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 TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 155,651, filed March 2, 2021, and entitled "HETEROCYCLIC COMPOUNDS AND RELATED METHODS," the contents of which are incorporated by reference in their entirety herein.

[0002] The present disclosure relates generally to therapeutics. In particular, the present disclosure relates to heterocyclic compounds and related methods. Pharmaceutical compositions containing such compounds and their useful therapies 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 occurs after disruption of the gut microbiome via antibiotic treatment, although sporadic and environmental cases do occur. There are over 500,000 cases of infection associated with over 15,000–20,000 deaths per year. An estimated 20–40% of cases relapse, with patients becoming symptomatic after completing their course of treatment (Rupnik et al. 2009). C. difficile microbes produce multiple toxins that disrupt the gut lining, resulting in inflammation and diarrhea. Two of the toxins primarily involved and associated with the pathogenesis of human disease are toxin A and toxin B (TCdA, TCdB), which are internalized into 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 and disrupts intestinal barrier function, resulting in inflammation, diarrhea, and, if left untreated, toxic megacolon, sepsis, and in some cases death.

[0004] Several antibiotics, including metronidazole (off-label), vancomycin, and fidaxomicin, are commonly used to treat CDAD (Kelly 2020). However, these treatments cause varying levels of relapse (Louie et al. 2011) and continue to disrupt the microbiota. Interventions focused on restoring normal microbiota in the gut 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. Active vaccination strategies have demonstrated robust immune responses to C. difficile toxins, but there is limited data on the ability of vaccines to suppress infection pathology, and no vaccine has been approved for the prevention of CDAD (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 burden of intravenous infusion combined with the high cost of monoclonal antibody therapy may limit its use, especially for non-hospitalized patients, while competing with other less expensive medicines.

[0005] Inhibitors of virulence factors that disrupt barrier function are being actively explored as another option for the treatment of CDAD (Stroke et al. 2018, Bender et al. 2015, Savidge et al. 2011). Such antivirulence strategies have the potential to suppress pathology without further disrupting normal microbiota and without providing selection pressure that promotes antibiotic resistance when additional antibiotic therapy is likely to be administered (Fleitas Martinez et al. 2019). Therefore, the identification of compounds that suppress the pathology of C. difficile infection while preserving normal microbiota and allowing their reconstitution would be a highly effective therapeutic intervention. Summary of the Invention

[0006] In one aspect, the disclosure provides compounds of Formula (I) and Formula (II), as well as their subgenus, including stereoisomers, tautomers, pharma- ceutically acceptable salts, and solvates thereof. In certain embodiments, the compounds are useful for treating C. difficile bacterial infections.

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

[0008] In another aspect, the present disclosure also provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and at least one of the compounds of the present disclosure, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof.

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

[0010] The compounds of the present disclosure may be used in the treatment of a disease, disorder, or condition associated with any infection caused by C. difficile bacteria in a patient in need of such treatment by administering to the patient a therapeutically effective amount of the compound, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, or solvate thereof. The disease, disorder, or condition may be associated with fever, abdominal pain, diarrhea, and colon inflammation. The compounds of the present disclosure may be used alone, in combination with one or more compounds of the present disclosure, or in combination with one or more, e.g., one to two, other therapeutic agents.

[0011] The compounds of the present disclosure can be used for the manufacture of a medicament for the treatment of a disease, disorder, or condition in a patient in need thereof.

[0012] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present application provides compounds according to formula (I) and formula (II), including all stereoisomers, solvates, and pharma- ceutically acceptable salts and solvates thereof. The present application also provides pharmaceutical compositions containing at least one compound according to formula (I) and formula (II), or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt or solvate thereof, and optionally at least one additional therapeutic agent. In addition, the present application provides a method for treating a patient suffering from C. 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 a pharma- ceutically acceptable salt or solvate thereof, optionally in combination with at least one additional therapeutic agent.

[0014] Compounds of the Disclosure In one embodiment, the disclosure provides a compound of formula (I):

[0015] [ka]

[0016] During the ceremony, X 1 , X 2 , and X 3 are each independently 2 , N, N.R. 5 , O, or S; X 4 and X 5 are each independently C or N; m is an integer of 0, 1, or 2; Z is a 6- to 10-membered aryl or a 5- to 10-membered 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 are each independently hydrogen, C 1-6 alkyl, alkylamino, haloalkyl, alkoxy, haloalkoxy, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are independently selected from 0 to 5 R 5 is replaced by R 5 is 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 is hydrogen or C 1-6 It is an alkyl.

[0017] The dashed circle is an X 1 , X 2 , X 3 It should be understood by one of ordinary skill in the art that the above refers to an aromatic ring formed by the aryl, ... and aromatic rings formed by the carbon atoms.

[0018] In any one of the preceding embodiments of Formula (I),

[0019] [ka]

[0020] The part is

[0021] [ka]

[0022] It can be.

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

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

[0025] [ka]

[0026] m is an integer of 0, 1, or 2; R 5 is as defined above.

[0027] In any one of the preceding embodiments of Formula (I),

[0028] [ka]

[0029] The part is

[0030] [ka]

[0031] It can be.

[0032] In any one of the preceding embodiments of Formula (I), the compound may be represented by Formula (Ia):

[0033] [ka]

[0034] In any one of the preceding embodiments of Formula (I), the compound may be represented by Formula (Ib):

[0035] [ka]

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

[0037] [ka]

[0038] wherein R 5 is as defined above.

[0039] In any one of the preceding embodiments of Formula (I), the compound may be represented by Formula (Ic):

[0040] [ka]

[0041] In any one of the preceding embodiments of Formula (I), the compound may be represented by Formula (Id):

[0042] [ka]

[0043] In any one of the foregoing embodiments of formula (I), the compound may be represented by formula (Ie):

[0044] [ka]

[0045] In any one of the foregoing embodiments of formula (I), the compound may be represented by formula (If):

[0046] [ka]

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

[0048] [ka]

[0049] During the ceremony, Y 1 , Y 2 , and X 3 are each independently 2 or N, with the proviso that at least one Y 1 , Y 2 , and Y 3 is N, X 4 and X 5 are each independently C or N; m is an integer of 0, 1, or 2; Z is a 6- to 10-membered aryl or a 5- to 10-membered 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 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R 3 and R 4are each independently hydrogen, 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 carbocyclyl, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the aryl, heteroaryl, carbocyclyl, and heterocyclyl are independently selected from 0 to 5 R 5 is replaced by R 5 is 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 is hydrogen or C 1-6 Alkyl The dashed circle is Y 1 , Y 2 , Y 3 It should be understood by one of ordinary skill in the art that the above refers to an aromatic ring formed by the aryl, ... and aromatic rings formed by the carbon atoms. In any one of the preceding embodiments of Formula (II),

[0050] [ka]

[0051] The part is

[0052] [ka]

[0053] may be selected from:

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

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

[0056] [ka]

[0057] where m is an integer of 0, 1, or 2; 5 is as defined above. In any one of the preceding embodiments of Formula (II),

[0058] [ka]

[0059] The part is

[0060] [ka]

[0061] It could be.

[0062] In any one of the preceding embodiments of Formula (II), the compound may be represented by Formula (IIa):

[0063] [ka]

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

[0065] [ka]

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

[0067] [ka]

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

[0069] [ka]

[0070] In one embodiment, the present disclosure provides:

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof. In one embodiment, the disclosure provides, inter alia, a compound selected from any one of the examples described herein, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

[0076] II. Pharmaceutical Compositions, Therapeutic Uses, and Combinations In another embodiment, the present disclosure provides a composition comprising at least one of the compounds of the present disclosure, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof. In another embodiment, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and at least one of the compounds of the present disclosure, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

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

[0078] In another embodiment, the disclosure provides a process for making the compounds of the disclosure.

[0079] In another embodiment, the disclosure provides intermediates for making the compounds of the disclosure.

[0080] In another embodiment, the present 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 disease, disorder, or condition associated with C. difficile infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

[0082] In another embodiment, the present disclosure provides a method for the treatment of 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 present disclosure, alone or optionally in combination with another compound of the present disclosure and / or at least one other type of therapeutic agent.

[0083] In another embodiment, the disclosure provides a method of inhibiting a C. difficile bacterial toxin in a cell, the method comprising administering to the cell a therapeutically effective amount of a compound of the disclosure, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof. In certain embodiments, the toxin is toxin B.

[0084] In another embodiment, the disclosure provides a method of reducing glycosylation of a Rho GTPase protein in a cell, the method comprising administering to the cell a therapeutically effective amount of a compound of the disclosure, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof.

