Inhibitors of infectious molluscum contagiosum and methods using the same

Abstract

The present disclosure provides novel compounds, compositions, and methods for treating, preventing, and / or ameliorating orthopoxvirus infections in subjects in need thereof. In certain embodiments, the orthopoxvirus infection is caused by molluscum contagiosum. TIFF2025517991000412.tif159128

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 344,874, filed on May 23, 2022, and the entire disclosure of that application is hereby incorporated by reference herein in its entirety.

[0002] Description of Research and Development Sponsored by the Federal Government This invention was made with government support under grants AI125005 and AI162385 awarded by the National Institutes of Health. The government has certain rights in the invention.

Background Art

[0003] Background Molluscum contagiosum (MC) is a skin disease caused by the Molluscum contagiosum virus (MCV), which is a poxvirus. MC presents as skin lesions that can last for months to years before resolving. MC lesions occur on the skin of children, adults, and immunosuppressed individuals. MCV is transmitted by direct skin - to - skin contact, sexual contact, self - inoculation by scratching lesions, and indirect inoculation from contaminated fomites. Lesions may become painful after treatment intended to suppress transmission. Lesions can also be psychologically distressing, especially when scarring occurs. MC occurs in 2 - 10% of the world's population and accounts for approximately 1% of all diagnosed skin diseases in the United States, approaching 5% in children. In immunocompromised individuals, this infectious disease can be both severe and prolonged. 5% - 18% of HIV patients have MC. In many cases, severe MC disease in AIDS patients begins to resolve while on highly active antiretroviral therapy (HAART). However, cases have been reported where MC lesions develop soon after the start of HAART, suggesting that immune reconstitution inflammatory syndrome (IRIS) may be involved in the re - emergence of MCV.

[0004] Current treatments for MC typically employ physical therapy or chemical agents, but these are not uniformly effective or safe, often unable to completely remove lesions and sometimes leaving scars. Furthermore, the broad-spectrum antiviral drug cidofovir, a dCMP analog (i.e., 1-((3-hydroxy-2-phosphonylmethoxy)propyl)cytosine), has been effectively used as a topical or intravenous agent for MC in immunocompromised patients. However, this drug has side effects, including for topical treatment, inflammation, ulceration and pain, and for systemic application, the potential for nephrotoxicity. To date, no antiviral therapeutic agents have been approved for specific treatment of MC. Development of such effective and safe treatments has been mainly hindered by the inability of MCV to grow in culture.

[0005] Processivity factors (PFs) are attractive antiviral therapeutic targets. Their function is to tether DNA polymerase (Pol) to the template and enable synthesis of the growing strand. PFs are specific for their cognate DNA Pol and are essential for DNA synthesis. All DNA Pols from phage to human function with a single cognate PF. However, poxviruses, including vaccinia virus (VV) and MCV, are somewhat special in that a heterodimer containing the A20 and D4 viral proteins constitutes the functional PF. D4, which can also function as a uracil DNA glycosylase repair enzyme, binds to its PF partner A20 but not to E9 Pol. On the other hand, A20 binds to both E9 and D4, suggesting that it functions, in part, as a bridge indirectly connecting D4 to E9.

[0006] D4 is also an attractive antiviral target because it is absolutely necessary for DNA synthesis by both MCV and VV (vaccinia virus). In particular, in in vitro DNA synthesis reactions, MCV D4 (mD4) can be equivalently replaced with VV D4 (vD4). This is consistent with mD4 having 55% amino acid sequence identity and 82% similarity to VV. Furthermore, the virtual 3-D structure of mD4 overlaps with the known crystal structure of vD4.

[0007] Thus, there is a need in the art for compounds that can be used to treat, prevent, and / or ameliorate MC infections in humans, and methods of using the same. The present disclosure addresses this need. SUMMARY OF THE INVENTION

[0008] Summary In one aspect, the present disclosure relates to a compound of formula (I), or a salt, solvate, enantiomer, diastereoisomer, geometric isomer, isotopologue, or tautomer thereof, TIFF2025517991000002.tif16128 wherein T 1 is TIFF2025517991000003.tif4128 and T 2 is R 3 or T 1 is R 3 and T 2 is TIFF2025517991000004.tif4128; R 1 is TIFF2025517991000005.tif4128; A 1 is TIFF2025517991000006.tif17128 and is selected from the group consisting of bonds; A 2 is Selected from the group consisting of TIFF2025517991000007.tif15128 and a combination; A 3 is Selected from the group consisting of TIFF2025517991000008.tif15128 and a combination; A 4 is Selected from the group consisting of TIFF2025517991000009.tif18128 and Y; L 1 , L 2 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 4f , R 4h , R 5a , R 5b , R 5c , R 5d , R 5e , m1, m2, m3, m4, X, and Y are each defined elsewhere in this specification.

[0009] In certain embodiments, the compound of formula (I) is a compound of formula (Ia) Of TIFF2025517991000010.tif15128.

[0010] In certain embodiments, the compound of formula (I) is a compound of formula (Ib) Of TIFF2025517991000011.tif15128.

[0011] In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable excipient.

[0012] In another aspect, the disclosure provides a method of treating, ameliorating, and / or preventing an orthopoxvirus infection in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one of a therapeutically effective amount of a compound of formula (I) of the disclosure or a pharmaceutical composition.

[0013] In certain embodiments, orthopoxvirus infections are caused by molluscum contagiosum virus (MCV).

[0014] In certain embodiments, the compound or pharmaceutical composition of formula (I) is administered topically. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The following detailed description of certain embodiments of the disclosure will be better understood when read in conjunction with the accompanying drawings. For purposes of illustration of the disclosure, certain embodiments are shown in the drawings. However, it should be understood that the disclosure is not limited to the exact arrangements and instrumentalities shown in the embodiments of the drawings.

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Mode for Carrying Out the Invention

[0016] Detailed Description The present invention relates, in part, to the unexpected discovery of novel inhibitors of molluscum contagiosum virus (MCV) infection in humans. MCV infects only humans, and the viral infection is limited to the skin and not systemic. In certain embodiments, any of the inhibitors described herein also block vaccinia, a prototype poxvirus. In another embodiment, other poxviruses, including but not limited to camelpox virus, cowpox virus, ectromelia virus, horsepox virus, monkey pox virus, raccoon pox virus, squirrel pox virus, variola major virus, yaba-like disease virus, deerpox virus, fowlpox virus, myxoma virus, orf virus, swinepox virus, can be inhibited by the compounds described herein.

[0017] In certain embodiments, the disclosed compounds or any composition containing them, when applied to the skin of an infected human, treat, prevent, and / or ameliorate MCV infection. In yet another embodiment, the disclosed compounds or any composition containing them are applied to at least one MCV lesion on the skin of an infected human.

[0018] Processivity factors (PFs) are essential for viral replication. DNA polymerases (Pol) from viruses to mammals cannot synthesize DNA in the absence of PF. Since viral PFs have no cellular homologs, they are specific drug targets. The catalytic efficiency of DNA Pol requires that they function continuously (i.e., they must be able to continuously incorporate nucleotides without dissociating from the template). The catalytic efficiency of Pol is achieved by binding Pol to its cognate PF that tethers Pol to DNA such that the rate of Pol nucleotide incorporation exceeds the rate of Pol dissociation from this template. Tethering of poxvirus E9 Pol to the DNA template by the D4 processivity factor and the A20 bridging protein is essential for the synthesis of extended DNA (FIGS. 1A-1B).

[0019] The crystal structure of D4 has played an important role in elucidating its role in processivity. Mutational and biophysical analyses have revealed that there are three amino acids (i.e., GFI) at the C-terminus of D4, which can induce self-folding by contacting amino acid residues located within its inner core. Point mutations and therapeutic interventions of GFI can disrupt the folding of D4 and abrogate processive DNA synthesis (Figure 2).

[0020] U.S. Patent Application No. 63 / 248,670, which is hereby incorporated by reference in its entirety, describes the identification and development of a specific class of substituted heterocycles, including substituted thiophenes, that can inhibit the folding and / or processivity of D4 and, thus, are suitable for the treatment, prevention, and / or amelioration of orthopoxviruses, including, without limitation, molluscum contagiosum virus (MCV), camelpox virus, vaccinia virus, mousepox virus, horsepox virus, monkeypox virus, arctic ground squirrelpox virus, tanapox virus, variola (smallpox) virus, yokaipox virus, celipox virus (cowpox), avipox virus (fowlpox), capripox virus (goatpox), lepripox virus (myxoma virus), parapox virus (orf virus), suipox virus (swinepox), and yatapox virus (yaba-like disease virus).

[0021] Compound 6407 was shown to block mD4-dependent processive DNA synthesis (IC 50 = 16.4 μM) and infection of the alternative virus mD4-VV (EC 50 = 21 μM) in vitro. 6407 showed specificity for preventing herpesvirus cell infection but cytotoxicity was observed (CC 50 = 30 μM), due to its low selectivity index (SI) of less than 2. The tetrasubstituted thiophene of compound 6407 was systematically modified at each of its four positions as well as the central thiophene ring itself, and compound 7269 (Figure 3) had IC 50 = 6.8 μM, EC 50 = 13.2 μM, CC 50= It emerged as an mD4 target lead compound with 103.2 μM. Compound 7269 also showed specificity against the alternative virus mD4-VV. The SI = 7.8 was improved, but the CC of compound 7269 50 showed the same toxicity as compound 6407.

[0022] Thus, the present disclosure relates, in part, to the development of antiviral agents having improved and / or desirable pharmacological properties, including, without limitation, low toxicity, high bioavailability, and / or high potency compared to compounds known in the art.

[0023] Definitions As used herein, the following terms have the meanings respectively associated with each term in this section.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but exemplary methods and materials are described below.

[0025] Generally, the nomenclature used herein and the experimental procedures in pharmacy and organic chemistry are those well known and commonly employed in the art.

