 5.04 (d, J = 3.2 Hz, 2H), 3.39 (s, J = 1.0 Hz, 3H), 1.44 –1.38 (m, 1H), 1.25 – 1.14 (m, 6H), 1.11 – 1.01 (m, 21H). Intermediate 8: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamide Step 1: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthoic acid A mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate (5.00 g, 9.53 mmol, 1.0 equiv) and Et3N (2.84 g, 28.05 mmol, 3.0 equiv) and butyl[(3R,5S,7s)-adamantan-1-yl][(1s,3R,5S,7s)-adamantan-1-yl]phosphane {2'-amino- [1,1'-biphenyl]-2-yl}palladiumylium methanesulfonate (3.41 g, 4.67 mmol, 0.5 equiv) in DMSO:H2O(100ml:10ml) was stirred for 16h at 80 °C under carbon monoxide (20 atm) atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm to afford 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 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 equiv) and DMF (127.3 mg, 1.742 mmol, 0.5 equiv) in DCM was added (COCl)2 (663.2 mg, 5.22 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 1h at 0 °C. The resulting mixture was concentrated under vacuum. To the above mixture was added THF (10 mL) at 0 °C, then added NH3.H2O (5 mL, 128.40 mmol, 36.8 equiv) at 0 °C. The resulting mixture was stirred for additional 1h at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 30 min; detector, UV 254 nm to afford 7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalene-1-carboxamide (540.0 mg, 34% yield) as a dark red solid. ESI- MS m / z =430.17 [M+H]+; Calculated MW: 429.211H NMR (400 MHz, DMSO-d6) δ 8.03 – 7.92 (m, 2H), 7.58 (d, J = 2.6 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 7.01 (s, 1H), 5.33 (s, 2H), 3.43 (s, 3H), 1.13 (d, J = 4.8 Hz, 21H). Intermediate 9: ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane -(methoxymethoxy) naphthalen-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 equiv) and UHP (4.17 g, 44.4 mmol, 4.0 equiv) in MeOH (40 mL) was stirred for 6 h at 40oC under nitrogen atmosphere. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc(6:1) to afford 8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-ol (2.00 g, 74% yield) as a light yellow oil. ESI-MS m / z =249.10 [M- H]-; Calculated MW: 250.10 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (1.00 g, 3.99 mmol, 1.0 equiv), K2CO3 (1.10 g, 7.99 mmol, 2.0 equiv) and 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonylmethanesulfonamide (1.71g, 4.79mmol, 1.2equiv) in THF (10 mL) was stirred for 5h at 40oC under nitrogen atmosphere. The resulting mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to afford 8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.50g, 98% yield) as a light yellow oil. ESI-MS m / z = 381.00 [M-H]-; Calculated MW: 382.05 ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.00 g, 2.61 mmol, 1.0 equiv), CuI (50.0 mg, 0.26 mmol, 0.1 equiv) and Pd(PPh3)2Cl2 (90.0 mg, 0.13 mmol, 0.05 equiv) in DMF (10 mL) was stirred for 5h at 80oC under argon atmosphere. The resulting mixture was cooled down to room temperature and diluted with EtOAc. 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, eluting with PE / EtOAc (8:1) to afford ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane (800.0 mg, 74% yield) as a light yellow oil. Calculated MW: 414.241H NMR (400 MHz, DMSO-d6) δ 7.82 (dd, J = 9.0, 6.0 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.42 (t, J = 9.3 Hz, 1H), 5.31 (s, 2H), 3.64 (qd, J = 7.3, 3.0 Hz, 2H), 3.42 (s, 3H), 1.26 (m, J = 7.3, 3.0 Hz, 3H), 1.2-1.11 (m, 21H). Intermediate 10: (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl)naphthalen-1- yl)methanol Step 1: 8-Ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-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 equiv) and UHP (4.17 g, 44.4 mmol, 4.0 equiv) in MeOH (40 mL) was stirred for 6 h at 40oC under argon atmosphere. The resulting mixture was cooled down to 20 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and eluted with PE / EtOAc (6:1) to afford 8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-ol (2.00 g, 74%) as a light yellow oil. ESI-MS m / z =249.10 [M-H]-; Calculated MW: 250.01 Step 2: 8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl trifluoromethanesulfonate A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (1.00 g, 3.99 mmol, 1.0 equiv), K2CO3 (1.10 g, 7.99 mmol, 2.0 equiv) and 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonylmethanesulfonamide (1.71g, 4.79mmol, 1.2equiv) in THF (10 mL) was stirred for 5h at 40oC under argon atmosphere. The resulting mixture was cooled down to 20 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to afford 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.50g, 98%) as a light yellow oil. ESI-MS m / z = 381.00 [M-H]-; Calculated MW: 382.05 Intermediate 11: 5-bromo-7-(methoxymethoxy)quinoline Step 1: To a stirred mixture of 5-bromo-7-methoxyquinoline (1.00 g, 4.20 mmol, 1.0 equiv) in toluene (10 mL) was added AlCl3 (1.68 g, 12.6 mmol, 3.0 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down 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 afford 5-bromoquinolin-7-ol (600.0 mg, 64% yield) as an orange solid. ESI-MS m / z = 224.0 / 226.0[M+H]+; Calculated MW: 223.1 / 225.1.1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.81 (dd, J = 4.3, 1.6 Hz, 1H), 8.33 (ddd, J = 8.5, 1.7, 0.9 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.45 – 7.41 (m, 1H), 7.30 (dd, J = 2.3, 0.9 Hz, 1H). Step 2: To a stirred mixture of 5-bromoquinolin-7-ol (440.0 mg, 4.46 mmol, 1.0 equiv) and DIEA (1.73 g, 13.4 mmol, 3.0 equiv) in DCM (20 mL) was added bromo(methoxy)methane (1.45 g, 11.6 mmol, 2.6 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 20 °C under nitrogen atmosphere. The reaction was poured into the ice / water and the resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography, eluting with DCM / MeOH (100%~10:1). The pure fractions were concentrated to afford 5-bromo-7-(methoxymethoxy)quinolone(410.0 mg, 99.% yield) as a yellow solid. ESI-MS m / z = 268.0 / 270.0 [M+H]+; Calculated MW: 267.1 / 269.1.1H NMR (300 MHz, DMSO-d6) δ 8.91 (dd, J = 4.3, 1.6 Hz, 1H), 8.42 (ddd, J = 8.5, 1.6, 0.8 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.64 – 7.51 (m, 2H), 5.41 (s, 2H), 3.44 (s, 3H). Intermediate 12: 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl) benzene 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 equiv) and imidazole (32.82 g, 482.0 mmol, 5.0 equiv) in DCM (400 mL) was added TBSCl (21.80 g, 144.6 mmol, 1.5 equiv) in portions at 0 °C under argon atmosphere. The resulting mixture was stirred for 2h at 20 °C under argon atmosphere. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 x400 mL). The combined organic layers were washed with brine (2x300 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 / EtOAc(10:1) to afford 3-bromo-5-chlorophenoxy(tert-butyl)dimethylsilane (27.00 g, 87% yield) as a yellow oil. Calculated MW: 320.0 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 equiv) in THF (200 mL) was added LDA (56 mL, 111.9 mmol, 2.0 equiv, 2M in THF) dropwise at -78 °C under argon atmosphere. The resulting mixture was stirred for 1h at -65 °C under argon atmosphere. To the above mixture was added DMF (20.45 g, 279.8 mmol, 5.0 equiv) dropwise over 1 h at -78 °C. The resulting mixture was stirred for additional 2 h at -65 °C. The mixture was warmed up to 0 °C. The reaction was quenched by the addition of sat. NH4Cl (aq.) (200 mL) at 0 °C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine (2x300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 2-bromo-6-chloro-4-hydroxybenzaldehyde was used in the next step directly without further purification.1H NMR (400 MHz, CD3OD-d4) δ 10.2 (s, 1H), 7.10 (s, 1H), 6.92 (s, 1H). 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 equiv) and DIEA (36.23 g, 280.3 mmol, 3.0 equiv) in DCM was added MOM-Cl (12.42 g, 186.8 mmol, 2.0 equiv) dropwise at 0 °C under argon atmosphere. The resulting mixture was stirred for 2 h at 0 °C under argon atmosphere. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with DCM (3 x 300 mL). The combined organic layers were washed with brine (2x300 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 / EtOAc (10:1) to afford 2-bromo-6-chloro-4-(methoxymethoxy) benzaldehyde (18.00 g, 69% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 5.16 (s, 2H), 3.20 (s, 3H). Step 4: (Z / E)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(prop-1-en-1-yl) benzene To a stirred mixture of ethyltriphenylphosphanium bromide (39.85 g, 107.3 mmol, 1.5 equiv) in THF (300 mL) at 0oC was added potassium tert-butoxide (107.3 mL, 107.3 mmol, 1.5 equiv, 1M in THF) under argon atmosphere. The resulting mixture was stirred for 1 h at 0 °C under argon atmosphere. To the above mixture was added 2-bromo-6-chloro-4-(methoxymethoxy) benzaldehyde (20.00 g, 71.5 mmol, 1.0 equiv) in THF (100 mL) dropwise over 30min at 0 °C. The resulting mixture was stirred for additional 1h at 20 °C. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2x300 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 / EtOAc (6:1) to afford (Z / E)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(prop-1-en- 1-yl) benzene (15.00 g, 72% yield) as a colorless oil. Calculated MW: 290.0 Step 5: 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl) benzene To a stirred mixture of diethylzinc (21.18 g, 171.4 mmol, 10 equiv) and TFA (19.55 g, 171.4 mmol, 10 equiv) in DCM (200 mL) at -40 °C under argon atmosphere. The resulting mixture was stirred for 1h at -40 °C under argon atmosphere. To the above mixture was added diiodomethane (45.93 g, 171.4 mmol, 10 equiv) dropwise over 10 min at -40oC. The resulting mixture was stirred for additional 1h at -40°C. To the above mixture was added (E / Z)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(prop-1- en-1-yl)benzene (5.00 g, 17.1 mmol, 1.0 equiv) dropwise over 10 min at -40°C. The resulting mixture was stirred for additional 20 h at 20°C. The mixture was allowed to cool down to 0°C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 x 300 mL). The combined organic layers were washed with brine (2x300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient in 2 h; detector, UV 254 nm to afford 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene (1.00 g, 19% yield) as a colorless oil. Calculated MW: 304.1H NMR (400 MHz, 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). Intermediate 13: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-amine Step 1: N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1,1- diphenylmethanimine To a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (6.00 g, 11.0 mmol, 1.0 equiv), Pd2(dba)3CHCl3(1.16 g, 1.10 mmol, 0.1 equiv) and Cs2CO3 (7.31 g, 22.4 mmol, 2.0 equiv) was added diphenylmethanimine (4.06 g, 22.4 mmol, 2.0 equiv) in toluene (100 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 110oC under argon atmosphere. The resulting mixture was cooled down to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3x100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to afford N-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1,1-diphenylmethanimine (3.55 g, 56% yield) as a black oil. ESI-MS m / z = 566.3 [M+H]+; Calculated MW: 565.3 Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-amine To a stirred mixture of N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-1,1-diphenylmethanimine (3.55 g, 6.27 mmol, 1.0 equiv) in THF (20 mL) was added HCl (4 mL, 1 M) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 30 min at room temperature under air atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase flash with the following conditions (Column: Xselect CSH Prep C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 70 mL / min; Gradient: 60% B to100% B in 30 min, 100% B; wavelength: 220 / 254 nm; RT1(min): 10.88; to afford 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-amine (1.65 g, 66% yield) as a black oil. ESI-MS m / z = 402.2 [M+H]+; Calculated MW: 401.2.1H NMR (400 MHz, DMSO-d6) δ 7.75 (dd, J = 9.2, 6.1 Hz, 1H), 7.32 (t, J = 8.9 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.56 (S, 2H), 6.53 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 3.42 (s, 3H), 1.12 (d, J = 3.9 Hz, 21H). Intermediate 14: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol Step 1: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol To a mixture of 7-fluoronaphthalene-1,3-diol (20.00 g, 112.3 mmol, 1.0 equiv), [RuCl2(Binap)2]Dichloro[(R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl]ruthenium (II) (8.92 g, 11.2 mmol, 0.1 equiv) and AcOK (22.03 g, 224.5 mmol, 2.0 equiv) in toluene were added (2- bromoethynyl)triisopropylsilane (29.33 g, 112.2 mmol, 1.0 equiv) at 0 ℃. The resulting mixture was stirred for additional 2 h at 110 ℃. The mixture was allowed to cool down to 20 °C. The resulting mixture was filtered with diatomite, the filter cake was washed with EtOAc (3x300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc to afford 7-fluoro-8-[2- (triisopropylsilyl)ethynyl]naphthalene-1,3-diol (40.00 g, 91% yield) as a dark yellow oil. ESI-MS m / z = 359.2 [M+H]+; Calculated MW: 358.2 Step 2: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-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 equiv) and DIEA (54.07 g, 418.3 mmol, 3.0 equiv) in DCM (500 mL) was added bromomethoxy-methane (26.14 g, 209.2 mmol,1.5equiv) dropwise at 0 °C under argon atmosphere. The resulting mixture was stirred for 1h at 20 °C under argon atmosphere. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (2x500 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 / EtOAc to afford 7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-ol) (30.00 g, 54% yield) as a brown oil. ESI-MS m / z = 403.0 [M+H]+; Calculated MW: 402.0 Intermediate 15: 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene Step 1: (3E)-4-(2,3-difluorophenyl)but-3-enoic acid To a stirred mixture of 2,3-difluorobenzaldehyde (50.00 g, 351.8 mmol, 1.0 equiv) and 3- (bromotriphenyl-lambda-5-phosphanyl) propanoic acid (160.70 g, 387.0 mmol, 1.1 equiv) in THF (500 mL) was added t-BuOK (703.7 mL, 703.7 mmol, 2.0 equiv, 1M in THF) dropwise at -70 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at -70 °C under nitrogen atmosphere. The mixture was warmed up to 20 °C and stirred for 1 h at 20 °C under 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 (1M aq.). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (500x2 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 / EtOAc (10:1-2:1), and the pure fraction was concentrated under reduced pressure to afford (3E)-4-(2,3-difluorophenyl)but-3-enoic acid (52.00 g, 75% yield) as a yellow oil.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). Step 2: 4-(2,3-Difluorophenyl) butanoic acid To a stirred solution of (3E)-4-(2,3-difluorophenyl)but-3-enoic acid (52.00 g, 262.4 mmol, 1.0 equiv) in EtOAc (1.5 L) was added 10% Pd / C (11.17g, 104.9 mmol, 0.4 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 20 °C under hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 200 mL). The filtrate was concentrated under reduced pressure to afford 4-(2,3-difluorophenyl) butanoic acid (50.00 g, 95% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 7.32 – 7.08 (m, 3H), 2.74 – 2.63 (m, 2H), 2.25 (t, J = 7.3 Hz, 2H), 1.81 (m, 2H). Steps 3-4: 5,6-Difluoro-3,4-dihydro-2H-naphthalen-1-one To a stirred solution of 4-(2,3-difluorophenyl)butanoic acid (50.00 g, 249.7 mmol, 1.0 equiv) and DMF (912.8 mg, 12.4 mmol, 0.05 equiv) in DCM (1 L) was added oxalyl chloride (63.40 g, 499.5 mmol, 2.0 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 20 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford the residue (50.00 g, yellow solid). To a stirred solution of the residue (50.00 g, yellow solid) in DCM (1 L) was added AlCl3 (50.31 g, 377.3 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 40 °C under nitrogen atmosphere. The reaction was quenched by the addition of water / ice (1 L) at 0 °C. The resulting mixture was extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (3 x 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 / EtOAc (100:1~2:1), and the pure fraction was concentrated under reduced pressure to afford 5,6-difluoro-3,4-dihydro-2H-naphthalen-1-one (43.00 g, 95% yield two steps) as a yellow oil. ESI-MS m / z = 183.1 [M+H]+; Calculated MW: 182.0 Steps 5-6: 3-Ethyl-7-(hydroxymethyl)-1,5-naphthyridin-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 equiv) and HBr / AcOH (2.0 mL, 22.5 mmol, 0.1 equiv, 33%) in AcOH (900 mL) was added Br2 (11.5 mL, 225.0 mmol, 1.0 equiv) in AcOH (50 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 20 °C under nitrogen atmosphere. The resulting mixture was diluted with DCM (500 mL). The resulting mixture was washed with water (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the residue. To a stirred solution of the residue in DMF (1 L) was added LiBr (23.75 g, 273.4 mmol, 1.7 equiv) and Li2CO3(20.21 g, 273.5 mmol, 1.7 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 160 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20 °C. The resulting mixture was diluted with EtOAc (2 L). The resulting mixture was washed with water (3 x 1 L). The combined organic layers were washed with brine (3 x 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 / EtOAc (100:1~10:1) and the pure fraction was concentrated under reduced pressure to afford 5,6-difluoronaphthalen-1-ol (26.00 g, 64% yield two steps) as a brown solid. ESI-MS m / z = 179.1 [M-H]-; Calculated MW: 180.0.1H NMR (400 MHz, 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). Step 7: 5,6-Difluoronaphthalen-1-yl trifluoromethanesulfonate To a stirred mixture of 5,6-difluoronaphthalen-1-ol (26.00 g, 144.3 mmol, 1.0 equiv) in DCM (300 mL) was added DIEA (46.63 g, 360.8 mmol, 2.5 equiv) and Tf2O (52.93 g, 187.6 mmol, 1.3 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 20 °C under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 x200 mL). The combined organic layers were washed with brine (3 x 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, eluted with PE / EtOAc (20:1~5:1) and the pure fraction was concentrated under reduced pressure to afford 5,6- difluoronaphthalen-1-yl trifluoromethanesulfonate (36.00 g, 80% yield) as a yellow oil. ESI-MS m / z = 310.9 [M-H]-; Calculated MW: 311.9.1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.3 Hz, 1H), 8.01 – 7.70 (m, 4H). Step 8: N-(5,6-difluoronaphthalen-1-yl)-1,1-diphenylmethanimine To a stirred mixture of 5, 6-difluoronaphthalen-1-yl trifluoromethanesulfonate (36.00 g, 115.3 mmol, 1.0 equiv) and α-phenyl-benzenemethanimine (62.69 g, 345.9 mmol, 3.0 equiv) in toluene (500 mL) were added Pd2(dba)3 (10.56 g, 11.5 mmol, 0.1 equiv), XantPhos (13.34 g, 23.1 mmol, 0.2 equiv) and Cs2CO3 (112.71 g, 345.9 mmol, 3.0 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20 °C. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 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 / EtOAc (100:1~5:1), and the pure fraction was concentrated under reduced pressure to afford N-(5,6-difluoronaphthalen-1-yl)- 1,1-diphenylmethanimine (34.00 g, 86% yield) as a yellow solid. ESI-MS m / z = 344.0 [M+H]+; Calculated MW: 343.1 Step 9: 5,6-Difluoronaphthalen-1-amine A solution of N-(5,6-difluoronaphthalen-1-yl)-1,1-diphenylmethanimine (34.00 g, 99.0 mmol, 1.0 equiv) in 4 M HCl(g) in MeOH (500 mL) was stirred for 4 h at 10 °C under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was neutralized to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 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 / EtOAc (50:1~3:1), and the pure fraction was concentrated under reduced pressure to afford 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 Step 10: 2,4-Dibromo-5,6-difluoronaphthalen-1-amine To a stirred solution of 5,6-difluoronaphthalen-1-amine (16.00 g, 89.3 mmol, 1.0 equiv) in AcOH (550 mL) was added a solution of Br2 (31.11 g, 194.7 mmol, 2.2 equiv) in AcOH (550 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20 °C. The precipitated solids were collected by filtration and washed with AcOH (550 mL). The residue was diluted with 15% aqueous of NaOH (200 mL). The resulting mixture was stirred for 20 min at 20 °C under air atmosphere. The precipitated solids were collected by filtration and washed with water (3 x 100 mL). The resulting mixture was concentrated under vacuum to afford 2,4-dibromo-5,6-difluoronaphthalen-1-amine (25.00 g, 83% yield) as an off-white solid. ESI-MS m / z =337.9 [M+H]+; Calculated MW: 336.9 Step 11: 5-Bromo-6,7-difluoronaphtho[1,2-d][1,2,3]oxadiazol To a stirred solution of 2,4-dibromo-5,6-difluoronaphthalen-1-amine (25.00 g, 74.1 mmol, 1.0 equiv) in AcOH (450 mL) was added propanoic acid (41.66 g, 562.3 mmol, 7.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 °C under nitrogen atmosphere. To the above mixture was added NaNO2 (7.68 g, 111.3 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for additional 1 h at 20 °C. The precipitated solids were collected by filtration and washed with water (3 x 200 mL). The residue was concentrated under vacuum to afford 5-bromo-6,7- difluoronaphtho[1,2-d][1,2,3]oxadiazole (17.40 g, 82% yield) as a yellow solid. ESI-MS m / z =284.9 [M+H]+; Calculated MW: 283.9 Step 12: 4-Bromo-5,6-difluoronaphthalen-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 equiv) in THF (70 mL) and EtOH (210 mL) was added NaBH4 (5.38 g, 142.2 mmol, 2.3 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (70 mL) at 20 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 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 / EtOAc (20:1~3:1), and the pure fraction was concentrated under reduced pressure to afford 4- bromo-5,6-difluoronaphthalen-2-ol (8.90 g, 56% yield) as a yellow solid. ESI-MS m / z =256.9 [M+H]+; Calculated MW: 257.9 Step 13: 8-Bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene To a stirred solution of 4-bromo-5,6-difluoronaphthalen-2-ol (8.90 g, 34.3 mmol, 1.0 equiv) and DIEA (11.10 g, 85.8 mmol, 2.5 equiv) in DCM (100 mL) was added bromomethoxy-methane (7.56 g, 60.4 mmol, 1.7 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 °C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 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 / EtOAc (20:1-5:1). The pure fraction was concentrated under reduced pressure to afford 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene (8.90 g, 85% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.89 – 7.56 (m, 4H), 5.36 (s, 2H), 3.45 (s, 3H). 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-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethynyl-6-fluoronaphthalen-2-ol Step 1: tert-butyl 3-(4,6-dichloro-1,3,5-triazin-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 equiv) in DCM (50 mL) was added DIEA (3.50 g, 27.1 mmol, 1.0 equiv) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (5.76 g, 27.1 mmol, 1.0 equiv) at 0oC. The resulting mixture was warmed to room temperature and stirred for 2h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100mL) and washed with water (50mL). The resulting mixture was concentrated under vacuum to afford tert-butyl 3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 82% yield) as an off-white solid. ESI-MS m / z = 360.15 [M+H]+; Calculated MW: 359.09. Step 2: tert-butyl 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of 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 equiv) , ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (3.54 g, 22.2 mmol, 1.0 equiv), DCM (60 mL) and DIEA (2.87 g, 22.2 mmol, 1.0 equiv). The resulting mixture was stirred 16h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to afford tert-butyl 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.00 g, 93% yield) as a white solid. ESI-MS m / z = 483.45 [M+H]+; Calculated MW: 482.22.1H NMR (300 MHz, 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, 13.5 Hz, 5H), 3.04 – 2.90 (m, 1H), 2.35 – 2.03 (m, 3H), 1.92 (d, J = 17.3 Hz, 5H), 1.73 – 1.56 (m, 2H), 1.50 (s, 9H). Step 3: tert-butyl 3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of tert-butyl 3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.20 g, 4.63 mmol, 1.0 equiv) ,7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate (2.48 g, 4.63 mmol, 1.0 equiv), Pd2(dba)3 (850.0 mg, 0.93 mmol, 0.2 equiv), P(p-Tol)3 (710.0 mg, 2.32 mmol, 0.5 equiv), DIEA (3.00 g, 23.2 mmol, 5.0 equiv), HCOOH (320.0 mg, 6.95 mmol, 1.5 equiv), TBAB (2.24 g, 6.95 mmol, 1.5 equiv) and DMF (15 mL). The resulting mixture was stirred for 1.5h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was added water (50mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc = 1:2) to afford tert-butyl 3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 33% yield) as a yellow solid. ESI-MS m / z = 859.45 [M+H]+; Calculated MW:.858.47. Step 4: tert-butyl 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of tert-butyl 3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.30 g, 1.51 mmol, 1.0 equiv), Zn (990.0 mg, 15.1 mmol, 10 equiv) and AcOH (15 mL). The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10:1) to afford tert-butyl 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 76% yield) as a yellow oil. ESI-MS m / z = 861.35 [M+H]+; Calculated MW:860.48. Step 5: 4-(2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol Into a 40 mL vial were added tert-butyl 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 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 equiv), dioxane (2 mL) and HCl(gas) in dioxane (6 mL) dropwise. The resulting mixture was stirred for 1 h at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 4-(2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (740.0 mg, 88% yield) as a yellow solid. ESI-MS m / z = 717.50 [M+H]+; Calculated MW: 716.40. Step 6: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethynyl-6-fluoronaphthalen-2-ol To a stirred solution of 4-(2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (730.0 mg, 1.02 mmol, 1.0 equiv), CsF (7.73 g, 50.9 mmol, 50 equiv) and DMF (15 mL). The resulting mixture was stirred for 1 h at 25 °C under nitrogen atmosphere. The resulting mixture was added water (20mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (DCM / MeOH= 5:1) to afford the crude product (150 mg ) as an off-white solid. The crude product was repurified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 57% B in 7 min; wavelength: 254nm / 220nm nm; RT1(min): 6.8) to afford 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethynyl-6- fluoronaphthalen-2-ol (41.7 mg, 7% yield, LCMS purity: 95.6% @254nm, 96.2% @220nm) as a white solid. ESI-MS m / z = 561.25 [M+H]+; Calculated MW: 560.27.1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.83 (dd, J = 9.1, 6.1 Hz, 1H), 7.39 (t, J = 8.9 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 5.25 (d, J = 54.4 Hz, 1H), 4.63 (d, J = 1.2 Hz, 1H), 4.28 (d, J = 12.4 Hz, 1H), 4.19 (d, J = 12.5 Hz, 1H), 4.00 (t, J = 10.6 Hz, 1H), 3.94 – 3.78 (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).19F NMR (377 MHz, DMSO-d6) δ -110.33, -172.13 (d, J = 4.3 Hz). Example 3: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)oxy)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol Step 1: Tert-butyl (1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-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 equiv) in THF (5 mL) was added NaH (74.5 mg, 3.10 mmol, 5.0 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 20oC under nitrogen atmosphere. To the above mixture was added tert-butyl (1R,5S)-3-(4-chloro- 6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 equiv) at 20°C. The resulting mixture was stirred for additional 2 h at 20oC. The reaction was quenched by the addition of water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1x30 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 / EtOAc (10:1~5:1) and the pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-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 Step 2: Tert-butyl (1R,5S)-3-(4-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-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-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.46 mmol, 1.0 equiv) in DMF (10 mL) was added CsF (704.0 mg, 4.63 mmol, 10 equiv) at 20oC under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 20 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1~5:1) and the pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-((8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280.0 mg, crude) as an off-white solid. ESI-MS m / z = 707.2 [M+H]+; Calculated MW: 706.3 Step 3: 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl) benzene A solution of tert-butyl (1R,5S)-3-(4-{[(2R,7S)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[8- ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]methoxy}-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.14 mmol, 1.0 equiv) in HCOOH (2 mL) was stirred for 4 h at 20 °C under nitrogen atmosphere. The residue was purified by reversed combi-flash chromatography with the following conditions: YMC-Actus Triart C18 ExRS Column, 30*150 mm, 5¦Ìm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 39% B to 59% B in 8 min; wavelength: 254nm / 220nm nm; RT1(min): 6.08. The pure fraction was concentrated and then lyophilized to afford 4-{[(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2- yl)oxy]methyl}-5-ethynyl-6-fluoronaphthalen-2-ol (14.1 mg, 17% yield, 97.3% @254 nm; 96.8% @220 nm) as a white solid. ESI-MS m / z = 563.2 [M+H]+; Calculated MW: 562.31H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J = 9.2, 6.1 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 6.07 (q, J = 13.1 Hz, 2H), 5.24 (d, J = 54.3 Hz, 1H), 4.60 (d, J = 1.1 Hz, 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 = 8.5 Hz, 1H), 2.06 (d, J = 3.7 Hz, 1H), 1.98 (s, 1H), 1.90 (d, J = 15.3 Hz, 1H), 1.82 (s, 1H), 1.74 (dd, J = 13.1, 7.9 Hz, 2H), 1.61 (s, 2H), 1.53 – 1.36 (m, 2H). Example 4: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-chloronaphthalen-2-ol Step 1: Tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6- vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of tert-butyl (1R,5S)-3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 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, 1.0 equiv) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (960.0 mg, 6.21 mmol, 1.5 equiv) in dioxane / water (24 mL, 5:1) were added Pd(DtBPF)Cl2 (270.0 mg, 0.41 mmol, 0.1 equiv) and K2CO3 (1.72 g, 12.4 mmol, 3.0 equiv) in portions at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20 °C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 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 PE / EtOAc (1:9). The pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.98 g, 83%, yield) as a yellow solid. ESI-MS m / z = 475.5 [M+H]+; Calculated MW: 474.3 Step 2: Tert-butyl (1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)vinyl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-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-pyrrolizin-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 equiv) and 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (629.0 mg, 2.08 mmol, 1.1 equiv) in dioxane (10 mL) were added 1,2,2,6,6-pentamethylpiperidine (883.4 mg, 5.68 mmol, 3.0 equiv), tris(2-methylphenyl)phosphane (115.4 mg, 0.37 mmol, 0.2 equiv) and Pd(OAc)2 (42.58 mg, 0.190 mmol, 0.1 equiv) in portions at 20 °C under nitrogen atmosphere. The resulting mixture was stirred 16 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:3). The pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphthalen- 1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (720.0 mg, 54.61%, yield) as a brown solid. ESI-MS m / z = 695.4 [M+H]+; Calculated MW: 694.3 Step 3: Tert-butyl (1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethyl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-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)naphthalen-1- yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (500.0 mg, 0.71 mmol, 1.0 equiv) in DCM (100 mL) was added Pt / C (841.8 mg, 4.31 mmol, 6.0 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 20 °C under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (0.1% FA), 70% to 80% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethyl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, 30% yield) as a yellow solid. ESI-MS m / z = 697.2 [M+H]+; Calculated MW: 696.3 Step 4: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-chloronaphthalen-2-ol To a stirred solution of tert-butyl (1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthalen-1- yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 equiv) in MeCN (1.5 mL) was added HCl(gas) in dioxane (0.3 mL) at 20 °C under air atmosphere. The resulting mixture was stirred for 1 h at 20 °C under air atmosphere. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 35% B to 41% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 9.6). The pure fraction was lyophilized to afford 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-chloronaphthalen-2-ol (13.6 mg, 11%, yield) as a white solid. ESI-MS m / z = 553.2 [M+H]+; Calculated MW: 552.2.1H NMR (400 MHz, 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, 12.5 Hz, 2H), 4.03 – 3.81 (m, 2H), 3.81 – 3.66 (m, 2H), 3.44 (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). Example 5: 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-ethyl-6-fluoronaphthalen-2-ol Step 1: 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-ethyl-6-fluoronaphthalen-2-ol To a stirred solution of tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]ethynyl}-1,3,5-triazin-2- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120.0 mg, 0.17 mmol, 1.0 equiv) in dioxane (2 mL) was added HCl(gas) in dioxane (3 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 2h at 0oC. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL). The residue was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 2% B to 2% B in 1 min, 2% B to 7% B in 1.5 min, 7% to 30% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 7.73 This resulted in 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-ethyl-6- fluoronaphthalen-2-ol (70.1 mg, 73% yield) as a light brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.27-8.15 (m, 2H), 7.75 (dd, J = 9.1, 5.9 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.44 – 7.34 (m, 2H), 5.27 (d, J = 54 Hz, 1H), 4.44 – 4.22 (m, 2H), 4.13 – 3.95 (m, 2H), 3.77 – 3.48 (m, 5H), 3.09-3.07 (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 = 7.3 Hz, 3H). Example 6: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2- methylcyclopropyl]phenol Steps 1-2: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-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-hexahydropyrrolizin-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 equiv) in MeOH (6 mL) was added Pd(OH)2 / C (150.4 mg, 1.07 mmol, 2.0 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 20 °C under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-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, 85% yield) as a brown solid. To a stirred mixture of tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 equiv) in MeCN (2 mL) was added HCl(gas) indioxane(2 mL, 4M) at 20oC under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 20 °C under air atmosphere. The mixture was concentrated to give the crude product (200.0 mg) which was purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3, Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 42% B to 57% B in 8 min; wavelength: 254nm / 220nm nm; RT1(min): 8.38). The pure fraction was lyophilized to afford 3-[2-(4- {[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol (40.0 mg, 21% yield 96.3% purity @254nm; 96.1%@220nm) as a white solid. ESI-MS m / z = 557.3 [M+H]+; Calculated MW: 556.21H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 6.59 (dd, J = 23.3, 2.5 Hz, 2H), 5.24 (d, J = 54.4 Hz 1H), 4.25 (dd, J = 45.1, 12.5 Hz, 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 = 5.8 Hz, 3H), 0.92 – 0.67 (m, 3H). Example 7: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2- methylcyclopropyl]phenol 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 equiv) and ethynyltris(propan-2-yl)silane (1.19 g, 6.54 mmol, 2.0 equiv) in DMF (10 mL) were added DIEA (1.27 g, 9.81 mmol, 3.0 equiv), Pd(PPh3)2Cl2 (229.6 mg, 0.32 mmol, 0.1 equiv) and CuI (124.6 mg, 0.65 mmol, 0.2 equiv) at 20oC under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100oC under nitrogen atmosphere. The mixture was allowed to cool down to 20oC. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed combi-flash chromatography with the following conditions: column, C18; mobile phase, A: FA (0.1%) in water, B: MeCN, 60% to 100% gradient in 20 min; detector, UV 254 nm. The pure fraction was concentrated under vacuum to afford {2-[3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2- methylcyclopropyl]phenyl]ethynyl}triisopropylsilane (1.16 g, 87% yield) as a brown solid. ESI-MS m / z = no Ms signal; Calculated MW: 406.2 Step 2: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 To a stirred mixture of tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.57 g, 3.24 mmol, 1.2 equiv) and {2-[3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2- methylcyclopropyl]phenyl]ethynyl}triisopropylsilane (1.16 g, 2.85 mmol, 1.0 equiv) in DMF (20 mL) were added CuI (108.5 mg, 0.57 mmol, 0.2 equiv) and Pd(PPh3)4(329.3 mg, 0.28 mmol, 0.1 equiv) at 20oC under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0oC under nitrogen atmosphere. To the above mixture was added CsF (1.30 g, 8.55 mmol, 3.0 equiv) at 0oC. The resulting mixture was stirred for additional 16 h at 40oC. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 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, eluted with PE / EtOAc (50:1~ 2:1) and the pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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, 66% yield) as a brown solid. ESI-MS m / z = 697.3 [M+H]+; Calculated MW: 696.3 Step 3: 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-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-fluoro-hexahydropyrrolizin-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 equiv) in MeCN (1 mL) was added HCl (gas) in dioxane (1 mL, 4M) at 20 °C under air atmosphere. The resulting mixture was stirred for 0.5 h at 20oC under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed combi-flash chromatography with the following conditions: Column: Xbridge Phenyl OBD Column, 19*150 mm, 5m; Mobile Phase A: water (10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 55% B in 8 min; wavelength: 254nm / 220nm nm; RT1(min): 6.9. The pure fraction was concentrated under vacuum to afford 3-[2-(4-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5- triazin-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2-methylcyclopropyl]phenol (28.0 mg, 17% yield, 95.7% purity @254nm, 95.5% @220nm) as a white solid. ESI-MS m / z = 553.2 [M+H]+; Calculated MW: 552.21H NMR (300 MHz, DMSO-d6) δ 6.94 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 5.26 (d, J = 54.4 Hz, 1H), 4.23 (t, J = 12.4 Hz, 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, 8.3 Hz, 1H), 2.10 (d, J = 4.8 Hz, 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 = 5.9 Hz, 3H), 1.08 (s, 1H), 0.92-0.75 (m, 2H). Example 8: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethyl-6-fluoronaphthalen-2-ol Step 1: Tert-butyl 3-(4-((8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of {2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl]ethynyl}triisopropylsilane (800.0 mg, 1.92 mmol, 1.0 equiv), tert-butyl 3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.11 g, 2.31 mmol, 1.2 equiv), CuI (73.4 mg, 0.38 mmol, 0.2 equiv) and Pd(PPh3)2Cl2 (135.4 mg, 0.19 mmol, 0.1 equiv) in DMF (8 mL) was added CsF (1.46 g, 9.64 mmol, 5.0 equiv) in portions at 0oC under argon atmosphere. The resulting mixture was stirred for 0.5h at 0oC under argon atmosphere. The resulting mixture was stirred for 5h at 40oC under argon atmosphere. The resulting mixture was cooled down to room temperature and diluted with EtOAc. 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, eluting with PE / EtOAc (1:1) to afford tert-butyl 3-(4-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800.0 mg, 59% yield) as a brown yellow oil. ESI-MS m / z = 705.45[M+H]+; Calculated MW: 704.35.1H NMR (400 MHz, DMSO-d6) δ 7.88 (dd, J = 9.1, 5.9 Hz, 1H), 7.74 (d, J = 2.7 Hz, 1H), 7.70 (d, J = 2.7 Hz, 1H), 7.48 (t, J = 9.3 Hz, 1H), 5.36 (s, 2H), 4.48 – 4.34 (m, 2H), 4.26 (s, 2H), 4.09 (t, J = 10.9 Hz, 1H), 4.01 (t, J = 10.1 Hz, 1H), 3.58 (d, J = 8.1 Hz, 2H), 3.43 (s, 3H), 3.28-3.20(m, 1H), 3.18 – 2.92 (m, 5H), 2.83 (d, J = 7.2 Hz, 1H), 2.10 (s, 1H), 2.03 (s, 1H), 1.98 (d, J = 10.2 Hz, 1H), 1.88 – 1.70 (m, 4H), 1.56 (d, J = 9.4 Hz, 2H), 1.44 (s, 9H), 1.35 – 1.31 (m, 3H). Step 2: Tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate A mixture of tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-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 equiv) and Pd(OH)2 / C (400.0 mg, 2.84 mmol, 5.0 equiv) in MeOH (20 mL) was stirred for 1h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. This resulted in tert-butyl 3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300.0 mg, 75% yield) as a light yellow solid. ESI-MS m / z = 709.35[M+H]+; Calculated MW: 708.381H NMR (400 MHz, DMSO-d6) δ 7.74 (dd, J = 9.0, 6.2 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.18 (d, J = 2.7 Hz, 1H), 5.26 (s, 2H), 4.44 (d, J = 12.8 Hz, 1H), 4.37 (d, J = 12.9 Hz, 1H), 4.21 (s, 2H), 4.07 – 3.99 (m, 1H), 3.97 – 3.87 (m, 1H), 3.54 (dd, J = 9.3, 6.3 Hz, 2H), 3.39 (s, 3H), 3.28 – 3.18 (m, 2H), 3.09 – 2.96 (m, 6H), 2.88 (t, J = 7.9 Hz, 2H), 2.81 (q, J = 8.7 Hz, 1H), 2.06 (d, J = 3.1 Hz, 1H), 2.00 – 1.96 (m, 1H), 1.96 – 1.89 (m, 1H), 1.82 (d, J = 7.2 Hz, 3H), 1.76 – 1.68 (m, 2H), 1.53 – 1.45 (m, 2H), 1.43 (d, J = 2.5 Hz, 9H), 1.24 (t, J = 7.4 Hz, 3H). Step 3: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethyl-6-fluoronaphthalen-2-ol To a stirred solution of tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6- {2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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 equiv) in dioxane (2 mL) was added HCl(gas) in dioxane (9 mL) dropwise at 0oC under argon atmosphere. The resulting mixture was stirred for 2h at room temperature under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 20% B in 7 min; wavelength: 254nm / 220nm nm; RT1(min): 6.35) to afford 4-[2-(4-{[(2R,7aS)- 2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5- triazin-2-yl)ethyl]-5-ethyl-6-fluoronaphthalen-2-ol (33.0 mg, 15% yield) as a light yellow solid. ESI- MS m / z = 565.25[M+H]+; Calculated MW: 564.301H NMR (400 MHz, DMSO-d6) δ9.59 (s, 1H), 8.24-8.18 (m, 1H), 7.61 (dd, J = 9.0, 6.2 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 7.02 (t, J = 2.3 Hz, 2H), 5.25 (d, J = 54.3 Hz, 1H), 4.35 (d, J = 12.7 Hz, 1H), 4.25 (d, J = 12.9 Hz, 1H), 4.12-3.17 (m, 3H), 3.55-3.53 (m, 2H), 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 = 7.3 Hz, 3H). Example 9: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloronaphthalen-2-ol Step 1: Tert-butyl (1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthalen-1-yl)ethynyl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate Into a 40 mL vial were added ((8-chloro-3-(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane (300.0 mg, 0.74 mmol, 1.0 equiv), tert-butyl 3-(4-chloro-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-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 equiv), CuI (28.3 mg, 0.14 mmol, 0.2 equiv), Pd(PPh3)4 (86.0 mg, 0.07 mmol, 0.1 equiv) and DMF (10 mL) at 0oC. The resulting mixture was stirred for 30 min at 0oC under argon atmosphere. To the above mixture was added CsF (565.3 mg, 3.72 mmol, 5.0 equiv) at 0oC under argon atmosphere. The resulting mixture was stirred for 16h at 40oC under argon atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The reaction was diluted with water. The resulting mixture was extracted with EtOAc. 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 prep- TLC (DCM / MeOH 10:1) to afford tert-butyl (1R,5S)-3-(4-((8-chloro-3- (methoxymethoxy)naphthalen-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (425.0 mg, 82% yield) as a black solid. ESI-MS m / z = 693.3 [M+H]+; Calculated MW: 692.3 Step 2: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloronaphthalen-2-ol To a stirred solution of tert-butyl (1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthalen-1- yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250.0 mg, 0.36 mmol, 1.0 equiv) in MeCN (6 mL) was added HCl (gas) in dioxane (6 mL) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile Phase A: 10 mmol / L NH4HCO3+ 0.05% NH3H2O, Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 31% B in 2 min, 31% to 50% B in 10 min; wavelength: 254 nm / 220 nm; RT1(min): 9.32) to afford 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloronaphthalen- 2-ol (31.0 mg, 15% yield, 96.5%@254 nm, 96.7%@220nm) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.59 (t, J = 3.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.22 – 7.15 (m, 2H), 5.29 (d, J = 53.4 Hz, 1H), 4.43-4.40 (m, 2H), 4.19 – 4.02 (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). Example 10: 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloro-4-((1S,2S)-2- methylcyclopropyl)phenol 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-pyrrolizin-7a(5H)- yl)methoxy)-1,3,5-triazin-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 equiv) and tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (654.9 mg, 1.35 mmol, 1.2 equiv) in DMF (10 mL) were added CuI (21.5 mg, 0.11 mmol, 0.1 equiv) and Pd(PPh3)4 (65.2 mg, 0.05 mmol, 0.05 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added CsF (858.2 mg, 5.65 mmol, 5.0 equiv) at 0 °C. The resulting mixture was stirred for additional 2 h at 40 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc 3:1) to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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, 30.50% yield) as a light yellow solid. ESI-MS m / z =697.3 [M+H]+; Calculated MW: 696.3 Step 2: 3-((4-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloro-4-((1S,2S)-2- methylcyclopropyl)phenol Into a 40 mL vial were added tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 (70.0 mg, 0.10 mmol, 1.0 equiv) and HCl(gas)in dioxane at 0 °C. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: 10mmol / L NH4HCO3+0.05%NH3H2O, Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 38% B in 2 min, 38% to 55% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 9.23) to afford 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-chloro-4-[(1R*,2S*)-2- methylcyclopropyl]phenol (18.0 mg, 32% yield, 98.8% purity @254nm; 98.9% purity @220nm) as an off-white solid. ESI-MS m / z =553.2. [M+H]+; Calculated MW: 552.2.1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 6.92 (dd, J = 23.3, 2.6 Hz, 2H), 5.26 (d, J = 54.3 Hz, 1H), 4.24 (t, J = 14.1 Hz, 2H), 4.12 – 3.91 (m, 2H), 3.50 (s, 2H), 3.12 – 2.97 (m, 5H), 2.86 – 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 = 5.9 Hz, 3H), 1.15 –1.01(m,1H), 0.91 – 0.76 (m, 2H). Example 11: 3-[2-(4-{[(2R,7aS)-2-Fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2- methylcyclopropyl]phenol Step 1: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 To a stirred mixture of tert-butyl 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6- ethenyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.31 g, 2.75 mmol, 1.2 equiv) and rel-1-bromo-3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]benzene (700.3 mg, 2.29 mmol, 1.0 equiv) in DMF (8 mL) were added DIEA (1.18 g, 9.17 mmol, 4.0 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added Pd2(dba)3 (209.8 mg, 0.23 mmol, 0.1 equiv) and P(p-Tol.)3 (139.5 mg, 0.46 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at 100°C. The resulting mixture was cooled down to room temperature and filtered, the filter cake was washed with EtOAc. The filtrate 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, eluting with EtOAc / PE (2:1) to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-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 (1.30 g, 81% yield) as a light yellow solid. ESI-MS m / z = 699.3 [M+H]+; Calculated MW: 698.3 Step 2: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 To a stirred mixture of tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 equiv) in EtOAc (10 mL) was added Pd(OH)2 / C (300.0 mg, 2.14 mmol, 5.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 30 min at room temperature under hydrogen atmosphere The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc) to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-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, 73% yield) as a white solid. ESI-MS m / z = 701.3 [M+H]+; Calculated MW: 700.4 Step 3: 3-[2-(4-{[(2R,7aS)-2-Fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-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-fluoro-hexahydropyrrolizin-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 equiv) in dioxane (2 mL) was added HCl(gas) (4M in dioxane) (6 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 30 min at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 0% B to 27% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 7.08 / 8.49). This resulted in 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2- methylcyclopropyl]phenol (37.0 mg, 22% yield, 96.0%purity @254nm; 96.8% purity @220nm) as a white solid. ESI-MS m / z = 557.3 [M+H]+; Calculated MW: 556.31H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.16 (d, J = 15.0 Hz, 1H), 6.62 (d, J = 2.5 Hz, 2H), 5.25 (d, J = 56.0 Hz, 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). Example 12: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5- triazine-2-carboxamide Step 1: 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-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-hexahydropyrrolizin-7a- yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 4.14 mmol, 1.0 equiv) and DIEA (2.68 g, 20.7 mmol, 5.0 equiv) in dioxane (20 mL) and water (2 mL) were added Pd(OAc)2 (139.45 mg, 0.62 mmol, 0.15 equiv) and DPPP (256.19 mg, 0.62 mmol, 0.15 equiv) in portions at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C under carbon monoxide atmosphere. The mixture was allowed to cool down 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 to 5:1) and the pure fraction was concentrated to afford 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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, 22% yield) as an off-white solid. ESI-MS m / z = 493.3 [M+H]+; Calculated MW: 492.2 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- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-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 equiv) and TEA (164.4 mg, 1.62 mmol, 4.0 equiv) in DCM (5 mL) was added (COCl)2 (103.1 mg, 0.81 mmol, 2.0 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30min at 20 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. A solution of 7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-amine (163.1 mg, 0.41 mmol, 1.0 equiv) and TEA (123.3 mg, 1.22 mmol, 3.0 equiv) in DCM (2 mL) at 0 °C was added the above mixture in DCM (2 mL) dropwise at 20°C. The resulting mixture was stirred for additional 3h at 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1 to 1:1) and the pure fraction was concentrated under vacuum to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]carbamoyl}-1,3,5-triazin-2-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 20% yield) as a brown solid. ESI-MS m / z = 876.4 [M+H]+; Calculated MW: 875.5 Step 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxamide To a stirred solution of tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-{[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1- yl]carbamoyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.08 mmol, 1.0 equiv) in MeCN (1 mL) was added HCl (gas) in dioxane (0.2 mL, 4M) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 20oC under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. To the above mixture was added DMF (1mL) and CsF (124.5 mg, 0.80 mmol, 10 equiv) at 20°C. The resulting mixture was stirred for additional 1 h at 50°C. The mixture was allowed to cool down to 20°C. The resulting mixture was filtered and the filter cake was washed with DMF (2x0.5 mL). The filtrate was concentrated under reduced pressure. The crude product (40.0 mg) was purified by prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10mmol / L NH4HCO3+0.05%NH3H20, Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 45% B in10 min; wavelength: 254nm / 220nm nm; RT1(min): 8.18). The pure fraction was concentrated and then lyophilized to afford 4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-N-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-1,3,5-triazine-2-carboxamide (7.2 mg, 16% yield, 96.38% @254nm, 95.99% @220nm) as a yellow solid. ESI-MS m / z = 576.35 [M+H]+; Calculated MW: 575.25. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.64 – 9.33 (m, 1H), 7.82 (dd, J = 9.2, 6.0 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.36 (t, J = 9.0 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 5.43 – 4.71 (m, 1H), 4.59 – 4.39 (m, 2H), 4.20 (d, J = 12.5 Hz, 1H), 4.01 (dt, J = 42.2, 10.6 Hz, 2H), 3.43 (s, 3H), 3.08 – 2.91 (m, 5H), 2.76 (td, J = 8.8, 5.7 Hz, 1H), 2.20 – 1.89 (m, 3H), 1.88 – 1.69 (m, 3H), 1.63 – 1.41 (m, 4H). Example 13: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)methoxy)-5-ethynyl-6-fluoronaphthalen-2-ol Step 1: Tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6- (methoxycarbonyl)-1,3,5-triazin-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-hexahydropyrrolizin-7a- yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.00 g, 8.28 mmol, 1.0 equiv) and TEA (2.51 g, 24.84 mmol, 3.0 equiv) in 2-methyloxolane / MeOH (4:1, 50 mL) were added Dppf (914.9 mg, 1.65 mmol, 0.2 equiv) and Pd(OAc)2 (185.9 mg, 0.82 mmol, 0.1 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under a carbon monoxide atmosphere. The mixture was allowed to cool down to 20 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1~3:1). The pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6- (methoxycarbonyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 33% yield) as a red solid. ESI-MS m / z = 507.25 [M+H]+; Calculated MW: 506.3 Step 2: Tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6- (hydroxymethyl)-1,3,5-triazin-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-pyrrolizin-7a(5H)- yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 3.55 mmol, 1.0 equiv) and CaCl2 (1.38 g, 12.4 mmol, 3.5 equiv) in THF / MeOH (2:1, 30 mL) was added NaBH4 (336.1 mg, 8.88 mmol, 2.5 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 20 °C under 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, eluting with DCM / MeOH (1:10~1:7). The pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 56% yield) as a white solid. ESI-MS m / z = 479.25 [M+H]+; Calculated MW: 478.3 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- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-ol (403.8 mg, 1.01 mmol, 1.2 equiv) and PPh3 (679.6 mg, 2.59 mmol, 3.1 equiv) in THF (10 mL) was added DIAD (507.1 mg, 2.51 mmol, 3.0 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 °C under nitrogen atmosphere. To the above mixture was added tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6- (hydroxymethyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.84 mmol, 1.0 equiv) at 20 °C. The resulting mixture was stirred for additional 16 h at 20 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 60% to 70% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 35% yield) as a yellow solid. ESI-MS m / z = 863.3 [M+H]+; Calculated MW: 862.5. Steps 4-5: 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)methoxy)-5-ethynyl-6-fluoronaphthalen-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- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.23 mmol, 1.0 equiv) in DMF (2 mL) was added CsF (351.9 mg, 2.32 mmol, 10 equiv) at 20 °C under air atmosphere. The resulting mixture was stirred for 2 h at 20 °C under air atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under vacuum to afford tert-butyl (1R,5S)-3-(4-(((8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, crude) as a brown oil. To a stirred solution of tert-butyl (1R,5S)-3-(4-(((8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, crude) in DCM (0.5 mL) was added FA (2 mL) at 20 °C under air atmosphere. The resulting mixture was stirred for 2 h at 20 °C under air atmosphere. The resulting mixture was purified by prep-HPLC with the following conditions (Column: Xbridge Phenyl OBD Column, 19*150 mm, 5m; Mobile Phase A: water (10mmol / L NH4HCO3+0.05%NH3.H2O, Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 27% B to 42% B in10 min; wavelength: 254nm / 220nm nm; RT1(min): 9.4). The pure fraction was lyophilized to afford 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)methoxy)-5- ethynyl-6-fluoronaphthalen-2-ol (23.4 mg, 14% yield) as a white solid. ESI-MS m / z = 563.15 [M+H]+; Calculated MW: 562.3.1H NMR (400 MHz, DMSO-d6) δ 7.73 (dd, J = 9.1, 5.7 Hz, 1H), 7.35 (t, J = 9.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 5.29 – 5.10 (m, 1H), 5.06 (s, 2H), 4.35 (s, 1H), 4.19 (d, J = 12.6 Hz, 1H), 4.05 (d, J = 12.5 Hz, 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 = 10.5 Hz, 1H), 1.33 – 1.21 (m, 1H). Example 14: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthalen- 2-ol