[0085] The compounds of the present disclosure can be administered by any suitable means for any of the uses described herein, for example orally, such as tablets, capsules (each including sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions; parenterally, such as sublingually, buccally, subcutaneously, intravenously, intramuscularly, or intrastemal injections or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment, or rectally, such as in the form of a suppository. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0086] The term "pharmaceutical composition" refers to a composition comprising a compound of the present disclosure in combination with at least one additional pharma- ceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, depending on the mode of administration and the nature of the dosage form, i.e., adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants, and dispensing agents. 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 to be formulated, the subject to which the drug-containing composition will be administered, the intended route of administration of the composition, and the therapeutic indication being targeted. 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 can contain a number of different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for a variety of reasons, e.g., for stabilization of the active agent, binders, etc., well known to those of skill in the art. Descriptions of suitable pharma- ceutically acceptable carriers, and the factors involved in their selection, can be found in a variety of readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

[0087] The term "treating" or "treatment" as used herein refers to an approach to obtain beneficial or desired results, including clinical results, by using a compound or composition of the present disclosure. For purposes of this disclosure, beneficial or desired clinical results 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 extent of or causing regression of a disease, disorder, or condition, stabilizing a disease, disorder, or condition (e.g., preventing or slowing the worsening of a disease, disorder, or condition), delaying or slowing the progression of a disease, disorder, or condition, ameliorating a disease, disorder, or condition, reducing the dose of one or more other pharmaceutical agents 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 administering a compound of the present disclosure, or a pharmaceutical composition comprising a compound of the present disclosure, directly to an isolated cell or animal, or administering another agent to the cell or animal to cause the presence or formation of a compound of the present disclosure in the cell or animal. Preferably, the method of the present disclosure comprises administering to a cell in vitro, or to a warm-blooded animal, particularly a mammal, more particularly a human, a pharmaceutical composition comprising an effective amount of a compound according to the present disclosure that causes the presence or formation of a compound of the present disclosure in the cell or animal.

[0089] Dosing regimens for the compounds of the present disclosure will, of course, vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition, and weight of the recipient, the nature and extent of symptoms, type of concomitant treatment, frequency of treatment, route of administration, renal and hepatic function of the patient, and the desired effect. By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, ranges from 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 doses range from about 0.01 to about 10 mg / kg / min during a constant rate infusion. The compounds of the present disclosure may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two, three, or four times daily. The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected for the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practice. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 0.1 mg to about 2000 mg of active ingredient per dosage 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 the present disclosure (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically adding at least one of the compounds of the present disclosure (250 mg) to a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of saline to obtain an injectable preparation.

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

[0091] The other therapeutic agents described above, when used in combination with the compounds of the present disclosure, may be used in amounts as prescribed in the Physicians' Desk Reference, e.g., as in the patents identified above, or as otherwise determined by one of skill in the art.

[0092] There is a possibility of chemical interaction between the combined active ingredients, especially when provided as a single dosage unit. For this reason, when the compounds of the present disclosure and the second therapeutic agent are combined in a single dosage unit, they are formulated so that the active ingredients are combined in a single dosage unit, but the physical contact between the active ingredients is minimized (i.e., reduced). For example, one active ingredient can be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also to control the release of one of these ingredients in the gastrointestinal tract, so that one of these ingredients is not released in the stomach, but rather in the intestine. One of the active ingredients can also be coated with a material that affects the sustained release throughout the gastrointestinal tract and functions to minimize the physical contact between the combined active ingredients. Furthermore, the sustained release component can be additionally enteric coated so that the release of this component occurs only in the intestine. Yet another approach involves formulating a combination product where one component is coated with a sustained release and / or enteric release polymer to further separate the active ingredients, and the other component is also coated with a polymer, such as low viscosity grades of hydroxypropylmethylcellulose (HPMC) or other suitable materials known in the art. The polymer coating serves to form an additional barrier to interaction with the other component.

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

[0094] The compounds of the present disclosure can 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 the present 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 can be administered simultaneously or sequentially in any order at different times. Thus, each component can be administered separately but sufficiently close in time to provide the desired therapeutic effect.

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

[0096] The present disclosure also encompasses articles of manufacture. As used herein, articles of manufacture is intended to include, but are not limited to, kits and packages. The articles of manufacture of the present disclosure include (a) a first container; (b) a pharmaceutical composition disposed within the first container, the composition comprising a first therapeutic agent comprising a compound of the present disclosure or a pharma- ceutically acceptable salt form thereof; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of C. difficile infection and its sequelae. In another embodiment, the package insert stating that the pharmaceutical composition can be used in combination (as defined above) with a second therapeutic agent for the treatment of C. difficile infection and its sequelae. The articles of manufacture can further include (d) a second container, where components (a) and (b) are disposed within the second container and component (c) is disposed within or outside the second container. Disposed within the first and second containers means that each container holds 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 sale. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream preparations), or any other container used to manufacture, hold, store, or distribute pharmaceutical products.

[0098] The second container is used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, adhesive, staples, or another attachment method, or can be contained within the second container without any physical attachment means to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferred that the package insert is physically attached via tape, adhesive, staples, or other attachment method. 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 that is placed in the first container. The information listed is usually determined by a regulatory agency (e.g., the United States Food and Drug Administration) that governs the territory in which the product is sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material that allows a person to read the information contained therein or therein. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper, plastic, etc.) on 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 is intended to encompass all stereo and optical isomers thereof, as well as racemic forms, if 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, ring systems, and the like, can also exist in the compounds, and all such stable isomers are contemplated in this disclosure. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of this disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. Optically active forms can be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare the compounds of this disclosure and intermediates made therein are considered to be part of this disclosure. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, chromatography or fractional crystallization. Depending on the process conditions, the final products of the present disclosure are obtained in either free (neutral) or salt form. Both the free form and the salts of these final products are within the scope of the present disclosure. If desired, one form of the compound can be converted to another form. Free bases or acids can be converted to salts, salts can be converted to free compounds or to other salts, and mixtures of isomeric compounds of the present disclosure can be separated into individual isomers. The compounds of the present disclosure, their free forms and salts, can exist in multiple tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule, resulting in a rearrangement of the chemical bonds between the atoms of the molecule. It should be understood that all tautomeric forms, insofar as they may exist, are included in the present disclosure. As used herein, "compounds of the disclosure" means one or more compounds encompassed by any one of formulas (I) and (II), or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt or solvate thereof.

[0101] As used herein, the terms "alkyl" or "alkylene" are intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified 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" means C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to include alkyl groups. 10 Alkylene" or "C 1-10 Alkylene" includes C1, C2, C3, C4, C5, C6C7, C8, C9, and C 10 It is intended to include alkylene groups. Further, for example, "C1-C6 alkyl" or "C 1-6 "Alkyl" refers to an alkyl having 1 to 6 carbon atoms, and is not limited to "C1-C6 alkylene" or "C 1-6 "Alkylene" refers to an alkylene having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted with at least one hydrogen replaced with 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 alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 8 carbons, and the terms "alkyl" and "alk" as used herein alone or as part of another group include both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 10 carbons, and more preferably 1 to 8 carbons in the main chain, 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 the various branched chain isomers thereof.

[0103] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom, such as O, N, or S. For example, when a carbon atom of an alkyl group that is attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH), an alkylamino (e.g., -NHCH, -N(CH), or a thioalkyl group (e.g., -SCH), respectively. When a non-terminal carbon atom of an alkyl group that is not attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CHCH-O-CH), an alkylaminoalkyl (e.g., -CHNHCH, -CHN(CH), or a thioalkyl ether (e.g., -CH-S-CH), respectively. When the terminal carbon atom of an alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or an alkylthiol group (e.g., -CH2CH2-SH), respectively. The heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C1-C6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

[0104] "Alkenyl" or "alkenylene" is intended to include a hydrocarbon chain of either a straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur at any stable point along the chain. "Alkenyl" refers to a monovalent radical, while "alkenylene" refers to a divalent radical. For example, "C2-C6 alkenyl" or "C 2-6 "(Alkenyl)" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl 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 include a hydrocarbon chain of either a straight or branched configuration with one or more, preferably one to three, carbon-carbon triple bonds that may occur at any stable point along the chain. "Alkynyl" refers to a monovalent radical, while "alkynylene" refers to a divalent radical. For example, "C2-C6 alkynyl" or "C 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0106] As used herein, an "arylalkyl" (also known as aralkyl), "heteroarylalkyl", "carbocyclylalkyl", or "heterocyclylalkyl" refers to an alkyl group that is heterocyclic or heterocyclic, and is defined as having a carbon atom, typically a terminal or sp 3It refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to the carbon atom is replaced with an aryl, heteroaryl, carbocyclyl, or heterocyclyl radical, respectively. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl, and the like. An aryl alkyl, heteroaryl alkyl, carbocyclyl alkyl, or heterocyclyl alkyl group can contain 4 to 20 carbon atoms and 0 to 5 heteroatoms, e.g., the alkyl portion can contain 1 to 6 carbon atoms.

