Diazepine derivatives useful in the treatment of Clostridium difficile

Abstract

The present disclosure describes compounds of formula (I) and formula (II), as well as stereoisomers, tautomers, and pharma- ceutically acceptable salts or solvates thereof, wherein all of the variables are as defined herein. The present disclosure also relates to pharmaceutical compositions comprising these compounds, and methods of treating diseases, disorders, or conditions by using the compounds and pharmaceutical compositions. [Formula 1] TIFF2024508924000107.tif28128

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 155,651, filed on 2 March 2021, entitled “Heterocyclic Compounds and Related Methods,” the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates, in general, to therapeutics. Specifically, this disclosure relates to heterocyclic compounds and related methods. Pharmaceutical compositions containing such compounds and useful therapies therein are disclosed herein. [Background technology]

[0003] Clostridium difficile (C. difficile) is a Gram-positive, spore-forming bacterium that causes C. difficile-associated diarrhea (CDAD). Typically, CDAD develops after disruption of the gut microbiome via antibiotic treatment, but sporadic and environmental cases also occur. There are over 500,000 infections associated with more than 15,000–20,000 deaths per year. An estimated 20–40% of cases relapse, and patients become symptomatic after completing their treatment course (Rupnik et al. 2009). The C. difficile microorganism produces multiple toxins that disrupt the intestinal lining, leading to inflammation and diarrhea. Two of the toxins primarily involved in the pathogenesis of the human disease are toxin A and toxin B (TCdA, TCdB), which are internalized within cells and glucosylate Rho GTPase proteins, thereby inactivating the main mechanism by which cells maintain their shape (Rupnik et al. 2009). This inactivation leads to cell death, disrupts the gut barrier, causes inflammation and diarrhea, and if left untreated, can lead to toxic megacolon, sepsis, and in some cases, death.

[0004] Several antibiotics, including metronidazole (off-label use), vancomycin, and fidaxomicin, are commonly used to treat CDAD (Kelly 2020). However, these treatments cause relapses at varying levels (Louie et al. 2011) and continue to disrupt the gut microbiome. Interventions focused on restoring the normal gut microbiome have also shown clinical efficacy (McGovern et al. 2020). However, such therapies are not without significant costs and risks, such as the transmission of drug-resistant E coli (DeFilipp et al. 2019). Antitoxin antibody therapy is also under active investigation and development. While aggressive vaccination strategies have demonstrated a robust immune response to C. difficile toxin, data on the ability of vaccines to suppress the pathology of the infection is limited, and no vaccine for the prevention of CDAD has been approved (Henderson et al. 2017). Monoclonal antibodies targeting toxin B have been shown to reduce relapses from 32% to 8% (Wilcox et al. 2017). However, the high cost of monoclonal antibody therapy, combined with the burden of intravenous infusion, may limit its use, especially for non-hospitalized patients, while competing with other less expensive medications.

[0005] Inhibitors of toxic pathogenic factors that disrupt barrier function are being actively explored as an alternative treatment option for CDAD (Stroke et al. 2018, Bender et al. 2015, Savidge et al. 2011). Such antitoxic strategies have the potential to suppress the pathology without further disrupting the normal bacterial flora and without providing the selective pressure that promotes antibiotic resistance when additional antibiotic therapy tends to be administered (Fleitas Martinez et al. 2019). Therefore, identifying compounds that suppress the pathology of C. difficile infection while preserving the normal bacterial flora and allowing their reconstruction would be a highly effective therapeutic intervention. [Overview of the Initiative]

[0006] In one embodiment, the disclosure provides compounds of formulas (I) and (II), as well as subgenera as species thereof, including their stereoisomers, tautomers, pharmaceutically acceptable salts, and solvates. In certain embodiments, the compounds are useful for treating C. difficile bacterial infections.

[0007] In another embodiment, the disclosure also provides processes and intermediates for producing the compounds of the disclosure.

[0008] In another embodiment, the Disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the Disclosure, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0009] In another embodiment, the compounds of this disclosure may be used for therapeutic purposes alone or in combination with one or more additional therapeutic agents.

[0010] The compounds of this disclosure may be used in the treatment of patients requiring treatment for any disease, disorder, or condition associated with any infection caused by C. difficile bacteria, by administering to the patient a therapeutically effective amount of the compound, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates. The disease, disorder, or condition may be associated with fever, abdominal pain, diarrhea, and colitis. The compounds of this disclosure may be used alone, in combination with one or more of the compounds of this disclosure, or in combination with one or more other therapeutic agents, for example, one or two other therapeutic agents.

[0011] The compounds of this disclosure may be used for the manufacture of pharmaceuticals for the treatment of patients who require treatment for a disease, disorder, or condition.

[0012] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0013] This application provides compounds according to formula (I) and formula (II), including all stereoisomers, solvates, and pharmaceutically acceptable salts and solvate forms thereof. This application also provides pharmaceutical compositions containing at least one compound according to formula (I) and formula (II), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, and optionally at least one additional therapeutic agent. In addition, this application provides a method for treating a patient suffering from Clostridium difficile infection by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one additional therapeutic agent.

[0014] The compounds of the present disclosure In one embodiment, the present disclosure provides a compound of formula (I),

[0015] [Chemical Formula]

[0016] wherein, X 1 、X 2 、and X 3 are each independently CR 2 、N、NR 5 、O、or S, X 4 and X 5 are each independently C or N, m is an integer of , 1, or 2, Z is a 6- to 10-member aryl or a 5- to 10-member heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, R 1 and R 2 are each independently hydrogen, halo, cyano, hydroxyl, amino, C 1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy R 3 and R 4 These are, independently, hydrogen and C 1-6 A 5-10 membered heteroaryl, 3-10 membered carbocyrill, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from alkyl, alkylamino, haloalkyl, alkoxy, haloalkoxy, 6-10 membered aryl, N, O, and S, and each aryl, heteroaryl, carbocyrill, and heterocyclyl independently contains 0-5 R 5 It has been replaced with, R 5 These are hydrogen, halo, cyano, hydroxyl, amino, and C. 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, hydroxycycloalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, or -C(O)OR 6 And, R 6 is hydrogen or C 1-6 It is alkyl.

[0017] The dashed circle is X 1 , X 2 , X 3 Those skilled in the art should understand that this indicates an aromatic ring formed by carbon atoms.

[0018] In any one of the prior embodiments of formula (I),

[0019] [ka]

[0020] The part is,

[0021] [ka]

[0022] It can be.

[0023] In any one of the prior embodiments of formula (I), R 3 It can be hydrogen, R 4 It can be a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and the heteroaryl independently contains 0-5 R 5 It has been replaced with.

[0024] In any one of the prior embodiments of formula (I), R 3 It can be hydrogen, R 4 teeth,

[0025] [ka]

[0026] m can be selected from, where m is an integer 0, 1, or 2, and R 5 This is the same as the definition above.

[0027] In any one of the prior embodiments of formula (I),

[0028] [ka]

[0029] The part is,

[0030] [ka]

[0031] It can be.

[0032] In any one of the prior embodiments of formula (I), the compound may be represented by formula (Ia).

[0033] [ka]

[0034] In any one of the prior embodiments of formula (I), the compound may be represented by formula (Ib).

[0035] [ka]

[0036] In any one of the prior embodiments of formula (I), R 3 It can be hydrogen, R 4 teeth,

[0037] [ka]

[0038] It can be selected from, in the formula, R 5 This is as defined above.

[0039] In any one of the prior embodiments of formula (I), the compound may be represented by formula (Ic).

[0040] [ka]

[0041] In any one of the prior embodiments of formula (I), the compound may be represented by formula (Id).

[0042] [ka]

[0043] In any of the aforementioned embodiments of formula (I), the compound may be represented by formula (Ie).

[0044] [ka]

[0045] In any of the aforementioned embodiments of formula (I), the compound may be represented by formula (If).

[0046] [ka]

[0047] In one embodiment, the present disclosure provides a compound of formula (II),

[0048] [ka]

[0049] During the ceremony, Y 1 , Y 2 , and X 3 Each of them operates independently, CR 2 or N, provided that at least one Y 1 , Y 2 , and Y 3 N is, X 4 and X 5 Each of them is independently either C or N, m is an integer of 0, 1, or 2. Z is a 6-10 membered aryl, or a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S. R 1 and R 2 These are, independently, hydrogen, halo, cyano, hydroxyl, amino, and C. 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy R 3 and R 4These are, independently, hydrogen and C 1-6 Alkyl, alkylamino, haloalkyl, alkoxy, or haloalkoxy, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, 3-10 membered carbocykryl, or 4-10 membered heterocyclil containing 1-3 heteroatoms independently selected from N, O, and S, wherein aryl, heteroaryl, carbocykryl, and heterocyclil independently contain 0-5 R 5 It has been replaced with, R 5 These are hydrogen, halo, cyano, hydroxyl, amino, and C. 1-6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, hydroxycycloalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, or -C(O)OR 6 And, R 6 is hydrogen or C 1-6 It is alkyl The dashed circle is Y 1 , Y 2 , Y 3 Those skilled in the art should understand that this indicates an aromatic ring formed by carbon atoms. In any one of the prior embodiments of formula (II),

[0050] [ka]

[0051] The part is,

[0052] [ka]

[0053] It can be selected from the following.

[0054] In any one of the prior embodiments of formula (II), R 3 It can be hydrogen, R4 It can be a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and the heteroaryl independently contains 0-5 R 5 It has been replaced with.

[0055] In any one of the prior embodiments of formula (II), R 3 It can be hydrogen, R 4 teeth,

[0056] [ka]

[0057] It can be selected from, where m is an integer 0, 1, or 2, and R 5 This is the same as the definition above. In any one of the prior embodiments of formula (II),

[0058] [ka]

[0059] The part is,

[0060] [ka]

[0061] It is possible.

[0062] In any one of the prior embodiments of formula (II), the compound may be represented by formula (IIa).

[0063] [ka]

[0064] In any one of the prior embodiments of formula (II), the compound may be represented by formula (IIb).

[0065] [ka]

[0066] In any one of the prior embodiments of formula (II), the compound may be represented by formula (IIc).

[0067] [ka]

[0068] In any one of the prior embodiments of formula (II), the compound may be represented by formula (IId).

[0069] [ka]

[0070] In one embodiment, the disclosure,

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] The present invention provides compounds that can be selected from, or their stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates. In one embodiment, the disclosure provides, in particular, a compound selected from any one of the examples described herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0076] II. Pharmaceutical compositions, therapeutic effects, and combinations In another embodiment, the Disclosure provides a composition comprising at least one of the compounds of the Disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. In another embodiment, the Disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the Disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0077] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the Disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0078] In another embodiment, the Disclosure provides a process for producing the compounds of the Disclosure.

[0079] In another embodiment, the Disclosure provides intermediates for preparing the compounds of the Disclosure.

[0080] In another embodiment, the disclosure provides a pharmaceutical composition as defined above, further comprising one or more additional therapeutic agents.

[0081] In another embodiment, the Disclosure provides a method for the treatment of a patient requiring treatment for a disease, disorder, or condition associated with C. difficile infection, the method comprising administering to the patient a therapeutically effective amount of the compound of the Disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0082] In another embodiment, the Disclosure provides a method for treating a disease, disorder, or condition, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the Disclosure, alone or optionally, in combination with another compound of the Disclosure and / or at least one other type of therapeutic agent.

[0083] In another embodiment, the Disclosure provides a method for inhibiting intracellular C. difficile bacterial toxin, the method comprising administering to cells a therapeutically effective amount of the compound of the Disclosure, or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates. In a particular embodiment, the toxin is toxin B.

[0084] In another embodiment, the Disclosure provides a method for reducing intracellular glucosylation of Rho GTPase proteins, the method comprising administering to cells a therapeutically effective amount of the compound of the Disclosure, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0085] The compounds of this disclosure may be administered by any suitable means for any of the uses described herein, for example, orally, such as in the form of tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions; parenterally, such as sublingual, oral, subcutaneous, intravenous, intramuscular, or intrastemmal injection, or infusion techniques (e.g., sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to the nasal membrane by inhalation sprays; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They may be administered alone, but generally, they are administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0086] The term “pharmaceutical composition” means a composition comprising the compounds of this disclosure in combination with at least one additional pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” means a medium generally accepted in the art for the delivery of biologically active drugs to animals, particularly mammals, depending on the nature of the method and form of administration, i.e., including adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants. pharmaceutically acceptable carriers are formulated according to several factors well within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the target to which the drug-containing composition is administered, the intended route of administration of the composition, and the targeted therapeutic indication. pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may contain several different components and additives in addition to the activator, and such additional components are included in the formulation for various reasons, such as stabilization of the activator, binder, etc., as are well known to those skilled in the art. A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, such as Remington's Pharmaceutical Sciences, 18th Edition (1990).

[0087] As used herein, the terms “to treat” or “treatment” refer to an approach to obtain beneficial or desired results, including clinical outcomes, by using the compounds or compositions of the Disclosure. For the purposes of the Disclosure, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing the severity and / or frequency of one or more symptoms resulting from a disease, disorder, or condition; reducing the degree of a disease, disorder, or condition or causing their regression; stabilizing a disease, disorder, or condition (e.g., preventing or delaying the worsening of a disease, disorder, or condition); delaying or slowing the progression of a disease, disorder, or condition; improving a disease, disorder, or condition; reducing the dose of one or more other medicinal substances required to treat a disease, disorder, or condition; and / or increasing quality of life.