[0082] Step 1: tert-butyl (1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A solution of added tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.07 mmol, 1.0 equiv) in NH3 / MeOH (7M, 15 mL) was stirred for 4h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20°C. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.20 g, crude) as a white solid. ESI-MS m / z = 464.2 [M+H]+; Calculated MW: 463.3 Step 2: ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphthalen-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 equiv) and PPh3 (151.1 mg, 0.58 mmol, 1.2 equiv) in DCM (2 mL) was added CBr4 (191.0 mg, 0.58 mmol, 1.2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1.5h at 0 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc, the pure fraction was concentrated under reduced pressure to afford ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane (220.0 mg, 96% yield) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 7.70 (dd, J = 9.0, 5.8 Hz, 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). 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- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-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-pyrrolizin- 7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.43 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (51.8 mg, 1.29 mmol, 3.0 equiv, 60%) in portions at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 20 °C under nitrogen atmosphere. To the above mixture was added ((8-(bromomethyl)-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (208.2 mg, 0.43 mmol, 1.0 equiv) at 20°C. The resulting mixture was stirred for additional 2 h at 50°C. The mixture was allowed to cool down 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 / EtOAc and the pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)- 3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methyl)amino)- 6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (210.0 mg, 56% yield) as an off-white solid. ESI-MS m / z = 862.5 [M+H]+; Calculated MW: 861.5 Step 4: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthalen-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- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.23 mmol, 1.0 equiv) in DMF (5 mL) was added CsF (352.3 mg, 2.32 mmol, 10 equiv) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 20 °C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (3x2 mL). The filtrate was concentrated under reduced pressure. To the above mixture was added HCOOH (3 mL) at 20°C. The resulting mixture was stirred for 16 h at 20 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: 10mmolNH4HCO3+0.05%NH3H2O, Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 28% B to 48% B in 8 min; wavelength: 254 / 220 nm; RT1(min): 9.37). The pure fraction was concentrated and then lyophilized to afford 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)amino)methyl)- 5-ethynyl-6-fluoronaphthalen-2-ol (15.4 mg, 12% yield) as a white solid. ESI-MS m / z = 562.30 [M+H]+; Calculated MW: 561.3.1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.85 (ddd, J = 8.8, 6.2, 1.8 Hz, 1H), 7.54 (dt, J = 48.7, 6.2 Hz, 1H), 7.40 (td, J = 9.0, 1.9 Hz, 1H), 7.21 – 6.99 (m, 2H), 5.45 – 5.01 (m, 3H), 4.86 (d, J = 1.3 Hz, 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). Example 15: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthamide Step 1: tert-Butyl 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamido)- 6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate A mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1- carboxamide (190.0 mg, 0.44 mmol, 1.0 equiv) and tert-butyl 3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (426.5 mg, 0.88 mmol, 2.0 equiv), Cs2CO3 (288.1 mg, 0.88 mmol, 2.0 equiv), XPhos (126.4 mg, 0.26 mmol, 0.6 equiv) and XPhos Pd G3 (112.2 mg, 0.13 mmol, 0.3 equiv) in dioxane was stirred 16h at 80 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 40 min; detector, UV 254 nm to afford tert-Butyl 3-(4-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-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 Step 2: tert-butyl 3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamido)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate The mixture of tert-Butyl 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1- naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.22 mmol, 1.0 equiv) and CsF (173.3 mg, 1.1 mmol, 5.0 equiv) in DMF was stirred for 0.5 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc . The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(4-(8- ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160.0 mg, 65% yield) as a reddish solid. ESI-MS m / z = 720.31; [M+H]+; Calculated MW: 719.32 Step 3: N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthamide A mixture of tert-butyl 3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamido)-6-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (160.0 mg, 0.15 mmol, 1.0 equiv) and HCl(gas) in dioxane (5 mL) was stirred for 3h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC with the following conditions (NH4HCO3 / MeCN / H2O) to afford N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1] octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthamide (36.3 mg, 40% yield) as a light yellow solid. ESI-MS m / z = 576.24; [M+H]+; Calculated MW: 575.251H NMR (400 MHz, 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 = 54.2 Hz, 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). Example 16: 4-(1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-1H-imidazol-4-yl)-5-ethynyl-6- fluoronaphthalen-2-ol