[0107] The term "benzyl", as used herein, refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group, which can be optionally substituted with 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" or "alkyloxy", "aryloxy" or "aralkoxy" refer to any of the above alkyl, aralkyl, or aryl groups attached to an oxygen atom. 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 an alkyl, aryl, or aralkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge, e.g., methyl-S- and ethyl-S-.

[0109] The term "alkanoyl" or "alkylcarbonyl" as used herein alone or as part of another group refers to an alkyl bonded to a carbonyl group. For example, alkylcarbonyl can 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] The term "alkylsulfonyl" or "sulfonamido" as used herein alone or as part of another group refers to an alkyl or amino bonded to a sulfonyl group. For example, an alkylsulfonyl can be represented as -S(O)2R' and a sulfonamido can be represented as -S(O)2NR c R d R' is a C1-C6 alkyl group, and R c and R d is the same as defined below for "amino".

[0111] The term "carbamate" as used herein alone or as part of another group refers to an oxygen attached to an amide group. For example, a carbamate is an N(R c R d )-C(O)-O-, R c and R d is the same as defined below for "amino".

[0112] The term "amide" as used herein alone or as part of another group refers to an amino bonded to a carbonyl group. For example, an amide is an N(R c R d )-C(O)-, R c and R d is the same as defined below for "amino".

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

[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 is N(R c1 R c2 )-alkylene-. 1 ~C6" or "C 1~6 "Aminoalkyl" (or aminoalkyl) is intended to include C1, C2, C3, C4, C5, and C6 aminoalkyl groups.

[0115] The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified 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 haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms. The term "polyhaloalkyl," as used herein, refers to an "alkyl" group as defined above that includes 2 to 9, preferably 2 to 5, halo substituents, such as polyfluoroalkyl, e.g., -CH2CF3, -CF3, or -CH2CF2CF3, such as F or Cl, preferably F.

[0116] "Haloalkoxy" or "haloalkyloxy" represents an ahaloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. 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 haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represent a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge, e.g., trifluoromethyl-S-, and pentafluoroethyl-S-. The term "polyhaloalkyloxy" as used herein refers to an "alkoxy" or "alkyloxy" group as defined above containing 2-9, preferably 2-5 halo substituents such as polyfluoroalkyloxy, e.g., -OCH2CF3, -OCF3, or -OCH2CF2CF3, etc., such as F or Cl, preferably F.

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

[0118] The term "cycloalkyl" refers to cyclized alkyl groups, including monocyclic, bicyclic, or polycyclic ring systems. 3-7 "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 norvomyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl."

[0119] The term "cycloheteroalkyl" refers to a cyclized heteroalkyl group, including monocyclic, bicyclic, or polycyclic ring systems. 3-7"Cycloheteroalkyl" is intended to include C, C, C, C, and C 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 "azacyclyl" refers to a cycloheteroalkyl 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, "carbocycle", "carbocyclyl", or "carbocyclic" 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, any of which may be saturated or partially unsaturated. Thus, the terms "carbocycle", "carbocyclyl", or "carbocyclic" include, but are not limited to, cycloalkyl and cycloalkenyl. Examples of such carbocycles 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 noted above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise indicated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and tetrahydronaphthyl. A bridged ring occurs when one or more, preferably 1 to 3, carbon atoms link two non-adjacent carbon atoms. A preferred bridge is one or two carbon atoms. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0122] Additionally, the term "carbocyclyl", including "cycloalkyl" and "cycloalkenyl", as used herein alone or as part of another group, includes saturated or partially unsaturated (containing one or two double bonds) cyclic hydrocarbon groups containing a total of 3 to 20 carbons, preferably 3 to 10 carbons, or 3 to 6 carbons, forming a ring and containing one to three rings, including monocyclic alkyl, bicyclic alkyl, and tricyclic alkyl, which may be fused to one or two aromatic rings as described for aryl, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, and cyclodecyl, cyclohexenyl, cyclohex ...

[0123] [ka]

[0124] any of which may be optionally substituted with 1-4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol, and / or alkylthio, and / or any of the alkyl substituents.

[0125] As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system consisting of carbon atoms, containing two fused rings. Of the two fused rings, one ring is a benzo ring fused to a second ring, the second ring being a 5- or 6-membered carbocyclic ring that is saturated or partially unsaturated. A bicyclic carbocyclic group may be attached to its pendant group at any carbon atom that results in a stable structure. The bicyclic carbocyclic groups described herein may be substituted at any carbon, provided 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 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 phenanthranyl. Aryl moieties are well known and are 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 containing 6 to 10 carbons in the ring portion, such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl. 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 An "aryl", or "aromatic residue", can be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, such as those 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 term "heterocycle", "heterocyclyl", or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic (including bicyclic and tricyclic) heterocycle that is saturated or partially unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and includes any polycyclic group in which any of the heterocyclic rings defined above are fused to a carbocyclic ring or an aryl (e.g., benzene) ring. Thus, the term "heterocycle", "heterocyclyl", or "heterocyclic group" includes non-aromatic ring systems such as heterocycloalkyl and heterocycloalkenyl. The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)). p where p is O, 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogen in the heterocyclic ring can be optionally quaternized. If the total number of S and O atoms in the heterocyclic ring exceeds 1, it is preferred that these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocyclic ring does not exceed 1. Examples of heterocyclyl include, but are not limited to, azetidinyl, piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl, and dihydrofuro[2,3-b]tetrahydrofuran.

[0128] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system comprising two fused rings and consisting of carbon atoms 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 5- or 6-membered monocyclic aromatic ring, including a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo ring, each of which is fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring, saturated, partially unsaturated, or unsaturated, including a 5-membered heterocycle, a 6-membered heterocycle, or a carbocycle (provided that if the second ring is a carbocycle, the first ring is not benzo). A bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The bicyclic heterocyclic groups described herein can be substituted on carbon or nitrogen atoms if the resulting compound is stable.If the total number of S and O atoms in the heterocyclic ring exceeds 1, these heteroatoms are preferably not adjacent to each other.The total number of S and O atoms in the heterocyclic ring is preferably not more than 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, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1.2.3.4-tetrahydro-quinazolinyl.

[0129] Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably 1-3 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. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on 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, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atoms are substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). p where p is 0, 1, or 2.

[0131] Examples of heteroaryl include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a / / -carbazolyl.Carbolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxa Zolyl, isoxazolopyridinyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathianyl, pheno Xazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4 / / -quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, Examples of thiadiazinyl include, but are 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 membered heteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxyindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5-6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0133] Unless otherwise indicated, "carbocyclyl" or "heterocyclyl" refers to a ring having one to three additional rings fused to a carbocyclic or heterocyclic ring, such as an aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl ring, e.g.,

[0134] [ka]

[0135] and optionally, via an available carbon atom, 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, heptane, and aryloxy, hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfumyl, arylsulfumylalkyl, arylsulfonylamino, and arylsulfoneaminocarbonyl, and / or alkyl substituents as set forth herein.

[0136] When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are used as part of another group, the number of carbon atoms and ring members are the same as defined for the terms themselves. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio, etc. each independently contain the number of carbon atoms that is the same 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, cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, etc. each independently include 3-6, 4-7, 6-10, 5-10, 5 or 6, etc., ring members that are the same as defined for the terms "cycloalkyl," "heterocyclyl," "aryl," and "heteroaryl."

[0137] As per convention used in the art, the formulas used herein are

[0138] [ka]

[0139] A bond depicted via a wavy or serpentine line, such as, indicates a bond that is the point of attachment of the moiety or substituent to a core or backbone structure.

[0140] By convention used in the art,

[0141] [ka]

[0142] Wavy or serpentine bonds in structural formulae such as: are used to indicate stereocenters at the carbon atoms to which X', Y', and Z' are attached and are intended to represent both enantiomers in a single drawing. That is, a structural formula having such wavy bonds is

[0143] [ka]

[0144] Each of the enantiomers, etc., are depicted individually as well as racemic mixtures thereof. When a wavy or tortuous bond is attached to a double bond (such as C=C or C=N) moiety, it includes cis- or trans- (or E- and Z-) geometric isomers, or mixtures thereof.

[0145] In this specification, when a carbocyclic or heterocyclic moiety may be bonded or otherwise connected to a specified substrate through different ring atoms without indicating a specific point of attachment, it is understood that all possible points are intended, whether through a carbon atom or, for example, through a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, etc.