[0088] As used herein, the phrases "treating with a compound" or "administering a compound" include either directly administering a compound of the Disclosure, or a pharmaceutical composition containing a compound of the Disclosure, to isolated cells or animals, or administering another agent to cells or animals to induce the presence or formation of a compound of the Disclosure within the cells or animals. Preferably, the method of the Disclosure includes administering, in vitro, to cells or to warm-blooded animals, particularly mammals, more specifically humans, a pharmaceutical composition containing an effective amount of a compound of the Disclosure to induce the presence or formation of a compound of the Disclosure within the cells or animals.

[0089] Dosage regimens for the compounds of this disclosure will, of course, vary depending on known factors such as the pharmacodynamic properties of the particular drug and its mode and route of administration, the recipient's species, age, sex, health, medical condition, and weight, the nature and severity of symptoms, the type of concomitant therapy, the frequency of treatment, the route of administration, the patient's renal and hepatic function, and the desired effect. According to general guidance, when used for the indicated effects, the daily oral dose of each active ingredient is in the range of about 0.01 to about 5000 mg per day, preferably about 0.01 to about 1000 mg per day, and most preferably about 0.01 to about 250 mg per day. Intravenously, the most preferred dose is in the range of about 0.01 to about 10 mg / kg / min during a constant rate infusion. The compounds of this disclosure may be administered as a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times per day. The compounds are typically administered in mixture with a suitable pharmaceutically acceptable diluent, excipient, or carrier (collectively referred to herein as a pharmaceutically acceptable carrier), which is preferably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and is consistent with conventional pharmaceutically practice. Suitable dosage forms (pharmaceutical compositions) may contain about 0.1 mg to about 2000 mg of the active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition. A typical capsule for oral administration contains at least one of the compounds of this disclosure (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules. A typical injectable preparation is prepared by aseptically adding at least one of the compounds of this disclosure (250 mg) to a vial, aseptically lyophilizing and sealing it. For use, mix the contents of the vial with 2 mL of physiological saline to obtain an injectable preparation.

[0090] The disclosure, to the extent of its scope, includes pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the disclosure in a therapeutically effective amount, either alone or in combination with a pharmaceutical carrier. Optionally, the compounds of the disclosure may be used alone, in combination with other compounds of the disclosure, or in combination with one or more, preferably one to three, other therapeutic agents, such as vancomycin, fidaxomicin, metronidazole, or other pharmaceutically active substances.

[0091] When used in combination with the compounds of this disclosure, the other therapeutic agents described above may be used in amounts indicated in the Physicians' Desk Reference, for example, as in the patents described above, or otherwise as determined by those skilled in the art.

[0092] In particular, when provided as a single dose unit, there is a possibility of chemical interactions between combined active ingredients. For this reason, when the compounds of this disclosure and a second therapeutic agent are combined in a single dose unit, they are formulated such that the active ingredients are combined in a single dose unit, but physical contact between the active ingredients is minimized (i.e., reduced). For example, one active ingredient may be enterically coated. By enterically coating one of the active ingredients, not only is contact between the combined active ingredients minimized, but the release of one of these ingredients in the gastrointestinal tract can also be controlled, thereby preventing one of these ingredients from being released in the stomach and instead releasing it in the intestines. One of the active ingredients may also be coated with a substance that affects sustained release throughout the gastrointestinal tract and functions to minimize physical contact between the combined active ingredients. Furthermore, a sustained-release ingredient may be additionally enterically coated so that its release occurs only in the intestines. Another approach involves formulations of combination products in which, to further isolate the active ingredients, one component is coated with a sustained-release and / or enteric-release polymer, and the other component is also coated with a polymer such as low-viscosity grade hydroxypropyl methylcellulose (HPMC) or other suitable materials known in the art. The polymer coating functions to form an additional barrier to interaction with the other component.

[0093] These methods for minimizing contact between components of the combination products of the present disclosure, as well as other methods, will be readily apparent to those skilled in the art once the present disclosure is given, whether administered in a single dose form or in separate forms but simultaneously by the same means.

[0094] The compounds of this disclosure may be administered alone or in combination with one or more, preferably one to three, additional therapeutic agents. “Administered in combination” or “combination therapy” means that the compounds of this disclosure and one or more, preferably one to three, additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component may be administered simultaneously or sequentially in any order at different time points. Thus, each component may be administered separately, but within sufficiently close time intervals, to provide the desired therapeutic effect.

[0095] The compounds of this disclosure are also useful as standards or reference compounds, e.g., quality standards or controls, in tests or assays involving C. difficile toxin antagonists. Such compounds may be available in commercially available kits for use in pharmaceutical research, for example, involving C. difficile toxin antagonist activity. For example, the compounds of this disclosure can be used as references in assays to compare their known activity with that of compounds having unknown activity. This ensures that the assay is being performed properly and provides a basis for comparison, especially when the test compound is a derivative of the reference compound. When developing new assays or protocols, the compounds of this disclosure can be used to test their effectiveness.

[0096] This disclosure also encompasses products. As used herein, products are intended to include, but are not limited to, kits and packages. Products of this disclosure include (a) a first container; (b) a pharmaceutical composition to be placed in the first container, comprising a first therapeutic agent comprising a compound of this disclosure or a pharmaceutically acceptable salt form thereof; and (c) a statement indicating that the pharmaceutical composition can be used for the treatment of C. difficile infection and its sequelae. In another embodiment, the statement indicating that the pharmaceutical composition can be used (as defined above) in combination with a second therapeutic agent for the treatment of C. difficile infection and its sequelae. Products may further include (d) a second container, wherein components (a) and (b) are placed inside the second container, and component (c) is placed inside or outside the second container. Being placed inside the first and second containers means that each container holds the items within its boundaries.

[0097] The first container is a receptacle used to hold a pharmaceutical composition. This container may be for manufacturing, storage, shipping, and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream preparations), or any other container used to manufacture, hold, store, or distribute pharmaceuticals.

[0098] The second container is used to hold the first container and, optionally, the accompanying documentation. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), wooden crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The accompanying documentation can be physically attached to the outside of the first container via tape, adhesive, staples, or other attachment methods, or it can be contained within the second container without any means of physical attachment to the first container. Alternatively, the accompanying documentation can be placed on the outside of the second container. If placed on the outside of the second container, it is preferable that the accompanying documentation be physically attached via tape, adhesive, staples, or other attachment methods. Alternatively, it can be adjacent to or in contact with the outside of the second container without being physically attached.

[0099] The package insert is a label, tag, marker, etc., that lists information about the pharmaceutical composition to be placed in the first container. The information listed is usually determined by the regulatory authority that controls the area in which the product is sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert may be made of any material from which a person can read the information therein or contained therein. Preferably, the package insert is made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive backing paper, or plastic) from which the desired information is formed (e.g., printed or applied).

[0100] III. Definition Throughout this specification and the appended claims, a given chemical formula or name shall encompass all its stereoisomers and optical isomers, as well as racemates, where such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this disclosure. Many geometric isomers, such as C=C double bonds, C=N double bonds, and cyclic systems, may also exist in the compounds, and all such stable isomers are intended in this disclosure. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of this disclosure are described and may be isolated as mixtures of isomers or as separated isomers. The compounds of the present invention may be isolated in optically active forms or in racemic forms. Optically active forms may be prepared by separation of racemic forms or by synthesis from optically active starting materials. All processes used to prepare the compounds of this disclosure and the intermediates produced therefrom are considered part of this disclosure. When preparing enantiomer or diastereomer products, they can be separated by conventional methods, such as chromatography or fractional crystallization. Depending on the process conditions, the final products of the Disclosure may be obtained in either a free (neutral) or salt form. Both the free and salt forms of these final products are within the scope of the Disclosure. If desired, one form of a compound may be converted to another form. A free base or acid may be converted to a salt, a salt may be converted to a free compound or another salt, and a mixture of isomers of the Disclosure may be separated into individual isomers. The compounds of the Disclosure, their free forms, and salts may exist in multiple tautomeral forms in which hydrogen atoms are transposed to other parts of the molecule, resulting in a rearrangement of the chemical bonds between atoms of the molecule. It should be understood that all tautomeral forms are included in the Disclosure insofar as they may exist. As used herein, “the Compounds(s) of the Disclosure” means one or more compounds encompassed in either one of formulas (I) and (II), or their stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0101] As used herein, the terms “alkyl” or “alkylene” are intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. “Alkyl” refers to a monovalent saturated aliphatic radical (such as ethyl), while “alkylene” refers to a divalent saturated aliphatic radical (such as ethylene). For example, “C1~C 10 "Alkyl" or "C1- 10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to contain alkyl groups. "C1~C 10 "Alkilen" or "C 1-10 Alkilen is C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to contain an alkylene group. Furthermore, for example, "C1-C6 alkyl" or "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and is also known as "C1-C6 alkylene" or "C 1-6 "Alkylene" refers to an alkylene having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted with at least one hydrogen atom replaced by another chemical group. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to indicate a direct bond.

[0102] Unless otherwise indicated, the term “lower alkyl” as used herein, either alone or as part of another group, includes both linear and branched hydrocarbons containing 1 to 8 carbon atoms, and the terms “alkyl” and “alk” as used herein, either alone or as part of another group, include both linear and branched hydrocarbons containing 1 to 20 carbon atoms in the positive chain, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and their various branched isomers.

[0103] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms such as O, N, or S. For example, when the carbon atoms of an alkyl group bonded to the parent molecule are replaced by heteroatoms (e.g., O, N, or S), the resulting heteroalkyl groups are alkoxy groups (e.g., -OCH3), alkylamino groups (e.g., -NHCH3, -N(CH3)2), or thioalkyl groups (e.g., -SCH3), respectively. When the non-terminal carbon atoms of an alkyl group not bonded to the parent molecule are replaced by heteroatoms (e.g., O, N, or S), the resulting heteroalkyl groups are alkyl ethers (e.g., -CH2CH2-O-CH3), alkylaminoalkyl groups (e.g., -CH2NHCH3, -CH2N(CH3)2), or thioalkyl ethers (e.g., -CH2-S-CH3), respectively. When the terminal carbon atoms of an alkyl group are replaced by heteroatoms (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, hydroxyalkyl groups (e.g., -CH2CH2-OH), aminoalkyl groups (e.g., -CH2NH2), or alkylthiol groups (e.g., -CH2CH2-SH). Heteroalkyl groups can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C1-C6 heteroalkyl groups refer to heteroalkyl groups having 1 to 6 carbon atoms.

[0104] "Alkenyl" or "alkenylene" is intended to be a hydrocarbon chain having a specific number of carbon atoms, either in a linear or branched structure, and containing one or more, preferably 1-2, carbon-carbon double bonds that can occur at any stable point along the chain. "Alkenyl" represents a monovalent radical, while "alkenylene" represents a divalent radical. For example, "C2-C6 alkenyl" or "C 2-6 Alkenyls (or alkenylenes) are intended to contain C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyls include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3,pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

[0105] "Alkynyl" or "Alkynylene" is intended to represent a hydrocarbon chain having one or more, preferably 1 to 3, carbon-carbon triple bonds that can occur at any stable point along the chain, and having either a linear or branched structure. "Alkynyl" represents a monovalent radical, while "Alkynylene" represents a divalent radical. For example, "C2-C6 Alkynyl" or "C 2-6 "Alkynnyl" (or alkynylene) is intended to contain C2, C3, C4, C5, and C6 alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0106] As used herein, “arylalkyl” (also known as “aralkyl”), “heteroarylalkyl”, “carbocykylalkyl”, or “heterocyclylalkyl” refers to carbon atoms, typically terminal or sp. 3This refers to an acyclic alkyl radil in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl, heteroaryl, carbocykyl, or heterocyclyl radical. Typical arylalkyls include, but are not limited to, benzyl, 2-phenylethane-l-yl, naphthylmethyl, 2-naphthylethane-l-yl, naphthobenzyl, and 2-naphthophenylethane-l-yl. Arylalkyls, heteroarylalkyls, carbocykylalkyls, or heterocyclylalkyls can contain 4 to 20 carbon atoms and 0 to 5 heteroatoms; for example, the alkyl portion may contain 1 to 6 carbon atoms.

[0107] As used herein, the term "benzyl" refers to a methyl group in which one of its hydrogen atoms is replaced by a phenyl group, which can optionally be replaced by 1 to 5 groups, preferably 1 to 3 groups, such as -OH, -OCH3, Cl, F, Br, I, -CN, -NO2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -OCF3, -C(=O)CH3, -SCH3, -S(=O)CH3, -S(=O)2CH3, -CH3, -CH2CH3, -CO2H, and -CO2CH3. "Benzyl" can also be represented by the formula "Bn".

[0108] The terms "lower alkoxy," "alkoxy," "alkyloxy," "aryloxy," or "aralkoxy" refer to any of the alkyl, aralkyl, or aryl groups bonded to an oxygen atom. "C1-C6 alkoxy" or "C 1-6"Alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "lower alkylthio," "alkylthio," "thioalkoxy," "arylthio," or "aralkylthio" represent the alkyl, aryl, or aralkyl groups defined above, such as methyl-S- and ethyl-S-, having the indicated number of carbon atoms linked through a sulfur bridge.

[0109] As used herein, either alone or as part of another group, the terms “alkanoyl” or “alkylcarbonyl” refer to an alkyl group bonded to a carbonyl group. For example, an alkylcarbonyl may be represented by alkyl-C(O)-. “C1-C6 alkylcarbonyl” (or alkylcarbonyl) is intended to include C1, C2, C3, C4, C5, and C6 alkyl-C(O)- groups.

