2-(3, 8-diazabicyclo [3.2. 1] oct-3-yl)-1, 3, 5-triazine derivatives as KRAS G12D inhibitors for treatment of cancer

Abstract

Compounds that can inhibit KRAS G12D are provided. Also provided are pharmaceutical compositions and medical uses thereof, including in the treatment or prophylaxis of a condition such as cancer.

Description

[0001] Compounds that can inhibit KRAS G12D are provided. Pharmaceutical compositions and their medical uses are also provided, including use in the treatment or prevention of conditions such as cancer. Summary of the Invention

[0002] Kirsten rat sarcoma type 2 virus oncogene homolog (“KRas” or “KRAS”) is a small GTPase and a member of the Ras oncogene family. KRAS acts as a molecular switch, cycling between an inactive (GDP-binding) state and an active (GTP-binding) state, transducing upstream cellular signals received from various tyrosine kinases to downstream effectors, thereby regulating a variety of processes, including cell proliferation.

[0003] Aberrant expression of KRAS accounts for up to 20% of all cancers, and oncogenic KRAS mutations that can stably bind to GTP and cause structural activation of KRAS and its downstream signaling have been reported in 25%-30% of lung adenocarcinoma cases. KRAS G12D mutations are present in 25.0% of pancreatic ductal adenocarcinoma patients, 13.3% of colorectal cancer patients, 10.1% of rectal cancer patients, 4.1% of non-small cell lung cancer patients and 1.7% of small cell lung cancer patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8):818-831. Dataset version 4).

[0004] The well-established role of KRAS in malignant tumors, and the high frequency of KRAS mutations found in different tumor types, make it a highly attractive target for the pharmaceutical industry in the field of cancer treatment. WO 2021 / 041671, WO 2023 / 098425 and WO 2023 / 274324 disclose KRAS G12D inhibitors based on a bicyclic (pyrido[4,3-d]pyrimidine) core.

[0005] Clearly, there remains a sustained interest and investment in the development of KRAS inhibitors, particularly inhibitors targeting activating KRAS mutants, especially KRAS G12D inhibitors for treating KRAS G12D-mediated cancers.

[0006] Accordingly, in the first aspect, this disclosure provides compounds having formula (0):

[0007]

[0008] (Equation (0))

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] R 1 It is a 6- to 10-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =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 where R 1 Yes -L 3 -R 1 ', where R 1 ' is a 5-membered, monocyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N ring atom, and wherein R 1’ Optionally substituted by one or more groups independently selected from the following: =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;

[0011] R 2It is a 5- to 9-membered (e.g., 5- to 8-membered), monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic and wherein at least one ring contains at least one ring atom that is N; or a fused 11- to 14-membered tricyclic group, wherein at least one ring is aromatic and wherein at least one ring contains at least one ring atom that is N;

[0012] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl;

[0013] R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl; or R 3 It is 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 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated heterocycle fused to an aryl ring or a heteroaryl ring, wherein the carbide ring, the aryl ring or the heteroaryl ring, or both, may optionally be substituted by one or more groups independently selected from the following: 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)ynyl;

[0014] L 1 It is a bond or -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This represents the attachment point to the triazole moiety of a compound having formula (0), and Indicates with R 2 Attachment point;

[0015] L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and Indicates the attachment point to the triazole moiety of a compound having formula (0);

[0016] L 3It is a bond or -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3)alkyl;

[0017] and

[0018] Among them, in R 1 R 2 and R 3 In, each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0019] In the embodiments, this disclosure provides compounds having formula (0), which are compounds having formula (I):

[0020]

[0021] (Formula (I))

[0022] Or a pharmaceutically acceptable salt thereof, wherein in formula (I):

[0023] R 1 It is a 6- to 10-membered bridged bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =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;

[0024] R 2It is a 5- to 8-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; or a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic, and at least one ring contains at least one ring atom that is N.

[0025] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl;

[0026] R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl;

[0027] L 1 It is -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This indicates the attachment point to the triazole moiety of a compound having formula (I), and Indicates with R 2 Attachment point;

[0028] L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and Indicates the attachment point to the triazole moiety of a compound having formula (I);

[0029] and

[0030] Among them, in R 1 R 2 and R 3 In, each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0031] Another aspect provides a pharmaceutical composition comprising a compound described herein (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0032] Another aspect provides a treatment method comprising administering to a subject in need a therapeutically effective amount of the disclosed compound (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of the disclosed compound (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament. In another related aspect, this disclosure provides the use of the disclosed compound (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in a therapeutic manner.

[0033] Another aspect provides a method for treating or preventing a KRAS G12D-mediated disease or disorder, or a disease or disorder involving KRAS G12D, in a subject in need, the method comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound disclosed herein (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing a KRAS G12D-mediated disease or disorder, or a disease or disorder involving KRAS G12D. In another related aspect, this disclosure provides a compound disclosed herein (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) for treating or preventing a KRAS G12D-mediated disease or disorder, or a disease or disorder involving KRAS G12D.

[0034] On the other hand, this disclosure provides a method for treating or preventing a KRAS G12D-related disease or disorder (e.g., cancer) in a subject in need, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing a KRAS G12D-related disease or disorder (e.g., cancer). In another related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof) for the treatment or prevention of a KRAS G12D-related disease or disorder (e.g., cancer).

[0035] On the other hand, this disclosure provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of cancer. In another related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the treatment or prevention of cancer.

[0036] On the other hand, this disclosure provides a method for inhibiting KRAS G12D activity, the method comprising contacting KRAS G12D (e.g., cells containing KRAS G12D) with a compound of the disclosure (e.g., a compound having 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, this disclosure provides an in vitro method for inhibiting KRAS G12D activity in cells, the method comprising contacting cells with a compound of the disclosure (e.g., a compound having formula (0) or formula (I) or a pharmaceutically acceptable salt thereof). Attached Figure Description

[0037] Figure 1 The synthesis of compound (1), which is described in further detail in Example 20, is shown.

[0038] Figure 2 The synthesis of compound (55), which is described in further detail in Example 21 herein, is shown.

[0039] Figure 3 The synthesis of compound (56), which is described in further detail herein in Example 22, is shown. Detailed Implementation

[0040] Although specific embodiments of this disclosure will now be described with reference to the specification and examples, it should be understood that such embodiments are by way of example only and illustrate only a small number of the many possible specific embodiments that may represent the application of the principles of this disclosure. In view of the benefits of this disclosure, various changes and modifications will be apparent to those skilled in the art and are considered to be within the spirit and scope of this disclosure as further defined in the appended claims.

[0041] definition

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, exemplary methods, apparatus, and materials are described hereafter. All technical and patent disclosures referenced herein are incorporated herein by reference in their entirety.

[0043] Unless otherwise stated, the practices disclosed herein will employ conventional techniques such as chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, recombinant DNA, etc., all of which are within the scope of the art. See, for example, Michael R. Green and Joseph Sambrook, *Molecular Cloning* (4th edition, Cold Spring Harbor Laboratory Press, 2012); the series edited by Ausubel et al. (2007); *Current Protocols in Molecular Biology*; the series *Methods in Enzymology* (Academic Press, Inc., New York); MacPherson et al. (1991) *PCR 1: A Practical Approach* (IRL Press at Oxford University Press); MacPherson et al. (1995) *PCR 2: A Practical Approach*; edited by Harlow and Lane (1999); *Antibodies*, *A Laboratory Manual*; and Freshney (2005) *Culture of Animal Cells: A Manual of Basic Technique*. [Animal Cell Culture: A Basic Technique Manual], 5th Edition; edited by Gait (1984) Oligonucleotide Synthesis; US Patent No. 4,683,195; edited by Hames and Higgins (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; edited by Hames and Higgins (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, 3rd Edition (Cold Spring Harbor Laboratory Press, 2002); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

[0044] All numerical designations, such as pH, temperature, time, concentration, molecular weight, etc. (including ranges), are approximate values ​​that vary (+) or (-) in increments of, for example, 0.1 or 1.0, where appropriate. It should be understood that, although not always explicitly stated, all numerical designations are preceded by the term "about" to indicate a typical level of variability. For example, a numerical designation for a given value "about" may vary by ±10% of said value; alternatively, the variation may be ±5%, ±2%, or ±1% of that value. It should also be understood that, although not always explicitly stated, the reagents described herein are merely exemplary, and their equivalents are known in the art.

[0045] As used in this article, the term “room temperature” refers to an ambient temperature in the range of about 20 to about 25°C, for example, about 20, about 21, about 22, about 23, about 24, or about 25°C.

[0046] As used in the specification and claims, the singular forms “a / an” and “the” include plural references unless the context clearly indicates otherwise. For example, the term “cell” includes a plurality of cells, including mixtures thereof. Unless explicitly stated or obvious from the context, the term “or” as used herein should be understood as inclusive. The term “comprising” as used herein means the phrase “including but not limited to” and may be used interchangeably with it.

[0047] As used herein, the term “comprising / comprises” is intended to mean that a composition and method includes the listed elements without excluding other elements. When used to define a composition and method, “consistently composed of” should mean excluding other elements that are of any significance to the stated purpose. Thus, a composition consisting essentially of elements as defined herein will not exclude trace contaminants from separation and purification methods, as well as pharmaceutically acceptable carriers such as phosphate-buffered saline, preservatives, etc. “Constitutes of” should mean excluding more than one trace element of other components and substantial method steps for administering the composition of this disclosure or process steps for producing the composition or achieving the intended results. Examples defined by each of these transitional terms are within the scope of this disclosure. The term “comprising” as used herein is intended to cover and disclose corresponding statements in which the term “comprising” is replaced by “consistently composed of” or “composes of”.

[0048] The terms “subject,” “individual,” or “patient” are used interchangeably herein and refer to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, racing animals, pets, and primates; for example, rats, rats, rabbits, apes, cattle, sheep, pigs, dogs, cats, horses, and humans. In a particular embodiment, the mammal is a human.

[0049] "Administration" is defined herein as the delivery of a drug or a composition containing such drug to a subject in a manner that causes the drug to come into contact with the subject's body (e.g., in vivo). Such administration can be performed via any route, including but not limited to oral, transdermal, transmucosal (e.g., through the vagina, rectum, or oral mucosa), injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or inhalation (e.g., oral or nasal). Administration can also include delivering a substance or composition to a portion of the surface of the subject's body, such as by topical application to the skin. Of course, pharmaceutical preparations are given in a form suitable for each route of administration.

[0050] The “treatment” of a disease includes: (1) preventing the disease, i.e., preventing the development of the clinical symptoms of the disease in patients who may be susceptible to the disease but have not yet experienced or shown symptoms of the disease; (2) suppressing the disease, i.e. preventing or reducing the development of the disease or its clinical symptoms; and / or (3) alleviating the disease, i.e., causing the disease or its clinical symptoms to subside.

[0051] The term "having" in relation to the term "treatment" refers to a patient or individual who has been diagnosed with or is susceptible to the disease. A patient may also be described as "at risk of having" the disease due to a family history of the disease or the presence of a gene mutation associated with it. Patients at risk of the disease have not yet developed all or some of the characteristic pathologies of the disease.

[0052] An “effective amount” or “therapeutic effective amount” is an amount sufficient to achieve a beneficial or desired outcome. An effective amount can be administered, applied, or dosed, either once or multiple times. This delivery depends on many variables, including the time period for which a single dose unit is used, the bioavailability of the therapeutic agent, the route of administration, etc. However, it should be understood that the specific dose level of the therapeutic agent disclosed herein for any particular subject depends on a variety of factors, including, for example, the activity of the specific compound used, the subject’s age, weight, general health condition, sex, and diet, the time of administration, the rate of excretion, the combination of drugs, the severity of the specific disorder being treated, and the form of administration. Therapeutic doses can often be adjusted to optimize safety and efficacy. Typically, dose-response relationships from in vitro and / or in vivo studies can initially provide useful guidance for the appropriate dose administered to a patient. Generally, it is desirable to administer an amount of compound effective to achieve serum levels equivalent to concentrations found to be effective in vitro. The determination of these parameters is well known to those skilled in 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 "therapeutic effective dose" 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 a single or divided dose and may fall outside the typical range given herein, depending on the physician's judgment.

[0053] As used herein, the terms “increased” and “enhanced” are used interchangeably and cover any measurable increase in biological function and / or biological activity and / or concentration. For example, an increase may be at least about 10%, such as 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, relative to a control or baseline amount or function, or activity or concentration, an increase may be at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, such as at least about 20, 25, 50, 100 times, or higher.

[0054] As used herein, the term “increased expression” and / or “increased activity” of a substance (such as KRAS G12D) in a sample, cancer, or patient typically refers to an increase in the amount of that substance (e.g., a mutant KRAS G12D protein), although it can also indicate an increase in the substance’s biological activity. For example, an increase could be an amount of about 5%, such as 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%. Therefore, as determined by techniques known in the art, an increase in the amount (or activity) of a substance (such as KRAS G12D) relative to one or more control samples (such as individuals or groups of individuals without a disease or disorder (e.g., cancer)) or internal controls can be about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, such as about 20, 25, 50, 100 times, or higher. An increase in the expression and / or activity of KRAS G12D relative to the mean or median amount of KRAS G12D in a retrospective analysis of the sample control group, sample baseline group, or patient samples can also be determined if the subject has an “increased expression” or “increased activity” of KRAS G12D. Such control or baseline expression levels can be predetermined, measured before measuring the sample or cancer or the subject, or obtained from a database of such control samples, as is practiced in the art.

[0055] As used herein, the term "pharmaceuticalally acceptable excipient" encompasses any standard pharmaceutical excipient, such as those described in Remington's Pharmaceutical Sciences (20th edition, Mack Publishing Co., 2000). Such excipients include carriers, such as phosphate-buffered saline solutions, water and emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. Pharmaceutical compositions may also contain stabilizers, preservatives, excipients, fillers, binders, lubricants, etc.

[0056] As used herein, the term "alkyl" refers to a saturated straight-chain 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 apparent to those skilled in the art in light of the benefits of this disclosure. The terms "(C1-C3)alkyl," "(C1-C6)alkyl," etc., have equivalent meanings of a saturated straight-chain 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 containing alkyl groups, such as "-O(C1-C3)alkyl-". The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, etc. One or more carbon atoms in the backbone of an alkyl group can be replaced by heteroatoms (or bonded to heteroatoms) via multiple bonds (e.g., double bonds); for example, carbon atoms in an alkyl group can be bonded to oxygen via double bonds (i.e., substituted with oxygen to provide a carbonyl functional group). The presence of such substituents does not prevent the carbon backbone of the group from being considered an alkyl group.

[0057] As used herein, the term "alkenyl" means an unsaturated straight-chain or branched functional group consisting essentially of carbon atoms and a corresponding number of hydrogen atoms and containing at least one carbon-carbon double bond. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (isopropenyl), etc. Other alkenyl groups will be apparent to those skilled in the art in light of the benefits of this disclosure. The terms "(C2-C3)alkenyl," "(C2-C6)alkenyl," etc., have equivalent meanings of an unsaturated straight-chain 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 containing alkenyl groups, such as "-O(C2-C3)alkenyl-". The term "halogenated alkenyl" means an alkenyl group substituted with one or more halogens. Where valence permits, one or more carbon atoms in the alkenyl group backbone can be replaced (or bonded to) a heteroatom via multiple bonds (e.g., double bonds); for example, a carbon atom in an alkenyl group can be bonded to oxygen via a double bond (i.e., substituted with oxygen to provide a carbonyl functional group), provided that such a carbon atom does not participate in a carbon-carbon double bond. The presence of such substituents does not prevent the carbon backbone of the group from being considered an alkenyl group.

[0058] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched functional group consisting essentially of carbon atoms and a corresponding number of hydrogen atoms and containing at least one carbon-carbon triple bond. Exemplary alkenyl groups include ethynyl, 1-propynyl, 2-propynyl (propynyl), etc. Other alkynyl groups will be apparent to those skilled in the art in light of the benefits of this disclosure. The terms "(C2-C3)alkynyl," "(C2-C6)alkynyl," etc., have equivalent meanings of an unsaturated straight-chain 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 containing alkynyl groups, such as "-O(C2-C3)alkynyl-". The term "halogenated alkynyl" refers to an alkynyl group substituted with one or more halogens. Where valence permits, one or more carbon atoms in the alkynyl group backbone can be substituted (or bonded to) a heteroatom via multiple bonds (e.g., double bonds); for example, a carbon atom in an alkynyl group can be bonded to oxygen via a double bond (i.e., substituted with oxygen to provide a carbonyl functional group), provided that such a carbon atom does not participate in a carbon-carbon double or triple bond. The presence of such a substituent does not prevent the carbon backbone of the group from being considered an alkynyl group.

[0059] As used herein, the term "cyclic group" means a saturated, partially or fully unsaturated or aromatic group having at least 3 to 10 ring-forming atoms (i.e., ring atoms). When a cyclic group is defined as having a certain number of members, the terms "member," "member," etc., are used to indicate the number of ring atoms in the cyclic group. For example, a 5-membered cyclic group (e.g., a 5-membered heterocyclic group) contains 5 ring atoms. It should be understood that a cyclic group can be part of a larger cyclic system; for example, bicyclic [4.3.0]nonane comprises two carbocyclic groups, namely a cyclohexyl group and a cyclopentyl group, which are fused to form a carbocyclic system constituting the molecule. The term "cyclic group" is intended to encompass both carbocyclic groups and heterocyclic groups. The term "carbocyclic" refers to a group having at least 3 to 10 ring-forming carbon atoms. The term "heterocyclic" refers to a group having at least 3 to 10 ring-forming atoms, wherein at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. Unless the context explicitly specifies otherwise (e.g., by specifically requiring a "saturated heterocyclic" group, an "unsaturated heterocyclic" group, or an "aromatic heterocyclic" group), the term "heterocyclic group" covers saturated, unsaturated, and aromatic (i.e., heteroaryl) groups, where, for example, "heterocyclic alkyl" groups must be saturated, "heterocyclic alkenyl" groups must be unsaturated, and "heteroaryl" groups must be aromatic.

[0060] As used herein, the term "spiro" or "spirocyclic" in relation to cyclic groups indicates that a first cyclic group in a polycyclic system is attached to a second cyclic group in the same polycyclic system, wherein the ring atoms of the first cyclic group and the ring atoms of the second cyclic group share only one common atom, i.e., the first and second cyclic groups share a common ring atom. For example, spiro[5.5]undecyl comprises two cyclohexane rings that share a common carbon ring atom.

[0061] As used herein, the term "fusion" in relation to cyclic groups refers to the attachment of a first cyclic group to a second cyclic group in a polycyclic system, wherein the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have two common adjacent atoms, i.e., the first and second cyclic groups share two common ring atoms. For example, a bicyclic [4.4.0]decyl group comprises two cyclohexane rings having two common adjacent carbon ring atoms.

[0062] As used herein, the term "bridging" in relation to cyclic groups refers to the attachment of a first cyclic group in a polycyclic system to a second cyclic group in the same system, wherein the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have more than two common adjacent atoms, i.e., the first and second cyclic groups share three or more common ring atoms. For example, a bicyclic [3.3.1]nonyl group comprises two cyclohexane rings having three common adjacent carbon ring atoms.

[0063] In the structural formulas described herein, any ring system (including any spirocyclic, fused, or bridged ring system) can be connected to other parts of the molecule via any atom having a suitable valence. For example, a bicyclic ring can be connected to another part of the molecule via a ring atom (e.g., a secondary carbon atom or a heteroatom such as N) or a bridgehead (e.g., a tertiary carbon atom). Spirocyclic, fused, and bridged rings can be fully unsaturated, partially unsaturated, or fully saturated, and can have aromatic characteristics in one or more of their constituent rings.

[0064] As used herein, the term "cycloalkyl" means a saturated group having at least 3 to 10 carbon atoms forming a ring (i.e., ring atoms). Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It should be understood that cycloalkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic). In the case of polycyclic cycloalkyl groups, there is an additional ring, for example, one or more additional rings, all of which contain 3 to 7 carbon atoms (i.e., ring atoms). Exemplary cycloalkyl groups having such additional rings include bicyclic [1.1.1]pentyl. The term "(C3-C7)cycloalkyl" indicates that the cycloalkyl group contains 3 to 7 carbon atoms in the ring portion of the group, which can be monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic), such as cyclopropyl (having 3 ring carbon atoms) or bicyclic [1.1.1]pentyl (having 5 ring carbon atoms). One or more ring atoms in a cycloalkyl group can be replaced by heteroatoms via a double bond (i.e., bonded to a heteroatom) (e.g., oxo-substituted cycloalkyl groups). The presence of such substituents does not prevent the carbon backbone of the group from being considered a cycloalkyl group.

[0065] 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) forming a ring. The term "cycloalkenyl" is not intended to cover cyclic groups having aromatic characteristics (those groups are considered aryl groups as defined herein). Exemplary cycloalkenyl groups include cyclohexenyl. It should be understood that cycloalkenyl groups can be monocyclic or polycyclic (e.g., bridged). In the case of polycyclic cycloalkenyl groups, there are additional rings, for example, one or more additional rings, all containing 3 to 10 carbon atoms (i.e., ring atoms). Those additional rings can be saturated or unsaturated. Exemplary cycloalkenyl groups having such additional rings include bicyclic [2.2.1]hept-5-enyl. The term "(C4-C8)cycloalkenyl" indicates that the cycloalkenyl group contains 4 to 8 carbon atoms in the ring portion of the group, such as cyclohexenyl (with 6 ring carbon atoms) or bicyclo[2.2.1]hept-5-alkenyl (with 7 ring carbon atoms). One or more double bonds in the cycloalkenyl group are usually located between ring carbon atoms (i.e., intracyclic double bonds), but may also be located between a ring carbon atom and an adjacent noncyclic carbon atom (i.e., exocyclic double bonds).

[0066] As used herein, the term "aryl" refers to an aromatic group having at least six carbon atoms forming a ring (i.e., ring atoms). It should be understood that aryl groups can be monocyclic or polycyclic (e.g., fused). In the case of polycyclic aryl groups, additional rings are present, such as one or more additional rings, all of which contain at least three carbon atoms (i.e., ring atoms). These additional rings may also contain one or more heteroatoms, and they may be saturated, unsaturated, or aromatic. Polycyclic aryl groups are typically attached to the remainder of the molecule via an aromatic ring and typically not via a ring containing heteroatoms. In the examples, the polycyclic aryl groups do not contain any cyclic heteroatoms. Examples of aryl groups include phenyl and naphthyl, as well as indenyl and indenyl. Other aryl groups include, for example, tetrahydroisoquinolinyl groups bonded to the remainder of the molecule via their benzene ring. The term "(C6-C)" is used in conjunction with the preceding text. 10 "Aryl" indicates that the aryl group contains 6 to 10 carbon atoms in the ring portion of the group, which can be monocyclic or polycyclic (e.g., fused), such as phenyl (with 6 ring carbon atoms) or indanyl (with 9 ring carbon atoms).