[0026] As used herein, the articles "a" and "an" refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0027] As used herein, the term "about" is understood by one of ordinary skill in the art and varies somewhat depending on the context in which it is used. As used herein when referring to measurable values such as amounts, lengths of time, etc., the term "about" is meant to encompass variations of ±20%, or ±10%, in certain other embodiments ±5%, in yet other embodiments ±1%, and in still other embodiments ±0.1% from the specified value, and such variations are suitable to practice the disclosed methods.

[0028] As used herein, the term "D4" refers to the D4 processability factor. Further, as used herein, the term "mD4" refers to the molluscum D4 processability factor.

[0029] As used herein, "disease" is the health condition of a subject in which the subject cannot maintain homeostasis and, if the disease is not improved, the subject's health continues to deteriorate.

[0030] As used herein, "disorder" in a subject is a health condition in which the subject can maintain homeostasis, but the subject's health condition is less favorable than it would be in the absence of the disorder. The disorder does not necessarily cause a further decline in the subject's health if left untreated.

[0031] As used herein, "ED 50 " or "ED50" refers to the effective dose of a formulation that produces about 50% of the maximum effect in a subject to whom the formulation is administered.

[0032] As used herein, an "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" of a compound is an amount of the compound sufficient to provide a beneficial effect to a subject to whom the compound is administered.

[0033] As used herein, an "Instructional Material" can include a document, audio guide, chart, or any other medium of expression used to convey the utility of the compositions and / or compounds of the present disclosure within a kit. The Instructional Material of a kit may, for example, be attached to a container containing a compound and / or composition of the present disclosure or may be shipped together with a container containing the compound and / or composition.

[0034] As used herein, a "patient" or "subject" can be a human or a non-human mammal or bird. Non-human mammals include, for example, livestock and pets such as sheep, cows, pigs, dogs, cats, and murine mammals. In certain other embodiments, the subject is a human.

[0035] As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful within the scope of the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

[0036] As used herein, the term "pharmaceutically acceptable" refers to a substance such as a carrier or diluent that does not inhibit the biological activity or properties of a compound useful within the scope of the present disclosure and is relatively non-toxic, i.e., the substance can be administered to a subject without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is included.

[0037] As used herein, the term "pharmaceutically acceptable carrier" means a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, or a pharmaceutically acceptable substance, composition, or carrier that is involved in carrying or transporting a compound within or to a patient so that the compound useful within the scope of the present disclosure can perform its intended function. Typically, such constructs are carried or transported from one organ, i.e., a part of the body, to another organ, i.e., another part of the body. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the patient, including a compound useful within the scope of the present disclosure. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyhydric alcohols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic and compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents that are compatible with the activity of the compounds useful within the scope of the present disclosure and physiologically acceptable to the subject. Supplementary active compounds can be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful within the scope of the present disclosure.Other additional components that may be included in the pharmaceutical compositions used in the practice of the present disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to salts of an administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and inclusion compounds thereof.

[0039] As used herein, the term "pharmaceutical composition" refers to a mixture of at least one compound useful within the scope of the present disclosure and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. Pharmaceutical compositions facilitate the administration of compounds to a living being. Various techniques for administering the compounds include, but are not limited to, intravenous, oral, aerosol, parenteral, intraocular, pulmonary, and topical administration.

[0040] The terms "prevent", "preventing", or "prevention", as used herein, mean avoiding or delaying the occurrence of symptoms associated with a disease or condition in a subject who has not developed such symptoms at the time when administration of an agent or compound is initiated. Diseases, conditions, and disorders are used interchangeably herein.

[0041] As used herein, the term "solvate" refers to a compound formed by solvation, which is the process of attraction and association of molecules of a solute or ion and molecules of a solvent. When the molecules or ions of a solute dissolve in a solvent, they diffuse and become surrounded by solvent molecules.

[0042] As used herein, the terms "treating," "treatment," or "treat" mean reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0043] As used herein, the term "alkyl," as itself or as part of another substituent, unless otherwise specified, means a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C 1 ~C 10 means 1 to 10 carbon atoms), and includes straight, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Non-limiting examples of (C 1 ~C 6 )alkyl such as ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl are most preferred.

[0044] As used herein, the term "alkylene," as itself or as part of another substituent, unless otherwise specified, means a straight or branched chain hydrocarbon group having the specified number of carbon atoms with two free valences (i.e., C 1 ~C 10 means 1 to 10 carbon atoms), and includes straight, branched, or cyclic substituents. Examples include methylene, 1,2-ethylene, 1,1-ethylene, 1,1-propylene, 1,2-propylene and 1,3-propylene.

[0045] As used herein, the term "cycloalkyl", either by itself or as part of another substituent, unless otherwise specified, means a cyclic chain hydrocarbon having the specified number of carbon atoms (i.e., C3-C6 means a cyclic group containing a ring group consisting of 3 to 6 carbon atoms), and includes straight-chain, branched-chain, or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Non-limiting examples include (C 3 ~C 6 ) cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are most preferred.

[0046] As used herein, the term "alkenyl", employed either alone or in combination with other terms, unless otherwise specified, means a stable mono-unsaturated or di-unsaturated straight-chain or branched-chain hydrocarbon group having the recited number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. The functional group representing an alkene is -CH 2 -CH=CH 2 is exemplified.

[0047] As used herein, the term "alkynyl", employed either alone or in combination with other terms, unless otherwise specified, means a stable straight-chain or branched-chain hydrocarbon group having a carbon-carbon triple bond with the recited number of carbon atoms. Non-limiting examples include ethynyl and propynyl and higher homologs and isomers. The term "propargyl" refers to the group exemplified by -CH 2 -C≡CH. The term "homopropargyl" refers to the group exemplified by -CH 2 CH 2 -C≡CH. The term "substituted propargyl" refers to -CR 2-C≡CR represents a group exemplified by -C≡CR, where R is, in each occurrence, independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, provided that at least one R group is not hydrogen. The term "substituted homopropargyl" refers to -CR 2 CR 2 -C≡CR represents a group exemplified by -C≡CR, where R is, in each occurrence, independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, provided that at least one R group is not hydrogen.

[0048] As used herein, the term "alkenylene", employed alone or in combination with other terms, means, unless otherwise specified, a stable mono-unsaturated or di-unsaturated straight-chain or branched-chain hydrocarbon group having the stated number of carbon atoms with two available valences.

[0049] As used herein, the term "alkynylene", employed alone or in combination with another term, means, unless otherwise specified, a stable straight-chain or branched-chain hydrocarbon group having the stated number of carbon atoms with a carbon-carbon triple bond and two available valences.

[0050] As used herein, the terms "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkylene", "substituted alkenylene", "substituted alkynylene", "substituted heteroalkyl", "substituted heteroalkenyl", "substituted heteroalkynyl", "substituted aryl", "substituted heteroaryl" or "substituted heterocycloalkyl" mean C 1 ~C 10 alkyl, halogen, perhaloalkyl, =O, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH 2 , -N(CH 3 ) 2 , phenyl, benzyl, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C 1 ~C4 ) alkyl, -C(=O)NH 2 , -C(=O)NH(C 1 ~C 4 ) alkyl, -C(=O)N((C 1 ~C 4 ) alkyl) 2 , -SO 2 NH 2 , -C(=NH)NH 2 , and -NO 2 substituted by 1, 2 or 3 substituents selected from the group consisting of, preferably halogen, -OH, alkoxy, -NH 2 , trifluoromethyl, -N(CH 3 )([[]]END]] 2 , and -C(=O)OH, more preferably containing 1 or 2 substituents selected from halogen, alkoxy and -OH, the alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, or heterocycloalkyl as defined above. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl. Further, the definition of a particular "substituted" moiety is defined elsewhere in this specification.

[0051] As used herein, the term "alkoxy", employed alone or in combination with another term, unless otherwise specified, has the specified number of carbon atoms and is connected to the remainder of the molecule through an oxygen atom, the alkyl group as defined above, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologues and isomers thereof. Non-limiting examples include (C 1 ~C 3 ) alkoxy such as ethoxy and methoxy are preferred.

[0052] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0053] As used herein, the term "heteroalkyl" by itself or in combination with other terms means, unless otherwise specified, a stable straight or branched chain alkyl group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached or at the bond to the most distal carbon atom in the heteroalkyl group. An example is -O-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 -CH 2 -OH, -CH 2 -CH 2 -NH-CH 3 , -CH 2 -S-CH 2 -CH 3 , and -CH 2 CH 2 -S(=O)-CH 3 For example, -CH 2 -NH-OCH 3 or -CH 2 -CH 2 -SS-CH 3 Up to two consecutive heteroatoms may be present, such as

[0054] As used herein, the term "heteroalkenyl," alone or in combination with other terms, unless otherwise specified, refers to a stable straight-chain or branched-chain mono- or di-unsaturated hydrocarbon group consisting of the recited number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be oxidized and the nitrogen heteroatom may be quaternized. The heteroatoms can be arranged up to two in a row. Examples are -CH=CH-O-CH 3 、-CH=CH-CH 2 -OH、-CH 2 -CH=N-OCH 3 、-CH=CH-N(CH 3 )-CH 3 、および-CH 2 -CH=CH-CH 2 -SH.

[0055] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that are aromatic, i.e., having (4n + 2) delocalized π (pi) electrons where n is an integer.

[0056] As used herein, the term "aryl," employed alone or in combination with another term, unless otherwise specified, means a carbocyclic aromatic system containing one or more rings (typically 1, 2, or 3 rings), where such rings can be connected together in a pendant fashion like biphenyl or can be fused like naphthalene. Examples include phenyl, anthracyl, and naphthyl. Phenyl and naphthyl are preferred, with phenyl being most preferred.