[0110] As used herein, either alone or as part of another group, the terms “alkylsulfonyl” or “sulfonamide” refer to an alkyl or amino group bonded to a sulfonyl group. For example, alkylsulfonyl may be represented as -S(O)2R' and sulfonamide as -S(O)2NR c R d It can be represented as follows: R' is a C1-C6 alkyl, and R c and R d This is the same as the definition of "amino" as follows:

[0111] As used herein, either alone or as part of another group, the term "carbamate" refers to an oxygen atom bonded to an amide group. For example, a carbamate is N(R c R d )-C(O)-O- can be expressed as R c and R d This is the same as the definition of "amino" as follows:

[0112] As used herein, either alone or as part of another group, the term "amide" refers to an amino group bonded to a carbonyl group. For example, an amide can be represented by N(R c R d )-C(O)-, where R c and R d are the same as those defined below for "amino".

[0113] The term "amino" is defined as -NR c1 R c2 , where R c1 and R c2 are independently H or C1-6 alkyl, or alternatively, R c1 and R c2 together with the atom to which they are attached form a 3- to 8-membered heterocyclic ring optionally substituted with one or more groups selected from halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, alkoxy, and aminoalkyl, etc. When R c1 or R c2 (or both of them) is C1-6 alkyl, the amino group can also be referred to as alkylamino. Examples of alkylamino groups include, but are not limited to, -NH2, methylamino, ethylamino, propylamino, isopropylamino, etc.

[0114] The term "aminoalkyl" refers to an alkyl group in which one of the hydrogen atoms is replaced by an amino group. For example, aminoalkyl can be represented by N(R c1 R c2 )-alkylene-. "C 1 ~C6" or "C 1~6 " aminoalkyl (or aminoalkyl) is intended to include C1, C2, C3, C4, C5, and C6 aminoalkyl groups.

[0115] As used herein, either alone or as part of another group, the terms “halogen” or “halo” refer to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred. “Haloalkyl” is intended to include both branched and linear saturated aliphatic hydrocarbon groups having a certain number of carbon atoms, substituted with one or more halogens. “C1-C6 haloalkyl” or “C 1-6 "Haloalkyl" (or "haloalkyl") is intended to include C1, C2, C3, C4, C5, and C6 haloalkyl groups. Examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyls also include "fluoroalkyls," which are intended to include both branched and linear saturated aliphatic hydrocarbon groups having a certain number of carbon atoms, substituted with one or more fluorine atoms. As used herein, the term "polyhaloalkyl" refers to a polyfluoroalkyl group, e.g., -CH2CF3, -CF3, or -CH2CF2CF3, which includes 2 to 9, preferably 2 to 5, halo substituents such as F or Cl, preferably F.

[0116] "Haloalkoxy" or "haloalkyloxy" refers to an ahaloalkyl group as defined above, having the indicated number of carbon atoms bonded through oxygen crosslinking. For example, "C1-C6 haloalkoxy" or "C 1-6"Haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents the haloalkyl group as defined above, having the indicated number of carbon atoms bonded through a sulfur bridge, e.g., trifluoromethyl-S- and pentafluoroethyl-S-. As used herein, the term "polyhaloalkyloxy" refers to the "alkoxy" or "alkyloxy" group as defined above, comprising 2 to 9, preferably 2 to 5, halo substituents such as F or Cl, preferably F, in polyfluoroalkyloxy groups such as -OCH2CF3, -OCF3, or -OCH2CF2CF3.

[0117] "Hydroxyalkyl" is intended to include both branched and straight saturated aliphatic hydrocarbon groups having a specific number of carbon atoms, substituted with one or more hydroxy(OH) groups. "C1-C6 hydroxyalkyl" (or hydroxyalkyl) is intended to include C1, C2, C3, C4, C5, and C6 hydroxyalkyl groups.

[0118] The term "cycloalkyl" refers to cycloalkyl groups, including monocyclic, bicyclic, or polycyclic ring systems. It can also refer to "C3-C7 cycloalkyl" or "C 3-7 The term "cycloalkyl" is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".

[0119] The term "cycloheteroalkyl" refers to cyclized heteroalkyl groups, including monocyclic, bicyclic, or polycyclic ring systems. It can also refer to "C3-C7 cycloheteroalkyl" or "C 3-7The term "cycloheteroalkyl" is intended to include C3, C4, C5, C6, and C7 cycloheteroalkyl groups. Exemplary cycloheteroalkyl groups include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. Branched cycloheteroalkyl groups such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyrididylmethyl, pyrimidylmethyl, and pyrazinylmethyl are included in the definition of "cycloheteroalkyl".

[0120] As used herein, the term "azacyryl" refers to a cycloheteralkyl group containing one or more nitrogen atoms in the ring. Exemplary azacyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

[0121] As used herein, “carbocyclic,” “carbocyrill,” or “carbocyclic formula” is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered polycyclic (including bicyclic or tricyclic) hydrocarbon ring, which may be saturated or partially unsaturated. That is, the terms “carbocyclic,” “carbocyrill,” or “carbocyclic formula” include, but are not limited to, cycloalkyl and cycloalkenyl compounds. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, indanyl, adamantyl, and tetrahydronaphthyl (tetralin). As shown above, cross-linked rings are also included in the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). Preferred carbocyclic rings, unless otherwise indicated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and tetrahydronaphthyl. A bridged ring occurs when one or more carbon atoms, preferably 1 to 3, bond to two non-adjacent carbon atoms. A preferred bridge consists of one or two carbon atoms. It should be noted that bridges always convert a monocyclic ring to a tricyclic ring. When a ring is bridged, the substituents listed for the ring may also be present in the bridge.

[0122] Furthermore, the terms "carbocyclyl," as used herein, either alone or as part of another group, include "cycloalkyl" and "cycloalkenyl," and encompass 1 to 3 rings of saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups, including monocyclic alkyl, bicyclic alkyl, and tricyclic alkyl groups, which comprise a total of 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, or 3 to 6 carbon atoms, and which form a ring and can be fused to 1 or 2 aromatic rings as described for aryl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, and cyclodecyl, cyclohexenyl.

[0123] [ka]

[0124] The group contains and any of the groups may be optionally substituted with any one to four substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamide, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol, and / or alkylthio, and / or alkyl substituents.

[0125] As used herein, the terms “bicyclic carbocyclic” or “bicyclic carbocyclic group” are intended to mean a stable nine- or ten-membered carbocyclic system consisting of two fused rings and carbon atoms. Of the two fused rings, one ring is a benzo ring fused to the second ring, and the second ring is a saturated or partially unsaturated five- or six-membered carbocyclic. The bicyclic carbocyclic group can be bonded to its pendant group at any carbon atom, resulting in a stable structure. The bicyclic carbocyclic groups described herein can be substituted at any carbon atom, provided that the resulting compound is stable. Examples of bicyclic carbocyclic groups include, but are not limited to, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0126] As used herein, the term “aryl” is used herein, either alone or as part of another group, to refer to monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons, including, for example, phenyl, naphthyl, anthracenyl, and phenantranyl. The aryl portion is well known and is described, for example, in Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). In one embodiment, the term “aryl” refers to monocyclic and bicyclic aromatic groups (such as phenyl or naphthyl containing 1-naphthyl and 2-naphthyl) containing 6 to 10 carbon atoms in the ring portion. For example, “C6 or C 10 "Aryl" or "C 6-10 "Aryl" refers to phenyl and naphthyl. Unless otherwise specified, "aryl," "C6 or C 10 "Aryl", "C 6-10 The "aryl" or "aromatic residue" may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, selected from -OH, -OCH3, F, Cl, Br, I, -CN, -NO2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -OCF3, -C(O)CH3, -SCH3, -S(O)CH3, -S(O)2CH3, -CH3, -CH2CH3, -CO2H, and -CO2CH3.

[0127] As used herein, the terms “heterocyclic,” “heterocyclyl,” or “heterocyclic group” are intended to mean stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 5-, 6-, 7-membered polycyclic (including bicyclic and tricyclic) heterocyclics that are saturated or partially unsaturated and contain a carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and include any polycyclic group in which any of the heterocyclic rings defined above is fused to a carbocyclic ring or an aryl (e.g., benzene) ring. That is, the terms “heterocyclic,” “heterocyclyl,” or “heterocyclic group” include non-aromatic ring systems such as heterocycloalkyls and heterocycloalkenyls. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N → O and S(O) p (wherein p is O, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H, or another substituent, if defined). The heterocyclic ring may be bonded to its pendant group with any heteroatom or carbon atom, resulting in a stable structure. The heterocyclic rings described herein may be substituted on the carbon or nitrogen atom if the resulting compound is stable. The nitrogen in the heterocyclic ring may be optionally quaternized. If the total number of S and O atoms in the heterocyclic ring is greater than 1, it is preferable that these heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in the heterocyclic ring is not greater than 1. Examples of heterocyclils include, but are not limited to, azetidinil, piperazinil, piperidinil, piperidonil, piperonil, pyranil, morpholinil, tetrahydrofuranil, tetrahydroisoquinolinil, tetrahydroquinolinil, morpholinil, and dihydroflo[2,3-b]tetrahydrofuran.

[0128] As used herein, the terms “bicyclic heterocycle” or “bicyclic heterocyclic group” are intended to mean a stable nine- or ten-membered heterocyclic ring system comprising two fused rings, consisting of a carbon atom and one, two, three, or four heteroatoms independently selected from the group consisting of N, O, and S. Of the two fused rings, one ring is a five- or six-membered monocyclic aromatic ring containing a five-membered heteroaryl ring, a six-membered heteroaryl ring, or a benzo ring, each fused to the second ring. The second ring is saturated, partially unsaturated, or unsaturated, and is a five- or six-membered monocyclic ring containing a five-membered heterocycle, a six-membered heterocycle, or a carbocyclic ring (except when the second ring is a carbocyclic ring, the first ring is not benzo). The bicyclic heterocyclic group can be bonded to its pendant group, which results in a stable structure, with any heteroatom or carbon atom. The bicyclic heterocyclic groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. If the total number of S and O atoms in the heterocycle exceeds 1, it is preferable that these heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in the heterocycle does not exceed 1. Examples of bicyclic heterocyclic groups include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanil, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

[0129] Bridged rings are also included in the definition of heterocycles. A bridged ring occurs when one or more atoms, preferably 1 to 3 atoms (i.e., C, O, N, or S), link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. Note that bridging always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, the substituents listed for the ring may also be present in the bridge.

[0130] As used herein, the term “heteroaryl” is intended to mean stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons containing at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, prinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanil, and benzodioxane. Heteroaryl groups may be substituted or unsubstituted. The nitrogen atom is either substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The nitrogen-sulfur heteroatom can optionally be oxidized (i.e., NO and S(O)). p (where p is 0, 1, or 2).

[0131] Examples of heteroaryls include acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzoxazolinil, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinil, carbazolyl, and 4a / / -carbazolyl.Carbolinyl, Chromanil, Clomenil, Synnolinil, Decahydroquinolinil, 2H,6H-1,5,2-Dithiadinyl, Furanil, Imidazolidinil, Imidazolinil, Imidazolyl, IH-Indazolyl, Imidazolopyridinil, Indrenyl, Indolinil, Indolidinil, Indolyl, 3H-Indolyl, Isatinoyl, Isobenzofuranil, Isochromanil, Isoindazolyl, Isoindolinil, Isoindolyl, Isoquinolinil, Isothiazolyl, Isothiazolopyridinil, Isoxa Zolyl, isoxazolopyridinyl, methylenedioxyphenyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxyndryl, pyrimidinyl, phenanthrolinyl, phenanthrolinyl, phenadinyl, phenothiazinyl, phenoxathiazinyl, pheno Xazadinyl, Phthalazinyl, Pteridinyl, Purinyl, Pyrazinyl, Pyrazolidinyl, Pyrazolinyl, Pyrazolopyridinyl, Pyrazolyl, Pyridadinyl, Pyridooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridinyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolidinyl, 2-Pyrrolidonyl, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4 / / -Quinolidinyl, Quinoxalinyl, Quinuclidinyl, Tetrazolyl, Tetrahydrofuranil, Tetrahydroisoquinolinyl, Tetrahydroquinol This includes, but is not limited to, linyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0132] Examples of 5-10 member heteroaryls include, but are not limited to, pyridinyl, furanil, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiadinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, lH-indazolyl, benzofuranil, benzothiofuranil, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxyindolyl, benzoxazolinil, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinil, octahydroisoquinolinil, isoxazolopyridinyl, quinazolinil, quinolinil, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5-6 member heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiadinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0133] Unless otherwise specified, "carbocyryl" or "heterocyclyl" refers to a carbon ring or heterocycle fused with one to three additional rings (e.g., aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl rings, e.g.,

[0134] [ka]

[0135] Includes, optionally, via available carbon atoms, hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfumyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, hetero They may be substituted with one, two, or three groups selected from loaryloxy, hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfumyl, arylsulfumylalkyl, arylsulfonylamino and arylsulfonaminocarbonyl, and / or alkyl substituents shown herein.