[0083] Step 1: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-(4- iodoimidazol-1-yl)-1,3,5-triazin-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-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.07 mmol, 1.0 equiv) and Cs2CO3(2.02 g, 6.21 mmol, 3.0 equiv) in DMF (20 mL) was added 4-iodo-1H- imidazole (601.4 mg, 3.10 mmol, 1.5 equiv) in portions at 25 °C. The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20°C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x50 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 afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-(4-iodoimidazol-1-yl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (860.0 mg, 65% yield) as a brown solid. ESI-MS m / z = 641.1 M+H]+; Calculated MW: 640.1 Step 2: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{4-[7- fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]imidazol-1-yl}-1,3,5- triazin-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-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-(4-iodoimidazol-1-yl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500.0 mg, 0.78 mmol, 1.0 equiv) and {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (600.1 mg, 1.17 mmol, 1.5 equiv) in water (2 mL) and dioxane (10 mL) were added K2CO3 (323.6 mg, 2.34 mmol, 3.0 equiv) and butyl[(3R,5S,7s)-adamantan-1-yl][(1s,3R,5S,7s)-adamantan-1-yl]phosphane {2'-amino-[1,1'- biphenyl]-2-yl}palladiumylium methanesulfonate (113.7 mg, 0.16 mmol, 0.2 equiv) in portions at 20°C. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20°C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (3x100 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 / EtOAc (1:1) and the pure fraction was concentrated to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)- 2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (285.0 mg, 41% yield) as a yellow solid. ESI-MS m / z = 899.4 [M+H]+; Calculated MW: 898.4 Step 3: Tert-butyl (1R,5S)-3-(4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1H- imidazol-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-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-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1- yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (285.0 mg, 0.32 mmol, 1.0 equiv) in DMF (5 mL) was added CsF (481.4 mg, 3.17 mmol, 10 equiv) in portions at 20°C. The resulting mixture was stirred for 2 h at 20°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. ESI-MS m / z = 743.3 [M+H]+; Calculated MW: 742.3 Step 4: 4-[1-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)imidazol-4-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; formic acid A mixture of tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{4- [8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (280.0 mg, 0.38 mmol, 1.0 equiv) in MeCN (4 mL) was added HCl(gas) in dioxane (4 mL, 4M) and the resulting mixture was stirred for 2 h at 20 °C under nitrogen atmosphere. The mixture was concentrated to give the product (280.0 mg, crude) which was purified by prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS Column, 19*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60mL / min; Gradient: 36%B to 56%B in10min; wavelength: 254nm / 220 nm; RT1(min): 6.4). The pure fraction was lyophilized to afford 4-[1-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)imidazol-4-yl]-5- ethynyl-6-fluoronaphthalen-2-ol (47.0 mg, 21% yield) as a yellow solid. ESI-MS m / z = 599.2 [M+H]+; Calculated MW:598.2.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.24 (s, 1H), 7.90 (t, J = 10.4, 0.0 Hz, 2H), 7.48 – 7.08 (m, 3H), 5.28 (d, J = 54.1 Hz, 1H), 4.56 (d, J = 13.0 Hz, 1H), 4.38 (d, J = 12.3 Hz, 1H), 4.24 (s, 1H), 4.10 (dt, J = 43.5, 10.2 Hz, 2H), 3.75 (s, 2H) 3.05 (d, J = 30.1 Hz, 3H), 2.83 (s, 1H), 2.20-1.83 (m, 3H), 1.81 (d, J = 31.8 Hz, 5H), 1.61 (s, 2H). Example 17: 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)oxy)methyl)-5,6-difluoronaphthalen-2-ol Step 1: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7,8- difluoro-3-(methoxymethoxy)naphthalen-1-yl]methoxy}-1,3,5-triazin-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 equiv) in THF (5 mL) was added LiHMDS (0.76 mL, 0.99 mmol, 1.2 equiv, 1.3 M in THF) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. To the above mixture was added tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (100.0 mg, 0.20 mmol, 1.0 equiv) at 0 °C. The resulting mixture was stirred for additional 2 h at 20°C. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 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 / EtOAc (10:1), and the pure fraction was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2- fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthalen-1- yl]methoxy}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280.0 mg, 48% yield) as a brown solid. ESI-MS m / z = 701.3 [M+H]+; Calculated MW: 700.3 Step 2: 4-{[(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)oxy]methyl}-5,6-difluoronaphthalen-2-ol Into a 8 mL vial were added tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl]methoxy}-1,3,5-triazin-2-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130.0 mg, 0.18 mmol, 1.0 equiv) and HCOOH (2 mL) at 20 °C. The resulting mixture was stirred for 2h at 20 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product (130.0 mg) was purified by prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 29% B to 38% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 9.8). The pure fraction was concentrated and lyophilized to afford 4-{[(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)oxy]methyl}-5,6- difluoronaphthalen-2-ol (26.9 mg, 26% yield) as a white solid. ESI-MS m / z = 557.4 [M+H]+; Calculated MW: 556.2.1H NMR (300 MHz, DMSO-d6) δ 10.12 (brs, 1H), 7.70-7.45 (m, 2H), 7.32 (d, J = 2.3 Hz, 1H), 7.20 (t, J = 2.2 Hz, 1H), 5.86-5.65 (m, 2H), 5.23 (d, J = 54.3 Hz, 1H), 4.21 (d, J = 12.5 Hz, 2H), 4.09 – 3.83 (m, 2H), 3.43 (s, 2H), 3.09 – 2.74 (m, 7H), 2.11-2.03 (m, 1H), 2.01-1.89 (m, 2H), 1.87 – 1.66 (m, 3H), 1.65-1.56 (m, 2H), 1.53-1.40 (m, 2H). tetrahydro- xy}-6-[(E)-2- [7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl]ethenyl]-1,3,5-triazin-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-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-ethenyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.11 mmol, 1.0 equiv) and 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene (702.5 mg, 2.32 mmol, 1.1 equiv) in dioxane (2 mL) were added DIEA (817.0 mg, 6.32 mmol, 3.0 equiv), PPh3 (55.3 mg, 0.21 mmol, 0.1 equiv) and Pd(OAc)2 (47.3 mg, 0.21 mmol, 0.1 equiv) in portions at 100 °C under nitrogen atmosphere. The resulting mixture was stirred for 16h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:4) to afford tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(E)-2- [7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl]ethenyl]-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (420.0 mg, 29% yield) as a yellow solid. ESI-MS m / z = 697.3 [M+H]+; Calculated MW: 696.3 Step 2: Tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[7,8- difluoro-3-(methoxymethoxy)naphthalen-1-yl]ethyl}-1,3,5-triazin-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-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-[(E)-2-[7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl]ethenyl]-1,3,5-triazin-2- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400.0 mg, 0.57 mmol, 1.0 equiv) in EtOAc (10 mL) was added Pd(OH)2 / C (305.5 mg, 2.87 mmol, 5.0 equiv) in portions at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at 20 °C under H2. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. This resulted in tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[7,8-difluoro-3-(methoxymethoxy)naphthalen-1- yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210.0 mg, 52% yield) as a white solid. ESI-MS m / z = 699.3 [M+H]+; Calculated MW: 698.3. Step 3: 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethyl]-5,6-difluoronaphthalen-2-ol Into a 8 mL vial were added tert-butyl (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-6-{2-[7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (180.0 mg, 0.26 mmol, 1.0 equiv) and HCOOH (2 mL) at 20°C. The resulting mixture was stirred for 16 h at 20 °C. The resulting mixture was concentrated under reduced pressure. The crude product (100.0 mg) was purified by prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 32% B to 40% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 9.1). The pure fraction was lyophilized to afford 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-1,3,5-triazin-2-yl)ethyl]-5,6-difluoronaphthalen-2-ol (17.4 mg, 12% yield) as a white solid. ESI-MS m / z = 555.3 [M+H]+; Calculated MW: 554.3.1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.64 – 7.41 (m, 2H), 7.02 (d, J = 20.7 Hz, 2H), 5.24 (d, J = 54.3 Hz, 1H), 4.25 (dd, J = 33.1, 12.5 Hz, 2H), 3.93 (dt, J = 42.1, 10.5 Hz, 2H), 3.51 – 3.38 (m, 4H), 3.08 – 2.77 (m, 8H), 2.06 (s, 1H), 2.00 – 1.88 (m, 2H), 1.85 – 1.67 (m, 3H), 1.65 – 1.54 (m, 2H), 1.45 (q, J = 8.3, 6.0 Hz, 2H).19F NMR (377 MHz, DMSO) δ -144.21, -146.09, -172.13. Example 19: Synthesis of compound (8) Compound (8) was synthesized based on the chemistry shown in the reaction scheme below: To a solution of SM-1 (25 g, 112 mmol) in 500 mL of DCM was added DIPEA(36.1 g, 2.5 eq) at 0oC, MOM-Br ( 23.8 g) was added and stirred at 0oC for 1 hr. The mixture was concentrated to give IX1733-c-1(21 g, 70%) as yellow oil. b. Synthesis of EXP-21-IX1733-c-2 To a solution of IX1733-c-1 (5 g, 18.7 mmol) in 50 mL TEA was added PdCl2(PPh3)2(657 mg, 0.05 eq) and CuI(356 mg, 0.1 eq) at 0oC, Trimethylsilylacetylene (3.68 g) was added and stirred at 70oC for 12 hrs. The mixture was concentrated and purified by gel column to give IX1733-c-2(5 g, 94%) as yellow solid. c. Synthesis of EXP-21-IX1733-c To a solution of IX1733-c-2(5 g, 17.6 mmol) in 50 mL MeOH was added K2CO3 (4.86 g, 2 eq) and stirred at rt for 2 hrs. The mixture was concentrated and purified by gel column to give IX1733- c(3.1 g, 84%) as yellow solid. d. Synthesis of EXP-21-IX1734-1 To a solution of SM-3 (1.74 g, 2 eq) in 5 mL DCM was added DIPEA (1.22 g, 2 eq) at -78oC, SM-2 (1 g) was added and stirred at -78oC for 1 hr. The mixture was concentrated and purified by gel column(PE / EA=4 / 1) to give IX1734-1 (1.55 g, 91%) as yellow solid. LCMS: M+1=267, Ref=2.254 min. e. Synthesis of EXP-21-IX1734-2 To a solution of IX1734-1 (0.17 g, 1 eq) in 3 mL MeCN was added DIPEA (122 mg, 2 eq) and Pd2dba3 (4.32 mg, 0.01 eq) and PPh3 (4.94 mg, 0.04 eq) and 1,10-phenanthroline (1.27 mg, 0.015 eq), IX1733-c (0.1 g) was added and stirred at 80oC for 12 hr under N2. The mixture was concentrated and purified by gel column (PE / EA=4 / 1) to give IX1734-2 (0.11 g, 44%) as yellow oil. To a solution of IX1734-2 (0.112 g, 1 eq) in 3 mL DCM was added DIPEA (54 mg, 2 eq) at -78oC, SM3 (0.024 g) was added and stirred at -78oC for 1 hr. The mixture was concentrated and purified by gel column (PE / EA=2 / 1) to give IX1734-3 (80 mg, 62%) as yellow oil.