[0057] As used herein, the term "aryl-(C 1 ~C 3 )alkyl" refers to a functional group in which an alkylene chain of 1 to 3 carbons is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl or -CH 2-phenyl(benzyl), preferably aryl-CH 2 -and aryl-CH(CH 3 ). The term "substituted aryl-(C 1 ~C 3 )alkyl" means an aryl-(C 1 ~C 3 )alkyl functional group in which the aryl group is substituted. Substituted aryl(CH 2 )-is preferred. Similarly, the term "heteroaryl-(C 1 ~C 3 )alkyl" means a functional group in which an alkylene chain having 1 to 3 carbon atoms is connected to a heteroaryl group, for example, -CH 2 CH 2 -pyridyl. Heteroaryl-(CH 2 )-is preferred. The term "substituted heteroaryl-(C 1 ~C 3 )alkyl" means a heteroaryl-(C 1 ~C 3 )alkyl functional group in which the heteroaryl group is substituted. Substituted heteroaryl-(CH 2 )-is preferred.

[0058] As used herein, the term "heterocycle" or "heterocyclyl" or "heterocyclic", either by itself or as part of another substituent, means an unsubstituted or substituted stable monocyclic or polycyclic heterocyclic system consisting of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, where nitrogen and sulfur heteroatoms may be oxidized and nitrogen atoms may be quaternized. The heterocyclic system can be attached to any heteroatom or carbon atom that results in a stable structure, unless otherwise specified. The heterocycle can be essentially aromatic or non-aromatic (e.g., heterocycloalkyl). In certain other embodiments, the heterocycle is heteroaryl.

[0059] As used herein, the terms "heteroaryl" or "heteroaromatic" refer to a heterocyclic ring having aromatic character. A polycyclic heteroaryl can include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0060] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophene, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

[0061] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, without limitation, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0062] Examples of polycyclic hetero rings include indolyl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinizinyl, and quinolizinyl.

[0063] The heterocyclyl and heteroaryl moieties listed above are intended to be representative and non-limiting.

[0064] As used herein, the term "substituted" means that an atom or group has replaced hydrogen as a substituent bonded to another moiety. Non-limiting examples of "substituted" groups are C 1 ~C 10 alkyl, halogen, perhaloalkyl, =O, -OH, alkoxy, -NH 2 , -N(CH 3 ) 2 , phenyl, benzyl, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, -C≡N, -C(=O)O(C 1 ~C 4 )alkyl, -C(=O)NH 2 , -C(=O)NH(C 1 ~C 4 )alkyl, -C(=O)N((C 1 ~C4 ) (alkyl) 2 , -SO 2 NH 2 , -C(=NH)NH 2 , and -NO 2 are included.

[0065] For aryl, aryl-(C 1 ~C 3 ) alkyl and heterocyclyl groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution, i.e., mono, di, tri, tetra, or penta substitution when such substitution is allowed. The substituents are independently selected and the substitution can be at any chemically accessible position. In certain other embodiments, the number of substituents varies between 1 and 4. In another embodiment, the number of substituents varies between 1 and 3. In yet another embodiment, the number of substituents varies between 1 and 2. In yet another embodiment, the substituents are independently selected from the group consisting of C 1~6 alkyl, -OH, C 1~6 alkoxy, halo, amino, acetamide, and nitro. As used herein, when a substituent is an alkyl or alkoxy group, the carbon chain can be branched, straight-chain, or cyclic, with a straight-chain being preferred. As used herein, the terms "substituted heterocycle" and "substituted heteroaryl" refer to a heterocycle or heteroaryl group having one or more substituents including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, carboxyalkyl (C(O)O alkyl), trifluoroalkyl such as CF 3 , aryloxy, alkoxy, aryl, or heteroaryl. A substituted heterocycle or heteroaryl group can have 1, 2, 3, or 4 substituents.

[0066] Throughout this disclosure, various aspects of the disclosure may be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, a range description should be considered to specifically disclose all the narrower ranges and individual numerical values within that range, and, where appropriate, fractional integers of the numerical values within the range. For example, a range description such as 1 to 6 is considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0067] Compounds and Compositions The present disclosure provides a compound of formula (I), or a salt, solvate, enantiomer, diastereoisomer, geometric isomer, isotopologue, or tautomer thereof, TIFF2025517991000012.tif16128wherein T 1 is TIFF2025517991000013.tif4128, and T 2 is R 3 or T 1 is R 3 and T 2 is TIFF2025517991000014.tif4128; R 1 is TIFF2025517991000015.tif4128; A 1 is selected from the group consisting of TIFF2025517991000016.tif18128 and a bond; A 2 is selected from the group consisting of TIFF2025517991000017.tif15128 and a bond; A 3 is TIFF2025517991000018.tif selected from the group consisting of 15128 and combination; A 4 is selected from the group consisting of TIFF2025517991000019.tif 18128 and Y; L 1 is combination, -N(R a )(optionally substituted C 1 ~C 6 alkylenyl)N(R b )-, -N(R a )S(optionally substituted C 1 ~C 6 alkylenyl)N(R b )-, -N(R a )(optionally substituted C 1 ~C 6 heteroalkylenyl)N(R b ), -N(R a )S(optionally substituted C 1 ~C 6 heteroalkylenyl)N(R b )-, -N(R a )(optionally substituted C 3 ~C 8 cycloalkylenyl)N(R b )-, -N(R a )S(optionally substituted C 3 ~C 8 cycloalkylenyl)N(R b )-, -N(R a )(optionally substituted C 2 ~C 6 heterocyclirenyl)N(R b )-, -N(R a )S(optionally substituted C 2 ~C 6 heterocyclirenyl)N(R b )-, -N(R a )(optionally substituted C 1 ~C 6 alkylenyl)C(=O)-, -N(R a )S(optionally substituted C 1 ~C 6(Alkenylenyl)C(=O)-, optionally substituted C 1 ~C 6 alkenylenyl, -N(R a )(optionally substituted phenylenyl)N(R b )-, and -N(R a )S(optionally substituted phenylenyl)N(R b )-; selected from the group consisting of L 2 is selected from the group consisting of -C(=O)-, N(R 6 ), and a bond; Y is N(R 5e )(R 5f ) and OR 5e ; selected from the group consisting of, wherein A 1 , A 2 , A 3 , A 4 , L 1 , L 2 , and Y are, A 1 , A 2 , A 3 , and A 4 ; any substituent selected from the group consisting of and A 1 , A 2 , A 3 , A 4 , L 1 , and L 2 ; when the bond between any substituent selected from the group consisting of exists, it is a C-N bond, Y and A 1 , A 2 , A 3 , and A 4 ; when the bond between any substituent selected from the group consisting of exists, it is a C-N or C-O bond selected as follows; R 2 is N(R a )C(=O)(optionally substituted C 1 ~C 6 alkyl), N(R a )C(=O)(optionally substituted C 3 ~C 8(cycloalkyl), N(C(=O)(optionally substituted C 3 ~C 8 (cycloalkyl)) 2 , N(R a )C(=O)O(optionally substituted phenyl), N(R a )C(=O)(optionally substituted C 2 ~C 8 (heterocyclyl), N(R a )C(=O)N(R b )(optionally substituted C 1 ~C 6 (alkyl), C(=O)OR a , and C(=O)N(R a )C(=O)(optionally substituted C 1 ~C 6 (alkyl) and is selected from the group consisting of; R 3 is H, optionally substituted C 1 ~C 6 (alkyl), optionally substituted phenyl, CN, NO 2 , C(=O)OR a , and C(=O)NR a R b and is selected from the group consisting of; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , and R 4h each occurrence is independently H, optionally substituted C 1 ~C 6 (alkyl), optionally substituted C 3 ~C 6 (cycloalkyl), optionally substituted C 2 ~C 6 (heteroalkyl), optionally substituted C 2 ~C 6 (alkenyl), optionally substituted C 2 ~C 6 (alkynyl), optionally substituted heterocyclyl, and optionally substituted phenyl and is selected from the group consisting of; R5a , R 5b , R 5c , R 5d , R 5e , and R 5f is, each time it appears, independently selected from the group consisting of H, optionally substituted C 1 ~C 6 -alkyl, optionally substituted C 3 ~C 8 -cycloalkyl, optionally substituted phenyl, C(=O)R a , and C(=O)OR a and is selected from the group consisting of, or or R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4i , R 4j , R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f Two vicinal substituents selected from the group consisting of and form, together with the atom to which they are attached, optionally substituted C 4 ~C 8 -heterocycloalkyl; R 6 is selected from the group consisting of H and optionally substituted C 1 ~C 6 -alkyl; X is selected from the group consisting of CR 6 and N; m1, m2, m3, and m4 are each independently an integer selected from the group consisting of 1, 2, 3, and 4; R a and R b are, each time they appear, independently selected from the group consisting of H, optionally substituted C 1 ~C 6 -alkyl, optionally substituted C 3 ~C 8 -cycloalkyl, optionally substituted C 1 ~C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 ~C 8 selected from the group consisting of heterocyclyl, or geminal R a and R b together with the atom to which they are attached may form an optionally substituted C 2 ~C 8 heterocyclyl.

[0068] One of ordinary skill in the art will understand that, unless otherwise described herein or implied from the specific context herein, the definitions of A 1 A 2 and A 3 are provided herein without implying directionality. As illustrated elsewhere herein, the same applies to any specific examples of A 1 A 2 and A 3 . By way of non-limiting example, A 1 = TIFF2025517991000020.tif15128 may correspond to either R 1 = TIFF2025517991000021.tif15128 or R 1 = TIFF2025517991000022.tif18128. In another non-limiting example, A 1 = TIFF2025517991000023.tif16128 may correspond to either R 1 = TIFF2025517991000024.tif16128 or R 1 = TIFF2025517991000025.tif17128. In another non-limiting example, A 2 = TIFF2025517991000026.tif15128 may correspond to R 1 = TIFF2025517991000027.tif15128 or R 1 = It may correspond to either TIFF2025517991000028.tif16128. In another non - limiting example, A 3 = TIFF2025517991000029.tif15128 is R 1 = TIFF2025517991000030.tif15128 or R 1 = It may correspond to either TIFF2025517991000031.tif16128.