[0136] When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocykyl, heterocyclyl, aryl, and heteroaryl are used as part of another group, the number of carbon atoms and ring members is the same as that defined for the terms themselves. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio, etc., each independently contain the same number of carbon atoms as defined for the term "alkyl," such as 1 to 4 carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly, cycloalkoxys, heterocyclyloxys, cycloalkylaminos, heterocyclylaminos, aralkylaminos, arylaminos, aryloxys, aralkyloxys, heteroaryloxys, heteroarylalkyloxys, and so on each independently contain ring members that are the same as defined for the terms "cycloalkyl," "heterocyclyl," "aryl," and "heteroaryl," such as 3-6 members, 4-7 members, 6-10 members, 5-10 members, or 5 or 6 members.

[0137] By convention used in the art, the structural formulas used herein are

[0138] [ka]

[0139] Bonds shown through wavy or curved lines, such as those shown above, indicate bonds that are attachment points of a partial or substituent to the core or skeletal structure.

[0140] According to conventions used in this technical field,

[0141] [ka]

[0142] Wavy or winding bonds in structural formulas such as are used to indicate the stereocenter of carbon atoms where X', Y', and Z' are bonded, and both enantiomers are intended to be represented in a single figure. That is, structural formulas with such wavy bonds are,

[0143] [ka]

[0144] This indicates each of the enantiomers individually, as well as racemic mixtures thereof. When a wavy or serpentine bond is attached to a double bond (such as C=C or C=N), it includes cis- or trans- (or E- and Z-) geometric isomers, or mixtures thereof.

[0145] In this specification, where a carbocyclic or heterocyclic moiety can be bonded or otherwise linked to a specified substrate via different ring atoms without exhibiting specific bonding points, it should be understood that all possible points are intended, whether via carbon atoms or, for example, trivalent nitrogen atoms. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, and the term "thienyl" means 2- or 3-thienyl, and so on.

[0146] If it is shown that the bond to a substituent spans a bond connecting two atoms in the ring, then such substituent may be bonded to any atom on the ring. If substituents are enumerated without indicating the atoms to which such substituent is bonded in the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. A combination of substituents and / or variables is permissible only if such combination results in a stable compound.

[0147] Those skilled in the art will recognize that the substituents and other parts of the compounds of the present disclosure should be selected to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptable and stable pharmaceutical compositions. Compounds of the present disclosure having such stability are intended to be included within the scope of the present disclosure.

[0148] The term "counterion" is used to refer to negatively charged species such as chlorides, bromides, hydroxides, acetic acid, and sulfuric acid. The term "metal ion" refers to alkali metal ions such as sodium, potassium, or lithium, and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.

[0149] Where used herein, the term “substituted” means that at least one hydrogen atom (bonded to a carbon atom or heteroatom) is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. When the substituent is oxo (i.e., =O), two hydrogens are replaced on the atom. Oxo substituents are not present in the aromatic moiety. Where a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted by a carbonyl group or double bond, the carbonyl group or double bond is intended to be part of the ring (i.e., internal). A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). With respect to alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocykrill, and heterocyclyl, the term “substituted” means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, arylalkyl, heteroaryl, heteroarylalkyl, carbocykrill, and heterocyclyl, respectively, in which one or more hydrogen atoms bonded to either a carbon or a heteroatom are independently substituted with one or more nonhydrogen substituents.

[0150] In cases where nitrogen atoms (e.g., amines) are present on the compounds of this disclosure, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to yield other compounds of this disclosure. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide (NO) derivatives.

[0151] If any variable appears two or more times in any component or formula of a compound, its definition in each appearance is independent of its definition in all other appearances. Therefore, for example, if a group is shown to be substituted with 0, 1, 2, or 3 R groups, that group is either unsubstituted when substituted with 0 R groups, or substituted with up to 3 R groups, and in each appearance, R is selected independently of the definition of R.

[0152] Furthermore, combinations of substituents and / or variables are only permissible if such combinations result in stable compounds.

[0153] As used herein, the term “tautomer” refers to each of two or more isomers of a compound that exist together in equilibrium and are readily exchanged by the migration of atoms or groups within the molecule. For example, those skilled in the art will readily understand that 1,2,3-triazole exists in the two tautomer forms defined above.

[0154] [ka]

[0155] Therefore, this disclosure is intended to cover all possible tautomers, even if the structure shows only one of them.

[0156] The term "pharmaceutically acceptable" is used herein to mean these compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues, within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and in proportion to a reasonable benefit-to-risk ratio.

[0157] The compounds of this disclosure may exist as salts, which are also within the scope of this disclosure. Pharmaceutically acceptable salts are preferred. As used herein, “chemically acceptable salt” means a derivative of the disclosed compound that is modified by the parent compound to produce an acid or base salt thereof. Pharmaceutically acceptable salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof, generally in non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of preferred salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0158] If the compounds of this disclosure have, for example, at least one basic center, they can form acid addition salts. These can be formed, for example, using a strong inorganic acid such as a mineral acid, e.g., sulfuric acid, phosphoric acid, or hydrohalic acid; using an organic carboxylic acid such as an alkane carboxylic acid with 1 to 4 carbon atoms, e.g., unsubstituted or substituted, e.g., acetic acid substituted with a halogen as chloroacetic acid; saturated or unsaturated dicarboxylic acid, e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid; hydroxycarboxylic acid, e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acid (e.g., aspartic acid or glutamic acid or lysine or arginine); or an organic sulfonic acid such as an unsubstituted or substituted (C1-C4) alkyl or aryl sulfonic acid, e.g., an organic sulfonic acid such as methyl- or p-toluenesulfonic acid, substituted with a halogen. Corresponding acid addition salts can also be formed, optionally having an additionally present basic center. Compounds of the present disclosure having at least one acidic group (e.g., COOH) can also form salts with bases. Suitable salts having bases include, for example, alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, or magnesium salts; or salts having ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono, di, or tri lower alkylamines, such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine; or mono, di, or trihydroxy lower alkylamines, such as mono, di, or triethanolamine. Corresponding internal salts may be further formed. Also included are salts that are not suitable for pharmaceutically use but can be used, for example, for the isolation or purification of the free compounds of formulas (I) and (II) or their pharmaceutically acceptable salts.

[0159] Preferred salts of the compounds of formula (I) and formula (II) containing a basic group include monohydrochloride, bisulfate, methanesulfonate, phosphate, nitrate, or acetate.

[0160] Preferred salts of the compounds of formulas (I) and (II) containing an acid group include sodium salts, potassium salts, and magnesium salts, as well as pharmaceutically acceptable organic amines.

[0161] In addition, the compounds of this disclosure may have prodrug forms. Any compound that is converted in vivo to provide a bioactive agent is a prodrug within the scope and spirit of this disclosure. As used herein, the term “prodrug” encompasses both prodrugs based on carboxylic acid residues, i.e., “prodrug esters,” and prodrugs based on arginine mimetic moieties, i.e., “arginine mimetic prodrugs.” Such prodrugs are often preferably administered orally, as hydrolysis often occurs primarily under the influence of digestive enzymes. Parenteral administration may be used if the ester itself is active, or if hydrolysis occurs in the blood.

[0162] The compounds of the present disclosure contain a carboxyl group that can be hydrolyzed in the body to form a physiologically hydrolyzable ester that functions as a prodrug, i.e., a “prodrug ester,” by producing the compounds of the present disclosure themselves. Examples of physiologically hydrolyzable esters of the compounds of the present disclosure include C1-C6 alkyl, C1-C6 alkylbenzy 1, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6 alkanoyloxy, C1-6 alkyl (e.g., acetoxymethyl, pivaloyloxymethyl, or propionyloxymethyl), C1-C6 alkoxycarbonyloxy-C1-C6 alkyl (e.g., methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3 dioxolen-4-yl)-methyl), and other well-known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin fields. Such esters can be prepared by conventional techniques known in the art. “Prodrug esters” can be formed by reacting the carboxylic acid moiety of the compounds of this disclosure with an alkyl or aryl alcohol, halide, or sulfonate using procedures known to those skilled in the art. Furthermore, various forms of prodrugs are well known in the art. Examples of such prodrug derivatives are described below. Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al, eds., Methods in Enzymology, 112:309-396, Academic Press (1985). Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, Krosgaard-Larsen, P. et al, eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991), Bundgaard, H., Adv.DrugDeliv.Rev.,8:1-38(1992), Bundgaard, H. et al., J Pharm. Sci., 77:285 (1988), and See Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

[0163] The preparation of prodrugs is well known in the art and is described, for example, in King, FD, ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999); and Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587, (2018).

[0164] This disclosure is intended to include all isotopes of the atoms appearing in the compound. Isotopes include these atoms that have the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium (symbol D or 2 H) and tritium (symbol T or 3 It contains H). The isotopes of carbon include: 13 C and 14The compound contains C. The isotope-labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described herein, using appropriate isotope-labeling reagents instead of unlabeled reagents used in other methods. Such compounds have a variety of potential uses, for example, as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to a target protein or receptor, or for imaging the compounds of this disclosure that bind to biological receptors in vivo or in vitro.

[0165] "Stable compound" and "stable structure" mean a compound that is robust enough to withstand isolation from a reaction mixture to a usable purity and formulation into an effective therapeutic agent. The compounds of this disclosure preferably do not contain N-halo, S(O)2H, or S(O)H groups.

[0166] The term “solvate” means the physical association of a compound of this disclosure with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. Solvent molecules in a solvate may exist in regular and / or unordered arrangements. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. “Solvate” encompasses both the solution phase and the separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanelates, and isopropanolates. Methods of solvation are known in the art.

[0167] The abbreviations used herein are defined as follows: "1×" means once, "2×" means twice, "3×" means three times, "℃" means Celsius temperature, "eq" means equivalent (plural), "g" means grams (plural), "mg" means milligrams (plural), "L" means liters (plural), "mL" means milliliters (plural), "pL" means microliters (plural), "N" means normal, "M" means mole, "mmol" means millimoles (plural), "min" means minutes (plural), "h" means hours (plural), "rt" means room temperature, "RBF" means round-bottom flask, "atm" means atmospheric pressure, "psi" means pounds per square inch, "cone." means concentrated, "RCM" means ring-closed metathesis, "sat" or "sat'd" means saturated, "SFC" means supercritical fluid chromatography, "MW" means molecular weight, "mp" means melting point, "ee" means enantiomer excess, "MS" or "Mass "Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LCMS" is liquid chromatography mass spectrometry, "HPLC" is high-pressure liquid chromatography, "RP HPLC" is reversed-phase HPLC, "TLC" or "tic" is thin-layer chromatography, "NMR" is nuclear magnetic resonance spectroscopy, "nOe" is nuclear Oberhauser effect spectroscopy, "1H" is proton, "δ" is delta, "s" is singleline, "d" is doubleline, "t" is tripleline, "q" is quadrupline, "m" is multiline, "br" is broad, "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical notations well known to those skilled in the art.

[0168] Abbreviation The following abbreviations are used in the schemes, examples, and elsewhere in this specification.

[0169] [Table 1-1]

[0170] [Table 1-2]

[0171] [Table 1-3]

[0172] [Table 1-4]

[0173] Preparation method The compounds of this disclosure can be prepared by several methods well known to those skilled in the art of organic synthesis, using the methods described below, along with synthetic methods known in the field of synthetic organic chemistry or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated herein by reference in their entirety. The reactions are carried out in a solvent or solvent mixture that is appropriate for the reagents and materials used and suitable for the transformations being affected. It will be understood by those skilled in organic synthesis that the functionalities present in the molecules should be consistent with the proposed transformations. This sometimes requires judgment to change the order of the synthetic steps or to choose one particular process scheme over another in order to obtain the desired compounds of this disclosure. Restrictions on substituents that are suitable for the reaction conditions will be readily apparent to those skilled in the art, and alternative methods should then be used. It will also be recognized that another major consideration in planning any synthetic route in this art is the wise selection of protecting groups used to protect the reactive functional groups present in the compounds described herein. A particularly useful overview of synthetic methods applicable to the preparation of the compounds disclosed herein can be found in Larock, RC, Comprehensive Organic Transformations, VCH, New York (1989).

[0174] The compounds of this disclosure may be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents suitable for the reagents and materials used and are suitable for the transformations to be performed. It should also be understood that in the descriptions of the synthetic methods described below, all proposed reaction conditions, including the solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedure, are selected to be standard conditions for the reaction, readily recognizable to those skilled in the art. Those skilled in the art in organic synthesis understand that the functionalities present in various parts of the indicator molecule must be compatible with the proposed reagents and reactions. Not all compounds of formula (I) or formula (II) belonging to a given class may be compatible with some of the reaction conditions required in some of the methods described. Such limitations on substituents compatible with the reaction conditions are readily apparent to those skilled in the art, and alternative methods should be used. A particularly useful outline of synthetic methods that may be applicable to the preparation of the compounds of this disclosure can be found in Larock, RC, Comprehensive Organic Transformations, VCH, New York (1989).

[0175] General scheme The compounds of this disclosure represented by formulas (I) and (II), or any subgenus or species thereof, can be prepared according to the general routes shown in schemes 1 to 4 below.