[0146] When a bond to a substituent is shown to span a bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. When substituents are listed without indicating the atom to which such substituent is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0147] One of ordinary skill in the art will recognize that the substituents and other moieties of the compounds of the present disclosure should be selected to provide compounds that are sufficiently stable to provide pharma- ceutically useful compounds that can be formulated into acceptable, 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 represent negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate. 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] As referred to herein, the term "substituted" means that at least one hydrogen atom (bonded to a carbon atom or heteroatom) is replaced with a non-hydrogen group, provided that normal valence is maintained and the replacement results in a stable compound. When a substituent is oxo (i.e., =O), two hydrogens are replaced at the atom. Oxo substituents are not present in aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or double bond, the carbonyl group or double bond is intended to be part of (i.e., within) the ring. 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). The term "substituted" with respect to alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl, respectively, means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl, wherein one or more hydrogen atoms bonded to either carbon or heteroatoms are each independently replaced with one or more non-hydrogen substituents.

[0150] In instances where nitrogen atoms (e.g., amines) are present on the compounds of the present disclosure, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the present disclosure. Thus, any nitrogen atom shown and claimed is considered to cover both the shown nitrogen and its N-oxide (NO) derivative.

[0151] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0, 1, 2, or 3 R groups, the group is unsubstituted when substituted with 0 R groups, or substituted with up to 3 R groups, and at each occurrence, R is independently selected from the definitions of R.

[0152] Also, combinations of substituents and / or variables are permissible only 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 easily interchanged by shifting atoms or groups within the molecule. For example, one skilled in the art will readily recognize that 1,2,3-triazole exists in two tautomeric forms as defined above.

[0154] [ka]

[0155] Therefore, the present disclosure is intended to cover all possible tautomers, even though the structures show only one of them.

[0156] The phrase "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0157] The compounds of the present disclosure can exist as salts, which are also within the scope of the present disclosure. Pharmaceutically acceptable salts are preferred. As used herein, "pharmaceutical acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by making its acid salt or base salt. The pharmaceutical acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two, and generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable 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] When the compounds of the present disclosure have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid, or hydrohalic acids, with organic carboxylic acids, such as alkane carboxylic acids of 1 to 4 carbon atoms, for example acetic acid, unsubstituted or substituted, for example substituted by halogens, as chloroacetic acid, saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid, hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid, amino acids (for example aspartic acid or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or aryl sulfonic acids, unsubstituted or substituted, for example substituted by halogens, for example methyl- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed, if desired, with an additionally present basic center. The compounds of the present disclosure having at least one acid group (e.g., COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts such as alkali metal salts or alkaline earth metal salts, for example, sodium salts, potassium salts, or magnesium salts, or salts with ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines, for example, ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine, or mono-, di-, or trihydroxy lower alkylamines, for example, mono-, di-, or triethanolamine. Corresponding inner salts can also be formed. Also included are salts that are not suitable for pharmaceutical use, but can be used, for example, for the isolation or purification of the free compounds of formula (I) and formula (II) or their pharma-ceutically acceptable salts.

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

[0160] Preferred salts of the compounds of formula (I) and formula (II) containing an acid group include sodium, potassium and magnesium salts, and pharma- ceutically acceptable organic amines.

[0161] In addition, the compounds of the present disclosure may have a prodrug form. Any compound that is converted in vivo to provide a bioactive agent is a prodrug within the scope and spirit of the present disclosure. The term "prodrug" as used herein includes 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 preferably administered orally, since hydrolysis often occurs primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active, or when hydrolysis occurs in blood.

[0162] The compounds of the present disclosure contain carboxy groups that can be hydrolyzed in the body to yield the compounds of the present disclosure themselves, thereby forming physiologically hydrolyzable esters that function as prodrugs, i.e., "prodrug esters." 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., methoxycarbonyl-oxymethyl 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 may be prepared by conventional techniques known in the art. "Prodrug esters" may be formed by reacting the carboxylic acid moiety of the compounds of the present disclosure with either an alkyl or aryl alcohol, a halide, or a sulfonate using procedures known to those of skill in the art. Additionally, various forms of prodrugs are well known in the art. Examples of such prodrug derivatives include: 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); Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587, (2018).

[0164] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (symbol D or 2 H) and tritium (symbol T or 3 H). Carbon isotopes include: 13 C and 14Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those of skill in the art or by processes similar to those described herein, substituting the appropriate isotopically labeled reagent for an otherwise non-labeled reagent. Such compounds have a variety of potential uses, such as, 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 compounds of the present disclosure binding to biological receptors in vivo or in vitro.

[0165] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Compounds of the present disclosure preferably do not contain N-halo, S(O)2H, or S(O)H groups.

[0166] The term "solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. The solvent molecules in a solvate may be in an ordered arrangement and / or a non-ordered arrangement. The solvate may contain either stoichiometric or non-stoichiometric amounts of the solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are known in the art.

[0167] Abbreviations used herein are defined as follows: "1x" is one time, "2x" is two times, "3x" is three times, "°C" is degrees Celsius, "eq" is equivalent(s), "g" is gram(s), "mg" is milligram(s), "L" is liter(s), "mL" is milliliter(s), "pL" is microliter(s), "N" is definition, "M" is mole, "mmol" is millimole(s), "min" is minute(s), "h" is hour(s), "rt" is room temperature, "RBF" is round bottom flask, "atm" is pressure, "psi" is pounds per square inch, "cone." is concentrated, "RCM" is ring closing metathesis, "sat" or "sat'd" is saturated, "SFC" is supercritical fluid chromatography, "MW" is molecular weight, "mp" is melting point, "ee" is enantiomeric 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 Overhauser effect spectroscopy, "1H" is proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quartet, "m" is multiplet, "br" is broad, "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to those of skill in the art.

[0168] Abbreviation The following abbreviations are used in the Schemes, Examples, and elsewhere herein:

[0169] [Table 1-1]

[0170] [Table 1-2]

[0171] [Table 1-3]

[0172] [Table 1-4]

[0173] Preparation method The compounds of the present disclosure can be prepared in several ways well known to those skilled in the art of organic synthesis, using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon 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 effected. It will be understood by those skilled in the art of organic synthesis that the functionality present in the molecule should be consistent with the proposed transformation. This sometimes requires judgment to change the order of synthetic steps or to select one particular process scheme over another to obtain the desired compounds of the present disclosure. Restrictions on the substituents that are compatible with the reaction conditions will be readily apparent to those skilled in the art, and then alternative methods must be used. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functionalities present in the compounds described in the present disclosure. A particularly useful overview of synthetic methods applicable to the preparation of compounds of the present disclosure can be found in Larock, RC, Comprehensive Organic Transformations, VCH, New York (1989).

[0174] The compounds of the present disclosure may be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents appropriate to the reagents and materials used and suitable for the transformations to be effected. It should also be understood that in the description of the synthetic methods described below, all proposed reaction conditions, including solvents, reaction atmospheres, reaction temperatures, duration of the experiments, and work-up procedures, are selected to be conditions that are standard for the reactions, readily recognized by those skilled in the art. Those skilled in the art of organic synthesis understand that the functionality present on the various moieties of the indicated molecule must be compatible with the proposed reagents and reactions. Not all compounds of formula (I) or formula (II) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such limitations on the substituents that are compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must be used. A particularly useful overview of synthetic methods that may be applicable to the preparation of the compounds of the present disclosure may be found in Larock, RC, Comprehensive Organic Transformations, VCH, New York (1989).

[0175] General Scheme The compounds of the present disclosure represented by Formula (I) and Formula (II), or any subgenera or species thereof, can be prepared according to the general routes depicted in Schemes 1-4 below.

[0176] Scheme 1

[0177] [ka]

[0178] Scheme 1 illustrates a method for preparing compounds of formula I. Intermediate 1, which is commercially available or readily synthesized by methods known in the literature, can be coupled with 2 by reductive amination using reagents such as, but not limited to, sodium cyanoborohydride and acetic acid in a suitable solvent such as methanol to give 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 give acyl chlorides, which can then be reacted with amine 3 in the presence of triethylamine in DCM to give amides of type 5. Staudinger reduction of 5 with an appropriate phosphine, such as tributylphosphine, in a solvent such as toluene can provide heteroaryl amines, which can be cyclized under acidic conditions, including, but not limited to, aqueous TFA in THF to give diazepine diones 6. Hydrolysis of the ester affords R 5 Depending on the nature of R, this can be achieved under acidic or basic conditions. 5 When is t-butyl, hydrolysis can be accomplished using conditions including, but not limited to, dilute TFA in dichloromethane at a suitable temperature and time to afford the desired carboxylic acid 7. Amide coupling of the amine intermediate 8 with the carboxylic acid 7 can be achieved through several possible conditions including, but not limited to, utilization of 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 time to afford the desired amide product I.