[0069] In certain embodiments, the compound of formula (I) is a compound of formula (Ia) TIFF2025517991000032.tif15128.

[0070] In certain embodiments, the compound of formula (I) is a compound of formula (Ib) TIFF2025517991000033.tif15128.

[0071] In certain embodiments, when present, the optionally substituted alkyl, optionally substituted alkenylenyl, optionally substituted cycloalkenylenyl, optionally substituted heterocyclenylenyl, optionally substituted phenylenyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted haloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl are, each occurrence, independently, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, C 1 ~C 3 haloalkoxy, phenoxy, halogen, CN, NO 2 、OR I 、N(R I )(RII )), SR I , C(=O)R I , C(=O)OR I , OC(=O)OR I , C(=O)N(R I )(R II ), S(=O) 2 N(R I )(R II ), N(R I )(R II ), N(R I )(R II )(R III )(R IV ), N(R I )(R 2 R II , an optionally substituted C 2 ~C 8 heterocyclyl, and an optionally substituted phenyl, and is optionally substituted with at least one substituent selected from the group consisting of, where R I , R II , R III , and R IV are each independently, at each occurrence, selected from the group consisting of H, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, benzyl, and an optionally substituted phenyl.

[0072] In certain embodiments, the optionally substituted phenyl and the optionally substituted heterocyclyl, when present, are each independently, at each occurrence, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, C 1 ~C 3 haloalkoxy, phenoxy, halogen, CN, NO 2 , OR i , N(R i )(R ii ), SR i, C(=O)R i , C(=O)OR i , OC(=O)OR i , C(=O)N(R i )(R ii ), S(=O) 2 N(R i )(R ii ), N(R i )(R ii ), N(R i )(C(=NR ii )(R iii )(R iv ), N(R i )(S(=O) 2 R ii , C 2 ~C 8 optionally substituted with at least one substituent selected from the group consisting of heterocyclyl and phenyl, wherein R i , R ii , R iii , and R iv are each independently, in each occurrence, selected from the group consisting of H, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, benzyl, and phenyl.

[0073] In certain embodiments, A 4 is TIFF2025517991000034.tif16128 and one of the following applies: (i) None of A 1 , A 2 and A 3 is a bond, (ii) One of A 1 , A 2 and A 3 is a bond, (iii) Two of A 1 , A 2 and A 3 are bonds, and (iv) A 1 , A 2and A 3 are each a bond.

[0074] In certain embodiments, A 1 is TIFF2025517991000035.tif17128, and A 4 is TIFF2025517991000036.tif16128, and one of the following applies: (i) Neither A 2 nor A 3 is a bond, (ii) One of A 2 and A 3 is a bond, and (iii) Both A 2 and A 3 are bonds.

[0075] In certain embodiments, A 1 is TIFF2025517991000037.tif17128, and A 4 is Y, and one of the following applies: (i) Neither A 2 nor A 3 is a bond, (ii) One of A 2 and A 3 is a bond, and (iii) Both A 2 and A 3 are bonds.

[0076] In certain embodiments, A 1 is selected from the group consisting of TIFF2025517991000038.tif16128 and a bond. In certain embodiments, A 1 is TIFF2025517991000039.tif14128. In certain embodiments, A 1 is TIFF2025517991000040.tif14128. In certain embodiments, A 1is TIFF2025517991000041.tif14128. In certain embodiments, A 1 is TIFF2025517991000042.tif14128.

[0077] In certain embodiments, A 2 is selected from the group consisting of TIFF2025517991000043.tif16128 and a combination. In certain embodiments, A 2 is TIFF2025517991000044.tif14128. In certain embodiments, A 2 is TIFF2025517991000045.tif14128. In certain embodiments, A 2 is TIFF2025517991000046.tif14128. In certain embodiments, A 2 is TIFF2025517991000047.tif14128.

[0078] In certain embodiments, A 3 is selected from the group consisting of TIFF2025517991000048.tif16128 and a combination. In certain embodiments, A 3 is TIFF2025517991000049.tif14128. In certain embodiments, A 3 is TIFF2025517991000050.tif14128. In certain embodiments, A 3 is TIFF2025517991000051.tif14128. In certain embodiments, A 3 is TIFF2025517991000052.tif14128.

[0079] In certain embodiments, A 4 is It is selected from the group consisting of TIFF2025517991000053.tif16128 and Y. In certain embodiments, A 4 is TIFF2025517991000054.tif15128. In certain embodiments, A 4 is TIFF2025517991000055.tif15128. In certain embodiments, A 4 is TIFF2025517991000056.tif15128. In certain embodiments, A 4 is TIFF2025517991000057.tif15128. In certain embodiments, A 4 is TIFF2025517991000058.tif14128. In certain embodiments, A 4 is TIFF2025517991000059.tif14128. In certain embodiments, A 4 is TIFF2025517991000060.tif14128. In certain embodiments, A 4 is TIFF2025517991000061.tif14128. In certain embodiments, A 4 is TIFF2025517991000062.tif14128. In certain embodiments, A 4 is TIFF2025517991000063.tif14128. In certain embodiments, A 4 is TIFF2025517991000064.tif14128. In certain embodiments, A 4 is TIFF2025517991000065.tif14128.

[0080] In certain embodiments, R 4a is H, methyl. In certain embodiments, R 4a is TIFF2025517991000066.tif is 7128. In certain embodiments, R 4a is TIFF2025517991000067.tif is 8128. In certain embodiments, R 4a is TIFF2025517991000068.tif is 8128. In certain embodiments, R 4a is TIFF2025517991000069.tif is 11128. In certain embodiments, R 4a is TIFF2025517991000070.tif is 4128. In certain embodiments, R 4a is TIFF2025517991000071.tif is 15128. In certain embodiments, R 4a is TIFF2025517991000072.tif is 4128. In certain embodiments, R 4a is TIFF2025517991000073.tif is 9128. In certain embodiments, R 4a is TIFF2025517991000074.tif is 4128. In certain embodiments, R 4a is TIFF2025517991000075.tif is 10128. In certain embodiments, R 4a is TIFF2025517991000076.tif is 10128. In certain embodiments, R 4a is TIFF2025517991000077.tif is 11128. In certain embodiments, R 4a is TIFF2025517991000078.tif is 10128. In certain embodiments, R 4a is TIFF2025517991000079.tif is 10128. In certain embodiments, R 4a is TIFF2025517991000080.tif is 5128. In certain embodiments, R4a is TIFF2025517991000081.tif13128. In certain embodiments, R 4a is TIFF2025517991000082.tif13128.

[0081] In certain embodiments, R 4b is H, methyl. In certain embodiments, R 4b is TIFF2025517991000083.tif7128. In certain embodiments, R 4b is TIFF2025517991000084.tif8128. In certain embodiments, R 4b is TIFF2025517991000085.tif8128. In certain embodiments, R 4b is TIFF2025517991000086.tif11128. In certain embodiments, R 4b is TIFF2025517991000087.tif4128. In certain embodiments, R 4b is TIFF2025517991000088.tif15128. In certain embodiments, R 4b is TIFF2025517991000089.tif4128. In certain embodiments, R 4b is TIFF2025517991000090.tif9128. In certain embodiments, R 4b is TIFF2025517991000091.tif4128. In certain embodiments, R 4b is TIFF2025517991000092.tif10128. In certain embodiments, R 4b is TIFF2025517991000093.tif10128. In certain embodiments, R 4b is TIFF2025517991000094.tif is 11128. In certain embodiments, R 4b is TIFF2025517991000095.tif is 10128. In certain embodiments, R 4b is TIFF2025517991000096.tif is 10128. In certain embodiments, R 4b is TIFF2025517991000097.tif is 5128. In certain embodiments, R 4b is TIFF2025517991000098.tif is 13128. In certain embodiments, R 4b is TIFF2025517991000099.tif is 13128.

[0082] In certain embodiments, R 4c is H, methyl. In certain embodiments, R 4c is TIFF2025517991000100.tif is 7128. In certain embodiments, R 4c is TIFF2025517991000101.tif is 8128. In certain embodiments, R 4c is TIFF2025517991000102.tif is 8128. In certain embodiments, R 4c is TIFF2025517991000103.tif is 10128. In certain embodiments, R 4c is TIFF2025517991000104.tif is 4128. In certain embodiments, R 4c is TIFF2025517991000105.tif is 15128. In certain embodiments, R 4c is TIFF2025517991000106.tif is 4128. In certain embodiments, R 4c is TIFF2025517991000107.tif is 9128. In certain embodiments, R 4c is TIFF2025517991000108.tif is 4128. In certain embodiments, R 4c is TIFF2025517991000109.tif is 10128. In certain embodiments, R 4c is TIFF2025517991000110.tif is 10128. In certain embodiments, R 4c is TIFF2025517991000111.tif is 11128. In certain embodiments, R 4c is TIFF2025517991000112.tif is 10128. In certain embodiments, R 4c is TIFF2025517991000113.tif is 10128. In certain embodiments, R 4c is TIFF2025517991000114.tif is 5128. In certain embodiments, R 4c is TIFF2025517991000115.tif is 13128. In certain embodiments, R 4c is TIFF2025517991000116.tif is 13128.