[0067] As used herein, the term "heterocyclic alkyl" means a saturated group having at least 3 to 10 ring-forming atoms (i.e., ring atoms), wherein at least 1 to 9 of the ring atoms are carbon and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. For example, the term "4 to 10-membered heterocyclic alkyl" means a saturated group containing 4 to 10 ring atoms (one or more of which are heterocyclic atoms). Heterocyclic alkyl rings may have oxo substituents (e.g., 2-oxopyrrolyl) typically adjacent to the heteroatom, but the oxygen atom does not form part of the ring and is not included in the number of ring atoms. The presence of such substituents does not prevent the group(s) from being considered a heterocyclic alkyl group. Exemplary heterocyclic alkyl groups include tetrahydrofuranyl, piperidinyl, morpholinyl, and piperazineyl. Any cyclic sulfur atom may optionally carry one or more side (i.e., acyclic) oxygen atoms, as found, for example, in sulfolane. In the case of polycyclic heterocyclic groups, there are additional rings, for example, one or more additional rings, all of which contain 3 to 7 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. The additional rings may be saturated, or partially or completely unsaturated (e.g., having aromatic characteristics). Polycyclic heterocyclic groups include fused, bridged, and spirocyclic ring systems. In the case of polycyclic heterocyclic alkyl groups containing unsaturated fused rings, the group is typically not bonded to the rest of the molecule via the fused ring. Exemplary heterocyclic groups having such additional rings include 2-oxaspiro[3.3]heptyl, tetrahydroisoquinolinyl, 1-azaspiro[3.3]hept-2-one, and 2-azabicyclo[4.1.0]heptyl. When a heterocyclic alkyl group is described as “X to Y units” (where X and Y are integers), this means that the heterocyclic alkyl group contains a total of X to Y ring atoms. Therefore, for example, "4 to 7-membered heterocyclic alkyl groups" contain a total of 4, 5, 6 or 7 ring atoms, such as tetrahydropyranyl (6 ring atoms).

[0068] As used herein, the term "heterocyclic alkenyl" means an unsaturated (i.e., partially or fully unsaturated) group having at least 3 to 6 ring-forming atoms (i.e., ring atoms), wherein at least 1 to 5 of the ring atoms are carbon and the remaining at least 1 to 5 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. The heterocyclic alkenyl ring may have oxygen substituents typically adjacent to the heteroatom, but the oxygen atom does not form part of the ring and is not included in the number of ring atoms. Exemplary heterocyclic alkenyl groups include tetrahydropyridyl. Any cyclic sulfur atom may optionally carry one or more side (i.e., acyclic) oxygen atoms. It should be understood that the heterocyclic alkenyl group may be monocyclic or polycyclic (e.g., bridged). In the case of polycyclic heterocyclic alkenyl groups, additional rings are present, for example, one or more additional rings, all containing 3 to 6 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. The additional ring can be saturated, or partially or completely unsaturated (e.g., having aromatic characteristics). Polycyclic heterocyclic alkenyl groups include fused, bridged, and spirocyclic ring systems. In the case where a polycyclic heterocyclic alkenyl group contains an unsaturated fused ring, the group is typically not bonded to the rest of the molecule via the fused ring. Exemplary heterocyclic alkenyl groups having such an additional ring include a tetrahydroindolyl group. When a heterocyclic alkenyl group is described as “X to Y members,” this means that the heterocyclic alkenyl group contains a total of X to Y ring atoms. Thus, for example, a “5 to 8 membered heterocyclic alkenyl group” contains a total of 5, 6, 7, or 8 ring atoms, such as a dihydropyranyl group (6 ring atoms).

[0069] As used herein, the term "heteroaryl" refers to an aromatic (i.e., aromatically characterized) group that typically contains 5 to 10 ring atoms, wherein 1 to 9 of the ring atoms are carbon and the remaining 1 to 9 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. It should be understood that heteroaryl groups can be monocyclic or polycyclic (e.g., fused). In the case of polycyclic heteroaryl groups, there are additional rings, for example, one or more additional rings, all containing at least 3 atoms (i.e., ring atoms), which may optionally be aromatic. Examples of heteroaryl groups include monocyclic groups such as pyridyl and 2-oxopyridyl, and polycyclic groups such as indolyl. When a heteroaryl group is described as "X to Y units," this means that the heteroaryl group contains a total of X to Y ring atoms. Therefore, for example, a "5 to 10-membered heteroaryl group" contains a total of 5, 6, 7, 8, 9, or 10 ring atoms, such as an indole group (9 ring atoms). A heteroaryl group can be equivalently described as "C xThe term "heteroaryl" refers to a group containing a total of 5 ring atoms, including any one or more heteroatoms and carbon atoms. For example, a "C5 heteroaryl" group contains a total of 5 ring atoms, including any one or more heteroatoms, provided that at least one heteroatom is present.

[0070] As used herein, the term "hydrogen" or "H" includes 1 H and 2 H (deuterium, "D"). Therefore, references to groups such as OH, (C1-C6)alkyl, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl groups include partially or fully deuterated groups as well as non-deuterated groups. For example, references to "OH" or "hydroxyl" therefore include OD, and references to "C1 alkyl", "methyl", "Me" or "CH3" therefore include, for example, CD3.

[0071] As used herein, the terms “halogenated group” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and can refer to a halogen functional group or the halogen atom itself. Those skilled in the art will be able to readily determine the intent in the context of the use of these terms in this disclosure.

[0072] As used herein, the term "CN" refers to a functional group having a carbon atom attached to a nitrogen atom via a triple bond. The CN group is attached via its carbon atom.

[0073] As used herein, the term "oxo" refers to a functional group in which an oxygen atom is attached via a double bond to the atom carrying the oxo group. For example, when a carbon atom carries an oxo group, a carbon-oxygen double bond is formed. It should be understood that not all atoms within a given structure can be oxo-substituted, and this will depend on the free valence of the atom to be substituted.

[0074] As used in this article, "-C(O)-" means "=O" means "-C(O)NH-" means "-C(O)NR-" means "-NHC(O)-" means And "-NRC(O)-" means As used in this article, “C(O)R” "meaning" “C(O)OR "meaning" “C(O)NR 2" means And "C(O)ONR 2" means .

[0075] The compounds disclosed herein are described, in particular, by structural formulas. It should be understood that these formulas typically represent only one form of the compound (e.g., resonance form, tautomer form, etc.), and some compounds may exist in more than one such form. This will be apparent to a skilled reader. This disclosure includes all possible tautomers of the compounds characterized by the structural formulas described above and below, including as a single tautomer or as any mixture of tautomers in any ratio. It should also be understood that some of the compounds of the invention may exist in one or more isomers (e.g., stereoisomers). This disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc., of the compounds described above and below, as well as their cis and trans forms and conformational isomers. Purification and separation of isomers can be accomplished by the methods described below and techniques known in the art. For example, optical isomers of a compound can be obtained by resolving racemic mixtures of its diastereomer salts (e.g., using optically active acids or bases, or by forming covalent diastereomers). One different method for separating optical isomers involves using chiral chromatography (e.g., HPLC columns using chiral phases), with or without conventional derivatization. Enzymatic separation (with or without derivatization) is also available, and the optically active compounds disclosed herein can also be obtained by chiral synthesis using optically active starting materials. This disclosure includes all possible stereoisomers of the compounds described herein, as a single stereoisomer, or as any mixture of said stereoisomers in any ratio, such as (R)- or (S)-isomers.

[0076] The compounds disclosed herein 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 having formula (0) (e.g., basic compounds having formula (I)) may be provided as pharmaceutically acceptable acid addition salts with acids (such as HCl). Methods for forming salts are described below and are also known in the art (see, for example, Berge et al., J Pharm Sci [Journal of Pharmaceutical Sciences]. (1977) 66:1-19).

[0077] As used herein, when used in combination with a salt, the term “pharmaceutically acceptable” means a salt of a currently disclosed compound that can be administered without any substantially undesirable one or more biological effects or any resulting harmful interactions with any other component of a pharmaceutical composition that may contain it.

[0078] The description of the list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. The description of embodiments of variables or aspects herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0079] The compositions and methods provided herein may be combined with one or more of any other compositions and methods provided herein.

[0080] The following abbreviations and empirical formulas are used in this article:

[0081]

[0082] compound

[0083] In the first aspect, this disclosure provides compounds having formula (0):

[0084]

[0085] (Equation (0))

[0086] Or its pharmaceutically acceptable salt, wherein:

[0087] R 1 It is a 6- to 10-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =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 where R 1 Yes -L 3 -R1 ', where R 1 ' is a 5-membered, monocyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N ring atom, and wherein R 1’ Optionally substituted by one or more groups independently selected from the following: =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;

[0088] R 2 It is a 5- to 9-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic and at least one ring contains at least one ring atom that is N; or a fused 11- to 14-membered tricyclic group, wherein at least one ring is aromatic and at least one ring contains at least one ring atom that is N;

[0089] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl;

[0090] R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl; or R 3 It is 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 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)ynyl; or R 3It is a fused 8- to 10-membered bicyclic group comprising a saturated heterocycle fused to an aryl ring or a heteroaryl ring, wherein the carbide ring, the aryl ring or the heteroaryl ring, or both, may optionally be substituted by one or more groups independently selected from the following: 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)ynyl;

[0091] L 1 It is a bond or -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This represents the attachment point to the triazole moiety of a compound having formula (0), and Indicates with R 2 Attachment point;

[0092] L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and Indicates the attachment point to the triazole moiety of a compound having formula (0);

[0093] L 3 It is a bond or -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3)alkyl;

[0094] and

[0095] Among them, in R 1 R 2 and R 3 In, each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0096] In the embodiments, the compound having formula (0) is the compound having formula (I):

[0097]

[0098] (Formula I)

[0099] Or a pharmaceutically acceptable salt thereof, wherein in formula (I):

[0100] R 1 It is a 6- to 10-membered bridged bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =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;

[0101] R 2 It is a 5- to 8-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; or a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic, and at least one ring contains at least one ring atom that is N.

[0102] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl;

[0103] R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl;

[0104] L 1 It is -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This indicates the attachment point to the triazole moiety of a compound having formula (I), and Indicates with R 2 Attachment point;

[0105] L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and Indicates the attachment point to the triazole moiety of a compound having formula (I);

[0106] and

[0107] Among them, in R 1 R 2 and R 3 In, each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0108] In the compounds disclosed herein, R 1 It can be -L 3 -R 1 ', where R 1 ' is a 5-membered monocyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N ring atom, and wherein R 1’ Optionally substituted by one or more groups independently selected from the following: =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 where L 3 It is a bond or -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3)alkyl, and each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0109] In the compounds disclosed herein, R 1 It can be a 6- to 10-membered monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR OC(O)R C(O)NHR CH2C(O)NHR C(O)NR 2. CH2C(O)NR 2. C(O)ONHR CH2C(O)ONHR C(O)ONR 2 and CH2C(O)ONR 2, where each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0110] In R 1 In the case of a double ring, R 1 It can be a bridging bicyclic, fused bicyclic, or spirocyclic group. Therefore, R 1 It can be a 6- to 10-membered bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which is a bridging, fused, or spirocyclic group containing at least one N ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR C(O)NHR CH2C(O)NHR C(O)NR 2. CH2C(O)NR 2. C(O)ONHR CH2C(O)ONHR C(O)ONR 2 and CH2C(O)ONR 2, where each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0111] In the compounds disclosed herein, R 1 It can be a 6- to 10-membered fused bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR OC(O)R C(O)NHR CH2C(O)NHR C(O)NR 2. CH2C(O)NR 2. C(O)ONHR CH2C(O)ONHR C(O)ONR 2 and CH2C(O)ONR 2, where each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0112] In the compounds disclosed herein, R 1 It can be a 6- to 10-membered spirocyclic bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR OC(O)R C(O)NHR CH2C(O)NHR C(O)NR 2. CH2C(O)NR 2. C(O)ONHR CH2C(O)ONHR C(O)ONR 2 and CH2C(O)ONR 2, where each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0113] In the compounds disclosed herein, R 1 It can be a 6- to 10-membered bridged bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR OC(O)R C(O)NHR CH2C(O)NHR C(O)NR 2. CH2C(O)NR 2. C(O)ONHR CH2C(O)ONHR C(O)ONR 2 and CH2C(O)ONR 2, where each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0114] In the compounds disclosed herein, R 1 It can be a 6- to 10-membered bridged bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =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;

[0115] Each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0116] R 1 It is a heterocyclic alkyl or heterocyclic alkenyl group as defined above, i.e., R 1 It is a saturated or unsaturated heterocyclic group; or R 1 It is -L3-R 1 ', where R 1 ' is a heterocyclic alkyl or heterocyclic alkenyl group as defined above. Therefore, R 1It is not an aromatic compound.

[0117] In the embodiment, R 1 Through R 1 The ring atom (which is N) is combined with the triazole moiety of a compound having formula (0) (e.g., a compound having formula (I)).

[0118] In the embodiment, R 1 Selected from:

[0119] , , , , , , ,and ,

[0120] Where X 1 X 2 X 3 X 4 X 5 X 6 and X 7 Each of them is independently selected from C(R) ')2、C=O、NR ', O, and S, and

[0121] Each R '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, where R It is as defined above. In R In the embodiment of ', R It is as defined according to equation (0). In R In the embodiment of ', R It is as defined according to equation (I). In the embodiment, each R 'Independently selected from H, CH2CH3, CH2=CH2, and CH2OCH3.

[0122] In the embodiment, R 1 yes

[0123] or ,

[0124] Where X 1 X 2 X 3 X 4 X 5 and R Each of the characters in ' is as defined above.

[0125] In the embodiment, R 1 yes

[0126] or ,

[0127] Where X 1 X 2 X 5 and R 'is as defined above.

[0128] In the embodiment, R 1 Selected from

[0129] and , where R 'is as defined above.

[0130] In the embodiment, R 1 yes or .

[0131] In the embodiment, R 1 Selected from

[0132] and , where R ' is as defined above. In the embodiment, R 1 yes or .

[0133] In the embodiment, R 1 Selected from

[0134] (include ), (include ), , , , , ,and .

[0135] In the embodiment, R 1 Selected from

[0136] (include ), (include ), , , , , ,and .

[0137] In the embodiment, R 1 yes or .

[0138] In the embodiment, R 1 yes .

[0139] In the embodiment, R 1 yes or X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; and each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R It is as defined above. In R In the embodiment of '', R It is as defined according to equation (0). In R In the embodiment of '', R It is as defined according to formula (I). In the embodiments, v is 1, 2, 3, or 4. In the embodiments, v is 1. In the embodiments, v is 2. In the embodiments, v is 3. In the embodiments, v is 4.

[0140] In the embodiment, R 1 yes X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; and each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R It is as defined above. In R In the embodiment of '', R It is as defined according to equation (0). In R In the embodiment of '', R It is as defined according to formula (I). In the embodiments, v is 1, 2, 3, or 4. In the embodiments, v is 1. In the embodiments, v is 2. In the embodiments, v is 3. In the embodiments, v is 4.

[0141] In the embodiment, R 1 yes or , where v is an integer from 0 to 4; and each R Independently, it is the group R as defined above. In the embodiments, v is 1, 2, 3, or 4. In the embodiments, v is 1. In the embodiments, v is 2. In the embodiments, v is 3. In the embodiments, v is 4.

[0142] In the embodiment, R 1 yes , or , where v is an integer from 0 to 4, and each R Independently, it is the group R as defined above. In the embodiments, v is 1, 2, 3, or 4. In the embodiments, v is 1. In the embodiments, v is 2. In the embodiments, v is 3. In the embodiments, v is 4.

[0143] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0144] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0145] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0146] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0147] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0148] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0149] In the embodiment, R 1 yes , ,or , where v is an integer from 0 to 4, and each R Independently, it is the group R as defined above. In the embodiments, v is 1, 2, 3, or 4. In the embodiments, v is 1. In the embodiments, v is 2. In the embodiments, v is 3. In the embodiments, v is 4.

[0150] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0151] In the embodiment, R 1 yes , where each R Independently, it is the group R as defined above. In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0152] In the embodiment, R 1 no:

[0153] In the compounds disclosed herein, R 2It is a 5- to 9-membered, monocyclic or bicyclic (e.g., fused, bridged or spirocyclic) heterocyclic alkyl or heterocyclic alkenyl group containing at least one N or O ring atom; a 5- or 6-membered monocyclic heteroaryl group containing at least one N ring atom; a fused 8- to 10-membered bicyclic group, one or both rings being aromatic, and at least one ring containing at least one N ring atom; or a fused 11- to 14-membered tricyclic group, at least one ring being aromatic, and at least one ring containing at least one N ring atom;

[0154] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl. In the examples, R It is as defined according to equation (0). In the embodiment, R It is as defined according to equation (I).

[0155] In the embodiment, R 2 It is a fused 11 to 14-membered tricyclic group, wherein at least one ring is aromatic, and wherein at least one ring contains at least one N ring atom;

[0156] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl. In the examples, R It is as defined according to equation (0). In the embodiment, R It is as defined according to equation (I).

[0157] In the embodiment, R 2 yes .

[0158] In the embodiment, R 2 It is a 5- to 8-membered, monocyclic or bicyclic (e.g., fused, bridged or spirocyclic) heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; or a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic, and at least one ring contains at least one ring atom that is N;

[0159] And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl, wherein R It is as defined above. In the embodiment, R It is as defined according to equation (0). In the embodiment, R It is as defined according to equation (I).

[0160] In the embodiment, R 2 Selected from:

[0161] Where q and r are each independently 0, 1, or 2, and R a and R b In each case, CN, Cl, F, and R are selected independently. 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)ynyl, wherein R It is as defined above, for example, as defined according to equation (0) or as defined according to equation (I);

[0162] , where X 8 X 9 X 10 and X 11 Each is independently selected from C(R) k 2. C=O, N(R) k ), O or S, provided that X 8 X 9 X 10 and X 11 At least one of them is N(R) k );

[0163] , where X 12 X 13 and X 14 Each is independently selected from C(R) k 2. C=O, N(R) k ), O or S, and X 15 and X 16 Each is independently selected from C and N, provided that X 12 X 13 and X 14 At least one of them is N(R) k ) and / or X 15 and X 16 At least one of them is N;

[0164] , where X 17 X 18 X 19 X 20 and X 21 Each is independently selected from C(R) k 2. C=O, N(R) k ), O or S, provided that X 17 X 18 X 19 X 20 and X 21 At least one of them is N(R) k ), O or S;

[0165] , where Y 1 Y 2 Y 3 and Y 4 Each is independently N, O, S, NR k or CR k The premise is that Y 1 Y 2 Y 3 and Y 4 At least one of them is N or NR k ;

[0166] , where Y 5 Y 6 and Y 7 Each is independently N, O, S, NR k or CR k And Y 8 and Y 9 Each is either N or C independently, provided that Y 5 Y 6 and Y 7 At least one of them is N or NR k and / or Y 8 and Y 9 At least one of them is N;

[0167] as well as Z 1 Z 2 Z 3 Z 4 and Z 5 Each is independently N, O, S or CR k The premise is Z 1 Z 2 Z 3 Z 4 and Z 5 At least one of them is N;

[0168] Each R k 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)ynyl, wherein R It is as defined above. In the embodiment, R It is as defined according to equation (0). In the embodiment, R It is as defined according to equation (I).

[0169] In the embodiment, R 2 yes , where q, r, R a and R b It is as defined above.

[0170] In the embodiment, R 2 yes or , where q, r, R a and R b It is as defined above.

[0171] In the embodiment, R 2 yes (where R) k (As defined above).

[0172] In the embodiment, R 2 Selected from:

[0173] (where R) b (and r is as defined above) , (For example, or ), (For example, or ), , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0174] In the embodiment, R 2 Selected from:

[0175] (where R) b (and r is as defined above) (where R) k (as defined above) , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0176] In the embodiment, R 2 Selected from:

[0177] (where R) b (and r is as defined above) (where R) (as defined above) (for example) or ), (where R) (as defined above) (for example) or ), , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0178] In the embodiment, R 2 yes , (For example, or ),or (For example, or ).

[0179] In the embodiment, R 2 yes .

[0180] In the embodiment, R 2 yes , where R b It is as defined above.

[0181] In the embodiment, R 2 yes , where each R b It is independent as defined above.

[0182] In the embodiment, R 2 yes or , where R b It is as defined above.

[0183] In the embodiment, R b It is either F or Cl.

[0184] In the embodiment, R 2 yes .

[0185] In the embodiment, R 2 yes .

[0186] In the embodiment, R 2 yes or .

[0187] In the embodiment, R 2 yes .

[0188] In the compounds disclosed herein, L 1 It is a bond or -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This indicates the attachment point to the triazole moiety of a compound having formula (0) (e.g., a compound having formula (I)). Indicates with R 2 The attachment point. In L 1 Yes (C) 2- C3)alkyl, -O(C2-C3 alkyl)- or -(C2-C3 alkyl)O- In this case, the C2 or C3 alkyl group is either straight-chain or branched, for example, -CH(CH3)-. -OCH(CH3)- ,or -CH(CH3)O- .

[0189] In the embodiment, L 1 It is -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This indicates the attachment point to the triazole moiety of a compound having formula (0) (e.g., a compound having formula (I)). Indicates with R 2 Attachment point.

[0190] In the embodiment, L 1 It is -O-, -(C2-C3)alkyl-, -O-(C2-C3)alkyl- , -(C2-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This indicates the attachment point to the triazole moiety of a compound having formula (0) (e.g., a compound having formula (I)). Indicates with R 2 Attachment point.

[0191] In the embodiment, L 1 It is -O-, -CH2CH2-, -OCH2- , -CH2O- , -OCH(CH3)- ,or -CH(CH3)O- .

[0192] In the embodiment, L 1 It is -O-, -CH2CH2-, -OCH2- ,or -CH2O- .

[0193] In the embodiment, L 1 Is -O- or -OCH2- .

[0194] In the embodiment, L 1 It is -O-, -CH2CH2-, -OCH2- , -OCH(CH3)- or -CH2O- .

[0195] In the embodiment, L 1 It is -O-、 -OCH(CH3)- or -OCH2- .

[0196] In the embodiment, L 1 Is -O- or -OCH(CH3)- .

[0197] In the embodiment, L 1 yes -OCH(CH3)- or -OCH2- .

[0198] In the embodiment, L 1 yes -OCH2- And R 2 yes , , , , , ,or , where q, r, R a R b X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X18 X 19 X 20 X 21 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Z 1 Z 2 Z 3 Z 4 and Z 5 It is as defined above.

[0199] In the embodiment, L 1 yes -OCH2- And R 2 yes , , , , , , , , , (For example, or ), (For example, or ), , , , , , , ,or .

[0200] In the embodiment, L 1 yes -OCH2- And R 2 yes , , , , , , , , (where R) k (as defined above) , , , , , , ,or .

[0201] In the embodiment, L 1 yes -OCH2- And R 2 yes , , , , , , , , (where R) (as defined above) (for example, or ), (where R) (as defined above) (for example, or ), , , , , , , ,or .

[0202] In the embodiment, L 1 yes -OCH2- And R 2 yes (where R) k (As defined above).

[0203] In the embodiment, L 1 yes -OCH2- And R 2 yes (where R) (as defined above) (for example, or ), (where R) (as defined above) (for example, or In the embodiment, L 1 yes -OCH2- And R 2 yes , (For example, or ), (For example, or ).

[0204] In the embodiment, L 1 yes -OCH2- And R 2 yes , where q, r, R a and R b It is as defined above.

[0205] In the embodiment, L 1 yes -OCH2- And R 2 yes , where R b It is as defined above.