[0179] Scheme 2 [ka]

[0180] Scheme 2 illustrates an alternative method of preparing compounds of formula I. Amide coupling of amine intermediate 8 with carboxylic acid 9 can be achieved through several possible conditions, including but not limited to, the use of coupling reagents 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 time to yield the desired amide product 10. Both 8 and 9 are commercially available and are readily prepared by methods known in the literature or by those skilled in the art. Preparation of aldehyde 11 can be achieved in a two-step process, the first step consisting of vinylation of 10 by means of a metal-mediated coupling with a reagent such as tributyl(vinyl)tin in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0) in a solvent such as DMF. Oxidative cleavage of the resulting olefin can be achieved through the use of reagents such as but not limited to OsO4 and NaIO4 in a mixture of THF / water or another suitable solvent system to afford aldehyde intermediate 11. Intermediate 11 can be coupled with intermediate 2 via reductive amination using reagents such as, but not limited to, sodium cyanoborohydride and acetic acid in a suitable solvent such as methanol to give intermediate 12. Amide coupling of amine intermediate 12 with carboxylic acid 4 can be accomplished through several possible conditions including, but not limited to, treatment of 4 with oxalyl chloride in DCM to give the acyl chloride, which can then be reacted with amine 12 in the presence of triethylamine in DCM to give amides of type 13. Staudinger reduction of 13 with an appropriate phosphine such as tributylphosphine in a solvent such as toluene gives the heteroaryl amine, which can be cyclized under a variety of conditions including, but not limited to, basic in THF, Lewis acidic, or acidic conditions such as aqueous TFA to give the desired diazepinedione compound I.

[0181] Scheme 3

[0182] [ka]

[0183] Scheme 3 illustrates a method for preparing compounds of formula II. Amino compounds 3 (preparation described in Scheme 1) and carboxylic acids 14, either commercially available or readily prepared by one skilled in the art, can be coupled to give acyl chlorides through several possible conditions, including but not limited to, treatment of 14 with oxalyl chloride in DCM, followed by reaction with amine 3 in the presence of triethylamine in DCM to give amides of type 15. Staudinger reduction of 15 with an appropriate phosphine, such as tributylphosphine, in a solvent such as toluene, gives heteroaryl amines, which can be cyclized under a variety of conditions, including but not limited to basic in THF, Lewis acidic, or acidic conditions such as aqueous TFA, to give diazepinedione intermediates 16. Hydrolysis of the ester affords R 5 Depending on the nature of R, this can be achieved under acidic or basic conditions. 5 When is t-butyl, hydrolysis can be accomplished using conditions including, but not limited to, dilute TFA in dichloromethane at a suitable temperature and time to afford the desired carboxylic acid 17. Amide coupling of amine intermediate 8 with carboxylic acid 17 can be achieved through several possible conditions including, but not limited to, utilization of 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 time to afford the desired amide product II.

[0184] Scheme 4

[0185] [ka]

[0186] Scheme 4 illustrates an alternative method of preparing compounds of formula II. Amino compounds 12 (preparation described in Scheme 2) and carboxylic acids 14, either commercially available or readily prepared by one skilled in the art, can be coupled to give acyl chlorides through several possible conditions, including but not limited to, treatment of 14 with oxalyl chloride in DCM, followed by reaction with amine 12 in the presence of triethylamine in DCM to give amides of type 18. Staudinger reduction of 15 with an appropriate phosphine, such as tributylphosphine, in a solvent such as toluene, gives heteroaryl amines, which can be cyclized under a variety of conditions, including but not limited to, basic in THF, Lewis acidic, or acidic conditions such as aqueous TFA, to give the desired diazepinedione compounds II.

[0187] Synthesis of Int2

[0188] [ka]

[0189] Synthesis of (R)-methyl 2-amino-3-(pyridin-2-yl)propanoate·2HCl (2): A solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(pyridin-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 added slowly at the same temperature. The reaction was stirred for 16 h and monitored by LCMS, which indicated consumption of starting material. The solvent was removed under reduced pressure and the crude product was triturated with diethyl ether (2 × 100 mL) and the solid was dried under vacuum to give (R)-methyl 2-amino-3-(pyridin-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), DMAP (7.78 g, 63.7 mmol) and the reaction was stirred for 10 min. Then, Boc2O (58.5 mL, 255 mmol) was added slowly at the same temperature (gas evolution was observed) and stirring was continued for 16 h at room temperature. The reaction was monitored by TLC and quenched with water. The reaction mixture was extracted with ethyl acetate (2×500 mL) and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was then purified by flash silica gel column chromatography eluting the product with 2-3% ethyl acetate in hexane to give 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 in portions (10 mL portions each) to the previous solution while maintaining the temperature below -65°C, the reaction mixture was stirred for 5 minutes, followed by the addition of DMF solution (8 mL). The addition was continued until complete addition of BuLi, and finally excess DMF (20 mL) was added to the reaction at -65°C. The reaction was then stirred for an additional 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), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography eluting the product with 3-4% ethyl acetate in hexanes to give 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-butyl 2-chloro-4-(((1-methoxy-1-oxo-3-(pyridin-2-yl)propan-2-yl)amino)methyl)benzoate (Int2): A solution of (R)-methyl 2-amino-3-(pyridin-2-yl)propanoate (2, 7.33 g, 29.1 mmol) in methanol (75 mL) was cooled to 0° C. and TEA (8.18 mL, 58.2 mmol) was added and stirred for 15 min followed by the addition of tert-butyl 2-chloro-4-formylbenzoate (5, 7.0 g, 29.0 mmol). The reaction was stirred for 1 h to give a clear solution, then NaCNBH3 (2.19 g, 34.9 mmol) was added and the reaction mixture was stirred for 15 min, followed by AcOH (1.33 mL, 23.3 mmol) and the reaction mixture was then stirred for 25-30 min and monitored by TLC. The reaction was quenched by the addition of 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 x 100 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by flash column chromatography eluting the product with 35-40% ethyl acetate in hexane to give (R)-tert-butyl 2-chloro-4-(((1-methoxy-1-oxo-3-(pyridin-2-yl)propan-2-yl)amino)methyl)benzoate (Int2, 5.6 g, 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]; 1H NMR (400 MHz, 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 = 8.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 8.45 (s, 1H). Note: Racemization was observed if the reaction was stirred for more than 30 min after 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) was added NaNO2 (6.58 g, 95.4 mmol) at 0 °C and the mixture was stirred for 30 min. The mixture was filtered to remove solids and the mother liquor was cooled to 0 °C followed by addition of NaN3 (5.0 g, 76.3 mmol) at 0 °C. The mixture was stirred for 30 min and the precipitated solid was filtered. The solid was then dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated to give a solid, triturated with pentane, and dried under vacuum to give methyl 3-azidothiophene-2-carboxylate (7, 9.5 g, 81%) as an off-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): To a solution of methyl 3-azidothiophene-2-carboxylate (7, 9.0 g, 49.1 mmol) in THF (45 mL) and methanol (45 mL) was added a solution of LiOH·HO (6.18 g, 147 mmol) in water (10 mL) at room temperature. The reaction mixture was stirred for 16 h when TLC showed consumption of starting material, the solvent was removed under reduced pressure, and then water (5 mL) was added, followed by HCl to bring the pH to about 2-3. The precipitated solid was then filtered, the solid was dissolved again in ethyl acetate, dried over anhydrous sodium sulfate, concentrated to give a solid, triturated with pentane, and dried under vacuum to give 3-azidothiophene-2-carboxylic acid (8, 8.0 g, 96%) as a white solid. Note: The solid should be properly dried to remove moisture before proceeding to the next step. 1 H NMR(400MHz,DMSO-d6) δ 7.07(d,J=5.2Hz,1H),7.85(d,J=5.6Hz,1H),13.24(br s,1H).