[0176] Scheme 1

[0177] [ka]

[0178] Scheme 1 describes a method for preparing the compound of formula I. Intermediate 1, which is commercially available or readily synthesized by methods known in the literature, can be combined with intermediate 2 by reductive amination using reagents such as sodium borocyanohydride and acetic acid in a suitable solvent such as methanol to obtain intermediate 3. Amide coupling of amine intermediate 3 with carboxylic acid 4 can be achieved by several possible conditions, including but not limited to treatment of 4 with oxalyl chloride in DCM, to produce an acyl chloride, which can then be reacted with amine 3 in the presence of triethylamine in DCM to obtain an amide of type 5. Staudinger reduction of 5 using a suitable phosphine such as tributylphosphine in a solvent such as toluene can yield a heteroarylamine, which can be cyclized under acidic conditions including but not limited to aqueous TFA in THF to obtain diazepine dione 6. Hydrolysis of the ester is R 5 Depending on its properties, this can be achieved under acidic or basic conditions. 5 If is t-butyl, hydrolysis can be achieved using conditions including, but not limited to, diluting TFA in dichloromethane at a suitable temperature and time to yield the desired carboxylic acid 7. Amide coupling of amine intermediate 8 and carboxylic acid 7 can be achieved through several possible conditions including, but not limited to, the use of a coupling reagent such as HATU or CMPU with a base such as triethylamine or a Hünig base in a solvent such as THF, dichloromethane, or DMF at a suitable temperature and time to yield the desired amide product I.

[0179] Scheme 2 [ka]

[0180] Scheme 2 describes an alternative method for preparing the compound of formula I. The amide coupling of amine intermediate 8 and carboxylic acid 9 can be achieved through several possible conditions, including but not limited to the use of a coupling reagent such as HATU or CMPU with a base such as triethylamine or a Hünig base in a solvent such as THF, dichloromethane, or DMF, at a suitable temperature and time to yield the desired amide product 10. Both 8 and 9 are commercially available and readily prepared by methods known in the literature or by those skilled in the art. The preparation of aldehyde 11 can be achieved in a two-step process, the first step being the vinylization of 10 by means of metal-mediated coupling with a reagent such as tributyl(vinyl)tin in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(O) in a solvent such as DMF. The oxidative cleavage of the resulting olefin can be achieved via the use of reagents such as but not limited to OsO4 and NaIO4 in a THF / water mixture or another suitable solvent system to obtain aldehyde intermediate 11. Intermediate 11 can be combined with intermediate 2 via reductive amination using reagents such as sodium borocyanohydride and acetic acid in a suitable solvent such as methanol to obtain intermediate 12. Amide coupling of amine intermediate 12 with carboxylic acid 4 can be achieved through several possible conditions, including but not limited to treatment of 4 with oxalyl chloride in DCM, to produce an acyl chloride, which can then be reacted with amine 12 in the presence of triethylamine in DCM to obtain an amide of type 13. Staudinger reduction of 13 with a suitable phosphine such as tributylphosphine in a solvent such as toluene yields a heteroarylamine, which can be cyclized under various conditions, including but not limited to basic, Lewis acidic, or acidic conditions such as aqueous TFA in THF, to obtain the desired diazepine dione compound I.

[0181] Scheme 3

[0182] [ka]

[0183] Scheme 3 illustrates a method for preparing the compound of formula II. Amino compound 3 (the preparation described in Scheme 1), which is commercially available or can be readily prepared by one of ordinary skill in the art, and carboxylic acid 14 can be coupled through several possible conditions including, but not limited to, treatment of 14 with oxalyl chloride in DCM to produce an acyl chloride, which can then be reacted with amine 3 in the presence of triethylamine in DCM to obtain an amide of type 15. Staudinger reduction of 15 with a suitable phosphine such as tributylphosphine in a solvent such as toluene produces a heteroaryl amine, which can be cyclized under various conditions including, but not limited to, basic, Lewis acidic, or acidic conditions such as aqueous TFA in THF to obtain diazepinedione intermediate 16. Hydrolysis of the ester can be achieved under acidic or basic conditions depending on the nature of R 5 and can be achieved using conditions including, but not limited to, diluting TFA in dichloromethane at a suitable temperature and for a time that provides the desired carboxylic acid 17 when R 5 is t-butyl. Amide coupling of amine intermediate 8 and carboxylic acid 17 can be achieved through several possible conditions including, but not limited to, using a coupling reagent such as HATU or CMPU with a base such as triethylamine or Hunig's base in a solvent such as THF, dichloromethane, or DMF at a suitable temperature and for a time that provides the desired amide product II.

[0184] Scheme 4

[0185]

Chemical formula

[0186] Scheme 4 describes alternative methods for preparing the compound of formula II. A commercially available amino compound 12 (the preparation described in Scheme 2) and a carboxylic acid 14, which are readily available or readily prepared by those skilled in the art, can be coupled through several possible conditions, including but not limited to treatment of 14 with oxalyl chloride in DCM, to produce an acyl chloride, which can then be reacted with amine 12 in the presence of triethylamine in DCM to obtain an amide of type 18. Staudinger reduction of 15 with a suitable phosphine, such as tributylphosphine, in a solvent such as toluene, produces a heteroarylamine, which can be cyclized under various conditions, including but not limited to basic, Lewis acidic, or acidic conditions such as aqueous TFA in THF, to obtain the desired diazepine dione compound II.

[0187] Int2 composition

[0188] [ka]

[0189] Synthesis of (R)-methyl2-amino-3-(pyridine-2-yl)propanoate·2HCl(2): A solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(pyridine-2-yl)propanoic acid (1, 50 g, 188 mmol) in methanol (500 mL) was cooled to 0°C, and TMSCl (120 mL, 939 mmol) was slowly added at the same temperature. The reaction mixture was stirred for 16 hours and monitored by LC-MS, indicating the consumption of the starting materials. The solvent was removed under reduced pressure, the crude product was pulverized with diethyl ether (2 × 100 mL), and the solid was dried under vacuum to obtain (R)-methyl2-amino-3-(pyridine-2-yl)propanoate·2HCl (2, 46 g, 97%) as a white solid. LCMS(ES) m / z=181.00[M+1] + ; 1H NMR(400MHz,DMSO-d6) δ 3.62(t,J=6.8Hz,2H) 3.66(s,3H),4.62-4.72(m,1H),7.77(t,J=6.0Hz,1H),7.90(d,J=7.6Hz,1H),8.34(t,J=7.6Hz,1H),8.73(d,J=4.8Hz,1H),8.98(br s,3H).

[0190] [ka]

[0191] Synthesis of tert-butyl 2-chloro-4-formylbenzoate (4): A solution of 4-bromo-2-chlorobenzoic acid (3, 50 g, 212 mmol) in THF (500 mL) was cooled to 0°C and treated with TEA (44.4 mL, 319 mmol) and DMAP (7.78 g, 63.7 mmol), and the reaction mixture was stirred for 10 minutes. Then, Boc2O (58.5 mL, 255 mmol) was slowly added at the same temperature (gas release was observed), and stirring was continued at room temperature for 16 hours. The reaction was monitored by TLC and quenched with water. The reaction mixture was extracted with ethyl acetate (2 × 500 mL), the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Next, the crude product was purified by flash silica gel column chromatography using 2-3% ethyl acetate in hexane to elute the product, yielding tert-butyl 4-bromo-2-chlorobenzoate (4, 51 g, 82%) as a yellow liquid. LCMS(ES): No ionization; 1 H NMR(400MHz,DMSO-d6) δ 1.53(s,9H),7.64-7.69(m,2H),7.83(s,1H).

[0192] Synthesis of tert-butyl 2-chloro-4-formylbenzoate (5): A solution of tert-butyl 4-bromo-2-chlorobenzoate (4, 50 g, 171 mmol) was dissolved in anhydrous THF (500 mL) and cooled to -70°C using dry ice acetone. A solution of DMF (16 mL, 206 mmol) in THF (66 mL) was prepared and cooled to -10°C. BuLi (82.3 mL, 206 mmol) was slowly added to the previous solution little by little (10 mL each) while maintaining a temperature below -65°C, and the reaction mixture was stirred for 5 minutes, followed by the addition of DMF solution (8 mL). The addition was continued until all BuLi had been added, and finally the excess DMF (20 mL) was added to the reactant at -65°C. The reactant was then stirred for a further 30 minutes, then quenched with ammonium chloride solution, and ethyl acetate (500 mL) was added. The organic layer was separated, the aqueous layer was back-extracted with ethyl acetate (2 × 500 mL), the combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography using 3-4% ethyl acetate in hexane to elute the product, yielding tert-butyl 2-chloro-4-formylbenzoate (5, 20 g, 48%) as a yellow liquid. LCMS(ES): No ionization; 1 H NMR(400MHz,DMSO-d6) δ 1.56(s,9H),7.86(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),8.03(s,1H),10.03(s,1H).

[0193] Synthesis of (R)-tert-butyl2-chloro-4-(((1-methoxy-1-oxo-3-(pyridine-2-yl)propan-2-yl)amino)methyl)benzoate (Int2): A solution of (R)-methyl2-amino-3-(pyridine-2-yl)propanoate (2, 7.33 g, 29.1 mmol) in methanol (75 mL) was cooled to 0°C, TEA (8.18 mL, 58.2 mmol) was added, and the mixture was stirred for 15 minutes, after which tert-butyl2-chloro-4-formylbenzoate (5, 7.0 g, 29.0 mmol) was added. The reaction mixture was stirred for 1 hour to obtain a clear solution. Then, NaCNBH3 (2.19 g, 34.9 mmol) was added and the reaction mixture was stirred for 15 minutes. Subsequently, AcOH (1.33 mL, 23.3 mmol) was added, and the reaction mixture was stirred for 25-30 minutes and monitored by TLC. The reaction mixture was quenched by adding NaHCO3 solution, and the solvent was removed under reduced pressure. Ethyl acetate and water were added to the mixture, and the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography using 35-40% ethyl acetate in hexane to obtain (R)-tert-butyl 2-chloro-4-(((1-methoxy-1-oxo-3-(pyridine-2-yl)propan-2-yl)amino)methyl)benzoate (Int2, 5.6g, 48%) as a pale yellow liquid. LCMS(ES) m / z=405.32[M+1] + ;Chiral HPLC purity 96:4 [CHIRALPAK IB N-5(4.6X250)mm,5μ,0.1% DEA in n-Hexane / EtOH= 60:40(v / v), flow rate 1mL / min]; 1¹H NMR (400MHz, DMSO-d6) δ 1.53(s,9H),2.82-2.92(m,1H),2.95-3.10(m,2H),3.57(s,3H),3.60-3.67(m,1H),3.76-3.86(m,1H),7.16-7.22(m,4H),7.56(d,J=8.0Hz,1H),7.69(t,J=7.6Hz,1H),8.45(s,1H). Note: Racemization was observed when the reaction mixture was stirred for more than 30 minutes after the addition of acetic acid.

[0194] Example 1 General method A

[0195] [ka]

[0196] Synthesis of methyl 3-azidothiophene-2-carboxylate (7): To a solution of methyl 3-aminothiophene-2-carboxylate (6, 10.0 g, 63.6 mmol) in HCl (50 mL) and water (50 mL), NaNO2 (6.58 g, 95.4 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. The mixture was filtered to remove the solid, the mother liquor was cooled to 0°C, and then NaN3 (5.0 g, 76.3 mmol) was added at 0°C. The mixture was stirred for 30 minutes, and the precipitated solid was filtered. The solid was then dissolved in ethyl acetate, dried on anhydrous sodium sulfate, filtered, concentrated to obtain a solid, pulverized with pentane, and dried under vacuum to obtain methyl 3-azidothiophene-2-carboxylate (7, 9.5 g, 81%) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6) δ 3.78(s,3H),7.15(d,J=5.6Hz,1H),7.93(d,J=5.6Hz,1H).

[0197] Synthesis of 3-azidothiophene-2-carboxylic acid (8): A solution of lithium hydroxide monohydrate (LiOH·H2O, 6.18 g, 147 mmol) in water (10 mL) was added dropwise to a solution of methyl 3-azidothiophene-2-carboxylate (7, 9.0 g, 49.1 mmol) in THF (45 mL) and methanol (45 mL) at room temperature. The reaction mixture was stirred for 16 h until TLC indicated consumption of the starting material. The solvent was removed under reduced pressure, then water (5 mL) was added, followed by addition of HCl to adjust the pH to about 2 - 3. The precipitated solid was filtered, redissolved in ethyl acetate, dried over anhydrous sodium sulfate, concentrated to give a solid, triturated with pentane, and dried under vacuum to afford 3-azidothiophene-2-carboxylic acid (8, 8.0 g, 96%) as a white solid. Note: The solid should be dried appropriately to remove moisture before proceeding to the next step. 1 H NMR (400 MHz, DMSO-d6) δ 7.07 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 5.6 Hz, 1H), 13.24 (br s, 1H).

[0198] Synthesis of 3-azidothiophene-2-carbonyl chloride (9): Oxalyl chloride (3.0 mL, 35.5 mmol) was added to a mixture of 3-azidothiophene-2-carboxylic acid (8, 4.0 g, 23.6 mmol) in dichloromethane (40 mL) at 0 °C, followed by addition of 2 drops of dimethylformamide. The reaction mixture was then stirred at room temperature for 2 h until TLC indicated consumption of the starting material. Volatiles were removed under reduced pressure and the crude product was dried under high vacuum to afford 3-azidothiophene-2-carbonyl chloride (9, 4.0 g, 90%) as a reddish-brown solid, which was used directly in the next step.