[0206] In the embodiment, L 1 and R 2 Together they form groups or , where q, r, R a and R b It is as defined above.

[0207] In the embodiment, L 1 and R 2 Together they form groups or , where R b It is as defined above.

[0208] In the embodiment, L 1 yes -OCH2- And R 2 yes .

[0209] In the embodiment, L 1 and R 2 Together they form groups or .

[0210] In the embodiment, L 1 It is -O-, and R2 yes , , , , , ,or , where q, r, R a R b X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Z 1 Z 2 Z 3 Z 4 and Z 5 It is as defined above.

[0211] In the embodiment, L 1 It is -O- and R 2 yes , , ,or .

[0212] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , , , , , , , , , (For example, or ), (For example, or ), , , , , , , ,or .

[0213] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , , , , , , , , (where R) k (as defined above) , , , , , , ,or .

[0214] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , , , , , , , , (where R) (as defined above) (for example, or ), (where R) (as defined above) (for example, or ), , , , , , , ,or .

[0215] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes (where R) k (As defined above).

[0216] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes (where R) (as defined above) (for example, or )or (where R) (as defined above) (for example, or ).

[0217] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , (For example, or ),or (For example, or ).

[0218] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , where X 8 X 9 X 10 and X 11 Each is independently selected from C(R) k 2. C=O, N(R) k O, or S, provided that X 8 X 9 X 10 and X 11 At least one of them is N(R) k ); where each R k 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)ynyl, wherein each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0219] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , where X 8 X 9 X 10 and X 11 Each is independently selected from C(R) k 2. C=O, N(R) k O, or S, provided that X 8 X 9 X 10 and X 11 At least one of them is N(R) k ); where each R k 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)ynyl, wherein each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0220] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes , where each R k 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)ynyl, wherein each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0221] In the embodiment, L 1 yes -OCH(CH3)- And R 2 yes (For example, ), (For example, ),or (where R) The group is selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may 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)ynyl, or O (C1-C3)alkyl), for example. or .

[0222] In the compounds disclosed herein, R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)); or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)); or R 3 It is 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 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)); or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated heterocycle fused to an aryl ring or a heteroaryl ring, wherein the carbide ring, the aryl ring or the heteroaryl ring, or both, may optionally be substituted by one or more groups independently selected from the following: 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)).

[0223] In the embodiment, R 3It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)); or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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) ynyl.

[0224] In the embodiment, R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)).

[0225] In the embodiment, R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)).

[0226] In the embodiment, R 3 Selected from

[0227] Where m is 1 or 2 and n is 0, 1 or 2; and each R c and R d Independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)ynyl, provided that at least one R c It is OH;

[0228] , where s is 1, 2, or 3, and where when s is 1, R g It is OH, and when s is 2 or 3, at least one R g It is OH and each remaining R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl; and

[0229] , where Y10 It is S, O, or NR''', where R''' is H, OH, CN, Cl, F, or (C1-C3) alkyl; t is 0, 1, 2, or 3, and u is 0, 1, or 2, provided that u is not zero when t is zero, and t is not zero when u is zero; and each R h and R i 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)).

[0230] In the embodiment, R 3 It is a naphthyl group, which is replaced by OH and optionally by one or more other 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)).

[0231] In the embodiment, R 3 yes When m is 1, R c It is OH, and when m is 2, at least one R c It is OH and other R c It is independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)ynyl.

[0232] In the embodiment, R 3 Selected from , , , , , , , ,and , where R c It is as defined above.

[0233] In the embodiment, R 3 Selected from , , , , , , , ,and , where R c R d , and n are defined as above.

[0234] In the embodiment, R 3 Selected from

[0235] , , , , , , , , ,and , where R c R d , and m are defined as above.

[0236] In the embodiment, R 3 Selected from

[0237] and , where R d It is as defined above.

[0238] In the embodiment, each R d It is independently selected from F, Cl, C≡CH, and CH2CH3.

[0239] In the embodiment, R 3 Selected from

[0240] , , , , , , , , , ,and .

[0241] In the embodiment, R 3 Selected from , , , , ,and .

[0242] In the embodiment, R 3 It is a phenyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)).

[0243] In the embodiment, R 3 yes

[0244] , where s is 1, 2, or 3, and where when s is 1, R g It is OH, and when s is 2 or 3, at least one R g It is OH and each remaining R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0245] In the embodiment, R 3 yes , where each Rg Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0246] In the embodiment, R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0247] In the embodiment, R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0248] In the embodiment, R 3 yes , where each R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0249] In the embodiment, R 3 yes , where each R gIndependently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0250] In the embodiment, R 3 yes , , ,or , where each R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0251] In the embodiment, R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0252] In the embodiment, R 3 yes , , ,or , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0253] In the embodiment, R 3 yes , where R g It is either F or Cl.

[0254] In the embodiment, R 3 yes , , ,or , where R g It is either F or Cl.

[0255] In the embodiment, R 3 yes .

[0256] In the embodiment, R 3 yes , , ,or .

[0257] In the embodiment, R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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) ynyl.

[0258] In the embodiment, R 3 It is a fused bicyclic group comprising a 6-membered saturated carbon ring fused to a 5-membered heterocycle, wherein the carbon ring, the heterocycle, 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)ynyl. In embodiments, the heterocycle contains at least one heteroatom, which is S. In embodiments, R 3 yes , where Y 10 It is S, O, or NR''', where R''' is H, OH, CN, Cl, F, or (C1-C3) alkyl; t is 0, 1, 2, or 3 and u is 0, 1, or 2, provided that when t is zero, u is not zero, and when u is zero, t is not zero; and each R h and R i 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)). In the embodiments, each R h and R i It is independently selected from F, Cl, CN, OH, NH2, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)ynyl.

[0259] In the embodiment, R 3 yes , where R h R i , t, and u are defined as above.

[0260] In a particular embodiment, R 3 yes , ,or , where R h R i , t, and u are defined as above.

[0261] In the embodiment, R 3 yes , where R h R i , and u are as defined above.

[0262] In a particular embodiment, R3 yes , ,or , where R h and R i It is as defined above.

[0263] In the embodiment, R 3 yes , where R h R i , and u are as defined above.

[0264] In a particular embodiment, R 3 yes , ,or , where R h and R i It is as defined above.

[0265] In the embodiment, R 3 yes , where R h R i , and u are as defined above.

[0266] In a particular embodiment, R 3 yes , ,or , where R h and R i It is as defined above.

[0267] In a more specific embodiment, R 3 yes or In even more specific embodiments, R 3 yes .

[0268] In the embodiment, R 3 It is a fused bicyclic group comprising a 6-membered saturated heterocycle fused to a 5-membered heteroaryl ring, wherein the saturated heterocycle, 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)ynyl. In embodiments, the saturated heterocycle comprises at least one heteroatom, which is N. In embodiments, the heteroaryl ring comprises at least one heteroatom, which is N.

[0269] In the embodiment, R 3 yes or Where t is 0, 1, 2, or 3 and u is 0, 1, or 2, provided that when t is zero, u is not zero, and when u is zero, t is not zero; and each R h and R i 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)ynyl, wherein R It is as defined above (e.g., according to equation (0) or according to equation (I)). In the embodiments, each R h and R i It is independently selected from F, Cl, CN, OH, NH2, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)ynyl.

[0270] In the compounds disclosed herein, L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and This indicates the attachment point to the triazole portion of a compound having formula (0) (e.g., a compound having formula (I)).

[0271] In the embodiment, L 2 It is a C5-heteroaryl group consisting of -(C1-C3)alkyl-, optionally substituted with one or more R'', and containing at least one N ring atom. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- , where R'' is as defined above.

[0272] In the embodiment, L 2 It is a C5-heteroaryl group consisting of -(C1-C3)alkyl-, optionally substituted with one or more R'', and containing at least two N-ring atoms. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- , where R'' is as defined above.

[0273] In the embodiment, L 2 It is -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- ; or L 2It is pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, or 2,4-diazafuran, any of which may optionally be replaced by one or more R'', wherein R'' is as defined above.

[0274] In the embodiment, L 2 It is -CH2CH2-, -CH=CH-, -C≡C-, -CH2O- , -OCH2- , -CH2NH- , -NHCH2- , -N(CH3)C(O)- , -C(O)N(CH3)- , -NHC(O)- , -C(O)NH- , , , , , , , , , , , , , , , , , , , , ,or .

[0275] In the embodiment, L 2 It is -CH2CH2, -C≡C-, ,or .

[0276] In the embodiment, R 1 yes And R 3 yes Thus, compounds having formula (II) are provided:

[0277]

[0278] (Formula (II))

[0279] Where R '、L 1 L 2 R 2 R c R d , n, and m are defined as above.

[0280] In the embodiment of formula (II), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes .

[0281] In the embodiment of formula (II), R 1 yes Thus, compounds having formula (IIa) are provided:

[0282]

[0283] (Formula (IIa))

[0284] Where L 1 L 2 R 2 R c R d , n, and m are defined as above.

[0285] In the embodiment of formula (II), R 1 yes Thus, compounds having formula (IIb) are provided:

[0286]

[0287] (Equation (IIb))

[0288] Where L 1 L 2 R 2 R c R d , n, and m are defined as above.

[0289] In the embodiment, R 1 yes And R 3 yes Thus, compounds having formula (III) are provided:

[0290]

[0291] (Formula (III))

[0292] Where R '、L 1 L 2 R 2 R c R d , and n are defined as above.

[0293] In the embodiment of formula (III), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes .

[0294] In the embodiment of formula (III), R 1 yes Thus, compounds having formula (IIIa) are provided:

[0295]

[0296] (Formula (IIIa))

[0297] Where L 1 L 2 R 2 R c R d , and n are defined as above.

[0298] In the embodiment of formula (III), R 1 yes Thus, compounds having formula (IIIb) are provided:

[0299]

[0300] (Equation (IIIb))

[0301] Where L 1 L 2 R 2 R c R d , and n are defined as above.

[0302] In embodiments of formula (III) (including formulas (IIIa) and (IIIb)), R 3 yes

[0303] , ,or , where R d It is as defined above.

[0304] In embodiments of formula (III) (including formulas (IIIa) and (IIIb)), R 3 yes , , , , , , , , ,or .

[0305] In embodiments of formula (III) (including formulas (IIIa) and (IIIb)), R 3 yes , , ,or .

[0306] In the embodiment, R 1 yes And R 3 yes Thus, compounds having formula (IV) are provided:

[0307]

[0308] (Formula (IV))

[0309] Where R '、L 1 L 2 R 2 , and s are as defined above, and each of R is a subset of R. g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0310] In the embodiment of formula (IV), R 1 yes In the embodiment, R 'Is H and therefore R' 1yes .

[0311] In the embodiment of formula (IV), R 1 yes Thus, compounds having formula (IVa) are provided:

[0312]

[0313] (Formula (IVa))

[0314] Where L 1 L 2 R 2 R g , and s are as defined above.

[0315] In the embodiment of formula (IV), R 1 yes Thus, compounds having formula (IVb) are provided:

[0316]

[0317] (Formula (IVb))

[0318] Where L 1 L 2 R 2 R g , and s are as defined above.

[0319] In embodiments of formula (IV) (including formulas (IVa) and (IVb)), R 3 yes , ,or , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0320] In embodiments of formula (IV) (including formulas (IVa) and (IVb)), R 3 yes , where R gIt is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0321] In the embodiment, R 1 yes And R 3 yes Thus, compounds having formula (V) are provided:

[0322]

[0323] (Equation (V))

[0324] Where L 1 L 2 and R 2 It is as defined above, and each R is... g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0325] In the embodiment of formula (V), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes .

[0326] In the embodiment of formula (V), R 1 yes Thus, compounds having the formula (Va) are provided:

[0327]

[0328] (Equation (Va))

[0329] Where L 1 L 2 and R 2 It is as defined above, and each R is... gIndependently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0330] In the embodiment of formula (V), R 1 yes Thus, compounds having the formula (Vb) are provided:

[0331]

[0332] (Equation (Vb))

[0333] Where L 1 L 2 and R 2 It is as defined above, and each R is... g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0334] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0335] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , , ,or , where each R gIndependently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0336] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0337] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , , ,or , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0338] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , where R g It is either F or Cl.

[0339] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , , or , where R g It is either F or Cl.

[0340] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes .

[0341] In embodiments of formula (V) (including formulas (Va) and (Vb)), R 3 yes , , ,or .

[0342] In the embodiment, R 1 yes And R 2 yes Thus, compounds having formula (VI) are provided:

[0343]

[0344] (Formula (VI))

[0345] Where R '、L 1 L 2 R 3 , q, r, R a and R b It is as defined above.

[0346] In the embodiment of formula (VI), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes .

[0347] In the embodiment of formula (VI), R 1 yes Thus, compounds having formula (VIa) are provided:

[0348]

[0349] (Formula (VIa))

[0350] Where L 1 L 2 R 3 , q, r, R a and R b It is as defined above.

[0351] In the embodiment of formula (VI), R 1 yes Thus, compounds having formula (VIb) are provided:

[0352]

[0353] (Formula (VIb))

[0354] Where L 1 L 2 R 3 , q, r, R a and R b It is as defined above.

[0355] In the embodiment, R 1 yes And R 2 yes Thus, compounds having formula (VI.I) are provided:

[0356]

[0357] (Formula (VI.I))

[0358] Where R ''、L 1 L 2 R 3 X, q, r, v, R a and R b It is as defined above.

[0359] In the embodiment of equation (VI.I), X is O and therefore R 1 yes In this embodiment, X is 0 and v is 2. In this embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0360] In the embodiment of formula VI.I, R 1 yes Thus, compounds having formula (VI.Ia) are provided:

[0361]

[0362] (Formula (VI.Ia))

[0363] Where L 1L 2 R 3 , q, r, R a and R b It is as defined above.

[0364] In the embodiment of formula VI.I, R 1 yes Thus, compounds having formula (VI.Ib) are provided:

[0365]

[0366] (Formula (VI.Ib))

[0367] Where L 1 L 2 R 3 , q, r, R a and R b It is as defined above.

[0368] In the embodiment, R 1 yes And R 2 yes Thus, compounds having formula (VII) are provided:

[0369]

[0370] (Equation (VII))

[0371] Where R '、L 1 L 2 R 3 and R b It is as defined above.

[0372] In the embodiment of formula (VII), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes .

[0373] In the embodiment of formula (VII), R 1 yes Thus, compounds having formula (VIIa) are provided:

[0374]

[0375] (Equation (VIIa))

[0376] Where L 1 L 2 R3 and R b It is as defined above.

[0377] In the embodiment of formula (VII), R 1 yes Thus, compounds having formula (VIIb) are provided:

[0378]

[0379] (Equation (VIIb))

[0380] Where L 1 L 2 R 3 and R b It is as defined above.

[0381] In the embodiment, R 1 yes And R 2 yes Thus, compounds having formula (VII.I) are provided:

[0382]

[0383] (Formula (VII.I))

[0384] Where R ''、L 1 L 2 R 3 X, v, and R b It is as defined above.

[0385] In the embodiment of equation (VII.I), X is O and therefore R 1 yes In this embodiment, X is 0 and v is 2. In this embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes In the embodiment, R 1 yes .

[0386] In the embodiment of formula VII.I, R 1 yes Thus, compounds having formula (VII.Ia) are provided:

[0387]

[0388] (Equation (VII.Ia))

[0389] Where L 1 L 2 R 3 and R b It is as defined above.

[0390] In the embodiment of formula VII.I, R 1 yes Thus, compounds having formula (VII.Ib) are provided:

[0391]

[0392] (Equation (VII.Ib))

[0393] Where L 1 L 2 R 3 and R b It is as defined above.

[0394] In embodiments of formula VI (including formulas (VIa) and (VIb)) and formula VI.I (including formulas (VI.Ia) and (VI.Ib)) and formula (VII) (including formulas (VIIa) and (VIIb)) and formula (VII.I) (including formulas (VII.Ia) and (VII.Ib)), R 2 yes In embodiments of formula VI (including formulas (VIa) and (VIb)) and formula VI.I (including formulas (VI.Ia) and (VI.Ib)) and formula VII (including formulas (VIIa) and (VIIb)) and formula VII.I (including formulas (VII.Ia) and (VII.Ib)), R 2 yes .

[0395] In the embodiment, R 2 yes And R 3 yes Thus, compounds having formula (VIII) are provided:

[0396]

[0397] (Formula (VIII))

[0398] Where L 1 L 2 R 1 R a R b R c R d , n, m, q, and r are defined as above.

[0399] In the embodiment of formula (VIII), R 2 yes , where R b It is as defined above.

[0400] In the embodiment of formula (VIII), R 3 yes , where R d And n is as defined above.

[0401] In the embodiment, R 2 yes And R 3 yes Thus, compounds having formula (IX) are provided:

[0402]

[0403] (Equation (IX))

[0404] Where L 1 L 2 R 1 R b R d , and n are defined as above.

[0405] In the embodiments of formulas (VIII) and (IX), R 2 yes In the embodiments of formulas (VIII) and (IX), R 2 yes .

[0406] In the embodiments of formulas (VIII) and (IX), R 3 yes

[0407] , ,or , where Rd It is as defined above.

[0408] In the embodiments of formulas (VIII) and (IX), R 3 yes , , , , , , , , ,or .

[0409] In the embodiments of formulas (VIII) and (IX), R 3 Selected from

[0410] , , , , ,and .

[0411] In the embodiments of formulas (VIII) and (IX), R 3 yes

[0412] , ,or , where R d It is as defined above, and R 2 yes .

[0413] In the embodiments of formulas (VIII) and (IX), R 2 yes And R 3 yes , ,or , where R d It is as defined above.

[0414] In the embodiments of formulas (VIII) and (IX), R 3 yes

[0415] , , , , , , , , ,or And R 2yes .

[0416] In the embodiments of formulas (VIII) and (IX), R 3 yes

[0417] , , , , , , , , ,or And R 2 yes .

[0418] In the embodiment, R 2 yes And R 3 yes Thus, compounds having formula (X) are provided:

[0419]

[0420] (Formula (X))

[0421] Where R 1 L 1 L 2 R a R b , q, r, and s are as defined above, and each of R is a function of q, r, and s. g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0422] In the embodiment of formula (X), R 2 yes , where R b It is as defined above.

[0423] In the embodiment of formula (X), R 3 yes , where each R gIndependently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0424] In the embodiment, R 2 yes And R 3 yes Thus, compounds having formula (XI) are provided:

[0425]

[0426] (Formula (XI))

[0427] Where R 1 L 1 L 2 and R b It is as defined above, and each R is... g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0428] In the embodiments of equations (X) and (XI), R 2 yes .

[0429] In the embodiments of equations (X) and (XI), R 2 yes .

[0430] In the embodiments of equations (X) and (XI), R 3 yes , where each R gIndependently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0431] In the embodiments of equations (X) and (XI), R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl.

[0432] In the embodiments of equations (X) and (XI), R 3 yes , , ,or , where each R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH.

[0433] In the embodiments of equations (X) and (XI), R 3 yes , , ,or , where R g The group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R group is present. g It is OH.

[0434] In the embodiments of equations (X) and (XI), R 3 yes , where each R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH, and R 2 yes .

[0435] In the embodiments of equations (X) and (XI), R 3 yes , where R g It is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, and R 2 yes .

[0436] In the embodiments of equations (X) and (XI), R 3 yes , , ,or , where each R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from the group consisting of F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, provided that at least one R g It is OH, and R 2 yes In the embodiments of equations (X) and (XI), R 3 yes , , ,or , where each R gIndependently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl itself may be substituted by one or more groups independently selected from: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl, and R 2 yes .

[0437] In the embodiments of equations (VIII), (IX), (X), and (XI), R 1 yes .

[0438] In the embodiments of equations (VIII), (IX), (X), and (XI), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes Therefore, in another embodiment, compounds having formulas (XII)-(XVIII) are provided, wherein L 1 L 2 R a R b R c R d R g , n, m, q, r, and s are defined as above:

[0439]

[0440] (Formula (XII))

[0441]

[0442] (Formula (XIII))

[0443]

[0444] (Formula (XIV))

[0445]

[0446] (Equation (XV))

[0447]

[0448] (Formula (XVI))

[0449]

[0450] (Formula (XVII))

[0451]

[0452] (Formula (XVIII))

[0453] In the embodiments of formulas (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R 1 yes or .

[0454] In the embodiments of formulas (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R 2 yes , where R b It is as defined above.

[0455] In the embodiments of formulas (XII), (XIII), (XIV), (XV), (XVI), (XVII), and (XVIII), R 1 yes And R 2 yes , where R b It is as defined above.

[0456] In the embodiments, compounds having the formula (XIX) are provided:

[0457]

[0458] (Formula (XIX))

[0459] Where L 2 R b R d , and n are defined as above.

[0460] In the embodiments, compounds having formula (XX) are provided:

[0461]

[0462] (Formula (XX))

[0463] Where L 2 R b R c R d , and n are defined as above.

[0464] In the embodiments, compounds having the formula (XXI) are provided:

[0465]

[0466] (Formula (XXI))

[0467] Where R g L 2 and R b It is as defined above.

[0468] In the embodiment, R 1 yes And R 3 yes Thus, compounds having the formula (XXII) are provided:

[0469]

[0470] (Formula (XXII))

[0471] Where R '、L 1 L 2 R 2 R h R i , t, u, and Y 10 It is as defined above.

[0472] In the embodiment, R 1 yes And R 3 yes Thus, compounds having the formula (XXII.I) are provided:

[0473]

[0474] (Formula (XXII.I))

[0475] Where R ''、L 1 L 2 X, R 2 R h R i t, u, v, and Y 10 It is as defined above.

[0476] In the embodiment, R 1 yes And R 3 yes Thus, compounds having formula (XXIII) are provided:

[0477]

[0478] (Formula (XXIII))

[0479] Where R '、L 1 L 2 R 2 R h R i , t, and u are defined as above.

[0480] In the embodiment, R 1 yes And R 3 yes Thus, compounds having the formula (XXIII.I) are provided:

[0481]

[0482] (Formula (XXIII.I))

[0483] Where R ''、L 1 L 2 X, R 2 R h R i , t, u, and v are as defined above.

[0484] In the embodiments of formula (XXIII) and formula (XXIII.I), R 3 yes , ,or , where R h R i , and t are defined as above.

[0485] In the embodiment, R 1 yes And R 3 yes Thus, compounds having the formula (XXIV) are provided:

[0486]

[0487] (Formula (XXIV))

[0488] Where R '、L 1 L 2 R 2 R h R i , and u are as defined above.

[0489] In the embodiment, R 1 yes And R 3yes Thus, compounds having the formula (XXIV.I) are provided:

[0490]

[0491] (Formula (XXIV.I))

[0492] Where R ''、L 1 L 2 X, R 2 R h R i , t, u, and v are as defined above.

[0493] In the embodiments of formula (XXIV) and formula (XXIV.I), R 3 yes or , where R h R i , and u are as defined above.

[0494] In the embodiments of formula (XXIV) and formula (XXIV.I), R 3 yes , ,or , where R h and R i It is as defined above.

[0495] In specific embodiments of formulas (XXIV) and (XXIV.I), R 3 yes , ,or , where R h and R i It is as defined above.

[0496] In specific embodiments of formulas (XXIV) and (XXIV.I), R 3 yes , ,or , where R h and R i It is as defined above.