[0083] In certain embodiments, R 4d is H, methyl. In certain embodiments, R 4d is TIFF2025517991000117.tif is 7128. In certain embodiments, R 4d is TIFF2025517991000118.tif is 8128. In certain embodiments, R 4d is TIFF2025517991000119.tif is 8128. In certain embodiments, R 4d is TIFF2025517991000120.tif is 10128. In certain embodiments, R 4d is TIFF2025517991000121.tif is 4128. In certain embodiments, R 4d is TIFF2025517991000122.tif is 15128. In certain embodiments, R 4d is TIFF2025517991000123.tif is 4128. In certain embodiments, R 4d is TIFF2025517991000124.tif is 9128. In certain embodiments, R 4d is TIFF2025517991000125.tif is 4128. In certain embodiments, R 4d is TIFF2025517991000126.tif is 10128. In certain embodiments, R 4d is TIFF2025517991000127.tif is 10128. In certain embodiments, R 4d is TIFF2025517991000128.tif is 11128. In certain embodiments, R 4d is TIFF2025517991000129.tif is 10128. In certain embodiments, R 4d is TIFF2025517991000130.tif is 10128. In certain embodiments, R 4d is TIFF2025517991000131.tif is 5128. In certain embodiments, R 4d is TIFF2025517991000132.tif is 13128. In certain embodiments, R 4d is TIFF2025517991000133.tif is 13128.

[0084] In certain embodiments, R 4eis H, methyl. In certain embodiments, R 4e is TIFF2025517991000134.tif7128. In certain embodiments, R 4e is TIFF2025517991000135.tif8128. In certain embodiments, R 4e is TIFF2025517991000136.tif8128. In certain embodiments, R 4e is TIFF2025517991000137.tif11128. In certain embodiments, R 4e is TIFF2025517991000138.tif4128. In certain embodiments, R 4e is TIFF2025517991000139.tif15128. In certain embodiments, R 4e is TIFF2025517991000140.tif4128. In certain embodiments, R 4e is TIFF2025517991000141.tif9128. In certain embodiments, R 4e is TIFF2025517991000142.tif4128. In certain embodiments, R 4e is TIFF2025517991000143.tif10128. In certain embodiments, R 4e is TIFF2025517991000144.tif10128. In certain embodiments, R 4e is TIFF2025517991000145.tif11128. In certain embodiments, R 4e is TIFF2025517991000146.tif10128. In certain embodiments, R 4e is TIFF2025517991000147.tif10128. In certain embodiments, R 4e is TIFF2025517991000148.tif is 5128. In certain embodiments, R 4e is TIFF2025517991000149.tif is 13128. In certain embodiments, R 4e is TIFF2025517991000150.tif is 13128.

[0085] In certain embodiments, R 4f is H, methyl. In certain embodiments, R 4f is TIFF2025517991000151.tif is 7128. In certain embodiments, R 4f is TIFF2025517991000152.tif is 8128. In certain embodiments, R 4f is TIFF2025517991000153.tif is 8128. In certain embodiments, R 4f is TIFF2025517991000154.tif is 11128. In certain embodiments, R 4f is TIFF2025517991000155.tif is 4128. In certain embodiments, R 4f is TIFF2025517991000156.tif is 15128. In certain embodiments, R 4f is TIFF2025517991000157.tif is 4128. In certain embodiments, R 4f is TIFF2025517991000158.tif is 9128. In certain embodiments, R 4f is TIFF2025517991000159.tif is 4128. In certain embodiments, R 4f is TIFF2025517991000160.tif is 10128. In certain embodiments, R 4f is TIFF2025517991000161.tif is 10128. In certain embodiments, R 4f is TIFF2025517991000162.tif is 11128. In certain embodiments, R 4f is TIFF2025517991000163.tif is 10128. In certain embodiments, R 4f is TIFF2025517991000164.tif is 10128. In certain embodiments, R 4f is TIFF2025517991000165.tif is 5128. In certain embodiments, R 4f is TIFF2025517991000166.tif is 13128. In certain embodiments, R 4f is TIFF2025517991000167.tif is 13128.

[0086] In certain embodiments, R 4g is H, methyl. In certain embodiments, R 4g is TIFF2025517991000168.tif is 7128. In certain embodiments, R 4g is TIFF2025517991000169.tif is 8128. In certain embodiments, R 4g is TIFF2025517991000170.tif is 8128. In certain embodiments, R 4g is TIFF2025517991000171.tif is 10128. In certain embodiments, R 4g is TIFF2025517991000172.tif is 4128. In certain embodiments, R 4g is TIFF2025517991000173.tif is 15128. In certain embodiments, R 4g is TIFF2025517991000174.tif is 4128. In certain embodiments, R 4g is TIFF2025517991000175.tif is 9128. In certain embodiments, R 4g is TIFF2025517991000176.tif is 4128. In certain embodiments, R 4g is TIFF2025517991000177.tif is 10128. In certain embodiments, R 4g is TIFF2025517991000178.tif is 10128. In certain embodiments, R 4g is TIFF2025517991000179.tif is 11128. In certain embodiments, R 4g is TIFF2025517991000180.tif is 10128. In certain embodiments, R 4g is TIFF2025517991000181.tif is 10128. In certain embodiments, R 4g is TIFF2025517991000182.tif is 5128. In certain embodiments, R 4g is TIFF2025517991000183.tif is 13128. In certain embodiments, R 4g is TIFF2025517991000184.tif is 13128.

[0087] In certain embodiments, R 4h is H, methyl. In certain embodiments, R 4h is TIFF2025517991000185.tif is 7128. In certain embodiments, R 4h is TIFF2025517991000186.tif is 8128. In certain embodiments, R 4h is TIFF2025517991000187.tif is 8128. In certain embodiments, R 4h is TIFF2025517991000188.tif is 10128. In certain embodiments, R 4h is TIFF2025517991000189.tif is 4128. In certain embodiments, R 4h is TIFF2025517991000190.tif is 15128. In certain embodiments, R 4h is TIFF2025517991000191.tif is 4128. In certain embodiments, R 4h is TIFF2025517991000192.tif is 9128. In certain embodiments, R 4h is TIFF2025517991000193.tif is 4128. In certain embodiments, R 4h is TIFF2025517991000194.tif is 10128. In certain embodiments, R 4h is TIFF2025517991000195.tif is 10128. In certain embodiments, R 4h is TIFF2025517991000196.tif is 11128. In certain embodiments, R 4h is TIFF2025517991000197.tif is 10128. In certain embodiments, R 4h is TIFF2025517991000198.tif is 10128. In certain embodiments, R 4h is TIFF2025517991000199.tif is 5128. In certain embodiments, R 4h is TIFF2025517991000200.tif is 13128. In certain embodiments, R 4h is TIFF2025517991000201.tif is 13128.

[0088] In certain embodiments, R 4a and R 4b at least one of is H. In certain embodiments, R 4c and R 4d at least one of is H. In certain embodiments, R 4e and R 4f at least one of is H. In certain embodiments, R 4g and R 4h at least one of is H.

[0089] In certain embodiments, R 5a is H. In certain embodiments, R 5b is H. In certain embodiments, R 5c is H. In certain embodiments, R 5d is H. In certain embodiments, R 5e is H. In certain embodiments, R 5e is C(=O)O(C(CH 3 ) 3 )). In certain embodiments, R 5f is H. In certain embodiments, R 5f is C(=O)O(C(CH 3 ) 3 ).

[0090] In certain embodiments, A 1 is TIFF2025517991000202.tif9128. In certain embodiments, A 1 is TIFF2025517991000203.tif13128. In certain embodiments, A 1 is TIFF2025517991000204.tif13128. In certain embodiments, A 1 is TIFF2025517991000205.tif16128. In certain embodiments, A 1 is TIFF2025517991000206.tif16128. In certain embodiments, A1 is TIFF2025517991000207.tif20128. In certain embodiments, A 1 is TIFF2025517991000208.tif20128.

[0091] In certain embodiments, A 2 is TIFF2025517991000209.tif9128. In certain embodiments, A 2 is TIFF2025517991000210.tif13128. In certain embodiments, A 2 is TIFF2025517991000211.tif13128. In certain embodiments, A 2 is TIFF2025517991000212.tif16128. In certain embodiments, A 2 is TIFF2025517991000213.tif16128. In certain embodiments, A 2 is TIFF2025517991000214.tif20128. In certain embodiments, A 2 is TIFF2025517991000215.tif20128.

[0092] In certain embodiments, A 3 is TIFF2025517991000216.tif9128. In certain embodiments, A 3 is TIFF2025517991000217.tif13128. In certain embodiments, A 3 is TIFF2025517991000218.tif13128. In certain embodiments, A 3 is TIFF2025517991000219.tif16128. In certain embodiments, A 3 is TIFF2025517991000220.tif is 16128. In certain embodiments, A 3 is TIFF2025517991000221.tif is 20128. In certain embodiments, A 3 is TIFF2025517991000222.tif is 20128.

[0093] In certain embodiments, A 4 is TIFF2025517991000223.tif is 9128. In certain embodiments, A 4 is TIFF2025517991000224.tif is 13128. In certain embodiments, A 4 is TIFF2025517991000225.tif is 13128. In certain embodiments, A 4 is TIFF2025517991000226.tif is 16128. In certain embodiments, A 4 is TIFF2025517991000227.tif is 16128. In certain embodiments, A 4 is TIFF2025517991000228.tif is 22128. In certain embodiments, A 4 is TIFF2025517991000229.tif is 22128. In certain embodiments, A 4 is TIFF2025517991000230.tif is 15128. In certain embodiments, A 4 is TIFF2025517991000231.tif is 15128. In certain embodiments, A 4 is TIFF2025517991000232.tif is 15128. In certain embodiments, A 4 is TIFF2025517991000233.tif is 16128. In certain embodiments, A 4 is TIFF2025517991000234.tif is 16128.