[0199] Synthesis of (R)-tert-butyl 4-((3-azido-N-(1-methoxy-1-oxo-3-(pyridine-2-yl)propan-2-yl)thiophene-2-carboxamide)methyl)-2-chlorobenzoate (10): A solution of Int2 (4.0 g, 9.88 mmol) in dichloromethane (40 mL) was cooled to 0°C, DIPEA (2.60 mL, 14.8 mmol) was added, and the mixture was stirred for 10 minutes. A solution of 3-azidothiophene-2-carbonyl chloride (9, 2.22 g, 11.9 mmol) in dichloromethane (10 mL) was slowly added at the same temperature. The reaction was monitored by TLC, and consumption of the starting materials was shown after 45 minutes. The reaction was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by flash silica gel column chromatography using 40-50% ethyl acetate in hexane. The fraction containing the product was concentrated to obtain a solid, which was pulverized with pentane and dried under vacuum to obtain (R)-tert-butyl 4-((3-azido-N-(1-methoxy-1-oxo-3-(pyridine-2-yl)propan-2-yl)thiophen-2-carboxamide)methyl)-2-chlorobenzoate (10, 5.0 g, 91%) as a yellowish liquid. LCMS(ES) m / z=556.38[M+1] + ; 1 H NMR(400MHz,DMSO-d6) δ 1.56(s,9H),3.32-3.50(m,2H),3.63(s,3H),4.30-5.50(m,3H),7.00-7.33(m,4H),7.39(s,1H),7.57(d,J=8.0Hz,1H),7.67(br s,1H),7.76(br s,1H),8.42(br s,1H).

[0200] Synthesis of (R)-tert-butyl 2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)benzoate (11): Tributylphosphene (2.66 g, 10.7 mmol) was added to a solution of (R)-tert-butyl 4-((3-azido-N-(1-methoxy-1-oxo-3-(pyridine-2-yl)propan-2-yl)thiophene-2-carboxamide)methyl)-2-chlorobenzoate (10, 5.0 g, 8.9 mmol) in toluene (50 ml) at room temperature, and the mixture was stirred at 70°C for 16 hours. After consuming the starting material confirmed by TLC, the solvent was removed under reduced pressure to obtain the crude product. Next, the crude product was dissolved in THF (50 mL) and water (5 mL) and treated with TFA (5 mL) at room temperature. The mixture was stirred for 12 hours, then quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography, eluting the product with 80-90% ethyl acetate in hexane, to obtain (R)-tert-butyl 2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)benzoate (11, 4.0 g, 89%) as a grayish-white solid. LCMS(ES) m / z=498.26[M+1] + 1 H NMR(400MHz,DMSO-d6) δ 1.53(s,9H),2.90-3.12 and 3.40-3.50(m,2H),3.80-5.20(m,3H),6.80-6.90(m,1H),7.00-7.30( m,3H),7.34(s,1H),7.61(d,J=7.6Hz,1H),7.67(t,J=7.2Hz,1H),7.89(d,J=5.2Hz,1H),8.43(br s,1H),11.12(br s,1H).

[0201] Synthesis of (R)-2-chloro-4-(((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)benzoic acid (12): (R)-tert-butyl2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)benzoate (11, 4.0g, 8.03) in dichloromethane (40mL) A solution of mmol) was cooled to 0°C, followed by the addition of TFA (4 mL). The reaction mixture was then stirred for 2 hours, and TLC showed the consumption of the starting material. The solvent was then removed under reduced pressure, and the mixture was pulverized with diethyl ether (2 × 25 mL) to obtain (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)benzoate TFA salt (12, 4.0 g, 100%) as a grayish-white solid. LCMS(ES) m / z=441.92[M+1] + Chiral HPLC purity 96:4 [ChiralPak IG(4.6X250)mm, 5μ Mobile phase: 0.2% TEA (60:40) in CO2 / MeOH, flow rate 3 mL / min. 1 H NMR(400MHz,DMSO-d6) δ 3.00-3.20 and 3.50-3.70(m,2H),4.10-5.15(m,3H),6.80-6.90(br s,1H),7.20-7.65(m,4H),7.70(d,J=8.0Hz,1H),7.90(d,J=5.2Hz,1H),7.93-8.05(m,1H),8.54(d,J=4.8Hz,1H),11.18(br s,1H),13.20(br s,1H).

[0202] Synthesis of (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide (Example 1): A solution of (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)benzoic acid TFA salt (12, 2.9 g, 6.56 mmol) in THF (30 mL) was stirred for 10 minutes, then cooled to 0°C, treated with DIPEA (3.5 mL, 19.68 mmol), and stirred for 15 minutes, after which a clear solution was observed. Next, HATU (3.74 g, 9.84 mmol) was added to the reaction at 0°C, and the cooling was removed after 10 minutes. The mixture was stirred at room temperature for 15 minutes, and a solution of 4-methoxy-2-aminopyridine (13, 0.98 g, 7.87 mmol) dissolved in THF (5 mL) was added. The reaction mixture was stirred at 70°C for 16 hours. After monitoring by TLC and LC-MS to confirm the completion of the reaction, the reaction mixture was cooled to room temperature, water was added, followed by ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was back-extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by flash silica gel column chromatography using 2-3% methanol in dichloromethane as the eluent to obtain (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepine-4(5H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide (Example 1, 2.6 g, 36%) as a white solid. The reaction was carried out twice on a 2.9 g scale, and both batches were combined and the compound purified to obtain the above yield. LCMS(ES) m / z=548.15[M+1] + (Purity 98.37%); Chiral HPLC purity 97.5:2.5 [CHIRALPAK IB N-5(4.6X250)mm, 5μ, CO2 / MeOH(0.2%TEA)(60:40), flow rate 3mL / min]. 1 H NMR(400MHz,DMSO-d6) δ 2.90-3.15 and 3.50-3.65(m,2H),3.84(s,3H),4.10-5.20(m,3H),6.75(dd,J=5.6 and 2.0Hz,1H),6.86(d,J=4.4Hz,1H),7.05-7.30(m ,3H),7.35(s,1H),7.47(d,J=8.0Hz,1H),7.70(t,J=7.2Hz,1H),7.79(s,1H),7.89(d,J=5.2Hz,1H),8.13(d,J=5.6Hz,1H),8.46(br s,1H),10.92(s,1H),11.14(br s,1H). Note: 1. Two to three purification steps are required to obtain a pure product. 2. The HATU complex of the acid is very stable and will persist during the reaction if the amine is less reactive. If the complex persists, the temperature can rise to 75-80°C.

[0203] Int6 composition

[0204] [ka]

[0205] Synthesis of 4-bromo-2-chloro-N-(4-methoxypyridine-2-yl)benzamide (15): To a solution of 4-bromo-2-chlorobenzoic acid (14, 30 g, 127 mmol) in THF (300 mL), DIPEA (49.4 g, 382 mmol) was added, followed by HATU (72.7 g, 191 mmol) at 0°C. The reaction mixture was stirred for 15 minutes, then 2-amino-4-methoxypyridine (13, 23.7 g, 191 mmol) was added, and the reaction mixture was heated at 75°C for 16 hours. After monitoring by TLC and completion, the reaction mixture was quenched with ice and stirred for 15 minutes. The precipitated solid was filtered, washed with water, and then the solid was dissolved in ethyl acetate and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was ground with pentane to obtain 4-bromo-2-chloro-N-(4-methoxypyridine-2-yl)benzamide (15, 40.0 g, 92%) as a grayish-white solid. LCMS(ES) m / z=341.16[M+1] + 1 ¹H NMR (400MHz, DMSO-d6): δ 3.85 (s, 3H), 6.78 (dd, J=5.6 and 2.4Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 7.63 (dd, J=8.0 and 1.6Hz, 1H), 7.79 (s, 1H), 7.83 (d, J=1.6Hz, 1H), 8.15 (d, J=5.6Hz, 1H), 11.02 (s, 1H).

[0206] Synthesis of 2-chloro-N-(4-methoxypyridine-2-yl)-4-vinylbenzamide (16): A solution of 4-bromo-2-chloro-N-(4-methoxypyridine-2-yl)benzamide (15, 38 g, 111 mmol) in DMF (200 mL) was treated with tributyl(vinyl)tin (38.8 g, 122 mmol), the mixture was degassed with argon for 10 minutes, and then tetrakis(triphenylphosphine)palladium (0) (6.43 g, 5.56 mmol) was added. The reaction mixture was further degassed with argon for 5 minutes and then heated at 110°C for 16 hours. The reaction mixture was monitored by TLC, and completion of the starting materials was indicated. The reaction mixture was cooled to room temperature and ethyl acetate was added. The solid was filtered on a Celite bed, the Celite bed was washed with ethyl acetate, the organic layer was separated, washed with water and brine, dried on anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography by eluting the product with 20-25% ethyl acetate in hexane. The solvent was removed under reduced pressure to obtain 2-chloro-N-(4-methoxypyridine-2-yl)-4-vinylbenzamide (16, 20 g, 62%) as a white solid. LCMS(ES) m / z=288.96[M+1] + 1 H NMR(400MHz,DMSO-d6) δ 3.85(s,3H),5.40(d,J=10.8Hz,1H),6.04(d,J=17.6Hz,1H),6.73-6.83(m,2H ),7.52(s,2H),7.65(s,1H),7.81(s,1H),8.15(d,J=5.6Hz,1H),10.95(s,1H).

[0207] Synthesis of 2-chloro-4-formyl-N-(4-methoxypyridine-2-yl)benzamide (17): To a solution of 2-chloro-N-(4-methoxypyridine-2-yl)-4-vinylbenzamide (16, 20 g, 69.3 mmol) in THF (50 mL) and water (50 mL), OsO4 (25 mL, 4% solution in water) was added at 0°C, and the reaction mixture was stirred for 2 hours. NaIO4 (44.4 g, 208 mmol) was slowly added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC and LCMS, and consumption of the starting materials was indicated. The reaction mixture was diluted with water (100 mL) and ethyl acetate (500 mL). The aqueous layer was back-extracted with ethyl acetate (2 × 200 mL), and the combined organic layers were washed with brine and dried on sodium sulfate. The solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting the product with 40-45% ethyl acetate in hexane. Nonpolar impurities (if present) were removed by grinding with diethyl ether, and the solid was dried under high vacuum to obtain 2-chloro-4-formyl-N-(4-methoxypyridine-2-yl)benzamide (17, 12.1 g, 60%) as a yellow solid. LCMS(ES) m / z=290.76[M+1] + 1 H NMR(400MHz,DMSO-d6) δ 3.86(s,3H),6.79(d,J=4.0Hz,1H),7.76(d,J=8.0Hz,1H),7.82(s,1H),7.92(d ,J=8.0Hz,1H),8.03(s,1H),8.16(d,J=5.6Hz,1H),10.04(s,1H),11.18(s,1H).

[0208] Synthesis of (R)-methyl 2-((3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)amino)-3-(pyridine-2-yl)propanoate (Int6): (R)-methyl 2-amino-3-(pyridine-2-yl)propanoate·2HCl (2, 3.72 g, 20.6 mmol) was dissolved in methanol (70 mL), and dichloromethane (30 mL) and triethylamine (7.5 mL) were added at 0°C. The mixture was stirred for 15 minutes, then 2-chloro-4-formyl-N-(4-methoxypyridine-2-yl)benzamide (17, 5.0 g, 17.2 mmol) was added, and the reaction was stirred for 45 minutes. NaCNBH3 (1.62 g, 25.7 mmol) was added gradually to the above reaction product over 5 minutes, the mixture was stirred for 10 minutes, and then acetic acid (1.0 g, 17.2 mmol) was added. Next, when the reaction product was stirred for 30 minutes, TLC showed that most of the starting material had been consumed, and the reaction product was quenched with NaHCO3 solution and water. Methanol was removed under reduced pressure, and then the mixture was extracted with ethyl acetate (2 × 200 mL), the organic layer was washed with brine, dried on anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography, eluting the product with 80-90% ethyl acetate in hexane, to obtain (R)-methyl 2-((3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)amino)-3-(pyridine-2-yl)propanoate (Int6, 4.0 g, 51%) as a yellow liquid. LCMS(ES) m / z=455.23[M+1] + Chiral HPLC purity 99.5:0.5 [Lux_Cellulose-2 (4.6 x 250 mm), 5 μl, 0.2% TEA (60:40) in CO2 / MeOH, flow rate 3 mL / min]. 1H NMR(400MHz,DMSO-d6) δ 2.80-2.90(m,1H),2.96-3.10(m,2H),3.59(s,3H),3.60-3.68(m,2H),3.80-3.83(m,1H),3.84(s,3H),6.76(dd,J=5.6 and 2.4Hz,1H),7. 17(d,J=8.0Hz,1H),7.20-7.30(m,3H),7.40(d,J=7.6Hz,1H),7.70(t,,J=7.6Hz,1H),7.80(s,1H),8.16(d,J=6.0Hz,1H),10.89(s,1H).

[0209] Example 2 General method B

[0210] [ka]

[0211] Synthesis of 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid (19): Compound 1 (100 g, 793 mmol, 1 eq) was gradually added at 25°C to a solution of HNO3 (55 g, 873 mmol, 1.10 eq) and H2SO4 (460 g, 4.60 mol, 250 mL, 98% purity, 5.80 eq). The resulting solution was stirred at 35°C for 1 hour. The reaction mixture was then heated to 75°C and stirred at 75°C for 2 hours. TLC showed that the starting materials were completely consumed. The reaction mixture was cooled to 25°C and poured into ice water (1.0 L). The resulting suspension was filtered, and the filter cake was rinsed with water (400 mL). The filter cake was dried under vacuum to obtain 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid (19, 90 g, 526 mmol, yield 66.3%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 3.95(s,3H),8.29(s,1H).