[0497] In more specific embodiments of formulas (XXIV) and (XXIV.I), R 3 yes or .

[0498] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 It is a 5- to 9-membered (e.g., 5- to 8-membered), monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, comprising at least one ring atom of N or O; a 5- or 6-membered monocyclic heteroaryl group, comprising at least one ring atom of 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 of N; and wherein R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl; and wherein each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0499] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 It is a 5- to 8-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, comprising at least one ring atom of N or O; a 5- or 6-membered monocyclic heteroaryl group, comprising at least one ring atom of 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 of N; and wherein R 2It can be substituted by one or more groups independently selected from the following: 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)ynyl; and wherein each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0500] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 It is a 5- to 9-membered, monocyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O, and wherein R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl. In the examples, each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, or 5 or 6-membered monocyclic heteroaryl group itself may 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)ynyl, or O (C1-C3)alkyl. In the examples, each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0501] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 yes , where X 8 X 9 X 10 and X 11 Each is independently selected from C(R) k 2. C=O, N(R) k O, or S, provided that X 8 X 9 X 10 and X 11 At least one of them is N(R) k ); where each R k 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)ynyl, wherein each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

[0502] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 yes , where X 8 X 9 X 10 and X 11 Each is independently selected from C(R) k 2. C=O, N(R) k O, or S, provided that X 8 X 9 X 10 and X 11 At least one of them is N(R) k ); where each R k 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)ynyl, wherein each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0503] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), and (XXIV.I), R 2 yes , where each R k 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)ynyl, wherein each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

[0504] In the embodiment, R 2 yes And R 3 yes Thus, compounds having the formula (XXV) are provided:

[0505]

[0506] (Formula (XXV))

[0507] Where L 1 L 2 R 1 R a R b R h R i q and r, t, u, and Y 10 It is as defined above.

[0508] In the embodiment, R 2 yes And R 3 yes Thus, compounds having the formula (XXVI) are provided:

[0509]

[0510] (Formula (XXVI))

[0511] Where L 1 L 2 R 1 R a R b R h R i , q, r, t, and u are defined as above.

[0512] In the embodiment, R 1 yes And R 2 yes Thus, compounds having formula (XXVII) are provided:

[0513]

[0514] (Formula (XXVII))

[0515] Where R ''、L 1 L 2 R 3 X, v, and R k It is as defined above.

[0516] In the embodiment, R 1 yes R 2 yes And R 3 yes Thus, compounds having the formula (XXVIII) are provided:

[0517]

[0518] (Formula (XXVIII))

[0519] Where R ''、L 1 L 2 X, R h R i R k , t, u, and v are as defined above.

[0520] In the embodiment of formula (XXVIII), R 3 yes (For example, or In a specific embodiment of formula (XXVIII), R 3 yes (For example, or In a more specific embodiment of formula (XXVIII), R 3 yes or .

[0521] In the embodiments of formulas (XXII), (XXII.I), (XXIII), (XXIII.I), (XXIV), (XXIV.I), (XXVII), and (XXVIII), R 2 yes (For example, or ), (For example, or ), or R 2 yes (where R) Selected from (C) 1- (C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl are used. 1- (C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl groups can be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O(C1-C3)alkyl), for example or , or R 2 yes (where R) Selected from (C) 1-(C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl are used. 1- (C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl groups can be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O(C1-C3)alkyl), for example or .

[0522] In the embodiments of formulas (XXII), (XXIII), (XXIV), (XXV), and (XXVI), R 1 yes In the embodiment, R 'Is H and therefore R' 1 yes .

[0523] In the embodiments of formulas (XXII), (XXIII), (XXIV), (XXV), and (XXVI), R 1 yes In the embodiments of formulas (XXII), (XXIII), (XXIV), (XXV), and (XXVI), R 1 yes .

[0524] In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes .

[0525] In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes .

[0526] In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes In the embodiments of formulas (XXII.I), (XXIII.I), (XXIV.I), (XXV), (XXVI), (XXVII), and (XXVIII), R 1 yes .

[0527] In the embodiments, compounds having formula (0) or formula (I) are not:

[0528] .

[0529] In the embodiments, compounds having formula (0) or formula (I) are not:

[0530] .

[0531] In the embodiments, the compound is selected from the group consisting of the compounds in Table 1 below and their stereoisomers (including their enantiomers and diastereomers, and mixtures of their stereoisomers, such as mixtures of enantiomers or diastereomers of the compounds in Table 1), where "#" represents the "compound number":

[0532] Table 1

[0533]

[0534] In the embodiments, the compounds disclosed herein are characterized according to their binding and / or inhibitory activity against KRAS G12D (e.g., measured according to the determinations described in the examples below).

[0535] In the embodiments, the compounds disclosed herein are based on their dissociation constant K related to KRAS G12D. D Characterization is performed, for example, when measured according to SPR, as described in the following examples.

[0536] In the examples, these compounds affect the K-type of KRAS G12D. D ≤ 10 μM. In the examples, the K of these compounds... D 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 the examples, these compounds are effective against the Kα of KRAS G12D. D Less than about 50 nM, for example, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM.

[0537] In the embodiments, the compounds disclosed herein are characterized based on their binding and / or inhibitory activity against GDP-binding KRAS G12D (e.g., measured according to the assays described in the examples below).

[0538] In the embodiments, these compounds are used in ICs that bind to KRAS G12D bound to GDP. 50Less than about 50 nM, for example, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, or less than about 5 nM. In the examples, these compounds are used to bind to KRAS G12D bound to GDP with an IC50 of less than about 2 nM, for example, less than about 1.5 nM, less than about 1.25 nM, less than about 1 nM, less than about 0.75 nM, or less than about 0.5 nM.

[0539] In the examples, these compounds exhibit a greater affinity for KRAS G12D than for wild-type (WT) KRAS. Therefore, in the examples, these compounds have a higher Kc affinity for WT KRAS than for KRAS G12D. D For example, when measured according to SPR, such as when measured according to SPR determination as described in the following examples. In the embodiments, the binding selectivity of the compound to KRAS G12D is at least 5 times that to WT KRAS (e.g., as by K D (WT KRAS) and K D The ratio of (KRAS G12D) is defined, for example, when measured according to SPR, such as when measured according to an SPR determination as described in the examples below. In the examples, the selectivity of the compound for KRAS G12D is at least about 10, 15, 20, 25, or 30 times that of WT KRAS (e.g., as by K...). D (WT KRAS) and K D The ratio of (KRAS G12D) is defined, for example, when measured according to SPR, such as when measured according to an SPR assay as described in the examples below. In the embodiments, these compounds show a significant improvement in cell potency compared to compounds known in the art.

[0540] In the embodiments, the compounds exhibit multimutant RAS cell inhibition without affecting WT KRAS, NRAS, and HRAS; therefore, these compounds act as pan-KRAS inhibitors that not only do not affect other RAS isotypes but also wild-type KRAS, while exhibiting multimutant KRAS inhibition. This has the beneficial effect of significantly expanding the patient population by approximately three times compared to compounds known in the art. In the embodiments, these compounds exhibit cell inhibition against KRAS mutant G12D and at least one or a combination of KRAS mutants G12A, G12C, G12V, Q61H, G13D, or other KRAS mutants (e.g., cell inhibition against KRAS G12D with at least two, three, four, or five of these mutants, such as KRAS G12D with any two, three, four, or five of these mutants), without affecting WT KRAS. In the examples, these compounds exhibit cell inhibition against KRAS mutant G12D and at least one or a combination of KRAS mutants G12A, G12C, G12V, Q61H, and G13D (e.g., cell inhibition against KRAS G12D and combinations of at least two, at least three, at least four, or all five mutants, such as any two, any three, any four, or all five mutants), without affecting WT KRAS. In the examples, these compounds exhibit cell inhibition against each of the KRAS mutants G12D, G12A, G12C, G12V, Q61H, and G13D, without affecting WT KRAS.

[0541] In the embodiments, the compounds disclosed herein are characterized based on their inhibitory effect on KRAS cell lines, for example, as measured by inhibition of KRAS-mediated ERK phosphorylation, as described in the examples below. In the embodiments, the IC50 of these compounds on ERK phosphorylation inhibition in WTKRAS cell lines is... 50 Greater than about 10 µM, and the IC50 value for ERK phosphorylation inhibition of KRAS mutant G12D and optionally KRAS mutants G12A, G12C, G12V, Q61H or G13D or combinations thereof (e.g., ERK phosphorylation inhibition of KRAS G12D with at least two, at least three, at least four or all five mutants, such as KRAS G12D with any two, any three, any four or all five mutants). 50 Less than about 500 nM, for example, 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.

[0542] In the embodiments, these compounds exhibit increased permeability and / or improved oral bioavailability compared to compounds known in the art.

[0543] Pharmaceutical Composition

[0544] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0545] In the examples, the pharmaceutical composition comprises a compound having formula (0) or a pharmaceutically acceptable salt thereof.

[0546] In the examples, the pharmaceutical composition comprises a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0547] In some embodiments, the pharmaceutical composition comprises a compound having formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (IIa) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (IIb) or a pharmaceutically acceptable salt thereof.

[0548] In one embodiment, the pharmaceutical composition comprises a compound having formula (III) or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises a compound having formula (IIIa) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the pharmaceutical composition comprises a compound having formula (IIIb) or a pharmaceutically acceptable salt thereof.

[0549] In some embodiments, the pharmaceutical composition comprises a compound having formula (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (Iva) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (IVb) or a pharmaceutically acceptable salt thereof.

[0550] In one embodiment, the pharmaceutical composition comprises a compound having formula (V) or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises a compound having formula (Va) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the pharmaceutical composition comprises a compound having formula (Vb) or a pharmaceutically acceptable salt thereof.

[0551] In some embodiments, the pharmaceutical composition comprises a compound having formula (VI) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (Via) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VIb) or a pharmaceutically acceptable salt thereof.

[0552] In some embodiments, the pharmaceutical composition comprises a compound having formula (VI.I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VI.Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VI.Ib) or a pharmaceutically acceptable salt thereof.

[0553] In some embodiments, the pharmaceutical composition comprises a compound having formula (VII) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VIIa) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VIIb) or a pharmaceutically acceptable salt thereof.

[0554] In some embodiments, the pharmaceutical composition comprises a compound having formula (VII.I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VII.Ia) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VII.Ib) or a pharmaceutically acceptable salt thereof.

[0555] In the examples, the pharmaceutical composition comprises a compound having formula (VIII) or a pharmaceutically acceptable salt thereof.

[0556] In the embodiments, the pharmaceutical composition comprises a compound having formula (IX) or a pharmaceutically acceptable salt thereof.

[0557] In the embodiments, the pharmaceutical composition comprises a compound having formula (X) or a pharmaceutically acceptable salt thereof.

[0558] In the embodiments, the pharmaceutical composition comprises a compound having formula (XI) or a pharmaceutically acceptable salt thereof.

[0559] In the examples, the pharmaceutical composition comprises a compound having formula (XII) or a pharmaceutically acceptable salt thereof.

[0560] In the examples, the pharmaceutical composition comprises a compound having formula (XIII) or a pharmaceutically acceptable salt thereof.

[0561] In the examples, the pharmaceutical composition comprises a compound having formula (XIV) or a pharmaceutically acceptable salt thereof.

[0562] In the examples, the pharmaceutical composition comprises a compound having formula (XV) or a pharmaceutically acceptable salt thereof.

[0563] In the examples, the pharmaceutical composition comprises a compound having formula (XVI) or a pharmaceutically acceptable salt thereof.

[0564] In the examples, the pharmaceutical composition comprises a compound having formula (XVII) or a pharmaceutically acceptable salt thereof.

[0565] In the examples, the pharmaceutical composition comprises a compound having formula (XVIII) or a pharmaceutically acceptable salt thereof.

[0566] In the embodiments, the pharmaceutical composition comprises a compound having the formula (XIX) or a pharmaceutically acceptable salt thereof.

[0567] In the embodiments, the pharmaceutical composition comprises a compound having formula (XX) or a pharmaceutically acceptable salt thereof.

[0568] In the examples, the pharmaceutical composition comprises a compound having the formula (XXI) or a pharmaceutically acceptable salt thereof.

[0569] In the examples, the pharmaceutical composition comprises a compound having the formula (XXII) or a pharmaceutically acceptable salt thereof.

[0570] In the examples, the pharmaceutical composition comprises a compound having the formula (XXII.I) or a pharmaceutically acceptable salt thereof.

[0571] In the embodiments, the pharmaceutical composition comprises a compound having formula (XXIII) or a pharmaceutically acceptable salt thereof.

[0572] In the embodiments, the pharmaceutical composition comprises a compound having formula (XXIII.I) or a pharmaceutically acceptable salt thereof.

[0573] In the embodiments, the pharmaceutical composition comprises a compound having the formula (XXIV) or a pharmaceutically acceptable salt thereof.

[0574] In the examples, the pharmaceutical composition comprises a compound having the formula (XXIV.I) or a pharmaceutically acceptable salt thereof.

[0575] In the embodiments, the pharmaceutical composition comprises a compound having the formula (XXV) or a pharmaceutically acceptable salt thereof.

[0576] In the examples, the pharmaceutical composition comprises a compound having the formula (XXVI) or a pharmaceutically acceptable salt thereof.

[0577] In the embodiments, the pharmaceutical composition comprises a compound having formula (XXVII) or a pharmaceutically acceptable salt thereof.

[0578] In the examples, the pharmaceutical composition comprises a compound having the formula (XXVIII) or a pharmaceutically acceptable salt thereof.

[0579] The pharmaceutical compositions disclosed herein can be formulated for application in solid or liquid form, for example, using conventional carriers or excipients. The compositions may be suitable for, for example, 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 administration using techniques known in the art (e.g., as an ointment, patch, or spray to be applied to the skin).

[0580] In the embodiments, the compounds exhibit good permeability and oral bioavailability (e.g., improved permeability and / or improved oral bioavailability compared to compounds known in the art). These properties are particularly advantageous because they reduce or completely eliminate the need for the use of lipid / liposome formulations to administer the compounds. Therefore, in the embodiments, the pharmaceutical compositions disclosed herein are not formulated as lipid formulations or liposome formulations.

[0581] Medical use

[0582] The compounds disclosed herein act as inhibitors of KRAS G12D, which confers their utility in the treatment of KRAS G12D-related disorders and conditions. In particular, the compounds disclosed herein may be used to treat cancers, especially KRAS G12D-related cancers.

[0583] From this perspective, this disclosure provides a treatment method comprising administering a therapeutically effective amount of the disclosed compound (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) to a subject in need. In a related aspect, this disclosure provides the use of the disclosed compound (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament. In another related aspect, this disclosure provides the use of the disclosed compound (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) in a therapeutic manner.

[0584] The compounds disclosed herein may be used to treat or prevent 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 inhibiting or antagonizing KRAS G12D activity is beneficial.

[0585] In one aspect, this disclosure provides a method for treating or preventing KRAS G12D-mediated diseases or disorders, or diseases or disorders involving KRAS G12D, in a subject in need, the method comprising administering to the subject an effective amount of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing KRAS G12D-mediated diseases or disorders, or diseases or disorders involving KRAS G12D. In other related aspects, this disclosure provides for the use of the compounds disclosed herein (e.g., compounds having formula (I) or pharmaceutically acceptable salts thereof, or compounds having formula (0) or pharmaceutically acceptable salts thereof) in the treatment or prevention of diseases or disorders mediated by or involving KRAS G12D.

[0586] On the other hand, this disclosure provides a method for treating or preventing a KRAS G12D-related disease or disorder (e.g., cancer, such as KRAS G12D-related cancer) in a subject in need, the method comprising administering to the subject an effective amount of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing a KRAS G12D-related disease or disorder (e.g., cancer, such as KRAS G12D-related cancer). In other related aspects, this disclosure provides for the use of the compounds disclosed herein (e.g., compounds having formula (I) or pharmaceutically acceptable salts thereof, or compounds having formula (0) or pharmaceutically acceptable salts thereof) in the treatment or prevention of diseases or disorders associated with KRAS G12D (e.g., cancers such as KRAS G12D-associated cancers).

[0587] On the other hand, this disclosure provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of cancer. In another related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof) in the treatment or prevention of cancer (e.g., KRASG12D-related cancers).

[0588] In the embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., partially or completely), reduces evasion of growth inhibition, reduces or inhibits the growth of cancerous or precancerous cells, inhibits the proliferation of cancerous or precancerous cells, and / or reduces the survival of cancerous or precancerous cells.

[0589] In this embodiment, the cancer is a KRAS G12D-associated cancer. In this embodiment, the cancer is characterized by increased KRAS G12D expression. In this embodiment, the cancer has elevated KRAS G12D activity. In this embodiment, one or more cancer cells express KRAS G12D.

[0590] In this embodiment, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In other embodiments, the cancer is leukemia (e.g., chronic lymphocytic leukemia, CLL; acute myeloid leukemia, AML; or chronic myeloid leukemia, CML).

[0591] In this embodiment, the cancer is a primary tumor. In other embodiments, the cancer is a secondary tumor (e.g., a metastatic tumor).

[0592] In the 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 carcinoma or adenocarcinoma of the breast), liver cancer, kidney cancer (e.g., renal cell carcinoma), prostate cancer, ovarian cancer, brain cancer (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer, cholangiocarcinoma (e.g., cholangiocarcinoma), nervous system cancers (e.g., neuroblastoma), and melanoma.

[0593] In the 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).

[0594] On the other hand, this disclosure provides a method for inhibiting KRAS G12D activity, the method comprising contacting KRAS G12D (e.g., cells containing KRAS G12D) with a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having 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, this disclosure provides an in vitro method for inhibiting KRAS G12D activity in cells, the method comprising contacting cells with a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof).

[0595] The compounds disclosed herein (e.g., compounds having formula (I) or formula (0)) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions, which may optionally contain one or more pharmaceutically acceptable excipients.

[0596] It should be understood that the methods and treatments of various aspects of this disclosure can be achieved by administering to a subject an effective amount of a compound of this disclosure in the form of a pharmaceutical composition (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a compound having formula (0) or a pharmaceutically acceptable salt thereof), which may optionally contain one or more pharmaceutically acceptable excipients as described herein.

[0597] The compounds disclosed herein can be used alone (e.g., as a monotherapy) or in combination with one or more cancer therapies.

[0598] As disclosed herein in general, the following non-limiting examples are provided to further illustrate this disclosure. Example

[0599] The preparation of exemplary compounds according to this disclosure is described below. Other compounds within the scope of this disclosure may be prepared according to methods and procedures similar to those described in detail below, based on techniques known to those skilled in the art.

[0600] Example 1: General Synthesis Scheme

[0601] Several synthetic schemes were used to produce the compounds described herein. These synthetic schemes share common intersections and can be used alternatively to synthesize the compounds described herein.

[0602] Option 1

[0603] The following scheme (Scheme 1) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0604] 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaneborane was reacted with UHP to give (92-21). (92-21) was reacted with PhN(OTf)2 and K2CO3 to give (92-22). (92-22) was coupled with ethynyltriisopropylsilane in the presence of a palladium catalyst to give intermediate 2. Intermediate 2 was coupled with intermediate 1 in the presence of a palladium catalyst to give intermediate (92-3). The triple bond of (92-3) was reduced by adding hydrogen and Pd(OH)2 / C to give (92-4), and the BOC protecting group of (92-4) was removed to give (92-0).

[0605]

[0606] Option 2

[0607] The following scheme (Scheme 2) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0608] 4-Bromo-5-chloronaphthyl-2-ol was reacted with MOMBr to give (94-1). (94-1) was coupled with ethynyltriisopropylsilane in the presence of a palladium catalyst to give intermediate 5. Intermediate 5 was coupled with intermediate 1 in the presence of a palladium catalyst to give intermediate (94-3), and the BOC protecting group of (94-3) was removed to give (94-0).

[0609]

[0610] Option 3

[0611] The following scheme (Scheme 3) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0612] In the presence of a palladium catalyst, (96-5) was coupled with ethynyltriisopropylsilane to give intermediate 7. In the presence of a palladium catalyst, intermediate 7 was coupled with intermediate 1 to give intermediate (96-2). The BOC protecting group of (96-2) was removed to give (96-0).

[0613]

[0614] Option 4

[0615] The following scheme (Scheme 4) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0616] In the presence of a palladium catalyst, the commercial product 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl ester of trifluoromethanesulfonate was coupled with CO to give intermediate (107-1). (107-1) was reacted with oxalyl chloride and ammonium hydroxide to give intermediate 8. Intermediate 8 was coupled with intermediate 1 in the presence of a palladium catalyst to give (107-3). The TIPS protecting group of (107-3) was removed to give (107-4). The BOC protecting group of (96-2) was removed to give (107-0).

[0617]

[0618] Option 5

[0619] The following scheme (Scheme 5) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0620] In the presence of a palladium catalyst, (91-1) is coupled with (96-5) to obtain (97-21). The double bond of (97-21) is reduced by adding hydrogen and Pd(OH)2 / C to obtain (97-22). The BOC protecting group of (97-22) is removed to obtain (97-0).

[0621]

[0622] Option 6

[0623] The following scheme (Scheme 6) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0624] In the presence of a palladium catalyst, the commercial product 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl ester of trifluoromethanesulfonate was coupled with (91-1) to give intermediate (21-40). The double bond of (21-40) was reduced by Zn and AcOH to give (21-51). The BOC protecting group of (21-51) was removed to give (21-19). The TIPS protecting group of (21-19) was removed to give (21-0).

[0625] Option 7

[0626] The following scheme (Scheme 7) illustrates an exemplary manner for preparing compounds according to this disclosure and examples.

[0627] The BOC protecting group of (92-24) is removed to obtain (85-0).

[0628]

[0629] Example 2 - 45: Synthesis Example

[0630] Examples 2 through 45 describe synthetic methods used to obtain the illustrative compounds disclosed herein. As those skilled in the art will understand, other compounds disclosed herein can be synthesized similarly.

[0631] In the subsequent synthesis scheme, R and S (or R and S The symbols R, R, and R are used to indicate the stereochemistry at a specific chiral center; therefore, unless otherwise explicitly stated, R, R, and R are indexed in the following specific examples. Or R The use should not be construed as referring to substituent R or R as defined in the Markush formula provided in the foregoing disclosure. .

[0632] Table 2 below lists the compounds synthesized in the following synthetic examples, which are identified according to the relevant example number and (where appropriate) the compound number assigned to such compounds in Table 1:

[0633] Table 2

[0634]

[0635] Experimental techniques

[0636] Unless otherwise stated, the following analysis techniques are used in Examples 2-45 below.

[0637] Using a 5mm PI HR-BBO400S1-BBF / H / D-5.0-Z SP probe (Bruker BioSpin AG, Switzerland), at 400 MHz (9.4 Tesla) AVANCE NEO 400MHz ( 1 H, 400 MHz; 13 A 400 MHz liquid NMR experiment was recorded on a 100 MHz (C, 100 MHz) timer.

[0638] Using a 5mm PABBO BB-1H / D Z-GRD probe (Brookby Beaspen GmbH, Switzerland), at 300 MHz (7.04 Tesla) AVANCE III HD 300MHz ( 1 H, 300 MHz; 13 Recording 300 MHz liquid NMR experiments on a 75 MHz (C, 75 MHz) scale.