[0094] In certain embodiments, R 1 is NH 2 In certain embodiments, R 1 is Ot-Bu. In certain embodiments, R 1 is TIFF2025517991000235.tif is 10128. In certain embodiments, R 1 is TIFF2025517991000236.tif is 8128. In certain embodiments, R 1 is TIFF2025517991000237.tif is 7128. In certain embodiments, R 1 is TIFF2025517991000238.tif is 16128. In certain embodiments, R 1 is TIFF2025517991000239.tif is 15128. In certain embodiments, R 1 is TIFF2025517991000240.tif is 17128. In certain embodiments, R 1 is TIFF2025517991000241.tif is 9128. In certain embodiments, R 1 is TIFF2025517991000242.tif is 16128. In certain embodiments, R 1 is TIFF2025517991000243.tif is 16128. In certain embodiments, R 1 is TIFF2025517991000244.tif is 20128. In certain embodiments, R 1 is TIFF2025517991000245.tif is 15128. In certain embodiments, R 1 is TIFF2025517991000246.tif is 15128. In certain embodiments, R1 is TIFF2025517991000247.tif15128. In certain embodiments, R 1 is TIFF2025517991000248.tif15128. In certain embodiments, R 1 is TIFF2025517991000249.tif16128. In certain embodiments, R 1 is TIFF2025517991000250.tif17128. In certain embodiments, R 1 is TIFF2025517991000251.tif17128. In certain embodiments, R 1 is TIFF2025517991000252.tif26128. In certain embodiments, R 1 is TIFF2025517991000253.tif15128. In certain embodiments, R 1 is TIFF2025517991000254.tif15128. In certain embodiments, R 1 is TIFF2025517991000255.tif17128. In certain embodiments, R 1 is TIFF2025517991000256.tif15128. In certain embodiments, R 1 is TIFF2025517991000257.tif17128. In certain embodiments, R 1 is TIFF2025517991000258.tif17128. In certain embodiments, R 1 is TIFF2025517991000259.tif17128. In certain embodiments, R 1 is TIFF2025517991000260.tif26128. In certain embodiments, R 1 is TIFF2025517991000261.tif is 24128. In certain embodiments, R 1 is TIFF2025517991000262.tif is 17128. In certain embodiments, R 1 is TIFF2025517991000263.tif is 15128. In certain embodiments, R 1 is TIFF2025517991000264.tif is 17128. In certain embodiments, R 1 is TIFF2025517991000265.tif is 15128. In certain embodiments, R 1 is TIFF2025517991000266.tif is 17128. In certain embodiments, R 1 is TIFF2025517991000267.tif is 15128. In certain embodiments, R 1 is TIFF2025517991000268.tif is 17128.

[0095] In certain embodiments, R 2 is TIFF2025517991000269.tif is 18128. In certain embodiments, R 2 is TIFF2025517991000270.tif is 18128. In certain embodiments, R 2 is TIFF2025517991000271.tif is 22128. In certain embodiments, R 2 is TIFF2025517991000272.tif is 17128. In certain embodiments, R 2 is TIFF2025517991000273.tif is 17128. In certain embodiments, R 2 is TIFF2025517991000274.tif is 18128. In certain embodiments, R 2 is TIFF2025517991000275.tif is 17128. In certain embodiments, R 2 is TIFF2025517991000276.tif is 17128. In certain embodiments, R 2 is TIFF2025517991000277.tif is 18128. In certain embodiments, R 2 is TIFF2025517991000278.tif is 17128.

[0096] In certain embodiments, R 3 is H.

[0097] In certain embodiments, L 1 is selected from the group consisting of TIFF2025517991000279.tif 110131, where R 7a R 7b R 7c R 7d R 7e R 7f R 7g and R 7h are each independently selected from the group consisting of H and C 1 ~C 6 alkyl; R 8a R 8b R 8c and R 8d are each independently selected from the group consisting of H, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 3 haloalkyl, C 1 ~C 6 alkoxy, halogen, CN, and NO 2 from the group consisting of.

[0098] In certain embodiments, R 7a R 7b R 7c R7d , R 7e , R 7f , R 7g , and R 7h at least one of is H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h at least two of are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h at least three of are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h at least four of are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h at least five of are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h at least six of are H. In certain embodiments, R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h at least seven of are H. In certain embodiments, R 7a , R 7b, R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are each H.

[0099] In certain embodiments, R 8a , R 8b , R 8c , and R 8d at least one of is H. In certain embodiments, R 8a , R 8b , R 8c , and R 8d at least two of are H. In certain embodiments, R 8a , R 8b , R 8c , and R 8d at least three of are H. In certain embodiments, R 8a , R 8b , R 8c , and R 8d are each H.

[0100] In certain embodiments, L 1 is TIFF2025517991000280.tif10128. In certain embodiments, L 1 is TIFF2025517991000281.tif7128. In certain embodiments, L 1 is TIFF2025517991000282.tif8128. In certain embodiments, L 1 is TIFF2025517991000283.tif9128.

[0101] In certain embodiments, L 2 is -C(=O)-.

[0102] In certain embodiments, X is C(CH 3 ).

[0103] In certain embodiments, the compound is Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-(((5S,8S,11S,14S)-14-amino-5,8,11-triisopropyl-15-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazapentadecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-(2-(2-aminoacetamido)acetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecane-19-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((R)-2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-(2-aminoacetamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5 - ((((6S,9S)-6,9 - diisopropyl - 2,2 - dimethyl - 4,7,10 - trioxo - 3 - oxa - 5,8,11 - triazatridecan - 13 - yl)carbamoyl)-4 - methyl - 2 - (2 - (4 - (trifluoromethyl)phenyl)butanamide)thiophene - 3 - carboxylate; Methyl 5 - ((2 - ((S)-2 - ((S)-2 - amino - 3 - methylbutanamide)-3 - methylbutanamide)ethyl)carbamoyl)-4 - methyl - 2 - (2 - (4 - (trifluoromethyl)phenyl)butanamide)thiophene - 3 - carboxylate; Methyl 4 - methyl - 2 - (2 - (4 - (trifluoromethyl)phenyl)butanamide)-5 - ((((6S,9S,12S)-6,9,12 - triisopropyl - 2,2 - dimethyl - 4,7,10,13 - tetraoxo - 3 - oxa - 5,8,11,14 - tetraazapentadecane - 16 - yl)carbamoyl)thiophene - 3 - carboxylate; Methyl 4 - methyl - 5 - ((((6S,9S,12S,15S)-6,9,12,15 - tetraisopropyl - 2,2 - dimethyl - 4,7,10,13,16 - pentaoxo - 3 - oxa - 5,8,11,14,17 - pentaazanonadecane - 19 - yl)carbamoyl)-2 - (2 - (4 - (trifluoromethyl)phenyl)butanamide)thiophene - 3 - carboxylate; Methyl 5 - ((2 - ((S)-2 - ((S)-2 - ((S)-2 - amino - 3 - methylbutanamide)-3 - methylbutanamide)-3 - methylbutanamide)ethyl)carbamoyl)-4 - methyl - 2 - (2 - (4 - (trifluoromethyl)phenyl)butanamide)thiophene - 3 - carboxylate; Methyl 5 - ((((5S,8S,11S,14S)-14 - amino - 5,8,11 - triisopropyl - 15 - methyl - 4,7,10,13 - tetraoxo - 3,6,9,12 - tetraazadecyl)carbamoyl)-4 - methyl - 2 - (2 - (4 - (trifluoromethyl)phenyl)butanamide)thiophene - 3 - carboxylate; Methyl 4-methyl-5-(((6S,9S)-2,2,6,9-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-aminopropanamido)propanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(piperazine-1-carbonyl)thiophene-3-carboxylate; (2-(5-Carbamoyl-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxamido)ethyl)carbamic acid tert-butyl; Methyl 5-(4-((tert-butoxycarbonyl)-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-(4-(L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; N 4 - (2-Aminoethyl)-5-(2-(4-fluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxamide; ((2S)-1-(((2S)-1-((2-(5-Carbamoyl-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxamido)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamic acid tert-butyl; N 4 - (2-((S)-2-((S)-2-Amino-3-methylbutanamido)-3-methylbutanamido)ethyl)-5-(2-(4-fluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxamide; Methyl 2-(2-(4-fluorophenyl)butanamido)-4-methyl-5-(((5S,8S,11S)-5,8,11-triisopropyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)thiophene-3-carboxylate; Methyl 5-(4-(L-valyl-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; ((7S,10S,13S)-1-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophen-3-yl)-7,10-diisopropyl-14-methyl-1,6,9,12-tetraoxo-2,5,8,11-tetraazapentadecane-13-yl)carbamic acid tert-butyl; Methyl 5-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((3-aminopropyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamido)-5-(((6S,9S)-6-isopropyl-2,2,9-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S,12S)-6,9-diisopropyl-2,2,12-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3,14-dioxa-5,8,11-triazapentadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((3-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-5-carbamoyl-4-methylthiophene-3-carboxylate; 2-(tert-Butyl)-4-methyl 5-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-3-methylthiophene-2,4-dicarboxylate; 2-(tert-Butyl)-4-methyl 5-(2-(3,5-difluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxylate; Methyl 5-carbamoyl-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-carbamoyl-2-(2-(4-cyanophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(3,5-difluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-cyanophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecan-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3,17-dioxa-5,8,11,14-tetraazanonadecan-19-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-(((8S,11S,14S)-14-amino-8,11-diisopropyl-15-methyl-7,10,13-trioxo-3-oxa-6,9,12-triazahexadecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; 2-(tert-Butyl)-4-methyl 5-(2-(3,4-difluorophenyl)butanamido)thiophene-2,4-dicarboxylate; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(m-tolyl)butanamido)thiophene-2,4-dicarboxylate; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-2,4-dicarboxylate; Methyl 5-carbamoyl-2-(2-(3,4-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(m-tolyl)butanamido)thiophene-3-carboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(3,4-difluorophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(m-tolyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; (5-(2-(4-Fluorophenyl)butanamido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valine; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(o-tolyl)butanamido)thiophene-2,4-dicarboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(o-tolyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(o-tolyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butanamido)thiophene-3-carboxylate; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(2-(trifluoromethyl)phenyl)butanamido)thiophene-2,4-dicarboxylate Methyl 5-carbamoyl-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate Methyl 4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate Methyl 5-(((R)-1-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; and (5-(2-(4-Fluorophenyl)butanamido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valyl-D-valine selected from the group consisting of

[0104] (Table 1) TIFF2025517991000284.tif38149TIFF2025517991000285.tif207149TIFF2025517991000286.tif220149TIFF2025517991000287.tif227149TIFF2025517991000288.tif213149TIFF2025517991000289.tif214149TIFF2025517991000290.tif222149TIFF2025517991000291.tif222149TIFF2025517991000292.tif201149TIFF2025517991000293.tif223149TIFF2025517991000294.tif221149TIFF2025517991000295.tif230149TIFF2025517991000296.tif219149TIFF2025517991000297.tif221149TIFF2025517991000298.tif218149TIFF2025517991000299.tif232149TIFF2025517991000300.tif75149

[0105] The compounds described herein can form salts with acids and / or bases, and such salts are included in the present disclosure. In certain alternative embodiments, the salts are pharmaceutically acceptable salts. The term "salt" encompasses addition salts of the free acids and / or bases useful within the scope of the methods of the present disclosure. Pharmaceutically unacceptable salts may nonetheless have properties such as high crystallinity and may be useful in the practice of the present disclosure, for example, in the processes of synthesizing, purifying, or formulating compounds useful within the scope of the methods of the present disclosure.