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

[0199] Synthesis of (R)-tert-butyl 4-((3-azido-N-(1-methoxy-1-oxo-3-(pyridin-2-yl)propan-2-yl)thiophene-2-carboxamido)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 min. A solution of 3-azidothiophene-2-carbonyl chloride (9, 2.22 g, 11.9 mmol) in dichloromethane (10 mL) was added slowly at the same temperature. The reaction was monitored by TLC, which showed consumption of starting material after 45 min. The reaction was quenched by 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 give the crude product. The crude product was then purified by flash silica gel column chromatography using 40-50% ethyl acetate in hexanes. The fractions containing the product were concentrated to give a solid, triturated with pentane and dried under vacuum to give (R)-tert-butyl 4-((3-azido-N-(1-methoxy-1-oxo-3-(pyridin-2-yl)propan-2-yl)thiophene-2-carboxamido)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-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoate (11): To a solution of (R)-tert-butyl 4-((3-azido-N-(1-methoxy-1-oxo-3-(pyridin-2-yl)propan-2-yl)thiophene-2-carboxamido)methyl)-2-chlorobenzoate (10, 5.0 g, 8.9 mmol) in toluene (50 ml) was added tributylphosphine (2.66 g, 10.7 mmol) at room temperature and the mixture was stirred at 70° C. for 16 hours. After consumption of starting material as confirmed by TLC, the solvent was removed under reduced pressure to give the crude product. The crude product was then dissolved in THF (50 mL), water (5 mL) and treated with TFA (5 mL) at room temperature. The mixture was stirred for 12 h, then quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 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 give (R)-tert-butyl 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoate (11, 4.0 g, 89%) as an off-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-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoic acid (12): (R)-tert-butyl 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoate (11, 4.0 g, 8.03 mL) in dichloromethane (40 mL). A solution of (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoic acid TFA salt (12, 4.0 g, 100%) was cooled to 0° C. followed by the addition of TFA (4 mL). The reaction was then stirred for 2 h when TLC indicated consumption of starting material. The solvent was then removed under reduced pressure and triturated with diethyl ether (2×25 mL) to give (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoic acid TFA salt (12, 4.0 g, 100%) as an off-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 in CO2 / MeOH (60:40), 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-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide (Example 1): A solution of (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)benzoic acid·TFA salt (12, 2.9 g, 6.56 mmol) in THF (30 mL) was stirred for 10 min, then cooled to 0 °C and treated with DIPEA (3.5 mL, 19.68 mmol) and stirred for 15 min when a clear solution was observed. Then HATU (3.74 g, 9.84 mmol) was added to the above reaction at 0° C. and cooling was removed after 10 min. The mixture was stirred at room temperature for 15 min, a solution of 4-methoxy-2-aminopyridine (13, 0.98 g, 7.87 mmol) dissolved in THF (5 mL) was added and the reaction mixture was stirred at 70° C. for 16 h. After the reaction was completed as monitored by TLC and LCMS, the reaction mixture was cooled to room temperature and 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 over 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 eluent to give (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-4(5H)-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide (Example 1, 2.6 g, 36%) as a white solid. The reaction was run twice on a 2.9 g scale and both batches were combined and the compound was purified to give 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 pure product. 2. The HATU complex of the acid is very stable and will remain in the reaction if the amine is less reactive. If the complex remains, the temperature may be increased to 75-80°C.

[0203] Synthesis of Int6

[0204] [ka]

[0205] Synthesis of 4-bromo-2-chloro-N-(4-methoxypyridin-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 min, then 2-amino-4-methoxypyridine (13, 23.7 g, 191 mmol) was added and the reaction mixture was heated at 75° C. for 16 h. After completion as monitored by TLC, the reaction was quenched with ice and stirred for 15 min. The precipitated solid was filtered and washed with water, followed by dissolving the solid in ethyl acetate and drying over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was triturated with pentane to give 4-bromo-2-chloro-N-(4-methoxypyridin-2-yl)benzamide (15, 40.0 g, 92%) as an off-white solid. LCMS(ES) m / z=341.16[M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 6.78 (dd, J = 5.6 and 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.0 and 1.6 Hz, 1H), 7.79 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 11.02 (s, 1H).

[0206] Synthesis of 2-chloro-N-(4-methoxypyridin-2-yl)-4-vinylbenzamide (16): A solution of 4-bromo-2-chloro-N-(4-methoxypyridin-2-yl)benzamide (15, 38 g, 111 mmol) in DMF (200 mL) was treated with tributyl(vinyl)tin (38.8 g, 122 mmol) and the mixture was degassed with argon for 10 min followed by the addition of tetrakis(triphenylphosphine)palladium(0) (6.43 g, 5.56 mmol). The reaction was degassed with argon for an additional 5 min and then heated at 110° C. for 16 h. The reaction was monitored by TLC which indicated completion of starting material, the reaction was cooled to room temperature and ethyl acetate was added. The solid was filtered over a bed of Celite, the Celite bed was washed with ethyl acetate, the organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the crude product, which was purified by silica gel column chromatography eluting the product with 20-25% ethyl acetate in hexanes. The solvent was removed under reduced pressure to give 2-chloro-N-(4-methoxypyridin-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-methoxypyridin-2-yl)benzamide (17): To a solution of 2-chloro-N-(4-methoxypyridin-2-yl)-4-vinylbenzamide (16, 20 g, 69.3 mmol) in THF (50 mL) and water (50 mL) at 0° C., OsO4 (25 mL, 4% solution in water) was added and the reaction mixture was stirred for 2 h. To the above reaction was slowly added NaIO4 (44.4 g, 208 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was monitored by TLC and LCMS, which showed consumption of starting material and 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 over sodium sulfate. The solvent was removed under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting the product with 40-45% ethyl acetate in hexanes, triturated with diethyl ether to remove non-polar impurities (if present), and the solid was dried under high vacuum to give 2-chloro-4-formyl-N-(4-methoxypyridin-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-methoxypyridin-2-yl)carbamoyl)benzyl)amino)-3-(pyridin-2-yl)propanoate (Int6): (R)-Methyl 2-amino-3-(pyridin-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 min, then 2-chloro-4-formyl-N-(4-methoxypyridin-2-yl)benzamide (17, 5.0 g, 17.2 mmol) was added and the reaction was stirred for 45 min. To the above reaction, NaCNBH3 (1.62 g, 25.7 mmol) was added in portions over 5 min, the mixture was stirred for 10 min, followed by the addition of acetic acid (1.0 g, 17.2 mmol). The reaction was then stirred for 30 min when TLC showed most of the starting material was consumed and the reaction was quenched with NaHCO3 solution and water. Methanol was removed under reduced pressure, then the mixture was extracted with ethyl acetate (2 x 200 mL) and the organic layer was washed with brine, 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 silica gel column chromatography eluting the product with 80-90% ethyl acetate in hexane to obtain (R)-methyl 2-((3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)amino)-3-(pyridin-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 (4.6X250) mm, 5μ, 0.2% TEA in CO2 / MeOH (60:40), flow rate 3mL / 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): 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) was added compound 1 (100 g, 793 mmol, 1 eq) in portions at 25 °C. The resulting solution was stirred at 35 °C for 1 h. The reaction was then heated to 75 °C and stirred at 75 °C for 2 h. TLC showed that the starting material was completely consumed. The reaction 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 give 1-methyl-4-nitro-1H-pyrazole-5-carboxylic acid (19, 90 g, 526 mmol, 66.3% yield) 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 h. A sample was taken (quenched with MeOH) and TLC (petroleum ether:ethyl acetate = 0:1, R of 19) was performed. f is 0.3, and the R f was 1.0) indicated complete consumption of the starting material. The reaction was concentrated in vacuo to give 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-methoxypyridin-2-yl)carbamoyl)benzyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamido)-3-(pyridin-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) was added a solution of 1-methyl-4-nitro-1H-pyrazole-5-carbonyl chloride (20, 89 g, 470 mmol, 1 eq) in DCM (200 mL) dropwise at 25° C. The resulting solution was stirred at 25° C. for 1 h. LCMS showed that the starting material was completely consumed. The reaction 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 over anhydrous Na2SO4, and concentrated under vacuum to give the crude product. The crude product was dissolved in EtOAc (1.5 L) at 25°C. The resulting solution was stirred at 10°C for 5 h to give a brown suspension. The suspension was filtered and the filter cake was rinsed with EtOAc (200 mL). The filter cake was dried under vacuum to give methyl (R)-2-(N-(3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamide)-3-(pyridin-2-yl)propanoate (21, 180 g, 296 mmol, 63.1% yield) as an off-white solid. LCMS(ES) m / z=608.3[M+H] + .

[0214] Synthesis of (R)-2-chloro-N-(4-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide (Example 2): Synthesis of methyl (R)-2-(N-(3-chloro)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide (Example 2) in MeOH (1 L) and HO (250 mL). To a solution of -4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)-1-methyl-4-nitro-1H-pyrazole-5-carboxamido)-3-(pyridin-2-yl)propanoate (21, 180 g, 296 mmol, 1 eq) and NH4Cl (127 g, 2.37 mol, 8 eq) was added Zn (96.8 g, 1.48 mol, 5 eq) portionwise at 25° C. The resulting suspension was stirred at 25° C. for 3 h. LCMS showed that the starting material was completely consumed. The reaction was filtered through Celite. The filter cake was rinsed with THF (500 mL). The filtrate was concentrated under vacuum to give a yellow solid (170 g, crude). A solution of the crude yellow solid (170 g, 294 mmol, 1 eq) in THF (1 L) was stirred at 65° C. for 12 h. TLC (dichloromethane:methanol=10:1, R f is 0.5, and R in Example 2 f The solubility in water was 0.75), indicating complete consumption of the starting material. The reaction was cooled to 25° C. and filtered through Celite. The filter cake was rinsed with THF (300 mL). The filtrate was concentrated in vacuo to give 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 give (R)-2-chloro-N-(4-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide (Example 2, 135 g, 247 mmol, 71.5% yield) 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 H NMR (400 MHz, DMSO-d6) δ 2.85-3.25 and 3.56-3.68 (m, 2H), 3.84 (s, 3H), 4.04 and 4.06 (2 x s, 3H), 4.60-5.15 (m, 3H), 6.76 (dd, J = 5.6 and 2.0 Hz, 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 = 6.0 Hz, 1H), 8.38 and 8.48 (m, 1H), 10.49 and 10.66 (2 x s, 1H), 10.93 (s, 1H).