[0639] Used for elucidation of resonance partitioning procedures and product structures (1D) 1 H, 2D 1 H- 1 H-COSY, 2D 1 H- 1 H-ROESY, 2D 1 H- 13 C-HSQC, 2D 1 H- 13All experiments in C-HMBC were recorded at 300 kJ. ¹H chemical shifts were reported in ppm as s (singleton), d (doublet), t (triplet), q (quartet), dd (doublet), m (multiplet), or br s (broad singlet). Chemical shift values ​​(8) were expressed in parts per million (ppm), with reference to tetramethylsilane (TMS) as an internal standard.

[0640] The following apparatus was used to record LCMS chromatographic analysis: Agilent 1260 (UV: Acquity PDA MS: QDa, ELSD).

[0641] Use Ascentis Express C18 (100) The device was tested at 4.6 mm. All used the following eluent combinations: water / 0.1% FA and acetonitrile / 0.1% FA, with positively charged ES+ as the ionization mode. UV detection was set at 220 and 254 nm.

[0642] Temperatures are given in degrees Celsius (°C). The reactants used in the examples below are available from commercial sources, or they can be prepared from commercially available starting materials as described herein or by methods known in the art. The progress of the reactions described herein is tracked by LC or TLC where appropriate, and the reaction time and temperature can be adjusted accordingly, as will be readily apparent to those skilled in the art.

[0643] Preparation of intermediates

[0644] The intermediates used in Examples 2-22 below were prepared according to the following method.

[0645] Intermediate 1: 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0646]

[0647] Step 1Under a nitrogen atmosphere at 0°C, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.21 g, 43.4 mmol, 0.8 equivalent) was added in portions to a stirred solution of cyanuric chloride (10.00 g, 54.2 mmol, 1.0 equivalent) and DIEA (10.51 g, 81.3 mmol, 1.5 equivalent) in DCM (250 mL). The resulting mixture was stirred at 20°C for 2 h under a 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 (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography with PE / EtOAc (30:1) to give (1R,5S)-3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-tert-butyl ester (13.70 g, 63% yield) as a white solid.

[0648] Step 2 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0649] Under a nitrogen atmosphere at 25°C, [(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methanol (6.63 g, 41.6 mmol, 1.5 equivalents) was added in portions to a stirred mixture of (1R,5S)-3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.00 g, 13.9 mmol, 1.0 equivalent) and Cs₂CO₃ (27.13 g, 83.3 mmol, 3 equivalents) in a MeCN (200 mL). The resulting mixture was stirred at 25°C for 2 h under a 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 (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE / EtOAc (5:1) to give (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-carboxylic acid tert-butyl ester (5.30 g, 79% yield) as a white solid.

[0650] Intermediate 2: ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0651]

[0652] Step 1 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol

[0653] A solution of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxane (4.00 g, 11.1 mmol, 1.0 equivalent) and UHP (4.17 g, 44.4 mmol, 4.0 equivalent) in MeOH (40 mL) was stirred at 40°C for 6 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (6:1), to give 8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-ol (2.00 g, 74% yield) as a pale yellow oil. ESI-MS m / z = 249.10 [MH] - Calculated MW: 250.01

[0654] Step 2 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate

[0655] A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-ol (1.00 g, 3.99 mmol, 1.0 equivalent), K₂CO₃ (1.10 g, 7.99 mmol, 2.0 equivalent), and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.71 g, 4.79 mmol, 1.2 equivalent) in THF (10 mL) was stirred at 40°C for 5 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1), to give 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl trifluoromethanesulfonate (1.50 g, 98% yield) as a pale yellow oil. ESI-MS m / z = 381.00 [MH] - Calculated MW: 382.05

[0656] Step 3 :((8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0657] A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl trifluoromethanesulfonate (1.00 g, 2.61 mmol, 1.0 equivalent), CuI (50.0 mg, 0.26 mmol, 0.1 equivalent), ethynyltriisopropylsilane (0.57 g, 3.13 mmol, 1.2 equivalent), and Pd(PPh3)2Cl2 (90.0 mg, 0.13 mmol, 0.05 equivalent) in DMF (10 mL) was stirred at 80°C for 5 h under an argon atmosphere. The resulting mixture was cooled 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 give ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane (800.0 mg, 74% yield) as a pale yellow oil.

[0658] 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).

[0659] Intermediate 3: 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline

[0660]

[0661] Step 1 6,8-Dibromo-3-fluoroquinoline-5-amine

[0662] Under a nitrogen atmosphere at -15°C, a solution of NBS (4.50 g, 25.2 mmol, 2.0 equivalent) in DMF (10 mL) was added dropwise to a stirred solution of 3-fluoroquinoline-5-amine (2.00 g, 12.3 mmol, 1.0 equivalent) in DMF (30 mL). The resulting mixture was stirred for 1 h under a nitrogen atmosphere at -15°C. The reaction was quenched at -15°C by adding water. The precipitated solid was collected by filtration and washed with water. This yielded 6,8-dibromo-3-fluoroquinoline-5-amine (4.00 g, 95% yield) as a yellow solid.

[0663] ESI-MS m / z = 318.9 [M+H] + Calculated MW: 317.9

[0664] Step 2 5-Bromo-8-fluoro-[1,2,3]oxadiazolo[4,5-f]quinoline

[0665] At 0°C, propionic acid (50 mL) was added to a mixture of 6,8-dibromo-3-fluoroquinoline-5-amine (4.00 g, 12.6 mmol, 1.0 equivalent) and NaNO2 (1.62 g, 23.4 mmol, 2.5 equivalent) in CH3COOH (50 mL). The resulting mixture was stirred at 0°C for 1 h under a 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 give 5-bromo-8-fluoro-[1,2,3]oxadiazolo[4,5-f]quinoline (2.20 g, 64% yield) as a yellow solid.

[0666] ESI-MS m / z = 267.9 [M+H] + Calculated MW: 266.9

[0667] Step 3 8-Bromo-3-fluoroquinoline-6-ol

[0668] At 0°C, NaBH4 (776.2 mg, 20.5 mmol, 2.5 equivalents) was added to a stirred solution of 5-bromo-8-fluoro-[1,2,3]oxadiazolo[4,5-f]quinoline (2.20 g, 8.20 mmol, 1.0 equivalent) in EtOH (50 mL) and THF (50 mL). The resulting mixture was stirred at 0°C for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with water at 0°C. The mixture was acidified to pH 7 with 1 M HCl (aqueous). 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 give 8-bromo-3-fluoroquinoline-6-ol (1.23 g, 53.2% yield) as a brown solid.

[0669] ESI-MS m / z = 242.0 [M+H] + Calculated MW: 241.0

[0670] 1 H 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 = 2.5Hz, 1H).

[0671] Step 4 8-Bromo-3-fluoro-6-(methoxymethoxy)quinolone

[0672] Under an argon atmosphere at 0°C, bromo(methoxy)methane (309.7 mg, 2.47 mmol, 1.2 equivalents) was added dropwise to a stirred solution of 8-bromo-3-fluoroquinoline-6-ol (500.0 mg, 2.06 mmol, 1.0 equivalents) and DIEA (533.9 mg, 4.13 mmol, 2.0 equivalents) in 10 mL of DCM. The resulting mixture was stirred at room temperature for 2 h under an argon atmosphere. The reaction mixture was diluted with water at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 2:1) to give 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline (433.0 mg, 73% yield) as a brown solid.

[0673] ESI-MS m / z = 286.0 [M+H] + Calculated MW: 285.0

[0674] 1 ¹H 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).

[0675] Intermediate 4: 3-Fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinolone

[0676]

[0677] Step 1 3-Fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinolone

[0678] At room temperature, 8-bromo-3-fluoro-6-(methoxymethoxy)quinoline (300.0 mg, 1.04 mmol, 1.0 equivalent), ethynyltriisopropylsilane (1.34 g, 7.34 mmol, 7.0 equivalent), CuI (39.9 mg, 0.21 mmol, 0.2 equivalent), Pd(PPh3)2Cl2 (73.6 mg, 0.10 mmol, 0.1 equivalent), DIEA (406.5 mg, 3.14 mmol, 3.0 equivalent), and DMF (15 mL) were added to a 40 mL vial. The resulting mixture was stirred at 100°C for 2 h under an argon atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The reaction mixture 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 preparative TLC (PE / EtOAc 4:1) to give 3-fluoro-6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinolone (322.0 mg, 79% yield) as a black oil.

[0679] ESI-MS m / z = 388.2 [M+H] + Calculated MW: 387.2

[0680] 1 ¹H 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).

[0681] Intermediate 5: ((8-chloro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0682]

[0683] Step 1 1-Bromo-8-chloro-3-(methoxymethoxy)naphthalene

[0684] Under an argon atmosphere at 0°C, bromo(methoxy)methane (1.94 g, 15.5 mmol, 2.0 equivalent) was added dropwise to a stirred solution of 4-bromo-5-chloronaphth-2-ol (2.00 g, 7.76 mmol, 1.0 equivalent) and DIEA (2.01 g, 15.5 mmol, 2.0 equivalent) in a 20 mL DCM solution. The resulting mixture was stirred at room temperature under an argon atmosphere for 2 h. The reaction was quenched at 0°C by the addition of water. 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 give 1-bromo-8-chloro-3-(methoxymethoxy)naphthyl (2.16 g, 93% yield) as a faint red solid.

[0685] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.70 - 7.62 (m, 2H), 7.50 (dd, J = 7.5, 1.3 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.34 - 7.24 (m, 1H), 5.27 (s, 2H), 3.51 (s, 3H).

[0686] Step 2 :((8-chloro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0687] Under an argon atmosphere at room temperature, acetylenyltriisopropylsilane (3.02 g, 16.5 mmol, 5.0 equivalent) was added to a stirred mixture of 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (1.00 g, 3.31 mmol, 1.0 equivalent), CuI (130.0 mg, 0.66 mmol, 0.2 equivalent), Pd(PPh3)2Cl2 (230.0 mg, 0.33 mmol, 0.1 equivalent), and DIEA (1.29 g, 9.94 mmol, 3.0 equivalent) in DMF (20 mL). The resulting mixture was stirred at 100°C for 16 h under an 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 preparative TLC (PE / EtOAc 3:1) to give ((8-chloro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane (1.30 g, 97% yield) as a black liquid.

[0688] 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).

[0689] Intermediate 6: 6-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)quinoline

[0690] 0095

[0691] Step 1 6,8-Dibromoquinoline-5-amine

[0692] At -10°C, NBS (12.34 g, 69.4 mmol, 2.0 equivalent) (dissolved in 30 mL DMF) was added dropwise to a stirred solution of 5-aminoquinoline (5.00 g, 34.7 mmol, 1.0 equivalent) in DMF (30 mL). The resulting mixture was stirred at -10°C for 1 h. 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 give 6,8-dibromoquinoline-5-amine (9.00 g, 81%) as a brown solid. ESI-MS m / z = 300.8 [M+H] + ; Calculated MW: 299.9.

[0693] 1 H 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).

[0694] Step 2 5-Bromo-[1,2,3]oxadiazolo[4,5-f]quinoline

[0695] At 0°C, NaNO₂ (3.02 g, 43.7 mmol, 1.5 equivalent) was added in portions to a stirred mixture of 6,8-dibromoquinoline-5-amine (8.80 g, 29.1 mmol, 1.0 equivalent) in AcOH (60 mL) and propionic acid (20 mL). The resulting mixture was stirred at 0°C for 1 h. 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 give 5-bromo-[1,2,3]oxadiazolo[4,5-f]quinoline (7.20 g, 96% yield) as a brown solid.

[0696] ESI-MS m / z = 249.8 [M+H] + Calculated MW: 249.0

[0697] Step 3 8-Bromoquinoline-6-ol

[0698] At 0°C, NaBH4 (2.44 g, 64.5 mmol, 2.3 equivalents) was added in portions to a stirred mixture of 5-bromo-[1,2,3]oxadiazolo[4,5-f]quinoline (7.00 g, 27.9 mmol, 1.0 equivalent) in EtOH (40 mL) and THF (40 mL). The resulting mixture was stirred at 0°C for 4 h under a nitrogen atmosphere. The resulting mixture was diluted with water. The mixture was neutralized to pH 7 with 1 M HCl (aqueous) and extracted with EtOAc. The combined organic layers were washed with brine. After filtration, the filtrate was concentrated under reduced pressure. This yielded 8-bromoquinoline-6-ol (6.20 g, 44% yield) as a brown solid. The crude product mixture was used directly for the next step without further purification. ESI-MS m / z = 223.8 [M+H] + Calculated MW: 223.0

[0699] Step 4 8-Bromo-6-(methoxymethoxy)quinoline

[0700] At 0°C, methane and bromo(methoxy)methane (4.42 g, 35.4 mmol, 1.3 equivalents) were added dropwise to a stirred mixture of 8-bromoquinoline-6-ol (6.10 g, 27.2 mmol, 1.0 equivalents) and DIEA (7.04 g, 54.5 mmol, 2.0 equivalents) in DCM (50 mL). The resulting mixture was stirred at 25°C for 1.5 h under a nitrogen atmosphere. The mixture was quenched with water and extracted with DCM. The combined organic layers were concentrated under reduced pressure to give 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.

[0701] 1 H 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).

[0702] Step 5 6-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]quinoline

[0703] DIEA (2.31 g, 17.9 mmol, 1.0 equivalent), CuI (14.2 mg, 0.07 mmol, 0.2 equivalent), and Pd(PPh3)2Cl2 (418.9 mg, 0.59 mmol, 0.1 equivalent) were added to a stirred mixture of 8-bromo-6-(methoxymethoxy)quinoline (1.60 g, 5.9 mmol, 1.0 equivalent) and ethynyltriisopropylsilane (5.44 g, 29.8 mmol, 5.0 equivalent) in DMF (15 mL). The resulting mixture was stirred at 100°C for 2 h under a nitrogen atmosphere. The mixture was cooled 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 preparative TLC (PE / EtOAc 5:1) to give 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

[0704] Intermediate 7:

[0705] ((3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl)ethynyl)triisopropylsilane

[0706]

[0707] Step 1 :((3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl)ethynyl)triisopropylsilane

[0708] Under a nitrogen atmosphere at 25°C, CuI (26.1 mg, 0.13 mmol, 0.1 equivalent) and Pd(PPh3)2Cl2 (48.2 mg, 0.06 mmol, 0.05 equivalent) were added to a stirred mixture of 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene (420.0 mg, 1.37 mmol, 1.0 equivalent), DIPA (1.39 g, 13.7 mmol, 10 equivalent), and ethynyltriisopropylsilane (300.7 mg, 1.64 mmol, 1.2 equivalent) in DMF (10 mL). The resulting mixture was stirred at 60°C for 2 h under a nitrogen atmosphere. Cooling to 30°C was permitted. The resulting mixture was diluted with water (10 mL) and 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 preparative TLC (PE / EtOAc 10:1) to give {2-[3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl]ethynyl}triisopropylsilane (459.1 mg, 78% yield) as a yellow solid. Calculated MW: 406.2. 1 ¹H NMR (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).

[0709] Intermediate 8: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthylcarbamate

[0710]

[0711] Step 1 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthoic acid

[0712] A mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl ester of trifluoromethanesulfonate (5.00 g, 9.53 mmol, 1.0 equivalent) and Et3N (2.84 g, 28.05 mmol, 3.0 equivalent) and [(3R,5S,7s)-adamantane-1-yl][(1s,3R,5S,7s)-adamantane-1-yl]phosphine{2'-amino-[1,1'-biphenyl]-2-yl}palladium methanesulfonate butyl ester (3.41 g, 4.67 mmol, 0.5 equivalent) in DMSO : H2O (100 mL : 10 mL) was stirred at 80°C for 16 h under a carbon monoxide (20 atm) atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% over 30 min; detector, UV 254 nm, to give 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxylic acid (1.50 g, 22%) as a brown oil.

[0713] ESI-MS m / z = 431.30 [M+H] + Calculated MW: 430.20

[0714] Step 2 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthylcarbamate

[0715] Under a nitrogen atmosphere at 0°C, (COCl)₂ (663.2 mg, 5.22 mmol, 1.5 equivalent) was added dropwise to a mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxylic acid (1.50 g, 3.48 mmol, 1.0 equivalent) and DMF (127.3 mg, 1.742 mmol, 0.5 equivalent) in DCM. The resulting mixture was stirred at 0°C for another 1 h. The resulting mixture was concentrated under vacuum. At 0°C, THF (10 mL) was added to the mixture, followed by NH₃·H₂O (5 mL, 128.40 mmol, 36.8 equivalent) at 0°C. The resulting mixture was stirred at 0°C for another 1 h. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% over 30 min; detector, UV 254 nm, to give 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxamide (540.0 mg, 34% yield) as a deep red solid. ESI-MS m / z = 430.17 [M+H] + Calculated MW: 429.21

[0716] 1 H 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).

[0717] Intermediate 9:

[0718] ((8-Ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0719]

[0720] Step 1 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol

[0721] A solution of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxane (4.00 g, 11.1 mmol, 1.0 equivalent) and UHP (4.17 g, 44.4 mmol, 4.0 equivalent) in MeOH (40 mL) was stirred at 40°C for 6 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (6:1), to give 8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-ol (2.00 g, 74% yield) as a pale yellow oil. ESI-MS m / z = 249.10 [MH] - Calculated MW: 250.10

[0722] Step 2 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate

[0723] A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-ol (1.00 g, 3.99 mmol, 1.0 equivalent), K₂CO₃ (1.10 g, 7.99 mmol, 2.0 equivalent), and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.71 g, 4.79 mmol, 1.2 equivalent) in THF (10 mL) was stirred at 40°C for 5 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1), to give 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl trifluoromethanesulfonate (1.50 g, 98% yield) as a pale yellow oil.

[0724] ESI-MS m / z = 381.00 [MH] - Calculated MW: 382.05

[0725] Step 3 :((8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0726] A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl trifluoromethanesulfonate (1.00 g, 2.61 mmol, 1.0 equivalent), CuI (50.0 mg, 0.26 mmol, 0.1 equivalent), and Pd(PPh3)2Cl2 (90.0 mg, 0.13 mmol, 0.05 equivalent) in DMF (10 mL) was stirred at 80°C for 5 h under an argon atmosphere. The resulting mixture was cooled to room temperature and diluted with EtOAc. The 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 give ((8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane (800.0 mg, 74% yield) as a pale yellow oil. Calculated MW: 414.24

[0727] 1 H 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).

[0728] Intermediate 10: (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methanol

[0729]

[0730] Step 1 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol

[0731] A solution of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxane (4.00 g, 11.1 mmol, 1.0 equivalent) and UHP (4.17 g, 44.4 mmol, 4.0 equivalent) in MeOH (40 mL) was stirred at 40°C for 6 h under an argon atmosphere. The resulting mixture was cooled to 20°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (6:1) to give 8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-ol (2.00 g, 74%) as a pale yellow oil. ESI-MS m / z = 249.10 [MH] - Calculated MW: 250.01

[0732] Step 2 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl trifluoromethanesulfonate

[0733] A mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-ol (1.00 g, 3.99 mmol, 1.0 equivalent), K₂CO₃ (1.10 g, 7.99 mmol, 2.0 equivalent), and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.71 g, 4.79 mmol, 1.2 equivalent) in THF (10 mL) was stirred at 40°C for 5 h under an argon atmosphere. The resulting mixture was cooled to 20°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1), to give 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl trifluoromethanesulfonate (1.50 g, 98%) as a pale yellow oil. ESI-MS m / z = 381.00 [MH] - Calculated MW: 382.05

[0734] Intermediate 11: 5-bromo-7-(methoxymethoxy)quinoline

[0735]

[0736] Step 1AlCl3 (1.68 g, 12.6 mmol, 3.0 equivalent) was added in portions to a stirred mixture of 5-bromo-7-methoxyquinoline (1.00 g, 4.20 mmol, 1.0 equivalent) in toluene (10 mL) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 100°C for 3 h under a nitrogen atmosphere. Cooling of the mixture to 20°C was permitted. 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 give 5-bromoquinoline-7-ol (600.0 mg, 64% yield) as an orange solid.

[0737] ESI-MS m / z = 224.0 / 226.0 [M+H] + ; Calculated MW: 223.1 / 225.1. 1 H 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).

[0738] Step 2 Under a nitrogen atmosphere at 0°C, bromo(methoxy)methane (1.45 g, 11.6 mmol, 2.6 equivalents) was added dropwise to a stirred mixture of 5-bromoquinoline-7-ol (440.0 mg, 4.46 mmol, 1.0 equivalents) and DIEA (1.73 g, 13.4 mmol, 3.0 equivalents) in DCM (20 mL). The resulting mixture was stirred at 20°C for 2 h under a nitrogen atmosphere. The reaction mixture was poured into 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 the residue, which was purified by silica gel column chromatography, eluting with DCM / MeOH (100%–10:1). The purified fraction was concentrated to give 5-bromo-7-(methoxymethoxy)quinolone as a yellow solid (410.0 mg, 99.% yield). 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, 1.6Hz, 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).

[0739] Intermediate 12: 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene

[0740]

[0741] Step 1 (3-Bromo-5-chlorophenoxy)(tert-butyl)dimethylsilane

[0742] Under an argon atmosphere at 0°C, TBSCl (21.80 g, 144.6 mmol, 1.5 equivalent) was added in portions to a stirred mixture of 3-bromo-5-chlorophenol (20.00 g, 96.4 mmol, 1.0 equivalent) and imidazole (32.82 g, 482.0 mmol, 5.0 equivalent) in DCM (400 mL). The resulting mixture was stirred at 20°C for 2 h under an argon atmosphere. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (2 x 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 3-bromo-5-chlorophenoxy(tert-butyl)dimethylsilane (27.00 g, 87% yield) as a yellow oil. Calculated MW: 320.0

[0743] Step 2 2-Bromo-6-chloro-4-hydroxybenzaldehyde

[0744] Under an argon atmosphere at -78°C, LDA (56 mL, 111.9 mmol, 2.0 equivalent, 2M in THF) was added dropwise to a stirred solution of (3-bromo-5-chlorophenoxy)(tert-butyl)dimethylsilane (18.00 g, 55.9 mmol, 1.0 equivalent) in 200 mL of THF. The resulting mixture was stirred at -65°C for 1 h under an argon atmosphere. After 1 h at -78°C, DMF (20.45 g, 279.8 mmol, 5.0 equivalent) was added dropwise to the mixture. The resulting mixture was stirred at -65°C for another 2 h. The mixture was heated to 0°C. The reaction was quenched at 0°C by adding 200 mL of saturated NH4Cl (aqueous). The resulting mixture was diluted with 200 mL of water. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 x 300 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 directly in the next step without further purification. 1 H NMR (400 MHz, CD3OD-d4) δ10.2 (s, 1H), 7.10 (s, 1H), 6.92 (s, 1H).

[0745] Step 3 2-Bromo-6-chloro-4-(methoxymethoxy)benzaldehyde

[0746] Under an argon atmosphere at 0°C, MOM-Cl (12.42 g, 186.8 mmol, 2.0 equivalent) was added dropwise to a stirred mixture of 2-bromo-6-chloro-4-hydroxybenzaldehyde (22.00 g, 93.4 mmol, 1.0 equivalent) and DIEA (36.23 g, 280.3 mmol, 3.0 equivalent) in DCM. The resulting mixture was stirred at 0°C for 2 h under an 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 (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 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).