[0106] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Examples of inorganic acids include sulfate, hydrogen sulfate, hemisulfate, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from organic acids of the fatty acid, alicyclic acid, aromatic acid, aromatic fatty acid, heterocyclic acid, carboxylic acid, and sulfonic acid classes, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, galacturonic acid, glycerophosphonic acid, and saccharin (e.g., saccharinate, saccharate).

[0107] Suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, for example, metal salts such as salts of alkali metals, alkaline earth metals, and transition metals, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as ammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine, etc.

[0108] All of these salts can be prepared from the corresponding compounds, for example, by reacting the compound with a suitable acid or base. The salts can contain less than 1 molar equivalent fraction, 1 molar equivalent, or more than 1 molar equivalent of an acid or base relative to any compound of the present disclosure. In certain alternative embodiments, at least one compound of the present disclosure is a component of a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

[0109] The compounds of the present disclosure may have one or more stereocenters, and each stereocenter may independently be present in either the (R) or (S) configuration. In certain alternative embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein include racemic, optically active, positional isomeric, and stereoisomeric forms, or combinations thereof, having the therapeutically useful properties described herein. The preparation of optically active forms is accomplished in any suitable manner including, by way of non-limiting example, resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain alternative embodiments, a mixture of one or more isomers is utilized as the therapeutic compounds described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers is accomplished by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0110] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound of the present disclosure, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include hydrates, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, and the like. In certain alternative embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In another embodiment, the compounds described herein exist in unsolvated forms.

[0111] In certain alternative embodiments, the compounds of the present disclosure exist as tautomers. All tautomers are included within the scope of the compounds recited herein.

[0112] In certain alternative embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" is a drug that is converted in vivo to the parent drug. In certain alternative embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In another embodiment, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

[0113] In certain alternative embodiments, for example, sites on the aromatic ring moiety of the compounds of the present disclosure are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway. In certain alternative embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl groups.

[0114] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but different atomic masses or mass numbers from those typically found in nature. Examples of isotopes preferably included in the compounds described herein are 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S, including but not limited to. In certain other embodiments, the isotopically labeled compounds are useful in tissue distribution studies of drugs and / or substrates. In another embodiment, substitution with heavier isotopes such as deuterium provides higher metabolic stability (e.g., increased in vivo half-life or decreased required dosage). In yet another embodiment, 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process using an appropriate isotopically labeled reagent in place of the unlabeled reagent that would otherwise be employed.

[0115] In certain other embodiments, the compounds described herein are labeled by other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0116] The compounds described herein, and other related compounds having different substituents, are synthesized using the techniques and materials described herein and in the art. The basic methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein.

[0117] Synthesis The present disclosure further provides methods for preparing the compounds of the present disclosure. The compounds of the present teachings can be prepared by those skilled in the art by employing standard synthetic methods and procedures known in the art from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, according to the procedures outlined herein. Standard synthetic methods and procedures for the preparation of organic molecules and for the transformation and manipulation of functional groups can be readily obtained from the relevant scientific literature or from standard textbooks in the art.

[0118] Even when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions may be used unless otherwise specified. The optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied to optimize the formation of the compounds described herein.

[0119] The processes described herein can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), by mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0120] The preparation of the compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection as well as the selection of suitable protecting groups can be readily determined by one of ordinary skill in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0121] The reactions or processes described herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in organic synthesis. Suitable solvents are typically substantially non-reactive with the reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected.

[0122] Pharmaceutical composition In one aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and at least one pharmaceutically acceptable carrier and / or excipient.

[0123] Method The present disclosure includes methods for treating, ameliorating, and / or preventing orthopoxvirus infections in a human subject. In certain embodiments, the orthopoxvirus infection is caused by molluscum contagiosum virus (MCV). In certain embodiments, the orthopoxvirus infection is caused by camelpox virus. In certain embodiments, the orthopoxvirus infection is caused by vaccinia virus. In certain embodiments, the orthopoxvirus infection is caused by mousepox virus. In certain embodiments, the orthopoxvirus infection is caused by horsepox virus. In certain embodiments, the orthopoxvirus infection is caused by monkeypox virus. In certain embodiments, the orthopoxvirus infection is caused by squirrelpox virus. In certain embodiments, the orthopoxvirus infection is caused by tanapox virus. In certain embodiments, the orthopoxvirus infection is caused by variola (smallpox virus). In certain embodiments, the orthopoxvirus infection is caused by yabapox virus. In certain embodiments, the orthopoxvirus infection is caused by parapoxvirus (orf virus). In certain embodiments, the orthopoxvirus infection is caused by swinepox virus. In certain embodiments, the orthopoxvirus infection is caused by yatapoxvirus (yaba-like disease virus). In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, geometric isomer, or tautomer thereof, or at least one pharmaceutical composition of the present disclosure.

[0124] In certain embodiments, the folding and / or function of the processivity factor mD4 is inhibited in the virus. In certain embodiments, the processivity of DNA polymerase is disrupted in the virus.

[0125] In certain embodiments, orthopoxvirus infection is caused by MCV.

[0126] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0127] In certain embodiments, at least one compound and / or pharmaceutical composition is administered locally.

[0128] Administration / Dosage / Formulation The dosing regimen can affect the effective amount. The therapeutic agent can be administered to the subject either before or after the onset of the disease or disorder contemplated in the present disclosure. Further, several divided doses, or different (staggered) doses can be administered daily or sequentially, or the dose can be administered continuously by infusion, or can be a bolus injection. Further, the dosage of the therapeutic agent can be increased or decreased proportionally to the urgency of the therapeutic or prophylactic situation.

[0129] Administration of the compositions of the present disclosure to a patient, preferably a mammal, more preferably a human, can be carried out using known procedures in an effective dosage and for a period effective to treat the diseases or disorders contemplated in the present disclosure. The effective amount of the therapeutic compound necessary to achieve a therapeutic effect can vary depending on factors such as the state of the disease or disorder in the patient; the patient's age, sex, and weight; and the ability of the therapeutic compound to treat the diseases or disorders contemplated in the present disclosure. The dosing regimen can be adjusted to provide an optimal therapeutic response. For example, several divided doses can be administered daily, or the dosage can be reduced proportionally to the urgency of the therapeutic situation. A non-limiting example of an effective dosage range for the therapeutic compounds of the present disclosure is about 1 to 5,000 mg / kg body weight / day. The pharmaceutical compositions useful for practicing the present disclosure can be administered to deliver dosages from 1 ng / kg / day to 100 mg / kg / day. One of ordinary skill in the art would be able to make a determination regarding the effective amount of the therapeutic compound by considering the relevant factors and without undue experimentation.

[0130] A medical doctor having ordinary skill in the art, such as a physician or veterinarian, would be able to readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian could start with a dosage of the compound of the present disclosure employed in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0131] In a specific embodiment, it is advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to physically discrete units suitable as a single dosage for the patient to be treated; each unit contains a predetermined quantity of the therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.

[0132] In certain other embodiments, the compositions of the present disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In another embodiment, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable carrier. In yet another embodiment, the compound of the present disclosure is the only biologically active agent in the composition (i.e., capable of treating, ameliorating, and / or preventing the diseases and disorders discussed herein). In yet another embodiment, the compound of the present disclosure is the only therapeutically effective amount of a biologically active agent in the composition (i.e., capable of treating, ameliorating, and / or preventing the diseases and disorders discussed herein).

[0133] In certain other embodiments, the compositions of the present disclosure are administered to a patient at a dosage range of 1 to 5 times or more per day. In another embodiment, the compositions of the present disclosure are administered to a patient at a dosage range that non - limitatively includes once a day, once every two days, once every three days, once a week, and once every two weeks. It will be readily apparent to those skilled in the art that the dosing frequency of the various combination compositions of the present disclosure will vary from individual to individual depending on a number of factors including, but not limited to, age, the disease or disorder to be treated, gender, general health status, and other factors. Thus, the present disclosure should not be construed as limited to any particular dosing regimen, and the exact dosage and composition to be administered to any patient will be determined by the attending physician taking into account all other factors relevant to the patient.

[0134] The compounds of the present disclosure for administration can be in the range of about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 300 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and can be any and all whole or partial increments therebetween.

[0135] In some embodiments, the dosage of the compounds of the present disclosure is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds of the present disclosure used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0136] In certain other embodiments, the disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical, and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated in the disclosure.

[0137] The formulations can be employed by mixing with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. The pharmaceutical preparations are sterilized and, if desired, can be mixed with auxiliaries, such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffers, colorings, flavorings and / or aromatic substances, etc. They can also be combined with other active agents, if desired.

[0138] The route of administration of any composition of the disclosure includes intravitreal, oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical routes. Compositions for use in the disclosure can be formulated for administration by any suitable route, such as oral or parenteral, e.g., transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., intravaginal and perivaginal), intranasal and (trans)rectal), intravitreal, intravesical, intralung, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intratracheal, inhalation, and for topical administration, etc.