[0212] Synthesis of 1-methyl-4-nitro-1H-pyrazole-5-carbonyl chloride (20): A solution of 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid (19, 80 g, 468 mmol, 1 eq) and DMF (342 mg, 4.68 mmol, 360 uL, 0.01 eq) in SOCl2 (656 g, 5.51 mol, 400 mL, 11.8 eq) was stirred at 75°C for 12 hours. Samples were taken (quenched with MeOH) and subjected to TLC (petroleum ether:ethyl acetate = 0:1, 19 R f The R of compound 20 is 0.3. f The value (which was 1.0) indicated that the starting material had been completely consumed. The reactants were concentrated under vacuum to obtain 1-methyl-4-nitro-1H-pyrazole-5-carbonyl chloride (20, 89 g, crude) as a brown oil, which was used directly in the next step.

[0213] Synthesis of methyl(R)-2-(N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamide)-3-(pyridine-2-yl)propanoate (21): To a solution of Int-6 (224 g, 493 mmol, 1.05 eq) and NaOAc (116 g, 1.41 mol, 3 eq) in DCM (1.5 L), a solution of 1-methyl-4-nitro-1H-pyrazole-5-carbonyl chloride (20, 89 g, 470 mmol, 1 eq) in DCM (200 mL) was added dropwise at 25°C. The resulting solution was stirred at 25°C for 1 hour. LC-MS showed that the starting materials were completely consumed. The reaction mixture was poured into water (1.2 L). The organic phase was collected, and the aqueous phase was extracted with DCM (400 mL x 2). The combined organic phase was washed with water (2 L), dried on anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was dissolved in ELISA (1.5 L) at 25°C. The resulting solution was stirred at 10°C for 5 hours to obtain a brown suspension. The suspension was filtered, and the filter cake was rinsed with ELISA (200 mL). The filter cake was dried under vacuum to obtain methyl(R)-2-(N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamide)-3-(pyridine-2-yl)propanoate (21, 180 g, 296 mmol, yield 63.1%) as a grayish-white solid. LCMS(ES) m / z=608.3[M+H] + .

[0214] Synthesis of (R)-2-chloro-N-(4-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)benzamide (Example 2): Methyl (R)-2-(N-(3-chloro)benzamide in MeOH (1 L) and H2O (250 mL) Zn (96.8 g, 1.48 mol, 5 eq) was gradually added at 25°C to a solution of -4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamide)-3-(pyridine-2-yl)propanoate (21, 180 g, 296 mmol, 1 eq) and NH4Cl (127 g, 2.37 mol, 8 eq). The resulting suspension was stirred at 25°C for 3 hours. LC-MS showed that the starting materials were completely consumed. The reaction mixture was filtered through Celite. The filter cake was rinsed with THF (500 mL). The filtrate was concentrated under vacuum to obtain a yellow solid (170 g, crude). A solution of crude yellow solid (170g, 294 mmol, 1eq) in THF (1L) was stirred at 65°C for 12 hours. TLC (dichloromethane:methanol = 10:1, crude intermediate R f R is 0.5, and R in Example 2 f The ratio (0.75) indicated that the starting materials had been completely consumed. The reaction mixture was cooled to 25°C and filtered through Celite. The filter cake was rinsed with THF (300 mL). The filtrate was concentrated under vacuum to obtain the product as a yellow solid. The crude product was dissolved in ACN (400 mL). The resulting solution was poured into water (5 L) with stirring. The resulting suspension was filtered, and the filter cake was rinsed with water (500 mL). The filter cake was dried under vacuum to obtain (R)-2-chloro-N-(4-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)benzamide (Example 2, 135 g, 247 mmol, yield 71.5%) as a pale yellow solid. LCMS(ES) m / z=546.20[M+1]+ (Purity 96.80%); Chiral HPLC purity >99% [Lux Amylose-1 (4.6X250) mm, 5μ, mobile phase: CO2 / MeOH (0.2%TEA) (60:40), flow rate 3mL / min]. 1 ¹H NMR (400MHz, DMSO-d6) δ values: 2.85-3.25 and 3.56-3.68 (m, 2H), 3.84 (s, 3H), 4.04 and 4.06 (2 xs, 3H), 4.60-5.15 (m, 3H), 6.76 (dd, J=5.6 and 2.0Hz, 1H), 7.15-7.35 (m, 5H), 7.43-7.50 (m, 1H), 7.65-7.73 (m, 1H), 7.78 (s, 1H), 8.14 (d, J=6.0Hz, 1H), 8.38 and 8.48 (m, 1H), 10.49 and 10.66 (2 xs, 1H), 10.93 (s, 1H).

[0215] Example 3 General method C

[0216] [ka]

[0217] [ka]

[0218] Synthesis of 3-amino-5-chloropiccolinonitrile (23): To a solution of 5-chloro-3-nitropiccolinonitrile (22, 50 g, 0.273 mol) in acetic acid (250 mL) cooled to 0°C, iron powder (76.5 g, 1.36 mol) was slowly added little by little. The reaction mixture was then stirred for 2 hours, and TLC showed consumption of the starting materials. The reaction mixture was then filtered over a Celite bed, and the Celite bed was washed with methanol. The combined mother liquor was evaporated under reduced pressure, the crude product was dissolved in ethyl acetate, and then washed with sodium carbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 3-amino-5-chloropiccolinonitrile (26, 40.0 g, 96%) as a grayish-white solid.

[0219] Synthesis of 3-amino-5-chloropicolinic acid as HCl salt (24): A solution of 3-amino-5-chloropicolinonitrile (23, 40 g, 0.261 mol) in HCl (150 mL, 36% aqueous solution) was heated at 100°C for 16 hours. After confirmation by TLC, volatile substances were removed under reduced pressure to obtain 3-amino-5-chloropicolinic acid as the 2HCl salt (24, 58 g, 90%) as a brownish-green solid.

[0220] Synthesis of methyl 3-amino-5-chloropicolinate (25): To a solution of 3-amino-5-chloropicolinic acid as the HCl salt (24, 58 g, 0.237 mol) in DMF (600 mL), K2CO3 (98 g, 0.711 mol) was added at 0°C. The reaction mixture was stirred for 15 minutes, and then methyl iodide (67.3 g, 0.474 mol) was added at 0°C. The reaction mixture was then stirred for 12 hours, and the consumption of the starting materials was observed by monitoring with TLC and LCMS. The reaction mixture was quenched with water, extracted with ethyl acetate (3 × 600 mL), and the organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography eluting with 40-50% ethyl acetate in hexane to obtain methyl 3-amino-5-chloropicolinate (25, 32 g, 78%) as a pale yellow liquid.

[0221] Synthesis of methyl 3-azido-5-chloropicolinate (26): To a solution of methyl 3-amino-5-chloropicolinate (25, 32 g, 0.172 mol) in HCl (180 mL) and water (180 mL), NaNO2 (17.8 g, 0.258 mol) was added at 0°C, and the mixture was stirred for 30 minutes. The particles were removed by filtration, the mother liquor was cooled to 0°C, and then NaN3 (22.4 g, 0.344 mol) was added at 0°C. The mixture was stirred for 30 minutes, and the precipitated solid was filtered. The mother liquor was extracted with ethyl acetate (2 × 300 mL), the solid was dissolved in ethyl acetate, dried on anhydrous sodium sulfate, filtered, concentrated to obtain a solid, ground with pentane, and dried under vacuum to obtain methyl 3-azido-5-chloropicolinate (26, 28 g, 77%) as a grayish-white solid.

[0222] Synthesis of 3-azido-5-chloropicolinic acid (27): To a solution of methyl 3-azido-5-chloropicolinic acid (26, 28.0 g, 0.132 mol) in THF (140 mL) and methanol (140 mL), a solution of LiOH·H2O (22.2 g, 0.528 mol) in water (80 mL) was added, and the reaction mixture was stirred for 16 hours. After monitoring the reaction by TLC and confirming completion, the solvent was removed under reduced pressure, the crude product was dissolved again in water (100 mL), cooled to 0°C, and treated with HCl to adjust the pH to approximately 4-5. The mixture was stirred for 10 minutes, then extracted with ethyl acetate (3 × 300 mL), dried on anhydrous sodium sulfate, and the solvent was removed to obtain a solid. The solid was pulverized with pentane and dried under high vacuum to obtain 3-azido-5-chloropicolinic acid (27, 22.0 g, 84%) as a yellow solid.

[0223] Synthesis of 3-azido-5-chloropicolinoyl chloride (28): A solution of 3-azido-5-chloropicolinic acid (27, 6.0 g, 0.030 mol) in dichloromethane (50 mL) was added to oxalyl chloride (4.23 g, 0.33 mol) at 0°C, followed by the addition of 4 drops of dimethylformamide. The reaction mixture was then stirred at room temperature for 2 hours. TLC showed consumption of the starting materials, and the mixture was quenched with methanol. Volatile substances were removed under reduced pressure, and the crude product was dried under high vacuum to obtain 3-azido-5-chloropicolinoyl chloride (28, 6.2 g) as a reddish-brown solid, which was used in the next reaction without further purification.

[0224] Synthesis of (R)-methyl 2-(3-azido-5-chloro-N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)picolinamide)-3-(pyridine-2-yl)propanoate (29): A solution of (R)-methyl 2-((3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)amino)-3-(pyridine-2-yl)propanoate (Int6, 4.9g, 0.0108mol) in dichloromethane (40mL) was cooled to 0°C, DIPEA (2.8mL, 0.016 mmol) was added, and the mixture was stirred for 10 minutes. A solution of 3-azido-5-chloropicolinoyl chloride (28, 2.5g, 0.0115mol) in dichloromethane (5mL) was slowly added at the same temperature. The reaction was monitored by TLC, and consumption of the starting materials was observed after 45 minutes. The reaction was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then purified by flash silica gel column chromatography using 70-80% ethyl acetate in hexane. The fraction containing the product was concentrated to obtain a solid, which was ground with pentane and dried under vacuum to obtain (R)-methyl 2-(3-azido-5-chloro-N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)picolinamide)-3-(pyridine-2-yl)propanoate (29, 3.9 g, 57%) as a brown viscous liquid.

[0225] Synthesis of (R)-methyl 2-(3-amino-5-chloro-N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)picolinamide)-3-(pyridine-2-yl)propanoate (30): A solution of (R)-methyl 2-(3-azido-5-chloro-N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)picolinamide)-3-(pyridine-2-yl)propanoate (29, 3.9 g, 6.15 mmol) in toluene (35 mL) was treated with tributylphosphene (1.57 g, 7.38 mmol) at room temperature, and the mixture was stirred at 70°C for 16 hours. After consumption of the starting material confirmed by TLC, the solvent was removed under reduced pressure to obtain the crude product. Next, the crude product was dissolved in THF (10 mL) and water (5 mL), treated with TFA (3 mL) at room temperature, and stirred for 30 minutes. The solvent was removed under reduced pressure, and then the crude product was dissolved in aqueous NaHCO3 and ethyl acetate. The organic layer was separated, and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting the product with 75-85% ethyl acetate in hexane, to obtain (R)-methyl 2-(3-amino-5-chloro-N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)picolinamide)-3-(pyridine-2-yl)propanoate (30, 2.7 g, 72%) as a brown solid.

[0226] Synthesis of (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-pyrido[3,2-e][1,4]diazepine-4(5H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide (Example 3): Triethylamine (4 mL) was added to a solution of (R)-methyl2-(3-amino-5-chloro-N-(3-chloro-4-((4-methoxypyridine-2-yl)carbamoyl)benzyl)picolinamide)-3-(pyridine-2-yl)propanoate (30, 2.7 g, 4.44 mmol) in tert-butyl alcohol (4 mL). The reaction mixture was then heated at 100-120°C for 72 hours, and TLC and LCMS showed consumption of the starting material. Next, the mixture was cooled to room temperature, quenched with water (20 mL), and then extracted with ethyl acetate. The organic layer was separated, the aqueous layer was back-extracted with ethyl acetate (2 × 50 mL), the combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting the product with 2-5% methanol in ethyl acetate, to obtain 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-pyrido[3,2-e][1,4]diazepine-4(5H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide (Example 4 racemic, 0.80 g) as a grayish-white solid. Next, the compound was purified by chiral preparative HPLC to obtain the desired isomer, (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-pyrido[3,2-e][1,4]diazepine-4(5H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide (Example 3, 320 mg). LCMS(ES) m / z=577.21[M+1] +(Purity 95.08%); Chiral purity (95:5); Column name: Chiralpak IB N-5 (4.6 x 250 mm), 5 μm; Mobile phase: 0.2% TEA (60:40) in CO2 / MeOH; Flow rate: 3.0 mL / min; Flow mode: Homogeneous solvent; Column temperature: 35°C; ABPR pressure: 1500 psi; 1 H NMR(400MHz,DMSO-d6) δ 2.70-2.86,3.10-3.20 and 3.50-3.60(m,2H),3.85(s,3H),4.40-4.90(m,3H),6. 73(d,J=5.2Hz,1H),6.90-7.32(m,3H),7.35(s,1H),7.40-7.50(m,2H),7.60(br s,1H),7.75(s,1H),8.13(d,J=5.2Hz,1H),8.28(s,1H),8.36(br s,1H),10.52(br s,1H).

[0227] Characterization data Table 1 shows the characterization data for the selected cases and EC using the cell-based morphological assay protocol described below. 50 Includes value. EC 50 The values ​​are specified as A, B, or C, where A < 0.1 μM, B = 0.1 to 0.99 μM, C = 1.0 to 9.9 μM, and D = 10 to 20 μM.