[0747] Step 4 (Z / E)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(prop-1-en-1-yl)benzene

[0748] Under an argon atmosphere at 0°C, potassium tert-butoxide (107.3 mL, 107.3 mmol, 1.5 equivalents, 1 M, in THF) was added to a stirred mixture of ethyltriphenylphosphonium bromide (39.85 g, 107.3 mmol, 1.5 equivalents) in THF (300 mL). The resulting mixture was stirred at 0°C for 1 h under an argon atmosphere. At 0°C, after 30 min, 2-bromo-6-chloro-4-(methoxymethoxy)benzaldehyde (20.00 g, 71.5 mmol, 1.0 equivalents) in THF (100 mL) was added dropwise. The resulting mixture was stirred again at 20°C for 1 h. 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 (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (6:1) to give (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

[0749] Step 5 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene

[0750] Under an argon atmosphere and at -40°C, a stirred mixture of diethylzinc (21.18 g, 171.4 mmol, 10 equivalents) and TFA (19.55 g, 171.4 mmol, 10 equivalents) in DCM (200 mL) was added. The resulting mixture was stirred at -40°C for 1 h under an argon atmosphere. After 10 min at -40°C, diiodomethane (45.93 g, 171.4 mmol, 10 equivalents) was added dropwise to the mixture. The resulting mixture was stirred again at -40°C for 1 h. After 10 min at -40°C, (E / Z)-1-bromo-3-chloro-5-(methoxymethoxy)-2-(prop-1-en-1-yl)benzene (5.00 g, 17.1 mmol, 1.0 equivalent) was added dropwise to the mixture. The resulting mixture was stirred again at 20°C for 20 h. The mixture was allowed to be cooled 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 (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, in a 10% to 100% gradient over 2 h; detector, UV 254 nm, to give 1-bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene (1.00 g, 19% yield) as a colorless oil. Calculated MW: 304. 1 H 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).

[0751] Intermediate 13: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-amine

[0752]

[0753] Step 1 N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-1,1-diphenylmethylene

[0754] Under an argon atmosphere at room temperature, diphenylmethyleneimine (4.06 g, 22.4 mmol, 2.0 equivalent) in toluene (100 mL) was added to a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl ester of trifluoromethanesulfonic acid (6.00 g, 11.0 mmol, 1.0 equivalent), Pd2(dba)3CHCl3 (1.16 g, 1.10 mmol, 0.1 equivalent), and Cs2CO3 (7.31 g, 22.4 mmol, 2.0 equivalent). The resulting mixture was stirred at 110°C for 2 h under an argon atmosphere. The mixture was cooled to room temperature. The mixture was filtered, and the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-1,1-diphenylmethyleneimine (3.55 g, 56% yield) as a black oil.

[0755] ESI-MS m / z = 566.3 [M+H] + Calculated MW: 565.3

[0756] Step 2 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-amine

[0757] Under air and at room temperature, HCl (4 mL, 1 M) was added dropwise to a stirred mixture of N-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-1,1-diphenylmethyleneamine (3.55 g, 6.27 mmol, 1.0 equivalent) in THF (20 mL). The resulting mixture was stirred under air and at room temperature for 30 min. The resulting mixture was concentrated under vacuum. The crude product was purified by reversed-phase flash chromatography under the following conditions (column: Xselect CSHPrep C18 column, 30 min). 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 70 mL / min; gradient: 60% B to 100% B, 100% B over 30 min; wavelength: 220 / 254 nm; RT1 (min): 10.88; to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-amine (1.65 g, 66% yield) as a dark oil.

[0758] ESI-MS m / z = 402.2 [M+H] + ; Calculated MW: 401.2. 1 H NMR (400 MHz, DMSO-d6) δ7.75 (dd, J = 9.2, 6.1 Hz, 1H), 7.32 (t, J = 8.9 Hz, 1H), 6.77 (d, J = 2.5Hz, 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).

[0759] Intermediate 14: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol

[0760]

[0761] Step 1 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0762] At 0°C, (2-bromoethynyl)triisopropylsilane (29.33 g, 112.2 mmol, 1.0 equivalent) was added to a mixture of 7-fluoronaphthyl-1,3-diol (20.00 g, 112.3 mmol, 1.0 equivalent), [RuCl2(Binap)2]dichloro[(R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl]ruthenium(II) (8.92 g, 11.2 mmol, 0.1 equivalent), and AcOK (22.03 g, 224.5 mmol, 2.0 equivalent) in toluene. The resulting mixture was stirred at 110°C for another 2 h. The mixture was allowed to cool to 20°C. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOAc (3 x 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc, to give 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1,3-diol (40.00 g, 91% yield), a deep yellow oil. ESI-MS m / z = 359.2 [M+H] + Calculated MW: 358.2

[0763] Step 2 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol

[0764] Under an argon atmosphere at 0°C, bromomethoxymethane (26.14 g, 209.2 mmol, 1.5 equivalent) was added dropwise to a stirred mixture of 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1,3-diol (50.00 g, 139.4 mmol, 1.0 equivalent) and DIEA (54.07 g, 418.3 mmol, 3.0 equivalent) in DCM (500 mL). The resulting mixture was stirred at 20°C for 1 h under an 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 (2 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, eluting with PE / EtOAc, to give 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-ol (30.00 g, 54% yield), a brown oil. ESI-MS m / z = 403.0 [M+H] + Calculated MW: 402.0

[0765] Intermediate 15: 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene

[0766]

[0767] Step 1 (3E)-4-(2,3-difluorophenyl)but-3-enoic acid

[0768] Under a nitrogen atmosphere at -70°C, t-BuOK (703.7 mL, 703.7 mmol, 2.0 equivalent, 1 M in THF) was added dropwise to a stirred mixture of 2,3-difluorobenzaldehyde (50.00 g, 351.8 mmol, 1.0 equivalent) and 3-(bromotriphenyl-λ-5-phosphoalkyl)propionic acid (160.70 g, 387.0 mmol, 1.1 equivalent) in THF (500 mL). The resulting mixture was stirred at -70°C for 1 h under a nitrogen atmosphere. The mixture was then heated to 20°C and stirred at 20°C for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with water (500 mL) and concentrated under reduced pressure. The resulting mixture was filtered and the filtrate was acidified to pH 2 with HCl (1 M aqueous). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (500 x 2 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 (10:1–2:1), and the pure fraction was concentrated under reduced pressure to give (3E)-4-(2,3-difluorophenyl)but-3-enoic acid (52.00 g, 75% yield) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform) δ 7.10 - 6.98 (m, 3H), 6.44 (d, J = 11.5, 1.7 Hz, 1H), 5.82 (td, J = 11.6, 7.2 Hz, 1H), 2.43 (dd, J = 7.3 Hz, 2H).

[0769] Step 2 4-(2,3-difluorophenyl)butyric acid

[0770] Under a nitrogen atmosphere at 20°C, 10% Pd / C (11.17 g, 104.9 mmol, 0.4 equivalent) was added to a stirred solution of (3E)-4-(2,3-difluorophenyl)but-3-enoic acid (52.00 g, 262.4 mmol, 1.0 equivalent) in EtOAc (1.5 L). The resulting mixture was stirred at 20°C for 2 h under a 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 give 4-(2,3-difluorophenyl)butyric 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).

[0771] Steps 3-4 5,6-Difluoro-3,4-dihydro-2H-naphth-1-one

[0772] Under a nitrogen atmosphere at 0°C, oxalyl chloride (63.40 g, 499.5 mmol, 2.0 equivalent) was added dropwise to a stirred solution of 4-(2,3-difluorophenyl)butyric acid (50.00 g, 249.7 mmol, 1.0 equivalent) and DMF (912.8 mg, 12.4 mmol, 0.05 equivalent) in DCM (1 L). The resulting mixture was stirred at 20°C for 0.5 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to give a residue (50.00 g, yellow solid). Under a nitrogen atmosphere at 0°C, AlCl3 (50.31 g, 377.3 mmol, 1.5 equivalent) was added to a stirred solution of the residue (50.00 g, yellow solid) in DCM (1 L). The resulting mixture was stirred at 40°C for 1 h under a nitrogen atmosphere. The reaction was quenched at 0°C by adding water / ice (1 L). 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, eluting with PE / EtOAc (100:1–2:1), and the pure fraction was concentrated under reduced pressure to give 5,6-difluoro-3,4-dihydro-2H-naphth-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

[0773] Steps 5-6 3-Ethyl-7-(hydroxymethyl)-1,5-naphthidium-2(1H)-one

[0774] Under a nitrogen atmosphere at 0°C, Br2 (11.5 mL, 225.0 mmol, 1.0 equivalent) in AcOH (50 mL) was added dropwise to a stirred solution of 5,6-difluoro-3,4-dihydro-2H-naphth-1-one (41.00 g, 225.0 mmol, 1.0 equivalent) and HBr / AcOH (2.0 mL, 22.5 mmol, 0.1 equivalent, 33%) in AcOH (900 mL). The resulting mixture was stirred at 20°C for 1 h under a 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 obtain the residue. Under a nitrogen atmosphere at 20°C, LiBr (23.75 g, 273.4 mmol, 1.7 equivalents) and Li₂CO₃ (20.21 g, 273.5 mmol, 1.7 equivalents) were added to a stirred solution of the residue in DMF (1 L). The resulting mixture was stirred at 160°C for 1 h under a nitrogen atmosphere. The mixture was allowed to cool 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 give 5,6-difluoronaphth-1-ol as a brown solid (26.00 g, 64% yield, two steps). ESI-MS m / z = 179.1 [MH] - ; Calculated MW: 180.0.

[0775] 1 H 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).

[0776] Step 7 5,6-Difluoronaphthyl-1-trifluoromethanesulfonic acid ester

[0777] Under a nitrogen atmosphere at 0°C, DIEA (46.63 g, 360.8 mmol, 2.5 equivalents) and Tf₂O (52.93 g, 187.6 mmol, 1.3 equivalents) were added dropwise to a stirred mixture of 5,6-difluoronaphth-1-ol (26.00 g, 144.3 mmol, 1.0 equivalents) in DCM (300 mL). The resulting mixture was stirred at 20°C for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 x 200 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, eluting with PE / EtOAc (20:1-5:1), and the pure fraction was concentrated under reduced pressure to give 5,6-difluoronaphthyl-1-trifluoromethanesulfonic acid (36.00 g, 80% yield) as a yellow oil.

[0778] ESI-MS m / z = 310.9 [MH] - Calculated MW: 311.9. 1 H NMR (400 MHz, DMSO-d6) δ8.20 (d, J = 7.3 Hz, 1H), 8.01 - 7.70 (m, 4H).

[0779] Step 8 N-(5,6-difluoronaphth-1-yl)-1,1-diphenylmethyleneamine

[0780] Under a nitrogen atmosphere at 20°C, Pd₂(dba)₃ (10.56 g, 11.5 mmol, 0.1 equivalent), XantPhos (13.34 g, 23.1 mmol, 0.2 equivalent), and Cs₂CO₃ (112.71 g, 345.9 mmol, 3.0 equivalent) were added to a stirred mixture of 5,6-difluoronaphthyl trifluoromethanesulfonic acid (36.00 g, 115.3 mmol, 1.0 equivalent) and α-phenylbenzylimine (62.69 g, 345.9 mmol, 3.0 equivalent) in toluene (500 mL). The resulting mixture was stirred at 90°C for 12 h under a nitrogen atmosphere. Cooling to 20°C was permitted. 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, eluting with PE / EtOAc (100:1–5:1), and the pure fraction was concentrated under reduced pressure to give N-(5,6-difluoronaphthyl-1-yl)-1,1-diphenylmethyleneamine (34.00 g, 86% yield) as a yellow solid. ESI-MS m / z = 344.0 [M+H] + Calculated MW: 343.1

[0781] Step 9 5,6-Difluoronaphthyl-1-amine

[0782] A solution of N-(5,6-difluoronaphthyl-1-yl)-1,1-diphenylmethyleneamine (34.00 g, 99.0 mmol, 1.0 equivalent) in 4M HCl (gas)-MeOH solution (500 mL) was stirred at 10°C for 4 h under air. The resulting mixture was concentrated under vacuum. The residue was neutralized to pH 8 with saturated NaHCO3 (aqueous). 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, eluting with PE / EtOAc (50:1–3:1), and the pure fraction was concentrated under reduced pressure to give 5,6-difluoronaphthyl-1-amine (16.00 g, 90% yield) as a yellow solid.

[0783] ESI-MS m / z = 180.0 [M+H] + Calculated MW: 179.0

[0784] Step 10 2,4-Dibromo-5,6-difluoronaphthyl-1-amine

[0785] Under a nitrogen atmosphere at 0°C, a solution of Br2 (31.11 g, 194.7 mmol, 2.2 equivalents) in AcOH (550 mL) was added dropwise to a stirred solution of 5,6-difluoronaphthyl-1-amine (16.00 g, 89.3 mmol, 1.0 equivalent) in AcOH (550 mL). The resulting mixture was stirred at 70°C for 1 h under a nitrogen atmosphere. The mixture was allowed to cool to 20°C. The precipitated solid was collected by filtration and washed with AcOH (550 mL). The residue was diluted with 15% NaOH aqueous solution (200 mL). The resulting mixture was stirred at 20°C for 20 min under an air atmosphere. The precipitated solid was collected by filtration and washed with water (3 x 100 mL). The resulting mixture was concentrated under vacuum to give 2,4-dibromo-5,6-difluoronaphthyl-1-amine (25.00 g, 83% yield) as a grayish-white solid. ESI-MS m / z = 337.9 [M+H] + Calculated MW: 336.9

[0786] Step 11 5-Bromo-6,7-difluoronaphthalene[1,2-d][1,2,3]oxadiazole

[0787] Under a nitrogen atmosphere at 0°C, propionic acid (41.66 g, 562.3 mmol, 7.5 equivalents) was added dropwise to a stirred solution of 2,4-dibromo-5,6-difluoronaphth-1-amine (25.00 g, 74.1 mmol, 1.0 equivalent) in AcOH (450 mL). The resulting mixture was stirred at 0°C for 0.5 h under a nitrogen atmosphere. NaNO2 (7.68 g, 111.3 mmol, 1.5 equivalents) was added to the mixture at 0°C. The resulting mixture was stirred again at 20°C for 1 h. The precipitated solid was collected by filtration and washed with water (3 x 200 mL). The residue was concentrated under vacuum to give 5-bromo-6,7-difluoronaphthano[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

[0788] Step 12 4-Bromo-5,6-difluoronaphth-2-ol

[0789] Under a nitrogen atmosphere at 0°C, NaBH4 (5.38 g, 142.2 mmol, 2.3 equivalents) was added to a stirred solution of 5-bromo-6,7-difluoronaphtho[1,2-d][1,2,3]oxadiazole (17.40 g, 61.0 mmol, 1.0 equivalent) in THF (70 mL) and EtOH (210 mL). The resulting mixture was stirred at 0°C for 0.5 h under a nitrogen atmosphere. The reaction was quenched at 20°C by adding water (70 mL). 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 give 4-bromo-5,6-difluoronaphth-2-ol (8.90 g, 56% yield) as a yellow solid. ESI-MS m / z = 256.9 [M+H] + Calculated MW: 257.9

[0790] Step 13 8-Bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene

[0791] Under a nitrogen atmosphere at 0°C, bromomethoxy-methane (7.56 g, 60.4 mmol, 1.7 equivalent) was added dropwise to a stirred solution of 4-bromo-5,6-difluoronaphthyl-2-ol (8.90 g, 34.3 mmol, 1.0 equivalent) and DIEA (11.10 g, 85.8 mmol, 2.5 equivalent) in 100 mL of DCM. The resulting mixture was stirred at 0°C for 0.5 h under a 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 give 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene (8.90 g, 85% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.89 - 7.56 (m, 4H), 5.36 (s, 2H), 3.45 (s, 3H).

[0792] Preparation of compounds

[0793] Example 2 :4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethynyl-6-fluoronaphthyl-2-ol

[0794]

[0795] Step 1 3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0796] At 0°C, DIEA (3.50 g, 27.1 mmol, 1.0 equivalent) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.76 g, 27.1 mmol, 1.0 equivalent) were added to a stirred solution of 2,4,6-trichloro-1,3,5-triazine (5.00 g, 27.1 mmol, 1.0 equivalent) in DCM (50 mL). The resulting mixture was heated to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with water (50 mL). The resulting mixture was concentrated under vacuum to give 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 a grayish-white solid. ESI-MS m / z = 360.15 [M+H] + Calculated MW: 359.09.

[0797] Step 2 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0798] Add to a stirred solution of 3-(4,6-dichloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.00 g, 22.2 mmol, 1.0 equivalent), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (3.54 g, 22.2 mmol, 1.0 equivalent), DCM (60 mL), and DIEA (2.87 g, 22.2 mmol, 1.0 equivalent). Stir the resulting mixture at room temperature for 16 h. Concentrate the resulting mixture under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (10:1) to give tert-butyl 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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.

[0799] 1 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).

[0800] Step 3 3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0801] To 3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.20 g, 4.63 mmol, 1.0 equivalent), trifluoromethanesulfonate 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-yl ester (2.48 g, 4.63 mmol, 1.0 equivalent), Pd2(dba)3 (850.0 mg, 0.93 mmol, 0.2 equivalent), P(p-Tol)3 (710.0 mg, 2.32 mmol, 0.5 equivalent), DIEA (3.00 g, 23.2 The mixture was prepared in a stirred solution of 15 mL of HCOOH (320.0 mg, 6.95 mmol, 1.5 equivalent), TBAB (2.24 g, 6.95 mmol, 1.5 equivalent), and DMF (15 mL). The resulting mixture was stirred at 120°C for 1.5 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. Water (50 mL) was added to the resulting mixture and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 1:2) to give 3-(4-((E)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)vinyl)-6-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.3 g, 33% yield) as a yellow solid. ESI-MS m / z = 859.45 [M+H] + ; Calculated MW: 858.47.

[0802] Step 4 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0803] Add tert-butyl octane-8-carboxylate (1.30 g, 1.51 mmol, 1.0 equivalent), Zn (990.0 mg, 15.1 mmol, 10 equivalent), and AcOH (15 mL) to a stirred solution. Stir the resulting mixture at 80°C for 1 h under a nitrogen atmosphere. Allow the mixture to cool to room temperature. Filter the resulting mixture and wash the filter cake with EtOAc (3 x 10 mL). Concentrate the filtrate under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.00 g, 76% yield) as a yellow oil.

[0804] ESI-MS m / z = 861.35 [M+H] + Calculated MW: 860.48.

[0805] Step 5 :4-(2-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol

[0806] Add dropwise 3-(4-(2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.00 g, 1.16 mmol, 1.0 equivalent), dioxane (2 mL), and HCl (gas)-dioxane solution (6 mL) to a 40 mL vial. Stir the resulting mixture at 25°C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 4-(2-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-ol (740.0 mg, 88% yield) as a yellow solid. ESI-MS m / z = 717.50 [M+H] + Calculated MW: 716.40.

[0807] Step 6 :4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethynyl-6-fluoronaphthyl-2-ol

[0808] Add 4-(2-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-ol (730.0 mg, 1.02 mmol, 1.0 equivalent), CsF (7.73 g, 50.9 mmol, 50 equivalent), and DMF (15 mL) to a stirred solution. Stir the resulting mixture at 25°C for 1 h under a nitrogen atmosphere. Add water (20 mL) to the resulting mixture and extract with EtOAc (3 x 50 mL). Wash the combined organic layers with brine (3 x 10 mL) and dry with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 5:1) to obtain a crude product (150 mg) as a grayish-white solid. The crude product was further purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS 30). 150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 30% B to 57% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.8), to obtain 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethynyl-6-fluoronaphthyl-2-ol (41.7 mg, 7% yield, LCMS purity: 95.6% at 254 nm and 96.2% at 220 nm) as a white solid.

[0809] ESI-MS m / z = 561.25 [M+H] + Calculated MW: 560.27.

[0810] 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 = 12.4Hz, 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).

[0811] 19 F NMR (377 MHz, DMSO-d6) δ -110.33, -172.13 (d, J = 4.3 Hz).

[0812] Example 3 : 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)oxy)methyl)-5-ethynyl-6-fluoronaphthyl-2-ol

[0813]

[0814] Step 1:(1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0815] Under a nitrogen atmosphere at 0°C, NaH (74.5 mg, 3.10 mmol, 5.0 equivalent) was added in portions to a stirred solution of [7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]methanol (258.8 mg, 0.62 mmol, 1.0 equivalent) in THF (5 mL). The resulting mixture was stirred under a nitrogen atmosphere at 20°C for 30 min. At 20°C, (1R,5S)-3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0 mg, 0.62 mmol, 1 equivalent) was added to the above mixture. The resulting mixture was stirred at 20°C for another 2 h. The reaction was quenched at 0°C by adding water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 30 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 give (1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (420.0 mg, 78%) as a yellow solid. ESI-MS m / z = 863.4 [M+H] + Calculated MW: 862.5

[0816] Step 2:(1R,5S)-3-(4-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0817] Under a nitrogen atmosphere at 20°C, CsF (704.0 mg, 4.63 mmol, 10 equivalents) was added to a stirred solution of (1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400.0 mg, 0.46 mmol, 1.0 equivalent) in DMF (10 mL). The resulting mixture was stirred at 20°C for 16 h under a nitrogen atmosphere. The resulting mixture 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 give (1R,5S)-3-(4-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)methoxy)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (280.0 mg, crude) as a grayish-white solid. ESI-MS m / z = 707.2 [M+H] + Calculated MW: 706.3

[0818] Step 3 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)benzene

[0819] A solution of (1R,5S)-3-(4-{[(2R,7S)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-{[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]methoxy}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100.0 mg, 0.14 mmol, 1.0 equivalent) in HCOOH (2 mL) was stirred at 20°C for 4 h under a nitrogen atmosphere. The residue was purified by reversed-phase combi-flash chromatography under the following conditions: YMC-ActusTriart C18 ExRS column, 30 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 39% B to 59% B over 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.08. The pure fraction was concentrated and then lyophilized to give 4-{[(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-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-fluoronaphthyl-2-ol (14.1 mg, 17% yield, 97.3% purity at 254 nm and 96.8% purity at 220 nm) as a white solid.

[0820] ESI-MS m / z = 563.2 [M+H] + Calculated MW: 562.3

[0821] 1H 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).