[0084] To a solution of IX1734-3 (0.08 g, 1 eq) in 3 mL EtOAc was added HCl / EtOAc (1 mL, 4 M) at 0oC and stirred at rt for 1 hr. The mixture was diluted with EtOAc, washed by NaHCO3(sat), separated, and the organic layer was concentrated and purified by reverse combi-flash(0 to 90% MeCN in water) to give Compound (8) (32 mg, 52%) as yellow solid. LCMS; M+H=471,Ref=1.937 mins.1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 6.4 Hz, 1H), 7.66 (dd, J = 8.0, 3.9 Hz, 1H), 7.45 – 7.36 (m, 3H), 7.23 (d, J = 2.5 Hz, 1H), 4.46 – 4.17 (m, 4H), 3.56 (s, 2H), 3.17 – 2.89 (m, 3H), 2.78 (d, J = 14.2 Hz, 2H), 2.58 (d, J = 6.9 Hz, 3H), 2.34 (s, 2H), 2.05 (d, J = 11.9 Hz, 3H), 1.88 (s, 2H), 1.61 (d, J = 6.8 Hz, 1H). Example 20: Synthesis of Compound (1) Compound (1) was synthesized based on the chemistry shown in the reaction scheme of Fig.1 and as now explained in further detail below. a. Synthesis of EXP-21-IX1749-1 To a solution of dimethyl butanedioate (49.6 g, 339 mmol) in toluene (400 mL) was added MeONa (20.8, 30% solution in MeOH) under N2, the mixture was stirred at 70 °C under N2 for 30 minutes, and then a solution of 2-bromo-4,5-difluoro-benzaldehyde (25 g, 113 mmol) in toluene (100 mL) was added dropwise, after addition the mixture was heated at 85 °C for 5 hours. The mixture was cooled down to room temperature, poured into water (200 mL) and washed with Et2O (100 mL x 2). The water layer was acidified to pH 2 and extracted with EtOAc (100 mL x 2), the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to leave a residue. To the residue was added Ac2O (85 mL) and NaOAc (11.1 g), the resulting mixture was stirred at 140 °C overnight. The mixture was concentrated in vacuum, the residue was diluted with water (100 mL), acidified to pH 2 and extracted with EtOAc (100 mL x 2), the combined organic was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (0~50% DCM in petrol) to give the target product of methyl 4-acetoxy-8-bromo-5,6-difluoro-naphthalene-2- carboxylate (19 g, 35% yield). b. Synthesis of EXP-21-IX1749-2 A mixture of methyl 4-acetoxy-8-bromo-5,6-difluoro-naphthalene-2-carboxylate (25.6 g, 49.9 mmol) and Pd-C (10%, 10.6 g) in DCM (200 mL) and MeOH (200 mL) was stirred at room temperature under H2(1 atm) for 2 h. LCMS showed the start material was consumed. The mixture was filtered and concentrated to leave the crude product, which was used in the next step without further purification. c. Synthesis of EXP-21-IX1749-3 A mixture of methyl 4-acetoxy-5,6-difluoro-naphthalene-2-carboxylate (17.2 g, 43 mmol) and K2CO3 (23.9 g, 129 mmo) in MeOH (400 mL) was stirred at room temperature for 3 h. The mixture was concentrated in vacuum, the residue was diluted with water (400 mL) and extracted with DCM (400 mL*2), the combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by column chromatography (0~40% DCM in Petrol) to give the target product of methyl 5,6-difluoro-4-hydroxy-naphthalene-2-carboxylate (8.6 g, 75% yield). LCMS: RT: 2.52 min; M+1=239.2 d. Synthesis of EXP-21-IX1749-4 A mixture of methyl 5,6-difluoro-4-hydroxy-naphthalene-2-carboxylate (8.6 g, 36.1 mmol), BnBr (7.41 g, 43.3 mmol) and K2CO3 (9.98 g, 72.2 mmol) in DMF (150 mL) was stirred at room temperature overnight. The mixture was diluted with water (500 mL) and extracted by EtOAc (1000 mL), the organic was washed with saturated LiCl solution (200 mL x 3), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (0~60% DCM in Petrol) to give the target product of methyl 4-benzyloxy-5,6-difluoro-naphthalene-2-carboxylate (10.2 g, 82% yield). LCMS: RT: 2.19 min; M+23=341.1 e. Synthesis of EXP-21-IX1749-5 To a stirred solution of methyl 4-benzyloxy-5,6-difluoro-naphthalene-2-carboxylate (1.2 g, 3.66) in THF (20 mL) was added LiAlH4 solution (3.66 mL, 2 M in THF, 2.0 eq) at 0 °C dropwise under N2, the mixture was stirred at 0 °C for 1 h, quenched carefully with 10% NaOH solution (5 mL) at 0 °C and diluted with EtOAc (100 mL), the organic was washed with water (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to leave crude product of (4-benzyloxy-5,6-difluoro-2- naphthyl)methanol as yellow solid (0.7 g, 63.8% yield). LCMS: RT: 2.03 min; M+23=323.1 f. Synthesis of EXP-21-IX1749-6 To a stirred solution of (4-benzyloxy-5,6-difluoro-2-naphthyl) methanol (12 g,1.0 eq) in CHCl3 (150 mL) was added MnO2 (17.4 g, 5.0 eq) at rt, then the mixture was stirred at reflux under N2 for 2 hours, the mixture was filtered and the filtrate was concentrated to leave crude product of 4-benzyloxy-5,6- difluoro-naphthalene-2-carbaldehyde (5.6 g, 47% yield) as yellow solid. LCMS: RT: 2.20 min; M+1=299.1 g. Synthesis of EXP-21-IX1749-7 To a stirred solution of 4-benzyloxy-5,6-difluoro-naphthalene-2-carbaldehyde (5.6 g,1.0 eq) in DCM (100 mL) was added m-CPBA (9.72 g, 3.0 eq) at rt, then the mixture was stirred at rt for 12 h, the mixture was partitioned between DCM (100 mL) and Na2SO3 solution (150 mL), the organic layer was separated, dried and concentrated to dryness to leave the crude product of [7,8-difluoro-3- (methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (5.3g,75.8% yield) as yellow solid. LCMS: RT: 2.17 min; M+1=315.0 h. Synthesis of EXP-21-IX1749-8 To a stirred solution of (4-benzyloxy-5,6-difluoro-2-naphthyl) formate (5.3 g,1.0 eq) in MeOH (50 mL) and DCM (50 mL) was added K2CO3 (11.7 g, 5.0 eq) at rt, then the mixture was stirred at rt for 12 h. The mixture was filtered and the filtrate was concentrated and purified by column chromatography on silica gel (DCM in PE=90%) to afford the product of 4-benzyloxy-5,6-difluoro- naphthalen-2-ol (1.2 g, 24.9% yield) as yellow solid. LCMS: RT: 2.08 min; MS was weak i. Synthesis of EXP-21-IX1749-9 To a stirred solution of 4-benzyloxy-5,6-difluoro-naphthalen-2-ol (400 mg, 1.4 mmol) in DCM (5 mL) was added DIEA (483 mg), the mixture was cooled to 0°C, bromo(methoxy)methane (262 mg, 1.5 eq) was added by dropwise, then the mixture was stirred at 0 °C under N2 for 1 h. The mixture was concentrated and purified by column chromatography on silica gel (DCM in PE=13%) to afford the product of 8-benzyloxy-1,2-difluoro-6-(methoxymethoxy)naphthalene (180 mg, 39% yield) as white solid. Synthesis of compound EXP-21-IX1749-10 To a stirred solution of 8-benzyloxy-1,2-difluoro-6-(methoxymethoxy)naphthalene (1 g, 1.0 eq) in DCM (20 mL) was added Pd / C (10%, 200 mg), the mixture was stirred at rt under H2 (1 atm) for 2 h and filtered, the filtrate was concentrated to dryness to leave the crude product of 7,8-difluoro-3- (methoxymethoxy)naphthalen-1-ol (680 mg, 93.5%) as white solid. LCMS: RT: 1.87 min; MS was weak j. Synthesis of compound EXP-21-IX1749-11 To a stirred solution of 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol (620 mg, 2.58 mmol) in DCM (15 mL) was added DIEA (1.33 g, 10.3 mmol) under N2, the mixture was cooled to 0°C, Tf2O (2.91 g, 10.3 mmol) was added and the resulting mixture was stirred at 0 °C for 1 h. The mixture was eluted with DCM (15 mL), washed by brine (10 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (0~85% DCM in petrol) to give the target product (510 mg, 53% yield). LCMS: RT: 2.20 min; MS was weak k. Synthesis of EXP-21-IX1749-12 A mixture of [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (510 mg, 1.37 mmol), CuI (26.1 mg, 0.14 mmol), Pd(PPh3)2Cl2 (96.2 mg, 0.14 mmol), PPh3 (71.9 mg, 0.27 mmol) and ethynyl(trimethyl)silane (404 mg, 4.11 mmol) in TEA (2 mL) and DMF (6 mL) was heated in a sealed tube at 80 °C under N2for 4 h. The mixture was diluted with EtOAc (20 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography (0~100% DCM in Petrol) to give the target product (365 mg, 83% yield). LCMS: RT: 2.43 min, MS was weak l. Synthesis of EXP-21-IX1749-13 A solution of 2-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]ethynyl-trimethyl-silane (365 mg, 1.14 mmol) and K2CO3 (476 mg, 3.42 mmol) in MeOH (6 mL) was stirred at rt for 2 h. The mixture was concentrated and purified by column chromatograph (0~100% DCM in Petrol) to give the target product (210 mg, 74% yield) as a gray solid. LCMS: RT: 2.11 min; MS was weak m. Synthesis of EXP-21-IX1749-14 To a solution of 8-ethynyl-1,2-difluoro-6-(methoxymethoxy)naphthalene (210 mg, 0.846 mmol) in MeCN (5 mL) was added DIEA (328 mg, 2.54 mmol), Pd2dba3 (77.5 mg, 0.085 mmol), PPh3 (22.2 mg, 0.085 mmol), 1,10-phenanthroline (15.2 mg, 0.085 mmol) and tert-butyl (1S,5R)-3-(4,6-dichloro- 1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (457 mg, 1.27 mmol), and the mixture was stirred at 85oC under N2 overnight. The mixture was concentrated and purified by column chromatography on silica gel (0~70% DCM in Petrol) to give EXP-21-IX1749-14 (180 mg, 37% yield) as yellow solid. LCMS: RT: 2.42 min; M+1=572.2 n. Synthesis of EXP-21-IX1749-15 To a mixture of EXP-21-IX1749-14 (180 mg, 0.317 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (101 mg, 0.634 mmol) in MeCN (5 mL) was added DIPEA (164 mg, 1.27 mmol), the mixture was heated at 60 °C overnight. The mixture was then concentrated and purified by column chromatography (0~90% DCM in Petrol) to give the target product of tert-butyl (1S,5R)-3-[4-[2-(7,8-difluoro-3-hydroxy-1-naphthyl)ethynyl]-6-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-1,3,5-triazin-2-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate(100 mg, 0.131 mmol, 85% purity) as solid. LCMS: RT: 1.85 min; M+1=695.3