[0215] Example 3 General method C

[0216] [ka]

[0217] [ka]

[0218] Synthesis of 3-amino-5-chloropicolinonitrile (23): To a solution of 5-chloro-3-nitropicolinonitrile (22, 50 g, 0.273 mol) in acetic acid (250 mL) cooled to 0° C., iron powder (76.5 g, 1.36 mol) was added slowly in portions. The reaction was then stirred for 2 hours when TLC indicated consumption of starting material. The reaction mixture was then filtered over a bed of celite and the bed of celite was washed with methanol. The combined mother liquor was evaporated under reduced pressure and the crude product was dissolved in ethyl acetate followed by washing 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 give 3-amino-5-chloropicolinonitrile (26, 40.0 g, 96%) as an off-white solid.

[0219] Synthesis of 3-amino-5-chloropicolinic acid as the 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 h. After completion as confirmed by TLC, the volatiles were removed under reduced pressure to give 3-amino-5-chloropicolinic acid as the diHCl 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) was added K2CO3 (98 g, 0.711 mol) at 0 °C. The reaction was stirred for 15 min and then methyl iodide (67.3 g, 0.474 mol) was added at 0 °C. The reaction was then stirred for 12 h and monitored by TLC and LCMS which showed consumption of starting material. The reaction was quenched with water and extracted with ethyl acetate (3 x 600 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the crude product and the product was purified by silica gel column chromatography eluting with 40-50% ethyl acetate in hexane to give 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 min. The particles were removed by filtration and the mother liquor was cooled to 0 °C followed by the addition of NaN3 (22.4 g, 0.344 mol) at 0 °C. The mixture was stirred for 30 min and the precipitated solid was filtered. The mother liquor was extracted with ethyl acetate (2 x 300 mL) and the solid was also dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give a solid, which was triturated with pentane and dried under vacuum to give methyl 3-azido-5-chloropicolinate (26, 28 g, 77%) as an off-white solid.

[0222] Synthesis of 3-azido-5-chloropicolinic acid (27): To a solution of methyl 3-azido-5-chloropicolinate (26, 28.0 g, 0.132 mol) in THF (140 mL), methanol (140 mL), a solution of LiOH·HO (22.2 g, 0.528 mol) in water (80 mL) was added and the reaction mixture was stirred for 16 h. After completion of the reaction as monitored by TLC, the solvent was removed under reduced pressure and the crude product was again dissolved in water (100 mL), cooled to 0 °C and treated with HCl to pH about 4-5. The mixture was stirred for 10 min, then extracted with ethyl acetate (3 × 300 mL), dried over anhydrous sodium sulfate and the solvent was removed to give a solid. The solid was triturated with pentane and dried under high vacuum to give 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), oxalyl chloride (4.23 g, 0.33 mol) was added at 0° C., followed by 4 drops of dimethylformamide. The reaction mixture was then stirred at room temperature for 2 h when TLC indicated consumption of starting material and quenched with methanol. Volatiles were removed under reduced pressure and the crude product was dried under high vacuum to give 3-azido-5-chloropicolinoyl chloride (28, 6.2 g) as a red-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-methoxypyridin-2-yl)carbamoyl)benzyl)picolinamido)-3-(pyridin-2-yl)propanoate (29): A solution of (R)-methyl 2-((3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)amino)-3-(pyridin-2-yl)propanoate (Int6, 4.9 g, 0.0108 mol) in dichloromethane (40 mL) was cooled to 0° C., DIPEA (2.8 mL, 0.016 mmol) was added, and the mixture was stirred for 10 min. A solution of 3-azido-5-chloropicolinoyl chloride (28, 2.5 g, 0.0115 mol) in dichloromethane (5 mL) was added slowly at the same temperature. The reaction was monitored by TLC, which showed consumption of starting material after 45 min. 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 give the crude product. The crude product was then purified by flash silica gel column chromatography using 70-80% ethyl acetate in hexanes. The fractions containing the product were concentrated to give a solid, triturated with pentane, and dried under vacuum to give (R)-methyl 2-(3-azido-5-chloro-N-(3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)picolinamido)-3-(pyridin-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-methoxypyridin-2-yl)carbamoyl)benzyl)picolinamido)-3-(pyridin-2-yl)propanoate (30): A solution of (R)-methyl 2-(3-azido-5-chloro-N-(3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)picolinamido)-3-(pyridin-2-yl)propanoate (29, 3.9 g, 6.15 mmol) in toluene (35 mL) was treated with tributylphosphine (1.57 g, 7.38 mmol) at room temperature and the mixture was stirred at 70° C. for 16 hours. After consumption of starting material as confirmed by TLC, the solvent was removed under reduced pressure to give the crude product. The crude product was then dissolved in THF (10 mL), water (5 mL), treated with TFA (3 mL) at room temperature and stirred for 30 min. 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 over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting the product with 75-85% ethyl acetate in hexane to give (R)-methyl 2-(3-amino-5-chloro-N-(3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)picolinamido)-3-(pyridin-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-(pyridin-2-ylmethyl)-2,3-dihydro-1H-pyrido[3,2-e][1,4]diazepin-4(5H)-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide (Example 3): To a solution of (R)-methyl 2-(3-amino-5-chloro-N-(3-chloro-4-((4-methoxypyridin-2-yl)carbamoyl)benzyl)picolinamido)-3-(pyridin-2-yl)propanoate (30, 2.7 g, 4.44 mmol) in tert-butyl alcohol (4 mL) was added triethylamine (4 mL). The reaction mixture was then heated at 100-120 °C for 72 h when TLC and LCMS indicated consumption of starting material. The mixture was then cooled to room temperature and quenched with water (20 mL) followed by extraction with ethyl acetate. The organic layer was separated, the aqueous layer back extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting the product with 2-5% methanol in ethyl acetate to give 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-pyrido[3,2-e][1,4]diazepin-4(5H)-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide (Example 4 racemic, 0.80 g) as an off-white solid. The compound was then purified by chiral preparative HPLC to give the desired isomer, (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-pyrido[3,2-e][1,4]diazepin-4(5H)-yl)methyl)-N-(4-methoxypyridin-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(4.6X250)mm, 5μ,Mobile phase: 0.2% TEA in CO2 / MeOH(60:40),Flow rate: 3.0mL / min,Flow mode: Isostatic,Column temperature: 35℃,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 selected examples and the ECs according to the cell-based morphology assay protocol described below. 50 Contains the value. EC 50 Values ​​are designated as A, B, or C, where A<0.1 μM, B=0.1-0.99 μM, C=1.0-9.9 μM, and D=10-20 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 Exemplary compounds of the present disclosure were tested in a cell-based morphology assay and the assay results, along with other analytical data, are reported in Table 1.

[0263] Cell-based assay details: Exemplary compounds of the present disclosure were tested in the Clostridium difficile toxin B morphological profiling assay and the results are reported in Table 1 along with other analytical data. Morphological outcomes induced by human umbilical vein endothelial cells (HUVECs) exposed to TCdB were assessed using an experimental protocol adapted from patent reference Bray et al., Nat Protoc. 2016 Sep;11(9):1757-1774 and quantified using Recursion's proprietary image analysis method described in US Patent No. 10,146,914. HUVECs (Lonza) were seeded in 1536-well microtiter plates (789866, Greiner bio-one) coated with PDL and collagen and incubated in EGM2 (Lonza) at 37C and 5% CO2 atmosphere for 24 hours. After 24 hours of incubation, HUVECs were pretreated with compounds dissolved in DMSO and exposed to 5ng / mL of TCdB (ListLabs) using an Echo acoustic dispenser (Labcyte). Upon completion of TCdB incubation 24 hours after toxin exposure, cells were treated with Mitotracker Deep Red (Invitrogen) and 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 images were processed in Cell Profiler to bring out 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 that rate all wells in the assay on a 0-1 scale (0 being healthy and 1 defined as toxin-treated). Profiles from compound-treated toxin exposure are projected onto this axis to approximate the level of similarity of the well to disease or healthy. Compound values ​​are then fitted to a four-parameter log agonist response equation to obtain the EC 50 Calculate the value.

[0264] Other features of the present disclosure will become apparent in the course of the above description of exemplary embodiments, which are presented for the purpose of illustrating the present disclosure and are not intended to be limiting thereto. The present disclosure may be embodied in other specific forms without departing from its spirit or essential attributes. The present disclosure includes all combinations of the preferred aspects of the present disclosure described herein. It should be understood that any and all embodiments of the present disclosure may be combined with other embodiment(s) to describe additional embodiments. It should also be understood that each individual element of an embodiment is an independent embodiment in itself. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe additional embodiments.