[0822] Example 4 : 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-chloronaphthyl-2-ol

[0823]

[0824] Step 1 :(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0825] Under a nitrogen atmosphere at 20°C, Pd(DtBPF)Cl2 (270.0 mg, 0.41 mmol, 0.1 equivalent) and K2CO3 (1.72 mg) were added in portions to a stirred solution of (1R,5S)-3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.00 g, 4.14 mmol, 1.0 equivalent) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxane / water (24 mL, 5:1) in dioxane / water (24 mL, 5:1). (g, 12.4 mmol, 3.0 equivalent). The resulting mixture was stirred at 80°C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool 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 give (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.98 g, 83% yield) as a yellow solid. ESI-MS m / z = 475.5 [M+H] + Calculated MW: 474.3

[0826] Step 2 :(1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphth-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0827] Under a nitrogen atmosphere at 20°C, tert-butyl octane-8-carboxylate (900.0 mg, 1.89 mmol, 1.0 equivalent) and 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (629.0 mg, 2.08 mmol, 1.1 equivalent) were added in portions to a stirred solution of (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900.0 mg, 1.89 mmol, 1.0 equivalent) and 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (629.0 mg, 2.08 mmol, 1.1 equivalent) in dioxane (10 mL). 42.58 mg (0.190 mmol, 0.1 equivalent) and Pd(OAc)2 (42.58 mg, 0.190 mmol, 0.1 equivalent). The resulting mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. The mixture was allowed to cool 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 give (1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphth-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (720.0 mg, 54.61% yield) as a brown solid. ESI-MS m / z = 695.4 [M+H] + Calculated MW: 694.3

[0828] Step 3 :(1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphth-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0829] Under a nitrogen atmosphere at 20°C, Pt / C (841.8 mg, 4.31 mmol, 6.0 equivalent) was added to a stirred mixture of (1R,5S)-3-(4-((E)-2-(8-chloro-3-(methoxymethoxy)naphth-1-yl)vinyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500.0 mg, 0.71 mmol, 1.0 equivalent) in DCM (100 mL). The resulting mixture was stirred at 20°C for 4 h under a 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-phase combi-flash chromatography under the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, 70% to 80% gradient over 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to give (1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthyl-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150.0 mg, 30% yield) as a yellow solid. ESI-MS m / z = 697.2 [M+H] + Calculated MW: 696.3

[0830] Step 4 : 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-chloronaphthyl-2-ol

[0831] In an air atmosphere at 20°C, 0.3 mL of HCl (gas)-dioxane solution was added to a stirred solution of (1R,5S)-3-(4-(2-(8-chloro-3-(methoxymethoxy)naphthyl-1-yl)ethyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150.0 mg, 0.21 mmol, 1.0 equivalent) in MeCN (1.5 mL). The resulting mixture was stirred in an air atmosphere at 20°C for 1 h. The resulting mixture was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30...). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 35% B to 41% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.6). The pure fraction was lyophilized to give 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-chloronaphth-2-ol (13.6 mg, 11%, yield) as a white solid. ESI-MS m / z = 553.2 [M+H] + ; Calculated MW: 552.2.

[0832] 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).

[0833] Example 5 : 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-ethyl-6-fluoronaphthyl-2-ol

[0834]

[0835] Step 1 : 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-ethyl-6-fluoronaphthyl-2-ol

[0836] Under a nitrogen atmosphere at 0°C, HCl (gas)-dioxane solution (3 mL) was added dropwise to a stirred solution of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (120.0 mg, 0.17 mmol, 1.0 equivalent) in dioxane (2 mL). The resulting mixture was stirred at 0°C for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL). The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column 30. 150 mm, 5 m; Mobile phase A: water (0.1% FA), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 2% B to 2% B in 1 min, 2% B to 7% B in 1.5 min, 7% B to 30% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.73. This produces 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-ethyl-6-fluoronaphthyl-2-ol (70.1 mg, 73% yield) as a light brown solid.

[0837] 1H NMR (400 MHz, DMSO-d6) δ 8.27-8.15 (m, 2H), 7.75 (dd, J = 9.1, 5.9Hz, 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).

[0838] Example 6 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol

[0839]

[0840] Step 1-2 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol

[0841] Under a nitrogen atmosphere at 20°C, Pd(OH)₂ / C (150.4 mg, 1.07 mmol, 2.0 equivalent) was added to a stirred solution of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-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-carboxylic acid tert-butyl ester (350.0 mg, 0.53 mmol, 1.0 equivalent) in MeOH (6 mL). The resulting mixture was stirred at 20°C for 3 h under a 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 give (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-carboxylic acid tert-butyl ester (300.0 mg, 85% yield) as a brown solid.

[0842] Under a nitrogen atmosphere at 20°C, HCl (gas)-dioxane solution (2 mL, 4 M) was added to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-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-carboxylic acid tert-butyl ester (200.0 mg, 0.28 mmol, 1.0 equivalent) in MeCN (2 mL). The resulting mixture was stirred at 20°C for 0.5 h under air. The mixture was concentrated to give a crude product (200.0 mg), which was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30...). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 42% B to 57% B over 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.38. The pure fraction was lyophilized to give 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1RS,2SR)-2-methylcyclopropyl]phenol as a white solid (40.0 mg, 21% yield, 96.3% purity at 254 nm and 96.1% purity at 220 nm). ESI-MS m / z = 557.3 [M+H] + Calculated MW: 556.2

[0843] 1 H 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).

[0844] Example 7 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2-methylcyclopropyl]phenol

[0845]

[0846] Step 1: {2-[3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl]ethynyl}triisopropylsilane

[0847] Under a nitrogen atmosphere at 20°C, DIEA (1.27 g, 9.81 mmol, 3.0 equivalent), Pd(PPh3)2Cl2 (229.6 mg, 0.32 mmol, 0.1 equivalent), and CuI (124.6 mg, 0.65 mmol, 0.2 equivalent) were added to a stirred mixture of 1-bromo-3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]benzene (1.00 g, 3.27 mmol, 1.0 equivalent) and ethynyltris(prop-2-yl)silane (1.19 g, 6.54 mmol, 2.0 equivalent) in DMF (10 mL). The resulting mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. Cooling of the mixture to 20°C was permitted. 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-phase combi-flash chromatography under the following conditions: column, C18; mobile phase, A: FA (0.1%) in water, B: MeCN, 60% to 100% gradient over 20 min; detector, UV 254 nm. The pure fraction was concentrated under vacuum to give {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

[0848] Step 2 :(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-carboxylic acid tert-butyl ester

[0849] Under a nitrogen atmosphere at 20°C, CuI (108.5 mg, 0.57 mmol, 0.2 equivalent) and Pd(PPh3)4 (329.3 mg, 0.28 mmol, 0.2 equivalent) were added to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.57 g, 3.24 mmol, 1.2 equivalent) and {2-[3-chloro-5-(methoxymethoxy)-2-[(1RS,2RS&)-2-methylcyclopropyl]phenyl]ethynyl}triisopropylsilane (1.16 g, 2.85 mmol, 1.0 equivalent) in DMF (20 mL). The resulting mixture was stirred at 0°C for 0.5 h under a nitrogen atmosphere. At 0°C, CsF (1.30 g, 8.55 mmol, 3.0 equivalent) was added to the mixture. The resulting mixture was stirred at 40°C for another 16 h. 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, eluting with PE / EtOAc (50:1–2:1), and the pure fraction was concentrated under reduced pressure to give (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-carboxylic acid tert-butyl ester (1.20 g, 66% yield) as a brown solid. ESI-MS m / z = 697.3 [M+H] + Calculated MW: 696.3

[0850] Step 3 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethynyl]-5-chloro-4-[(1S,2S)-2-methylcyclopropyl]phenol

[0851] Under air atmosphere and at 20°C, a solution of HCl (gas)-dioxane (1 mL, 4 M) was added to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-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-carboxylic acid tert-butyl ester (200.0 mg, 0.28 mmol, 1.0 equivalent) in MeCN (1 mL). The resulting mixture was stirred under air atmosphere at 20°C for 0.5 h. The resulting mixture was then concentrated under vacuum. The residue was purified by reversed-phase combi-flash chromatography under the following conditions: column: Xbridge Phenyl OBD column, 19... 150 mm, 5 m; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 40% B to 55% B over 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.9. The pure fraction was concentrated under vacuum to give 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-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 at 254 nm and 95.5% purity at 220 nm) as a white solid.

[0852] ESI-MS m / z = 553.2 [M+H]+; Calculated MW: 552.2

[0853] 1H NMR (300 MHz, DMSO-d6) δ 6.94 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.5Hz, 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).

[0854] Example 8 : 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethyl-6-fluoronaphthyl-2-ol

[0855]

[0856] Step 1 3-(4-((8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0857] Under an argon atmosphere at 0°C, CsF (1.46 mg) was added in portions to a stirred mixture of {2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl]ethynyl}triisopropylsilane (800.0 mg, 1.92 mmol, 1.0 equivalent), 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-carboxylic acid tert-butyl ester (1.11 g, 2.31 mmol, 1.2 equivalent), CuI (73.4 mg, 0.38 mmol, 0.2 equivalent), and Pd(PPh3)2Cl2 (135.4 mg, 0.19 mmol, 0.1 equivalent) in DMF (8 mL). (g, 9.64 mmol, 5.0 equivalents). The resulting mixture was stirred at 0°C for 0.5 h under an argon atmosphere. The resulting mixture was stirred at 40°C for 5 h under an argon atmosphere. The resulting mixture was cooled 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 give a brownish-yellow oil, 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (800.0 mg, 59% yield). ESI-MS m / z = 705.45 [M+H] + ; Calculated MW: 704.35.

[0858] 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).

[0859] Step 2 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0860] A mixture of 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]ethynyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400.0 mg, 0.56 mmol, 1.0 equivalent) and Pd(OH)2 / C (400.0 mg, 2.84 mmol, 5.0 equivalent) in MeOH (20 mL) was stirred at room temperature for 1 h under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. This produces 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0 mg, 75% yield), a pale yellow solid. ESI-MS m / z = 709.35 [M+H] + Calculated MW: 708.38

[0861] 1H 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 = 2.5Hz, 9H), 1.24 (t, J = 7.4 Hz, 3H).

[0862] Step 3 : 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5-ethyl-6-fluoronaphthyl-2-ol

[0863] Under an argon atmosphere at 0°C, HCl (gas)-dioxane solution (9 mL) was added dropwise to a stirred solution of 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-{2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (280.0 mg, 0.39 mmol, 1.0 equivalent) in dioxane (2 mL). The resulting mixture was stirred at room temperature under an argon atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: YMC-ActusTriart C18 ExRS 30). 150 mm, 5 m; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 5% B to 20% B over 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.35, to obtain 4-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-ethyl-6-fluoronaphthyl-2-ol (33.0 mg, 15% yield) as a pale yellow solid. ESI-MS m / z = 565.25 [M+H] + Calculated MW: 564.30

[0864] 1H 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).

[0865] Example 9 : 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloronaphthyl-2-ol

[0866]

[0867] Step 1 :(1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphth-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0868] At 0°C, ((8-chloro-3-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane (300.0 mg, 0.74 mmol, 1.0 equivalent), 3-(4-chloro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (431.4 mg, 0.89 mmol, 1.2 equivalent), CuI (28.3 mg, 0.14 mmol, 0.2 equivalent), Pd(PPh3)4 (86.0 mg, 0.07 mmol, 0.1 equivalent), and DMF (10 mL) were added to a 40 mL vial. The resulting mixture was stirred at 0°C for 30 min under an argon atmosphere. Under an argon atmosphere at 0°C, CsF (565.3 mg, 3.72 mmol, 5.0 equivalents) was added to the above mixture. The resulting mixture was stirred at 40°C for 16 h under an argon atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The reaction 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 preparative TLC (DCM / MeOH 10:1) to give (1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthyl-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (425.0 mg, 82% yield) as a black solid. ESI-MS m / z = 693.3 [M+H] + Calculated MW: 692.3

[0869] Step 2 : 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloronaphthyl-2-ol

[0870] Under a nitrogen atmosphere at 0°C, HCl (gas)-dioxane solution (6 mL) was added dropwise to a stirred solution of (1R,5S)-3-(4-((8-chloro-3-(methoxymethoxy)naphthyl-1-yl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (250.0 mg, 0.36 mmol, 1.0 equivalent) in MeCN (6 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under 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% B to 50% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.32), to obtain 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloronaphthyl-2-ol (31.0 mg, 15% yield, 254 nm) as a yellow solid. The purity is 96.5% at 20 nm and 96.7% at 220 nm. 1 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).

[0871] Example 10: 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloro-4-((1S,2S)-2-methylcyclopropyl)phenol

[0872]

[0873] Step 1 :(1R,5S)-3-(4-((3-chloro-5-(methoxymethoxy)-2-((1S,2S)-2-methylcyclopropyl)phenyl)ethynyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0874] Under a nitrogen atmosphere at 0°C, CuI (21.5 mg, 0.11 mmol, 1.0 equivalent) and Pd(PPh3)4 (65.2 mg, 0.05 mmol, 0.05 equivalent) were added to a stirred mixture of {2-[3-chloro-5-(methoxymethoxy)-2-(2-methylcyclopropyl)phenyl]ethynyl}triisopropylsilane (460.0 mg, 1.13 mmol, 1.0 equivalent) and {2-[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-chloro-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (654.9 mg, 1.35 mmol, 1.2 equivalent) in DMF (10 mL). The resulting mixture was stirred at 0°C for 30 min under a nitrogen atmosphere. CsF (858.2 mg, 5.65 mmol, 5.0 equivalent) was added to the mixture at 0°C. The mixture was then stirred at 40°C for 2 h. 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 preparative TLC (PE / EtOAc 3:1) to give (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-carboxylic acid tert-butyl ester (55 mg, 30.50% yield). ESI-MS m / z = 697.3 [M+H] + Calculated MW: 696.3

[0875] Step 2 : 3-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethynyl)-5-chloro-4-((1S,2S)-2-methylcyclopropyl)phenol

[0876] At 0°C, add (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-triazine-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70.0 mg, 0.10 mmol, 1.0 equivalent) and HCl (gas)-dioxane solution. The resulting mixture was stirred at 0°C for 1 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: XBridge PrepPhenyl 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 38% B in 2 min, 38% B to 55% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.23), to obtain a grayish-white solid 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-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 at 254 nm and 98.9% purity at 220 nm). ESI-MS m / z = 553.2. [M+H] + ; Calculated MW: 552.2.

[0877] 1 H 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).

[0878] Example 11 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2-methylcyclopropyl]phenol

[0879]

[0880] Step 1 :(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]vinyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0881] Under a nitrogen atmosphere, at room temperature, DIEA (1.18 g, 9.17 mmol, 4.0 equivalent) was added to a stirred mixture of 3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.31 g, 2.75 mmol, 1.2 equivalent) and rel-1-bromo-3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]benzene (700.3 mg, 2.29 mmol, 1.0 equivalent) in DMF (8 mL). Under a nitrogen atmosphere and at room temperature, Pd₂(dba)₃ (209.8 mg, 0.23 mmol, 0.1 equivalent) and P(p-Tol.)₃ (139.5 mg, 0.46 mmol, 0.2 equivalent) were added to the above mixture. The resulting mixture was stirred at 100°C for another 2 h. The mixture was cooled to room temperature and filtered, and 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 give (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]vinyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.30 g, 81% yield) as a pale yellow solid. ESI-MS m / z = 699.3 [M+H] + Calculated MW: 698.3

[0882] Step 2 :(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-carboxylic acid tert-butyl ester

[0883] Under a nitrogen atmosphere and at room temperature, Pd(OH)₂ / C (300.0 mg, 2.14 mmol, 5.0 equivalent) was added to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(E)-2-[3-chloro-5-(methoxymethoxy)-2-[(1R,2R)-2-methylcyclopropyl]phenyl]vinyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0 mg, 0.43 mmol, 1.0 equivalent) in EtOAc (10 mL). The resulting mixture was stirred again at room temperature under a hydrogen atmosphere for 30 min. 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 preparative TLC (EtOAc) to give (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-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-carboxylic acid tert-butyl ester (220.0 mg, 73% yield) as a white solid. ESI-MS m / z = 701.3 [M+H] + Calculated MW: 700.4

[0884] Step 3 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)ethyl]-5-chloro-4-[(1R,2R)-2-methylcyclopropyl]phenol

[0885] Under a nitrogen atmosphere at 0°C, HCl (gas) (4M, in dioxane) (6 mL) (6 M, 4 M, in dioxane) was added dropwise to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-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-carboxylic acid tert-butyl ester (210.0 mg, 0.30 mmol, 1.0 equivalent) in dioxane (2 mL). The resulting mixture was stirred at 0°C for another 30 min. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column 30). 150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 0% B to 27% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.08 / 8.49). This produces 3-[2-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-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 at 254 nm and 96.8% purity at 220 nm) as a white solid. ESI-MS m / z = 557.3 [M+H] + Calculated MW: 556.3

[0886] 1 H 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).

[0887] Example 12 : 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-N-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxamide

[0888]

[0889] Step 1: 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxylic acid

[0890] Under a nitrogen atmosphere at 20°C, Pd(OAc)2 (139.45 mg, 0.62 mmol, 0.15 equivalent) and DPPP (256.19 mg, 0.62 mmol, 0.15 equivalent) were added in portions to a stirred solution of (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-carboxylic acid tert-butyl ester (2.00 g, 4.14 mmol, 1.0 equivalent) and DIEA (2.68 g, 20.7 mmol, 5.0 equivalent) in dioxane (20 mL) and water (2 mL) in portions. The resulting mixture was stirred at 100°C for 16 h under a carbon monoxide atmosphere. The mixture was allowed to be cooled to 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (1:0 to 5:1), and the pure fraction was concentrated to give 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazine-2-carboxylic acid (450.0 mg, 22% yield) as a grayish-white solid. ESI-MS m / z = 493.3 [M+H] + Calculated MW: 492.2

[0891] Step 2 :(1R,5S)-3-(4-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)carbamoyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0892] Under a nitrogen atmosphere at 0°C, (COCl)₂ (103.1 mg, 0.81 mmol, 2.0 equivalent) was added dropwise 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]octane-3-yl]-1,3,5-triazine-2-carboxylic acid (200.0 mg, 0.41 mmol, 1.0 equivalent) and TEA (164.4 mg, 1.62 mmol, 4.0 equivalent) in DCM (5 mL). The resulting mixture was stirred at 20°C for 30 min under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. At 20°C, a solution of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthyl-1-amine (163.1 mg, 0.41 mmol, 1.0 equivalent) and TEA (123.3 mg, 1.22 mmol, 3.0 equivalent) in DCM (2 mL) at 0°C was added dropwise to the above mixture in DCM (2 mL). The resulting mixture was stirred at 20°C for another 3 h. The resulting mixture was then 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 give (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]carbamoyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70.0 mg, 20% yield) as a brown solid. ESI-MS m / z = 876.4 [M+H] + Calculated MW: 875.5

[0893] Step 3 : 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-N-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazine-2-carboxamide

[0894] Under a nitrogen atmosphere at 20°C, a solution of HCl (gas) in dioxane (0.2 mL, 4 M) was added to a stirred solution of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-{[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]carbamoyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70.0 mg, 0.08 mmol, 1.0 equivalent) in MeCN (1 mL). The resulting mixture was stirred at 20°C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0895] At 20°C, DMF (1 mL) and CsF (124.5 mg, 0.80 mmol, 10 equivalents) were added to the above mixture. The resulting mixture was stirred at 50°C for another 1 h. The mixture was allowed to cool to 20°C. The resulting mixture was filtered, and the filter cake was washed with DMF (2 x 0.5 mL). The filtrate was concentrated under reduced pressure. The crude product (40.0 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30...). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 30% B to 45% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.18. The pure fraction was concentrated and then lyophilized to give 4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-N-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-1,3,5-triazine-2-carboxamide (7.2 mg, 16% yield, 96.38% purity at 254 nm and 95.99% purity at 220 nm) as a yellow solid. ESI-MS m / z = 576.35 [M+H] + Calculated MW: 575.25.

[0896] 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).

[0897] Example 13 : 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)methoxy)-5-ethynyl-6-fluoronaphthyl-2-ol

[0898]

[0899] Step 1 :(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0900] Under a nitrogen atmosphere and at 20°C, Dppf (914.9 mg, 1.65 mmol, 0.2 equivalent) and Pd(OAc)2 (185.9 mg, 0.82 mmol, 0.1 equivalent) were added to a stirred solution of (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-carboxylic acid tert-butyl ester (4.00 g, 8.28 mmol, 1.0 equivalent) and TEA (2.51 g, 24.84 mmol, 3.0 equivalent) in 2-methyloxacyclopentane / MeOH (4:1, 50 mL). The resulting mixture was stirred at 90°C for 16 h under a carbon monoxide atmosphere. The mixture was allowed to be cooled 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 give (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.80 g, 33% yield) as a red solid. ESI-MS m / z = 507.25 [M+H] + Calculated MW: 506.3

[0901] Step 2 :(1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0902] Under a nitrogen atmosphere at 0°C, NaBH4 (336.1 mg, 8.88 mmol, 2.5 equivalents) was added in portions to a stirred solution of (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(methoxycarbonyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.80 g, 3.55 mmol, 1.0 equivalent) and CaCl2 (1.38 g, 12.4 mmol, 3.5 equivalent) in THF / MeOH (2:1, 30 mL). The resulting mixture was stirred at 20°C for 16 h under a nitrogen atmosphere. The reaction was quenched with water at 20°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (1:10–1:7). The pure fraction was concentrated under reduced pressure to give (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.00 g, 56% yield) as a white solid. ESI-MS m / z = 479.25 [M+H] + Calculated MW: 478.3

[0903] Step 3 :(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0904] Under a nitrogen atmosphere at 0°C, DIAD (507.1 mg, 2.51 mmol, 3.0 equivalent) was added dropwise to a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-ol (403.8 mg, 1.01 mmol, 1.2 equivalent) and PPh3 (679.6 mg, 2.59 mmol, 3.1 equivalent) in 10 mL of THF. The resulting mixture was stirred at 0°C for 0.5 h under a nitrogen atmosphere. At 20°C, (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(hydroxymethyl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400.0 mg, 0.84 mmol, 1.0 equivalent) was added to the above mixture. The resulting mixture was stirred at 20°C for another 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, in a 60% to 70% gradient over 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give (1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (250 mg, 35% yield) as a yellow solid. ESI-MS m / z = 863.3 [M+H] + Calculated MW: 862.5.

[0905] Steps 4-5 : 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)methoxy)-5-ethynyl-6-fluoronaphthyl-2-ol

[0906] CsF (351.9 mg, 2.32 mmol, 10 equivalents) was added to a stirred solution of (1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200.0 mg, 0.23 mmol, 1.0 equivalent) in DMF (2 mL). The resulting mixture was stirred at 20°C for 2 h in air. The resulting mixture was filtered, and the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under vacuum to obtain (1R,5S)-3-(4-(((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200.0 mg, crude product), which was a brown oil. Under air atmosphere and at 20°C, FA (2 mL) was added to a stirred solution of (1R,5S)-3-(4-(((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)oxy)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200.0 mg, crude) in DCM (0.5 mL). The resulting mixture was stirred under air atmosphere at 20°C for 2 h. The resulting mixture was purified by preparative HPLC under the following conditions (column: Xbridge Phenyl OBD column, 19). 150 mm, 5 m; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.05% NH4CO3) 3.H2O), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 27% B to 42% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.4). The pure fraction was lyophilized to give 4-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)methoxy)-5-ethynyl-6-fluoronaphthyl-2-ol (23.4 mg, 14% yield) as a white solid.

[0907] ESI-MS m / z = 563.15 [M+H] + ; Calculated MW: 562.3.

[0908] 1 H 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).