[0085] o. Synthesis of Compound (1) To a solution of EXP-21-IX1749-15 (100 mg, 0.13 mmol) in EtOAc (5 mL) was added HCl (4 mL, 3 M in dioxane) at room temperature. The mixture was stirred at rt for 6 hours and neutralized by saturated NaHCO3 solution, the mixture was extracted with EtOAc (50 mL), the organic layer was dried over anhydrous Na2SO4, concentrated and purified by prep-HPLC (MeCN / H2O / 0.05%NH3.H2O) to give the target product (11.9 mg, 0.022 mmol, 17% yield) as a yellow solid. LCMS: RT: 1.76 min; M+1=551.21H NMR (400 MHz, CD3OD) δ (ppm) 7.60 – 7.50 (m, 2H), 7.41 (td, J = 9.6, 7.4 Hz, 1H), 7.29 (t, J = 1.8 Hz, 1H), 5.44 – 5.20 (m, 1H), 4.53 (dd, J = 36.9, 13.0 Hz, 2H), 4.19 (dd, J = 26.7, 10.7 Hz, 2H), 3.68 (s, 2H), 3.23 (dt, J = 24.8, 7.3 Hz, 5H), 3.02 (td, J = 9.3, 5.7 Hz, 1H), 2.26 (ddd, J = 24.3, 17.1, 6.1 Hz, 2H), 2.08 (d, J = 9.1 Hz, 1H), 2.03 – 1.81 (m, 5H), 1.79 – 1.68 (m, 2H). Synthesis of compound (55): (S)-4-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-1,2,4-oxadiazol- 5-yl)-2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile Compound (55) was synthesised according to the synthetic route shown in detail in Fig.2 and as now further described in the following protocol. Intermediate 1 was synthesized in line with the method described above. The following steps were then performed: (a) to a stirred mixture of intermediate 1 (2.00 g, 4.14 mmol, 1.0 equiv) and Zn(CN)2 (970.1 mg, 8.28 mmol, 2.0 equiv) in DMF were added Xantphos Pd G4 (800.0 mg, 0.82 mmol, 0.2 equiv) at RT under argon atmosphere. The resulting mixture was stirred for 2h at 80 °C under argon atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. 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 / EA (1:5) to afford tert-butyl (1R,5S)-3-(4- cyano-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 51%) as a white solid. ESI-MS m / z = 474.2 [M+H]+; Calculated MW: 473.3. (b) to a stirred solution of tert-butyl (1R,5S)-3-(4-cyano-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate(1.50 g, 3.17 mmol, 1.0 equiv) in THF(10mL) was added NH2OH(50% in water)(1.05 g, 31.7 mmol, 10 equiv) dropwise at 0oC under argon atmosphere. The resulting mixture was stirred for additional 1h at RT. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-6-(N-hydroxycarbamimidoyl)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate(1.50 g, 93% yield) as a yellow solid. ESI-MS m / z = 507.3 [M+H]+ ; Calculated MW: 506.3 (c) to a stirred solution of tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-6-(N-hydroxycarbamimidoyl)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (750.0 mg, 1.48 mmol, 1.0 equiv) and (S)-2-amino- 3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylic acid (524.7 mg, 2.22 mmol, 1.5 equiv) in DMF(10 mL) were added DIEA(1.91 g, 14.8 mmol, 10 equiv) and HATU (1.13 g, 2.96 mmol, 2.0 equiv) at 0oC under argon atmosphere. The resulting mixture was stirred for additional 1h at 0 °C to RT. The resulting mixture was diluted with water (20mL). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl(aq), 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 / EtOAc (1:1) to afford tert-butyl (1R,5S)-3-(4-(N-(((S)-2- amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)carbamimidoyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900.0 mg, 90% yield) as a brown solid. ESI-MS m / z = 725.3 [M+H]+; Calculated MW: 724.3.1H NMR (400 MHz, DMSO-d6) δ 8.28 – 8.24 (m, 1H), 7.30 – 7.25 (m, 1H), 6.90 – 6.84 (m, 2H), 5.23 – 5.18 (m, 1H), 4.06 – 4.02 (m, 2H), 3.19 – 3.11 (m, 6H), 2.89 – 2.81 (m, 3H), 2.78 – 2.74 (m, 1H), 2.46 – 2.37 (m, 2H), 2.03 – 1.82 (m, 14H), 1.60 (s, 3H), 1.24 (s, 9H). (d) To a stirred solution of tert-butyl (1R,5S)-3-(4-(N-(((S)-2-amino-3-cyano-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)carbamimidoyl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (900.0 mg, 1.24 mmol, 1.0 equiv) in DMF (10 mL) was added DBU (10 mL) dropwise at 25oC under argon atmosphere. The resulting mixture was stirred for additional 1h at 60oC. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20mL). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl(aq) 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 / EtOAc (1:1) to afford tert-butyl (1R,5S)-3-(4-(5-((S)-2-amino-3-cyano-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (700.0 mg, 90% yield) as a brown solid. ESI-MS m / z = 707.3 [M+H]+; Calculated MW: 706.3.1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 2H), 5.24 – 5.14 (m, 1H), 4.50 – 4.41 (m, 2H), 4.15 – 4.08 (m, 2H), 3.21 – 3.16 (m, 3H), 3.14 – 3.06 (m, 3H), 3.04 – 2.98 (m, 1H), 2.87 – 2.77 (m, 1H), 2.60 – 2.52 (m, 2H), 2.13 – 1.71 (m, 15H), 1.61 – 1.52 (m, 2H), 1.43 (s, 9H). (e) To a stirred solution of tert-butyl (1R,5S)-3-(4-(5-((S)-2-amino-3-cyano-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate(250.0 mg, 0.35 mmol, 1.0 equiv) in 1,4-dioxane(1mL) was added HCl(gas)in 1,4- dioxane (4mL) dropwise at 0oC under argon atmosphere. The resulting mixture was stirred for additional 1h at 0oC to RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 30% B in 2 min, 30% to 47% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 7.98) to afford (S)-4-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-1,2,4- oxadiazol-5-yl)-2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile(48.6 mg, 22% yield, 95.1%@254nm, 97.7%@220nm) as a white solid. ESI-MS m / z = 607.3 [M+H]+; Calculated MW: 606.3.1H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 2H), 5.33-5.20 (m, 1H), 4.40-4.32 (m, 2H), 4.13-4.08 (m, 1H), 3.99-3.97 (m, 1H), 3.64 (s, 1H), 3.17-3.07 (m, 4H), 3.00 (s, 1H), 2.85-2.79 (m, 1H), 2.57-2.53 (m, 2H), 2.12-2.04 (m, 3H), 1.97-1.95 (m, 2H), 1.84-1.75 (m, 8H), 1.72-1.70 (m, 2H), 1.57-1.54 (m, 2H). Total proton count from structure: 35. Total proton count from spectrum: 34. Example 22: Synthesis of compound (56) Compound (56) was synthesised according to the synthetic route shown in detail in Fig.3 and as now further described in the following protocol. Synthesis was performed in line with the synthesis of compound (55) according to Example 21, up to and including step (b) of that Example, to generate tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(N-hydroxycarbamimidoyl)-1,3,5-triazin-2- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.60 g, 99% yield) as a yellow solid. The crude product was used in the next step directly without further purification. ESI-MS m / z = 507.3 [M+H]+ ; Calculated MW: 506.3. Subsequently, the following steps were performed: a. To a stirred solution of tert-butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-6-(N-hydroxycarbamimidoyl)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (800.0 mg, 1.58 mmol, 1.0 equiv) and (R)-2-amino- 3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylic acid (560.7 mg, 2.37 mmol, 1.5 equiv) in DMF(10 mL) were added DIEA(2.10 g, 15.8 mmol, 10 equiv) and HATU(1.20 g, 3.12 mmol, 2.0 equiv) at 0oC under argon atmosphere. The resulting mixture was stirred for additional 1h at 0oC to RT. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl(aq), 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 / EtOAc (1:1) to afford tert-butyl (1R,5S)-3-(4-(N-(((R)-2- amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)carbamimidoyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(1.08 g, 94% yield) as a brown solid. ESI-MS m / z = 725.3 [M+H]+; Calculated MW: 724.3 b. To a stirred solution of tert-butyl (1R,5S)-3-(4-(N-(((R)-2-amino-3-cyano-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)carbamimidoyl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate(1.00g, 1.38 mmol, 1.0 equiv) in DMF(10 mL) was added DBU(10 mL, 66.9 mmol, 48 equiv) dropwise at 25oC under argon atmosphere. The resulting mixture was stirred for additional 1h at 60oC. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl(aq), 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 / EtOAc (1:1) to afford tert-butyl (1R,5S)-3-(4-(5-((R)-2-amino-3-cyano-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate(860.0 mg, 88% yield) as a brown solid. ESI-MS m / z = 707.3 [M+H]+; Calculated MW: 706.3 c. To a stirred solution of tert-butyl (1R,5S)-3-(4-(5-((R)-2-amino-3-cyano-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophen-4-yl)-1,2,4-oxadiazol-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate(250.0 mg, 0.35 mmol, 1.0 equiv) in 1,4-dioxane(1mL) was added HCl(gas)in 1,4- dioxane (4mL) dropwise at 0oC under argon atmosphere. The resulting mixture was stirred for additional 1h at 0oC to RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 30% B in 2 min, 30% to 47% B in 10 min; wavelength: 254nm / 220nm nm; RT1(min): 7.98) to afford (R)-4-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-1,2,4- oxadiazol-5-yl)-2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile(117.2 mg, 54% yield, 98.6%@254nm, 99.2%@220nm) as a white solid. ESI-MS m / z = 607.3 [M+H]+; Calculated MW: 606.3.1H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 2H), 5.33-5.20 (m, 1H), 4.40-4.22 (m, 2H), 4.15-3.95 (m, 2H), 3.54 (s, 2H), 3.14-2.96 (m, 5H), 2.85-2.79 (m, 1H), 2.57-2.53 (m, 2H), 2.12-2.04 (m, 3H), 1.97-1.95 (m, 2H), 1.84-1.75 (m, 8H), 1.72-1.70 (m, 2H), 1.57-1.54 (m, 2H). Total proton count from structure: 35. Total proton count from spectrum: 34. Example 23: Synthesis of Compounds (89) and (90) Step 1: Rac-6-[(tert-butyldiphenylsilyl)oxy]-6-methyl-1,4-oxazepane To a stirred mixture of rac-6-methyl-1,4-oxazepan-6-ol hydrochloride (5.00 g, 29.8 mmol, 1.0 equiv), Imidazole (6.09 g, 89.5 mmol, 3.0 equiv) and DIEA (11.57 g, 89.5 mmol, 3.0 equiv) in DCM (100 mL) was added tert-butyl(chloro)diphenylsilane (9.84 g, 35.7 mmol, 1.2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 20°C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracte...