[0228] [Table 2-1]

[0229] [Table 2-2]

[0230] [Table 2-3]

[0231] [Table 2-4]

[0232] Table 2-5

[0233] Table 2-6

[0234] Table 2-7

[0235] Table 2-8

[0236] Table 2-9

[0237] Table 2-10

[0238] Table 2-11

[0239] Table 2-12

[0240] Table 2-13

[0241] Table 2-14

[0242] Table 2-15

[0243] Table 2-16

[0244] Table 2-17

[0245] Table 2-18

[0246] Table 2-19

[0247] Table 2-20

[0248] Table 2-21

[0249] Table 2-22

[0250] Table 2-23

[0251] Table 2-24

[0252] Table 2-25

[0253] Table 2-26

[0254] Table 2-27

[0255] Table 2-28

[0256] Table 2-29

[0257] Table 2-30

[0258] Table 2-31

[0259] Table 2-32

[0260] Table 2-33

[0261] Table 2-34

[0262] biology review The exemplary compounds described herein were tested using cell-based morphological assays, and the assay results, along with other analytical data, are reported in Table 1.

[0263] Details of cell-based assays: The compounds illustrated in this disclosure were tested using a Clostridium difficile toxin B morphological profiling assay, and the results, along with other analytical data, are reported in Table 1. Morphological results induced by human umbilical vein endothelial cells (HUVECs) exposed to TCdB were evaluated using an experimental protocol adapted from the patent reference Bray et al., Nat Protoc. 2016 Sep;11(9):1757-1774, and quantified using Recursion's proprietary image analysis method described in U.S. Patent No. 10,146,914. HUVECs (Lonza) were seeded on 1536-well microtiter plates (789866, Greiner bio-one) coated with PDL and collagen and incubated in EGM2 (Lonza) at 37C and a 5% CO2 atmosphere for 24 hours. After 24 hours of incubation, HUVEC cells were pretreated with compounds dissolved in DMSO and exposed to 5 ng / mL TCdB (ListLabs) using an Echo acoustic dispenser (Labcyte). After 24 hours following toxin exposure, the TCdB incubation was completed. Cells were then treated with Mitotracker Deep Red (Invitrogen), subsequently fixed in 2.6% PFA, permeabilized in TritonX-100 solution, and stained with solutions of Hoechst, ConA, Syto14, WGA, and phalloidin (all Invitrogen) in HBSS. Cells were then imaged, and the images were processed with Cell Profiler to extract cellular-level morphological features. A proprietary algorithm was then used to determine feature profiles associated with toxin exposure compared to healthy, unexposed cells. These profiles were used to define vectors evaluating all wells in the assay on a 0-1 scale (0 representing healthy, and 1 representing toxin treatment). The profiles from compound-treated toxin exposure are projected onto this axis to approximate the level of similarity between disease and health in the wells. The compound values ​​are then fitted to a four-parameter log-agonist response equation, and the EC (European Coherence) is calculated. 50 Calculate the value.

[0264] Other features of this disclosure will become apparent in the course of the above description of exemplary embodiments, but they are shown for illustrative purposes only and are not intended to limit the scope of this disclosure. This disclosure may be embodied in other specific forms without departing from its spirit or essential attributes. This disclosure encompasses all combinations of preferred embodiments of this disclosure as described herein. It should be understood that any and all embodiments of this disclosure may, in conjunction with other embodiments, describe additional embodiments. It should also be understood that each individual element of an embodiment is an independent embodiment in itself. Furthermore, it is intended that any element of an embodiment may be combined with any and all other elements from any embodiment to describe additional embodiments.

Claims

1. Compound of formula (I), 【Chemistry 1】 Or its stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate, wherein the formula, X １ , X ２ , and X ３ However, each operates independently, CR ２ , N, NR ５ , O, or S, X ４ and X ５ However, each is independently either C or N, m is an integer of 0, 1, or 2, Z is a 6-10 membered aryl, or a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S. R １ and R ２ are each independently hydrogen, halo, cyano, hydroxyl, amino, C １－６ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy, R ３ and R ４ However, each independently, hydrogen, C １－６ A 5-10 membered heteroaryl, 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from alkyl, alkylamino, haloalkyl, alkoxy, haloalkoxy, 6-10 membered aryl, N, O, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl independently contain 0-5 R ５ It has been replaced with, R ５ However, hydrogen, halo, cyano, hydroxyl, amino, C １－６ Alkyl, alkylamino, haloalkyl, hydroxyalkyl, hydroxycycloalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, or -C(O)OR ６ And, R ６ However, hydrogen or C １－６ Alkyl compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates. 【Request Item 2】 【Chemistry 2】 The part, 【Transformation 3】 The compound, stereoisomer, tautomer, salt, or solvate described in claim 1.

3. R ３ However, it is hydrogen, R ４ but, 【Chemistry 4】 A compound, stereoisomer, tautomer, salt, or solvate according to claim 1 or 2, selected from such that m is an integer of 0, 1, or 2.

4. A compound, stereoisomer, tautomer, salt, or solvate according to claim 1, represented by formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or formula (If): 【Transformation 5】 。

5. R ３ However, it is hydrogen, R ４ but, 【Transformation 7】 The compound, stereoisomer, tautomer, salt, or solvate described in claim 1.

6. A compound represented by formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate, 【Chemistry 12】 、 During the ceremony, Y １ , Y ２ , and X ３ However, each operates independently, CR ２ or N, provided that at least one Y １ , Y ２ , and Y ３ However, N is, X ４ and X ５ However, each is independently either C or N, m is an integer of 0, 1, or 2, Z is a 6-10 membered aryl, or a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S. R １ and R ２ However, each is independent of hydrogen, halo, cyano, hydroxyl, amino, and C. １－６ Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy R ３ and R ４ However, each independently, hydrogen, C １－６ A 5-10 membered heteroaryl, 3-10 membered carbocyryl, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from alkyl, alkylamino, haloalkyl, alkoxy, or haloalkoxy, 6-10 membered aryl, N, O, and S, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the aryl, heteroaryl, carbocyryl, and heterocyclyl independently contain 0-5 R ５ It has been replaced with, R ５ However, hydrogen, halo, cyano, hydroxyl, amino, C １－６ Alkyl, alkylamino, haloalkyl, hydroxyalkyl, hydroxycycloalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, or -C(O)OR ６ And, R ６ However, hydrogen or C １－６ It is alkyl, The dashed circle is Y １ , Y ２ , Y ３ Compounds, stereoisomers, tautomers, salts, or solvates exhibiting aromatic rings formed by carbon atoms. 【Request Item 7】 【Chemistry 13】 The part, 【Chemistry 14】 The compound, stereoisomer, tautomer, salt, or solvate described in claim 6.

8. R ３ However, it is hydrogen, R ４ but, 【Chemistry 15】 A compound, stereoisomer, tautomer, salt, or solvate according to claim 6 or 7, selected from, where m is an integer of 0, 1, or 2.

9. R ３ However, it is hydrogen, R ４ but, 【Chemistry 16】 The compound, stereoisomer, tautomer, salt, or solvate described in claim 6.

10. A compound, stereoisomer, tautomer, salt, or solvate according to claim 6, represented by formula (IIa), formula (IIb), formula (IIc), or formula (IId). 【Chemistry 17】 【Request Item 11】 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 A compound, stereoisomer, tautomer, salt, or solvate according to claim 1, selected from the above. 【Request Item 12】 【Chemistry 12-1】 A compound, stereoisomer, tautomer, salt, or solvate according to claim 6, selected from the above.

13. (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; (R)-2-chloro-N-(4-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)benzamide; (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((7-methyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methylpyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(1H-pyrrolo[2,3-c]pyridine-5-yl)benzamide; (R)-2-chloro-N-(4-cyclopropylpyridine-2-yl)-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)benzamide; (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(1H-pyrrolo[3,2-c]pyridine-6-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(6-methoxypyrimidine-4-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(imidazo[1,2-a]pyrazine-8-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(imidazo[1,5-a]pyrazine-8-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(1H-pyrazolo[3,4-c]pyridine-5-yl)benzamide; 2-Chloro-N-(4-cyclopropoxypyridine-2-yl)-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridazine-3-yl)benzamide; 4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-3-fluoro-N-(pyridine-2-yl)benzamide; 4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-3-fluoro-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-N-(4-(difluoromethoxy)pyridine-2-yl)-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-(trifluoromethoxy)pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(imidazo[1,2-a]pyrazine-6-yl)benzamide; 4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-3-fluoro-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 6-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)nicotinamide; 5-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)picolinamide; 5-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridine-2-yl)picolinamide; 2-Chloro-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-N-(5-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)benzamide; 2-Chloro-4-((5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((2-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(pyridine-2-yl)benzamide; 6-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)nicotinamide; 6-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridine-2-yl)nicotinamide; 5-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)picolinamide; 2-Chloro-N-(4-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)benzamide; 2-Chloro-4-((5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((2-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(4H)-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-N-(4-methoxypyridine-2-yl)-4-((2-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(4H)-yl)methyl)benzamide; 2-Chloro-N-(5-methoxypyridine-2-yl)-4-((2-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(4H)-yl)methyl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,4-e][1,4]diazepine-4(5H)-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-2,3-dihydro-1H-thieno[3,4-e][1,4]diazepine-4(5H)-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((7-cyclopropyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((7-cyclopropyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 4-((7-(tert-butyl)-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-2-chloro-N-(pyridine-2-yl)benzamide; 4-((7-(tert-butyl)-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-2-chloro-N-(4-methoxypyridine-2-yl)benzamide; 4-((7-(tert-butyl)-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-2-chloro-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-N-(4-methoxypyridine-2-yl)-4-((2-methyl-4,7-dioxo-6-(pyridine-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepine-5(4H)-yl)methyl)benzamide; 2-Chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(4H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(4H)-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-N-(4-methoxypyridine-2-yl)-4-((2-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)benzamide; 2-Chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(pyridine-2-yl)benzamide; 4-((2-(tert-butyl)-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-2-chloro-N-(pyridine-2-yl)benzamide; 4-((2-(tert-butyl)-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-2-chloro-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((4,7-dioxo-6-(pyridine-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepine-5(4H)-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((4,7-dioxo-6-(pyridine-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepine-5(4H)-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((4,7-dioxo-6-(pyridine-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepine-5(4H)-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((7-cyclopropyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydroimidazo[4,5-e][1,4]diazepine-7(1H)-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-N-(4-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydroimidazo[4,5-e][1,4]diazepine-7(1H)-yl)methyl)benzamide; 2-Chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepine-7-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydroimidazo[4,5-e][1,4]diazepine-7(1H)-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 6-(2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)benzamide) ethyl nicotinate; 6-(2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)benzamide)methyl nicotinate; (R)-4-((7-bromo-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-2-chloro-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 4-((7-bromo-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-2-chloro-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxy-5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methyl-5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((7-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridazine-3-yl)benzamide; (S)-2-chloro-N-(4-methoxypyridine-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridine-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepine-7(1H)-yl)methyl)benzamide; And, (R)-2-chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridazine-3-yl)benzamide A compound, stereoisomer, tautomer, salt, or solvate according to claim 1, selected from the above.

14. (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((8-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-N-(4-methoxypyridine-2-yl)-4-((8-methyl-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-yl)methyl)benzamide; 2-Chloro-4-((8-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(pyridine-2-yl)benzamide; 2-Chloro-4-((8-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; 2-Chloro-4-((8-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide; 2-Chloro-4-((8-Chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridazine-3-yl)benzamide; 2-Chloro-4-((2,5-dioxo-3-(pyridine-2-ylmethyl)-8-(trifluoromethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-methoxypyridazine-3-yl)benzamide; (S)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(4-methoxypyridine-2-yl)benzamide; And, (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridine-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepine-4-yl)methyl)-N-(5-(trifluoromethyl)pyridine-2-yl)benzamide A compound, stereoisomer, tautomer, salt, or solvate according to claim 6, selected from the above.

15. A pharmaceutical composition for use in treating C. difficult infection, comprising a compound, stereoisomer, tautomer, or solvate described in any one of claims 1 to 14.

16. A method for producing a compound, stereoisomer, tautomer, or solvate according to any one of claims 1 to 5, 11, and 13, according to scheme 1 or 2 below, 【Chemistry 16-1】 【Chemistry 16-2】 m, X1, X2, X3, X4, X5, R1, R2, R3, R4, R5, and R6 are as defined in claim 1, In Scheme 1, Intermediate 1 and intermediate 2 are linked by reductive amination to provide intermediate 3. By amide coupling intermediate 3 and carboxylic acid 4, amide 5 is provided. By reducing amide 5, diazepine dione 6 is provided. By hydrolyzing diazepine dione 6, carboxylic acid 7 was obtained. Product I is obtained by amide coupling amine intermediate 8 and carboxylic acid 7. In Scheme 2, Intermediate 10 is obtained by amide coupling amine intermediate 8 and carboxylic acid 9. After vinylization of intermediate 10, oxidative cleavage provides aldehyde intermediate 11. By linking intermediate 11 and intermediate 2, intermediate 12 is provided. The amide 13 is provided by amide coupling the intermediate 12 with the carboxylic acid 4, A method for reducing amide 13 to obtain product I.

17. A pharmaceutical composition for inhibiting C. difficultile bacterial toxin in cells, comprising a compound, stereoisomer, tautomer, or solvate according to any one of claims 1 to 14.

18. A pharmaceutical composition for reducing the glucosylation of Rho GTPase protein in cells, comprising a compound, stereoisomer, tautomer, salt, or solvate described in any one of claims 1 to 14.

Images