Claims

1. A compound of formula (I), 【Chemistry 1】 or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof, wherein: X １ , X ２ , and X ３ However, each independently, CR ２ , N.R. ５ , O, or S; X ４ and X ５ are each independently C or N; m is an integer of 0, 1, or 2; Z is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S; R １ and R ２ each independently represents hydrogen, halo, cyano, hydroxyl, amino, C １－６ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R ３ and R ４ each independently represents hydrogen, C １－６ alkyl, alkylamino, haloalkyl, alkoxy, haloalkoxy, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, 3-10 membered carbocyclyl, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein said aryl, heteroaryl, carbocyclyl, and heterocyclyl are independently selected from 0-5 R ５ is replaced by R ５ is 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 is hydrogen or C １－６ or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof, wherein: 【Request 2】 【Chemistry 2】 The part is, 【Chemistry 3】 2. The compound, stereoisomer, tautomer, salt or solvate of claim 1,

3. R ３ is hydrogen, R ４ but, 【Chemistry 4】 and m is an integer of 0, 1, or 2.

4. 2. The compound, stereoisomer, tautomer, salt, or solvate of claim 1, represented by formula (Ia), (Ib), (Ic), (Id), (Ie), or (If): 【Chemistry 5】 。

5. R ３ is hydrogen, R ４ but, 【Chemistry 7】 2. The compound, stereoisomer, tautomer, salt, or solvate of claim 1, wherein:

6. A compound represented by formula (II) or a stereoisomer, tautomer, or pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 12】 、 During the ceremony, Y １ , Y ２ , and X ３ However, each independently, CR ２ or N, with the proviso that at least one Y １ , Y ２ , and Y ３ is N, X ４ and X ５ are each independently C or N; m is an integer of 0, 1, or 2; Z is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S; R １ and R ２ each independently represents hydrogen, halo, cyano, hydroxyl, amino, C １－６ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R ３ and R ４ each independently represents hydrogen, 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 carbocyclyl, or 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, wherein said aryl, heteroaryl, carbocyclyl, and heterocyclyl are independently selected from 0-5 R ５ is replaced by R ５ is 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 is hydrogen or C １－６ is alkyl, The dashed circle is Y １ , Y ２ , Y ３ and an aromatic ring formed by carbon atoms. 【Request 7】 【Chemical 13】 The part is, 【Chemistry 14】 7. The compound, stereoisomer, tautomer, salt, or solvate of claim 6, wherein:

8. R ３ is hydrogen, R ４ but, 【Chemistry 15】 and m is an integer of 0, 1, or 2.

9. R ３ is hydrogen, R ４ but, 【Chemistry 16】 7. The compound, stereoisomer, tautomer, salt, or solvate of claim 6, wherein:

10. 7. The compound, stereoisomer, tautomer, salt, or solvate of claim 6, represented by formula (IIa), formula (IIb), formula (IIc), or formula (IId). 【Chemistry 17】 【Request 11】 【Chemical 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 2. The compound, stereoisomer, tautomer, salt, or solvate of claim 1 selected from: 【Request 12】 【Chemical 12-1】 7. The compound, stereoisomer, tautomer, salt, or solvate of claim 6 selected from: Claim 13: (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; (R)-2-chloro-N-(4-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide; (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((7-methyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methylpyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(1H-pyrrolo[2,3-c]pyridin-5-yl)benzamide; (R)-2-chloro-N-(4-cyclopropylpyridin-2-yl)-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)benzamide; (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(6-methoxypyrimidin-4-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(imidazo[1,2-a]pyrazin-8-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(imidazo[1,5-a]pyrazin-8-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(1H-pyrazolo[3,4-c]pyridin-5-yl)benzamide; 2-chloro-N-(4-cyclopropoxypyridin-2-yl)-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridazin-3-yl)benzamide; 4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-3-fluoro-N-(pyridin-2-yl)benzamide; 4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-3-fluoro-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-N-(4-(difluoromethoxy)pyridin-2-yl)-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-(trifluoromethoxy)pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(imidazo[1,2-a]pyrazin-6-yl)benzamide; 4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-3-fluoro-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 6-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)nicotinamide; 5-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)picolinamide; 5-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridin-2-yl)picolinamide; 2-chloro-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-N-(5-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide; 2-chloro-4-((5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((2-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(pyridin-2-yl)benzamide; 6-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)nicotinamide; 6-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridin-2-yl)nicotinamide; 5-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)picolinamide; 2-chloro-N-(4-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide; 2-chloro-4-((5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((2-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(4H)-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-N-(4-methoxypyridin-2-yl)-4-((2-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(4H)-yl)methyl)benzamide; 2-chloro-N-(5-methoxypyridin-2-yl)-4-((2-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(4H)-yl)methyl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,4-e][1,4]diazepin-4(5H)-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-thieno[3,4-e][1,4]diazepin-4(5H)-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((7-cyclopropyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((7-cyclopropyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 4-((7-(tert-butyl)-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-2-chloro-N-(pyridin-2-yl)benzamide; 4-((7-(tert-butyl)-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-2-chloro-N-(4-methoxypyridin-2-yl)benzamide; 4-((7-(tert-butyl)-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-2-chloro-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-N-(4-methoxypyridin-2-yl)-4-((2-methyl-4,7-dioxo-6-(pyridin-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepin-5(4H)-yl)methyl)benzamide; 2-chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(4H)-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-2,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(4H)-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-N-(4-methoxypyridin-2-yl)-4-((2-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)benzamide; 2-chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(pyridin-2-yl)benzamide; 4-((2-(tert-butyl)-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-2-chloro-N-(pyridin-2-yl)benzamide; 4-((2-(tert-butyl)-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-2-chloro-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((4,7-dioxo-6-(pyridin-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepin-5(4H)-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((4,7-dioxo-6-(pyridin-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepin-5(4H)-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((4,7-dioxo-6-(pyridin-2-ylmethyl)-2,6,7,8-tetrahydropyrazolo[3,4-e][1,4]diazepin-5(4H)-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((7-cyclopropyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydroimidazo[4,5-e][1,4]diazepin-7(1H)-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-N-(4-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydroimidazo[4,5-e][1,4]diazepin-7(1H)-yl)methyl)benzamide; 2-chloro-4-((2-cyclopropyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydro-7H-thiazolo[4,5-e][1,4]diazepin-7-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydroimidazo[4,5-e][1,4]diazepin-7(1H)-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; Ethyl 6-(2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)benzamido)nicotinate; 6-(2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)benzamido)methyl nicotinate; (R)-4-((7-bromo-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-2-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; 4-((7-bromo-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-2-chloro-N-(pyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxy-5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methyl-5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((7-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridazin-3-yl)benzamide; (S)-2-chloro-N-(4-methoxypyridin-2-yl)-4-((1-methyl-5,8-dioxo-6-(pyridin-2-ylmethyl)-4,5,6,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-7(1H)-yl)methyl)benzamide; and, (R)-2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-thieno[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridazin-3-yl)benzamide 2. The compound, stereoisomer, tautomer, salt, or solvate of claim 1 selected from: Claim 14: (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridin-2-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-N-(4-methoxypyridin-2-yl)-4-((8-methyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepin-4-yl)methyl)benzamide; 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(pyridin-2-yl)benzamide; 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide; 2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridazin-3-yl)benzamide; 2-chloro-4-((2,5-dioxo-3-(pyridin-2-ylmethyl)-8-(trifluoromethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-methoxypyridazin-3-yl)benzamide; (S)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(4-methoxypyridin-2-yl)benzamide; and, (R)-2-chloro-4-((8-chloro-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,5-tetrahydro-4H-pyrido[3,2-e][1,4]diazepin-4-yl)methyl)-N-(5-(trifluoromethyl)pyridin-2-yl)benzamide 7. The compound, stereoisomer, tautomer, salt, or solvate of claim 6 selected from:

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

16. A method for making 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, comprising: 【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 coupled by reductive amination to provide intermediate 3; Amide coupling of intermediate 3 with carboxylic acid 4 provides amide 5; Reduction of amide 5 provides diazepinedione 6, Diazepinedione 6 is hydrolyzed to give carboxylic acid 7, Amide coupling of amine intermediate 8 with carboxylic acid 7 gives product I, In Scheme 2, Amide coupling of amine intermediate 8 with carboxylic acid 9 provides intermediate 10; Vinylation of intermediate 10 followed by oxidative cleavage provides aldehyde intermediate 11; coupling intermediate 11 with intermediate 2 to provide intermediate 12; Amide coupling of intermediate 12 with carboxylic acid 4 to provide amide 13; and The amide 13 is reduced to give the product I.

17. 15. A pharmaceutical composition for inhibiting C. difficile bacterial toxins in a cell, comprising a compound, stereoisomer, tautomer, or solvate according to any one of claims 1 to 14.

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

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