Claims

CLAIMS:

1. A compound of Formula (0):5 or a pharmaceutically acceptable salt thereof, wherein: R1is a 6- to 10-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1is optionally substituted by 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, 10 CH2C(O)NR*2,C(O)ONHR*, CH2C(O)ONHR*, C(O)ONR*2and CH2C(O)ONR*2; or wherein R1is -L3-R1’, wherein R1’ is a 5-membered, monocyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N, and wherein R1’is optionally substituted by 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; 15 R2is a 5- to 9-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group comprising at least one ring atom which is N; a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; or a fused, 11- to 14-membered tricyclic group wherein at least one ring is aromatic, and wherein at 20 least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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; R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by one or more 25 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; or R3is a fused, 8-to-10-membered bicyclic group comprising a saturated carbocyclic ring fused to a heterocyclic ring, wherein the carbocyclic ring, the 364heterocyclic ring, or both, may optionally be substituted by 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 R3is a fused, 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring 5 fused to an aryl ring, wherein the carbocyclic ring, the aryl ring, or both, may be optionally substituted by 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 R3is a fused, 8- to 10-membered bicyclic group comprising a saturated heterocyclic ring fused to an aryl or heteroaryl ring, wherein the 10 carbocyclic ring, the aryl or heteroaryl ring, or both, may be optionally substituted by 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; L1is a bond or is -O-, -(C1-C3)alkyl-, *-O-(C1-C3)alkyl-**, *-(C1-C3)alkyl-O-**, *-C(O)NR’-**, or *- 15 NR’C(O)-**, wherein R’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (0) and ** denotes a point of attachment to R2; L2is -(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’’-**, 20 wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (0); L3is a bond or is -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3) alkyl; and wherein in R1, R2, and R3, each R* is independently selected from (C1-C4)alkyl, (C2-C3)alkenyl, (C3-25 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 may itself be substituted by 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. 30 2. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (I): 365wherein in Formula (I): R1is a 6- to 10-membered bridged bicyclic heterocycloalkyl or heterocycloalkenyl group comprising 5 at least one ring atom which is N, and wherein R1is optionally substituted by 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; R2is a 5- to 8-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered monocyclic heteroaryl group 10 comprising at least one ring atom which is N; or a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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*, 15 C(O)NR*2, C(O)ONH2, C(O)ONHR*, C(O)ONR*2, =O, (C2-C3)alkenyl, and (C2-C3)alkynyl; R3is a phenyl or naphthalenyl group which is substituted by OH and optionally by 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; or R3is a fused, 8-to-10-membered bicyclic group 20 comprising a saturated carbocyclic ring fused to a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both, may optionally be substituted by 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; L1is -O-, -(C1-C3)alkyl-, *-O-(C1-C3)alkyl-**, *-(C1-C3)alkyl-O-**, *-C(O)NR’-**, or *-NR’C(O)- 25 **, wherein R’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and * denotes a point of attachment to the triazole moiety of the compound of Formula (I) and ** denotes a point of attachment to R2; L2is -(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- 366C3)alkyl-**, *-C(O)NR’’-**, *-NR’’C(O)-**, *-NR’’-(C1-C3)alkyl-**, or *-(C1-C3)alkyl-NR’’-**, wherein R’’ is H, OH, CN, Cl, F, or (C1-C3)alkyl, and wherein * denotes a point of attachment to R3and ** denotes a point of attachment to the triazole moiety of the compound of Formula (I); and 5 wherein in R1, R2, and R3, 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 by 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. 10 3. The compound or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein R1CH3or 4. R1O ,367, 5. inR3is selected from (Rc)m5 wherein m is 1 or 2 and n is 0, 1, or 2; and each Rcand Rdis independently selected OH, (C-C)alkyl, (C-C)alkenyl, and (c1 3 2 3C2-C3)alkynyl, provided that at least one R is OH; ,wherein s is 1, 2, or 3, and wherein when s is 1 Rgis OH, and when s is 2 or 3, at leastand each remaigning R is independently F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, 10 (C2-C3)alkynyl, or (C3-C6)cycloalkyl, wherein said (C3-C6)cycloalkyl may itself be substituted by one or more groups independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2- C3)alkynyl; and 368, wherein Y10is S, O, or NR’’’ wherein R’’’ is H, OH, CN, Cl, F, or (C1-nd u is 0, 1, or 2, with the proviso that when t is zero, u is nonzero, and that when u is zero, t is nonzero; and each Rhand Riis 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, 5 C(O)ONH2, C(O)ONHR*, C(O)ONR*2, (C2-C3)alkenyl, and (C2-C3)alkynyl, wherein R* is as defined in claim 1 or claim 2.

6. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 5, wherein R3is selected from: in 107. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 6, wherein R3is selected from: 369Rd3 , d 58. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 7, wherein L2is selected from: 370-CH2CH2-, -C≡C-, *-CH2O-**, *-OCH2-**, *-C(O)-NH-**, *-CH2NH-**, *-N(CH3)C(O)-**, *- ,laim 1 or claim 2.

9. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 8, wherein R25 is selected from: , wherein q and r are each independently 0, 1, or 2, and each instance ofently 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, wherein R* is as defined in claim 1 or claim 10 2; , wherein X8, X9, X10, and X11are each independently selected from C(Rk)2, C=O, provided that at leas8 9 10 11 kt one of X , X , X , and X is N(R ); , wherein X12, X13, and X14are each independently selected from C(Rk)2, 15X15and X16are each independently selected from C and N, provided that at least one of X12, X13, and X14is N(Rk) and / or at least one of X15and X16is N; 371, wherein X17, X18, X19, X20, and X21are each independently selected from , O, or S, provided that at lea17 18 19 20 21 kst one of X , X , X , X , and X is N(R), O, or S; , wherein Y1, Y2, Y3, and Y4are each independently N, O, S, NRk, or CRk, provided 5 of Y1, Y2, Y3, and Y4is N okr NR; , wherein Y5, Y6, and Y7are each independently N, O, S, NRk, or CRk, pendently5 6 7 kN or C, provided that at least one of Y, Y, and Y is N or NR and / or at least one of Y8and Y9is N; , wherein Z1, Z2, Z3, Z4, and Z5are each independently N, O, S, or CRk, 10 e of Z1, Z2, Z3, Z4, and Z5is N;wherein each Rkis 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 wherein R* is as defined in claim 1 or claim 2.

10. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 9, wherein R215 is selected from: 372wherein Rband r are as defined in claim 9 as, ), ,5 ,373,11. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 10, wherein 5.

12. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 10, wherein 9.10 13. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 10, wherein .

14. The compound or pharmaceutically acceptable salt of any of claims 1 to 13, wherein L1is -O- , *-OCH(CH3)-**, or *-O-CH2-**. 15 37415. The compound or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein the compound is a compound of Formula (III), Formula (IV), Formula (XXII) or Formula (XXII.I): 53755 wherein in each of Formula (III), Formula (IV), Formula (XXII), L1is as defined in claim 1, claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; R*’ is selected from H, CN, Cl, F, R*, OR*, NR*2, CHO, C(O)R*, C(O)OR*, C(O)NR*2, and C(O)ONR*2, wherein R* is as defined in claim 1 or claim 2; and R2is as defined in any of claims 9-13; 10 in Formula (III), Rc, Rd, n and m are as defined in claim 5; 376in Formula (IV), Rgand s are as defined in claim 5; and in Formula (XXII), Rh, Ri, t, u, and Y10are as defined in claim 5; and in Formula (XXII.I), L1is as defined in claim 1, claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; R2is as defined in any of claims 9-13; Rh, Ri, t, u, and Y10are as defined in claim 5 5; X is selected from NH, N(C1-3)alkyl, O, or CH2; v is an integer from 0 to 4; and 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, wherein R* is as defined in claim 1 or claim 2.

16. The compound or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein the compound is a compound of Formula (VI) or Formula (VI.I): 10(Formula (VI.I)) wherein, in Formula (VI), L1is as defined in claim 1, claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; R*’ is selected from H, CN, Cl, F, R*, OR*, NR*2, CHO, C(O)R*, C(O)OR*, C(O)NR*2, and C(O)ONR*2, wherein R* is as defined in claim 1 or claim 2; and R3is as defined in 5 any of claims 5-7; and in Formula (VI.I), L1is as defined in claim 1, claim 2, or claim 10; L2is as defined in claim 1, claim 2, or claim 8; X is selected from NH, N(C1-3)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, wherein R* is as defined in claim 1 or claim 2; and R3is as defined in any of claims 5-7. 10 17. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein the compound is a compound of Formula (XXIII.I) or Formula (XXIV.I) (Formula (XXIII.I))378wherein, in each of Formula (XXIII.I) and Formula (XXIV.I): 5 L1is as defined in claim 1, claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; Rh, Ri, t, and u are as defined in claim 5; X is selected from NH, N(C1-3)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, wherein R* is as defined in claim 1 or claim 2; and R2is as defined in any of claims 9-13. 10 18. A compound of Formula (XXII) or Formula (XXII.I) as defined in claim 15 or a compound of Formula (XXIII.I) or Formula (XXIV.I) as defined in claim 17, or a pharmaceutically acceptable salt thereof, wherein R2is a 5- to 9-membered, monocyclic or bicyclic heterocycloalkyl or heterocycloalkenyl group comprising at least one ring atom which is N or O; a 5- or 6-membered 15 monocyclic heteroaryl group comprising at least one ring atom which is N; a fused, 8- to 10-membered bicyclic group wherein one or both rings are aromatic, and wherein at least one ring comprises at least one ring atom which is N; and wherein R2may be substituted by 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 20 (C2-C3)alkynyl; and wherein 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, 379wherein said (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5- or 6- membered monocyclic heteroaryl may itself be substituted by 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. 5 19. A compound or pharmaceutically acceptable salt thereof of claim 18, wherein R2is , wherein X8, X9, X10, and X11are as defined in claim 9. 202pharmaceutically acceptable salt thereof of claim 18 or claim 19, wherein R is as defined in claim 12 or claim 13.

21. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein the 10 compound is a compound of Formula (VIII), Formula (X), or Formula (XXV): 15R1)qwhereinin each of Formula (VIII), Formula (X), and Formula (XXV), L1is as defined in claim 1, 5 claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; R1is as defined in claim 1, claim 2, or claim 3; and Ra, Rb, q, and r are as defined in claim 9; in Formula (VIII), Rc, Rd, n, and m are as defined in claim 5; in Formula (X), Rgand s are as defined in claim 5; and in Formula (XXV), Rh, Ri, t, u, and Y10are as defined in claim 5. 10 22. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein the compound is a compound of Formula (XXVII) or Formula (XXVIII):(Formula (XXVII))5 wherein in Formula (XXVII), L1is as defined in claim 1, claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; Rkis as defined in claim 9; X is selected from NH, N(C1-3)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, wherein R* 10 is as defined in claim 1 or claim 2; and R3is as defined in any of claims 5-7; and in Formula (XXVIII), L1is as defined in claim 1, claim 2, or claim 14; L2is as defined in claim 1, claim 2, or claim 8; Rkis as defined in claim 9; X is selected from NH, N(C1-3)alkyl, O, or CH2; v is an integer from 0 to 4; each R*’’ is independently selected from H, CN, Cl, 15 F, R*, OH, OR*, NR*2, CHO, C(O)R*, C(O)OR*, C(O)NR*2, and C(O)ONR*2, wherein R* is as defined in claim 1 or claim 2; and wherein RhRit and u are as defined in claim 523. A pharmaceutical composition comprising the compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient 20 or carrier.

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

26. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for 30 use according to claim 25, wherein the cancer is a KRAS G12D-associated cancer. 38227. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for use according to claim 25 or claim 26, wherein the cancer is selected from colorectal cancer, lung cancer, and pancreatic cancer. 5 28. A method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1-22, or a pharmaceutical composition according to claim 23.

29. A method of treating or preventing a disease or disorder mediated by KRAS G12D, or a disease or disorder in which KRAS G12D is implicated, in a subject in need thereof, the method 10 comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1-22, or a pharmaceutical composition according to claim 23.

30. A method of treating or preventing a disease or disorder associated with KRAS G12D in a subject in need thereof, the method comprising administering to the subject an effective15 amount of a compound or pharmaceutically acceptable salt according to any one of claims 1- 22, or a pharmaceutical composition according to claim 23.

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

32. A method of treating or preventing cancer in a subject in need thereof, the method comprising 20 administering to the subject an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1-22, or a pharmaceutical composition according to claim 23.

33. A method of inhibiting KRAS G12D activity, the method comprising contacting KRAS G12D with a compound or pharmaceutically acceptable salt according to any one of claims 1-22, or 25 a pharmaceutical composition according to claim 23.

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

35. A method according to claim 31, 32 or 34, wherein the cancer is selected from colorectal cancer, lung cancer, and pancreatic cancer. 30 383

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