[0909] Example 14 : 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthyl-2-ol

[0910]

[0911] Step 1 :(1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0912] The solution of (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-carboxylic acid tert-butyl ester (1.00 g, 2.07 mmol, 1.0 equivalent) in NH3 / MeOH (7M, 15 mL) was stirred at 50°C for 4 h under a nitrogen atmosphere. Cooling of the mixture to 20°C was permitted. The resulting mixture was concentrated under reduced pressure to give (1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.20 g, crude) as a white solid. ESI-MS m / z = 464.2 [M+H] + Calculated MW: 463.3

[0913] Step 2 :((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane

[0914] Under a nitrogen atmosphere at 0°C, CBr4 (191.0 mg, 0.48 mmol, 1.0 equivalent) was added dropwise to a stirred solution of [7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]methanol (200.0 mg, 0.48 mmol, 1.0 equivalent) and PPh3 (151.1 mg, 0.58 mmol, 1.2 equivalent) in DCM (2 mL). The resulting mixture was stirred at 0°C for 1.5 h under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc, and the pure fraction was concentrated under reduced pressure to give ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane (220.0 mg, 96% yield) as a white solid.

[0915] 1¹H 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).

[0916] Step 3 :(1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methyl)amino)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0917] Under a nitrogen atmosphere at 20°C, NaH (51.8 mg, 1.29 mmol, 3.0 equivalent, 60%) was added in portions to a stirred solution of (1R,5S)-3-(4-amino-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200.0 mg, 0.43 mmol, 1.0 equivalent) in DMF (10 mL). The resulting mixture was stirred for 1 h under a nitrogen atmosphere at 20°C. At 20°C, add ((8-(bromomethyl)-2-fluoro-6-(methoxymethoxy)naphth-1-yl)ethynyl)triisopropylsilane (208.2 mg, 0.43 mmol, 1.0 equivalent) to the above mixture. Stir the resulting mixture at 50°C for another 2 h. Allow the mixture to cool to 20°C. Quench the reaction with water at 0°C. Concentrate the resulting mixture under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc, and the pure fraction was concentrated under reduced pressure to give (1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methyl)amino)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (210.0 mg, 56% yield) as a grayish-white solid. ESI-MS m / z = 862.5 [M+H] + Calculated MW: 861.5

[0918] Step 4 : 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthyl-2-ol

[0919] Under a nitrogen atmosphere at 20°C, CsF (352.3 mg, 2.32 mmol, 10 equivalents) was added to a stirred solution of (1R,5S)-3-(4-(((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)methyl)amino)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200.0 mg, 0.23 mmol, 1.0 equivalent) in DMF (5 mL). The resulting mixture was stirred at 20°C for 16 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DMF (3 x 2 mL). The filtrate was concentrated under reduced pressure. HCOOH (3 mL) was added to the mixture at 20°C. The resulting mixture was stirred at 20°C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30). 150 mm, 5 m; Mobile phase A: 10 mmol NH4HCO3 + 0.05% NH3H2O, Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 28% B to 48% B over 8 min; Wavelength: 254 / 220 nm; RT1 (min): 9.37). The pure fraction was concentrated and then lyophilized to give 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)amino)methyl)-5-ethynyl-6-fluoronaphthyl-2-ol (15.4 mg, 12% yield) as a white solid. ESI-MS m / z = 562.30 [M+H] + ; Calculated MW: 561.3.

[0920] 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.85 (ddd, J = 8.8, 6.2, 1.8Hz, 1H), 7.54 (dt, J = 48.7, 6.2 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).

[0921] Example 15 :N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-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-naphthylcarboxamide

[0922]

[0923] Step 1 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0924] 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1-carboxamide (190.0 mg, 0.44 mmol, 1.0 equivalent) and 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-carboxylic acid tert-butyl ester (426.5 mg, 0.88 mmol, 2.0 equivalent), Cs2CO3 (288.1 mg, 0.88 mmol, 2.0 equivalent), XPhos (126.4 mg, 0.26 mmol, 0.6 equivalent), and XPhos Pd G3 (112.2 mg, 0.13 equivalent) were administered. The mixture of mmol (0.3 equivalents) in dioxane was stirred at 80°C for 16 h under a nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% over 40 min; detector, UV 254 nm, to give 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 65%) as a faint red solid. ESI-MS m / z = 876.56 [M+H] + Calculated MW: 875.46

[0925] Step 2 3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0926] A mixture of 3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200.0 mg, 0.22 mmol, 1.0 equivalent) and CsF (173.3 mg, 1.1 mmol, 5.0 equivalent) in DMF was stirred at room temperature under a nitrogen atmosphere for 0.5 h. 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 give 3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (160.0 mg, 65% yield), a slightly reddish solid. ESI-MS m / z = 720.31; [M+H] + Calculated MW: 719.32

[0927] Step 3 :N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-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-naphthylcarboxamide

[0928] A mixture of 3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthamido)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (160.0 mg, 0.15 mmol, 1.0 equivalent) and HCl (gas)-dioxane solution (5 mL) was stirred at room temperature under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (NH4HCO3 / MeCN / H2O) to obtain N-(4-(((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-8-ethynyl-7-fluoro-3-hydroxy-1-naphthylcarboxamide (36.3 mg, 40% yield) as a pale yellow solid.

[0929] ESI-MS m / z = 576.24; [M+H] + Calculated MW: 575.25

[0930] 1 H 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).

[0931] Example 16: 4-(1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-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-fluoronaphthyl-2-ol

[0932]

[0933] Step 1 :(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-(4-iodomizo-1-yl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0934] At 25°C, 4-iodo-1H-imidazole (601.4 mg, 3.10 mmol, 1.5 equivalent) was added in portions to a stirred mixture of (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-carboxylic acid tert-butyl ester (1.00 g, 2.07 mmol, 1.0 equivalent) and Cs₂CO₃ (2.02 g, 6.21 mmol, 3.0 equivalent) in DMF (20 mL). The resulting mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. Cooling of the mixture to 20°C was permitted. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 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 DCM / MeOH (10:1), and the pure fraction was concentrated to give (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-(4-iodomizo-1-yl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (860.0 mg, 65% yield) as a brown solid. ESI-MS m / z = 641.1 M+H + Calculated MW: 640.1

[0935] Step 2:(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0936] At 20°C, K₂CO₃ (323.6 mg) was added in portions to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-(4-ioimidazole-1-yl)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500.0 mg, 0.78 mmol, 1.0 equivalent) and {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)naphth-1-yl]ethynyl}triisopropylsilane (600.1 mg, 1.17 mmol, 1.5 equivalent) in water (2 mL) and dioxane (10 mL). 113.7 mg (2.34 mmol, 3.0 equivalent) and [(3R,5S,7s)-adamantane-1-yl][(1s,3R,5S,7s)-adamantane-1-yl]phosphine{2'-amino-[1,1'-biphenyl]-2-yl}palladium methanesulfonate butyl ester (113.7 mg, 0.16 mmol, 0.2 equivalent). The resulting mixture was stirred at 100°C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to 20°C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 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 (1:1), and the pure fraction was concentrated to give (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (285.0 mg, 41% yield) as a yellow solid. ESI-MS m / z = 899.4 [M+H] + Calculated MW: 898.4

[0937] Step 3:(1R,5S)-3-(4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-1H-imidazol-1-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0938] At 20°C, CsF (481.4 mg, 3.17 mmol, 10 equivalents) was added in portions to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-{4-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (285.0 mg, 0.32 mmol, 1.0 equivalent) in DMF (5 mL). The resulting mixture was stirred at 20°C for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. ESI-MS m / z = 743.3 [M+H] + Calculated MW: 742.3

[0939] Step 4 : 4-[1-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)imidazol-4-yl]-5-ethynyl-6-fluoronaphth-2-ol; formic acid

[0940] To a mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-{4-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl]imidazol-1-yl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (280.0 mg, 0.38 mmol, 1.0 equivalent) in MeCN (4 mL), HCl (gas)-dioxane solution (4 mL, 4 M) was added and the resulting mixture was stirred at 20°C for 2 h under a nitrogen atmosphere. The mixture was concentrated to give the product (280.0 mg, crude), which was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS column, 19...). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 36% B to 56% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.4). The pure fraction was lyophilized to give 4-[1-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)imidazol-4-yl]-5-ethynyl-6-fluoronaphthyl-2-ol (47.0 mg, 21% yield) as a yellow solid. ESI-MS m / z = 599.2 [M+H] + ; Calculated MW: 598.2. 1 H 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).

[0941] Example 17 : 4-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)oxy)methyl)-5,6-difluoronaphthyl-2-ol

[0942]

[0943] Step 1:(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]methoxy}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate

[0944] Under a nitrogen atmosphere at 0°C, LiHMDS (0.76 mL, 0.99 mmol, 1.2 equivalents, 1.3 M in THF) was added dropwise to a stirred solution of [7,8-difluoro-3-(methoxymethoxy)naphth-1-yl]methanol (252.7 mg, 0.99 mmol, 1.2 equivalents) in THF (5 mL). The resulting mixture was stirred at 0°C for 1 h under a nitrogen atmosphere. At 0°C, (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-carboxylic acid tert-butyl ester (100.0 mg, 0.20 mmol, 1.0 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at 20°C for another 2 h. 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, eluting with PE / EtOAc (10:1), and the pure fraction was concentrated under reduced pressure to give (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]methoxy}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (280.0 mg, 48% yield) as a brown solid. ESI-MS m / z = 701.3 [M+H] + Calculated MW: 700.3

[0945] Step 2 : 4-{[(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)oxy]methyl}-5,6-difluoronaphthyl-2-ol

[0946] At 20°C, (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]methoxy}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (130.0 mg, 0.18 mmol, 1.0 equivalent) and HCOOH (2 mL) were added to an 8 mL vial. The resulting mixture was stirred at 20°C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product (130.0 mg) was purified by preparative HPLC under the following conditions (column: Kinetex EVO C18 column, 30...). 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 29% B to 38% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.8). The pure fraction was concentrated and lyophilized to give 4-{[(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl]-1,3,5-triazin-2-yl)oxy]methyl}-5,6-difluoronaphthyl-2-ol (26.9 mg, 26% yield) as a white solid. ESI-MS m / z = 557.4 [M+H] + ; Calculated MW: 556.2. 1 H NMR (300 MHz, DMSO-d6) δ10.12 (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 = 12.5Hz, 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).

[0947] Example 18: 4-(2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,5-triazin-2-yl)ethyl)-5,6-difluoronaphthyl-2-ol

[0948]

[0949] Step 1 :(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-[(E)-2-[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]vinyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0950] Under a nitrogen atmosphere and at 100°C, DIEA (817.0 mg, 6.32 mmol, 3.0 equivalent), PPh3 (55.3 mg, 0.21 mmol, 0.1 equivalent), and Pd(OAc)2 (47.3 mg, 0.21 mmol, 0.1 equivalent) were added in portions to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-vinyl-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.00 g, 2.11 mmol, 1.0 equivalent) and 8-bromo-1,2-difluoro-6-(methoxymethoxy)naphthalene (702.5 mg, 2.32 mmol, 1.1 equivalent) in dioxane (2 mL). (mmol, 0.1 equivalent). The resulting mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. Cooling of the mixture to 20°C was permitted. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:4) to give (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(E)-2-[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]vinyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (420.0 mg, 29% yield) as a yellow solid. ESI-MS m / z = 697.3 [M+H] + Calculated MW: 696.3

[0951] Step 2:(1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-6-{2-[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]ethyl}-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0952] Under a nitrogen atmosphere at 20°C, Pd(OH)₂ / C (305.5 mg, 2.87 mmol, 5.0 equivalent) was added in portions to a stirred mixture of (1R,5S)-3-(4-{[(2R,7aS)-2-fluoro-hexahydropyrrolazin-7a-yl]methoxy}-6-[(E)-2-[7,8-difluoro-3-(methoxymethoxy)naphthyl-1-yl]vinyl]-1,3,5-triazin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400.0 mg, 0.57 mmol, 1.0 equivalent) in EtOAc (10 mL). The resulting mixture was stirred at 20°C for 1 h under a H₂ atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x...

Claims

1. A compound having formula (0): (Equation (0)) Or its pharmaceutically acceptable salt, wherein: R 1 It is a 6- to 10-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =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 where R 1 Yes -L 3 -R 1 ', where R 1 ' is a 5-membered, monocyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N ring atom, and wherein R 1’ Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR C(O)NHR C(O)NR 2. C(O)ONHR and C(O)ONR 2; R 2 It is a 5- to 9-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic and at least one ring contains at least one ring atom that is N; or a fused 11- to 14-membered tricyclic group, wherein at least one ring is aromatic and at least one ring contains at least one ring atom that is N; And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl; R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl; or R 3 It is 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 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated heterocycle fused to an aryl ring or a heteroaryl ring, wherein the carbide ring, the aryl ring or the heteroaryl ring, or both, may optionally be substituted by one or more groups independently selected from the following: 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)ynyl; L 1 It is a bond or -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This represents the attachment point to the triazole moiety of a compound having formula (0), and Indicates with R 2 Attachment point; L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and Indicates the attachment point to the triazole moiety of a compound having formula (0); L 3 It is a bond or -(C1-C3)alkyl-, -O-, -NH- or -N(C1-C3)alkyl; and Among them, in R 1 R 2 and R 3 In, each R The group is independently selected from (C1-C4)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, and 5 or 6-membered monocyclic heteroaryl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound having formula (I): (Formula (I)) In equation (I): R 1 It is a 6- to 10-membered bridged bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one N-ring atom, and wherein R 1 Optionally substituted by one or more groups independently selected from the following: =O, CN, Cl, F, R OH, OR NH2, NHR NR 2. CHO, C(O)OH, C(O)NH2, C(O)ONH2, C(O)R C(O)OR C(O)NHR C(O)NR 2. C(O)ONHR and C(O)ONR 2; R 2 It is a 5- to 8-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, which contains at least one ring atom that is N or O; a 5- or 6-membered monocyclic heteroaryl group, which contains at least one ring atom that is N; or a fused 8- to 10-membered bicyclic group, wherein one or both rings are aromatic, and at least one ring contains at least one ring atom that is N. And R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl; R 3 It is a phenyl or naphthyl group, which is substituted with OH and optionally substituted with one or more other 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)ynyl; or R 3 It is a fused 8- to 10-membered bicyclic group comprising a saturated carbocyclic ring fused with a heterocyclic ring, wherein the carbocyclic ring, the heterocyclic ring, or both may optionally be substituted by one or more groups independently selected from the following: 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)ynyl; L 1 It is -O-, -(C1-C3)alkyl-, -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- , -C(O)NR'- ,or -NR'C(O)- Where R' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and This indicates the attachment point to the triazole moiety of a compound having formula (I), and Indicates with R 2 Attachment point; L 2 It is a -(C1-C3)alkyl-, C5-heteroaryl group optionally substituted with one or more R''. -O-(C1-C3)alkyl- , -(C1-C3)alkyl-O- -(C2-C3)alkenyl-, -(C2-C3)ynyl-, -(C1-C3)alkyl-NR''- , -NR''(C1-C3)alkyl- , -C(O)NR''- , -NR''C(O)- , -NR''-(C1-C3)alkyl- ,or -(C1-C3)alkyl-NR''- R'' is H, OH, CN, Cl, F, or (C1-C3) alkyl, and wherein Indicates with R 3 The attachment point, and Indicates the attachment point to the triazole moiety of a compound having formula (I); and Among them, in R 1 R 2 and R 3 In, each R The group is independently selected from (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, wherein the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkenyl group itself may be substituted by one or more groups independently selected from the following: F, Cl, CN, OH, NH2, NH ((C1-C3)alkyl), (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or O (C1-C3)alkyl.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1 yes , , ,or .

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1 yes , , , , , , or .

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from Where m is 1 or 2 and n is 0, 1 or 2; and each R c and R d Independently selected from F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, and (C2-C3)ynyl, provided that at least one R c It is OH; , where s is 1, 2, or 3, and where when s is 1, R g It is OH, and when s is 2 or 3, at least one R g It is OH and each remaining R g Independently, it is F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, (C2-C3)ynyl, or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl group itself may be substituted by one or more groups independently selected from: F, Cl, CN, OH, (C1-C3)alkyl, (C2-C3)alkenyl, or (C2-C3)ynyl; and , where Y 10 It is S, O, or NR''', where R''' is H, OH, CN, Cl, F, or (C1-C3) alkyl; t is 0, 1, 2, or 3, and u is 0, 1, or 2, provided that u is not zero when t is zero, and t is not zero when u is zero; and each R h and R i 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)ynyl, wherein R As defined in claim 1 or claim 2.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: , ,and , where R c R d R g R h R i , n and u are as defined in claim 5.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: , , , , , , and , where R d R g and R i As defined in claim 5.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein L 2 Selected from: -CH2CH2-, -C≡C-, -CH2O- , -OCH2- , -C(O)-NH- , -CH2NH- , -N(CH3)C(O)- , - NHC(O)- ,and , And among them and As defined in claim 1 or claim 2.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: Where q and r are each independently 0, 1, or 2, and R a and R b In each case, CN, Cl, F, and R are selected independently. 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)ynyl, wherein R As defined in claim 1 or claim 2; , where X 8 X 9 X 10 and X 11 Each is independently selected from C(R) k 2. C=O, N(R) k ), O or S, provided that X 8 X 9 X 10 and X 11 At least one of them is N(R) k ); , where X 12 X 13 and X 14 Each is independently selected from C(R) k 2. C=O, N(R) k ), O or S, and X 15 and X 16 Each is independently selected from C and N, provided that X 12 X 13 and X 14 At least one of them is N(R) k ) and / or X 15 and X 16 At least one of them is N; , where X 17 X 18 X 19 X 20 and X 21 Each is independently selected from C(R) k 2. C=O, N(R) k ), O or S, provided that X 17 X 18 X 19 X 20 and X 21 At least one of them is N(R) k ), O or S; , where Y 1 Y 2 Y 3 and Y 4 Each is independently N, O, S, NR k or CR k The premise is that Y 1 Y 2 Y 3 and Y 4 At least one of them is N or NR k ; , where Y 5 Y 6 and Y 7 Each is independently N, O, S, NR k or CR k And Y 8 and Y 9 Each is either N or C independently, provided that Y 5 Y 6 and Y 7 At least one of them is N or NR k and / or Y 8 and Y 9 At least one of them is N; as well as Z 1 Z 2 Z 3 Z 4 and Z 5 Each is independently N, O, S or CR k The premise is Z 1 Z 2 Z 3 Z 4 and Z 5 At least one of them is N; Each R k 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)ynyl, wherein R As defined in claim 1 or claim 2.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: , where R b and r as defined in claim 9, , where R k As defined in claim 9 (e.g., where yes , , , , ,or ), , , , , , , , , , , , , , , , , , , , , , , ,and .

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 yes .

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 yes , where R k As defined in claim 9.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 yes , or .

14. The compound or pharmaceutically acceptable salt of any one of claims 1 to 13, wherein L 1 It is -O-、 -OCH(CH3)- ,or -O-CH2- .

15. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having formula (III), formula (IV), formula (XXII), or formula (XXII.I): (Formula (III)) (Formula (IV)) (Formula (XXII)) (Formula (XXII.I)) in In each of equations (III), (IV), and (XXII), L 1 As defined in claim 1, claim 2, or claim 14; L 2 As defined in claim 1, claim 2, or claim 8; R 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, where R As defined in claim 1 or claim 2; and R 2 As defined in any one of claims 9-13; In equation (III), R c R d , n and m are as defined in claim 5; In equation (IV), R g and s as defined in claim 5; and In equation (XXII), R h R i t, u, and Y 10 As defined in claim 5; and In equation (XXII.I), L 1 As defined in claim 1, claim 2, or claim 14; L 2 As defined in claim 1, claim 2, or claim 8; R 2 As defined in any one of claims 9-13; R h R i t, u, and Y 10 As defined in claim 5; X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; and each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R As defined in claim 1 or claim 2.

16. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having formula (VI) or formula (VI.I): (Formula (VI)) (Formula (VI.I)) In equation (VI), L 1 As defined in claim 1, claim 2, or claim 14; L 2 As defined in claim 1, claim 2, or claim 8; R 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, where R As defined in claim 1 or claim 2; and R 3 As defined in any one of claims 5-7; and in formula (VI.I), L 1 As defined in claim 1, claim 2, or claim 10; L 2 As defined in claim 1, claim 2, or claim 8; X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R As defined in claim 1 or claim 2; and R 3 As defined in any one of claims 5-7.

17. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein the compound is a compound having formula (XXIII.I) or formula (XXIV.I). (Formula (XXIII.I)) (Formula (XXIV.I)) In each of equations (XXIII.I) and (XXIV.I): L 1 As defined in claim 1, claim 2, or claim 14; L 2 As defined in claim 1, claim 2, or claim 8; R h R i , t, and u are as defined in claim 5; X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R As defined in claim 1 or claim 2; and R 2 As defined in any one of claims 9-13.

18. A compound having formula (XXII) or (XXII.I) as defined in claim 15, or a compound having formula (XXIII.I) or (XXIV.I) as defined in claim 17, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a 5- to 9-membered, monocyclic or bicyclic heterocyclic alkyl or heterocyclic alkenyl group, comprising at least one ring atom of N or O; a 5- or 6-membered monocyclic heteroaryl group, comprising at least one ring atom of 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 of N; and wherein R 2 It can be substituted by one or more groups independently selected from the following: 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)ynyl; and wherein each R The group 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 the (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5 or 6-membered monocyclic heteroaryl can 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)ynyl, or O (C1-C3)alkyl.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 2 yes , where X 8 X 9 X 10 and X 11 As defined in claim 9.

20. The compound of claim 18 or claim 19, or a pharmaceutically acceptable salt thereof, wherein R 2 As defined in claim 12 or claim 13.

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

22. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein the compound is a compound having formula (XXVII) or formula (XXVIII): (Formula (XXVII)) (Formula (XXVIII)) in In equation (XXVII), L 1 As defined in claim 1, claim 2, or claim 14; L 2 As defined in claim 1, claim 2, or claim 8; R k As defined in claim 9; X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R As defined in claim 1 or claim 2; and R 3 As defined in any one of claims 5-7; and In equation (XXVIII), L 1 As defined in claim 1, claim 2, or claim 14; L 2 As defined in claim 1, claim 2, or claim 8; R k As defined in claim 9; X is selected from NH, N(C) 1-3 Alkyl, O, or CH2; v is an integer from 0 to 4; each R Independently selected from H, CN, Cl, F, R OH, OR NR 2. CHO, C(O)R C(O)OR C(O)NR 2. and C(O)ONR 2, where R As defined in claim 1 or claim 2; and wherein R h R i , t and u are as defined in claim 5.

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

24. The compound or pharmaceutically acceptable salt of any one of claims 1-22, or the pharmaceutical composition of claim 23, for use in a therapeutic manner.

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

26. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition as described in claim 25, wherein the cancer is a KRAS G12D-related cancer.

27. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as described in claim 25 or claim 26, wherein the cancer is selected from colorectal cancer, lung cancer, and pancreatic cancer.

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

29. A method for treating or preventing a disease or disorder mediated by KRAS G12D or involving KRASG12D in a subject of need, the method comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as described in any one of claims 1-22, or a pharmaceutical composition as described in claim 23.

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

31. The method of treating or preventing a disease or disorder as described in claim 30, wherein the disease or disorder is cancer.

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

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

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

35. The method of claim 31, 32 or 34, wherein the cancer is selected from colorectal cancer, lung cancer and pancreatic cancer.

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