[0139] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powder formulations or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions considered useful in the disclosure are not limited to the specific formulations and compositions described herein.

[0140] As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by a physical breaching of the tissue of a subject and administration of the pharmaceutical composition into the tissue through the breach. Thus, parenteral administration includes, without limitation, administration of the pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a non-surgical wound penetrating the tissue, and the like. In particular, parenteral administration is contemplated to include, without limitation, subcutaneous, intravenous, intravitreal, intraperitoneal, intramuscular, intracardiac injection, and renal dialysis infusion techniques.

[0141] Topical administration A barrier to topical administration of pharmaceuticals is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes keratinocytes and living cells. One of the factors limiting the penetration rate (flux) of a compound through the stratum corneum is the amount of active substance that can be applied or applied onto the skin surface. The greater the amount of active substance applied per unit area of skin, the greater the concentration gradient between the skin surface and the underlying layer of the skin, and in turn the greater the driving force for diffusion of the active substance through the skin. Thus, formulations containing the active substance at a higher concentration are more likely to penetrate the active substance through the skin and at a more consistent rate, if other conditions are the same, than formulations with a lower concentration.

[0142] Formulations suitable for topical administration include, without limitation, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes, and solutions or suspensions. Formulations capable of topical administration may contain, for example, from about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further contain one or more of the additional ingredients described herein.

[0143] Penetration enhancers can be used. These substances increase the penetration rate of drugs passing through the skin. Typical enhancers in the art include ethanol, glyceryl monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acid, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0144] One acceptable vehicle for some topical delivery of the compositions of the present disclosure may contain liposomes. The composition of liposomes and their use are known in the art (see, for example, U.S. Patent No. 6,323,219).

[0145] In an alternative embodiment, the topically active pharmaceutical composition may optionally be combined with other ingredients such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, thickening agents, buffering agents, preservatives, and the like. In another embodiment, a permeation or penetration enhancer is included in the composition and is effective to improve the transdermal penetration of the active ingredient into and through the stratum corneum as compared to a composition that does not contain the penetration enhancer. Various penetration enhancers including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acid, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone are known to those skilled in the art. In another aspect, the composition can further include a hydrotrope agent that functions to increase disruption of the stratum corneum structure and thus allows for an increase in transport through the stratum corneum. Various hydrotrope agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate are known to those skilled in the art.

[0146] Topically active pharmaceutical compositions should be applied in an effective amount to effect the desired change. As used herein, "effective amount" means an amount sufficient to cover the area of the skin surface where the change is desired. The active compound should be present in an amount of from about 0.0001% to about 15% by weight / volume of the composition. More preferably, it should be present in an amount of from about 0.0005% to about 5% of the composition; most preferably, it should be present in an amount of from about 0.001% to about 1% of the composition. Such compounds can be synthetic or of natural origin.

[0147] Buccal administration The pharmaceutical compositions of the present disclosure can be prepared, packaged, or sold as a formulation suitable for buccal administration. Such formulations can be, for example, in the form of tablets or lozenges made by conventional methods, and can contain the active ingredient, for example, in an amount of 0.1 to 20% (w / w), the balance being an orally soluble or degradable composition and optionally one or more additional ingredients described herein. Alternatively, a formulation suitable for buccal administration can include a powder or an aerosolized or nebulized solution or suspension containing the active ingredient. Such powdered, aerosolized, or nebulized formulations, when dispersed, preferably have an average particle or droplet diameter in the range of from about 0.1 to about 200 nanometers and can further contain one or more additional ingredients described herein. The examples of formulations described herein are not exhaustive, and the present disclosure is understood to include further modifications of these formulations and other formulations known to those skilled in the art but not described herein.

[0148] Controlled release formulations and drug delivery systems In certain other aspects, the formulations of the present disclosure can be, without limitation, short-term release formulations, rapid-offset formulations, or controlled release formulations such as sustained release formulations, delayed release formulations, and pulsatile release formulations.

[0149] The term "sustained release" is used in its conventional sense to refer to a pharmaceutical formulation that provides a gradual release of a drug over an extended period of time and that can result in a substantially constant blood concentration of the drug over an extended period of time, although not necessarily. The period can be long, up to one month or more, and should result in a longer release than would be obtained by administering the same amount of drug in bolus form. In certain embodiments, the compounds of the present disclosure can be formulated for sustained release over a period of 3 to 12 months.

[0150] For sustained release, the compounds can be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compound. Thus, compounds useful within the scope of the methods of the present disclosure can be administered in the form of microparticles, for example, by injection, or by implantation in the form of a wafer or disk.

[0151] In one embodiment of the present disclosure, the compounds of the present disclosure are administered to a patient, alone or in combination with other pharmaceuticals, using a sustained release formulation.

[0152] The term "delayed release" is used herein in its conventional sense to refer to a pharmaceutical formulation that provides an initial release of a drug after a degree of delay following drug administration and that can include a delay of from about 10 minutes up to a maximum of about 12 hours, although not necessarily.

[0153] The term "pulsatile release" is used herein in its conventional sense to refer to a pharmaceutical formulation that provides release of a drug in a manner that produces a pulsatile plasma profile of the drug following drug administration.

[0154] The term "immediate release" is used in its conventional sense to refer to a pharmaceutical formulation that provides release of a drug immediately following drug administration.

[0155] As used herein, short term refers to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes, or about 1 minute or less after drug administration, and any period that is any or all of these overall or partial increments.

[0156] As used herein, rapid onset of disappearance refers to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes or less, or about 1 minute or less after drug administration, and any period that is any and all of these overall or partial increments.

[0157] Dosage The therapeutically effective amount or dosage of the compounds of the present disclosure will vary depending on the age, sex and weight of the patient, the current medical condition of the patient, and the degree of progression of the disease or disorder contemplated in the present disclosure. One of ordinary skill in the art can determine the appropriate dosage according to these and other factors.

[0158] Suitable dosages of the compounds of the present disclosure can range from about 0.01 mg to about 5,000 mg per day, for example, from about 0.1 mg to about 1,000 mg per day, for example, from about 1 mg to about 500 mg, and by way of example from about 5 mg to about 250 mg. The dosage can be a single dose or multiple doses, for example, it can be administered 1 to 5 times or more per day. When multiple doses are used, each dose can be the same or different. For example, a dosage of 1 mg per day can be administered as two 0.5 mg doses with an interval of about 12 hours between doses.

[0159] The amount of the compound administered per day can be understood, in non-limiting examples, to be administered daily, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.

[0160] If the patient's condition improves, administration of the inhibitors of the present disclosure may optionally be continued at the discretion of the physician; alternatively, the dosage of the administered drug may be temporarily reduced or temporarily discontinued (i.e., "withdrawn") for a certain period. The length of drug withdrawal may vary arbitrarily from 2 days to 1 year, and by way of example only, includes 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dosage reduction during drug withdrawal includes 10% to 100%, and by way of example only, includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0161] If improvement in the patient's condition occurs, a maintenance dose may be administered as needed. Subsequently, the dosage or dosing frequency, or both, are reduced to a level at which improvement of the disease is maintained as a function of the disease or disorder. In certain alternative embodiments, the patient will require long-term intermittent treatment upon any recurrence of symptoms and / or infection.

[0162] The compounds for use in the methods of the present disclosure can be formulated as unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as a single dosage for each patient being treated, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect, optionally accompanied by a suitable pharmaceutical carrier. The unit dosage form can be for once-daily dosing or multiple-daily dosing (by way of example, about 1 to 5 times or more per day). When multiple-daily dosing is used, the unit dosage form can be the same or different for each dose.

[0163] The toxicity and therapeutic efficacy of such treatment regimens are determined by LD 50 (the dose lethal to 50% of the population) and ED 50(The dose therapeutically effective in 50% of the population), including but not limited to the determination of, is optionally determined in cell culture or experimental animals. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which is expressed as the ratio of LD 50 to ED 50 . Data obtained from cell culture assays and animal experiments are optionally used in formulating the dosage range for use in humans. The dosage of such compounds is preferably within the range of circulating concentrations that include the minimum toxicity and ED 50 . The dosage may vary within this range depending on the dosage form employed and the route of administration utilized.

[0164] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures, aspects, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and are embraced by the claims appended hereto. For example, it should be understood that it is within the scope of this application to vary reaction times, reaction scale / volume, and reaction conditions including, but not limited to, experimental reagents such as solvents, catalysts, pressure, ambient conditions such as nitrogen atmosphere, and reducing / oxidizing agents, and to use no more than routine experimentation.

[0165] The following examples further illustrate aspects of the disclosure. However, they are in no way intended to limit the teachings or disclosure of the disclosure described herein.

Examples

[0166] The present disclosure will be described with reference to the following examples. These examples are provided for illustrative purposes only and the present disclosure is not limited to these examples, but rather encompasses all variations that become apparent as a result of the teachings provided herein.

[0167] Example 1: Compound Synthesis Synthesis of Core Intermediate Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate TIFF2025517991000301.tif24128

[0168] Step (1): 2-(4-(Trifluoromethyl)phenyl)butanoic acid TIFF2025517991000302.tif19128Diisopropylamine (1.95 g, 19.3 mmol) was dissolved in anhydrous tetrahydrofuran. The solution was cooled to -78 °C using a dry ice / acetone bath, and n-butyllithium (2.5 M in hexane, 7.70 mL, 19.3 mmol) was slowly added. The solution was stirred at -78 °C for 1 hour. Ethyl 4-(trifluoromethyl)phenylacetate (4.47 g, 19.3 mmol) was added. The solution was stirred at -78 °C for 1 hour, then ethyl iodide (3.00 g, 19.3 mmol) was added. The cooling bath was removed, and the reaction was warmed to room temperature and stirred overnight. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated and subjected to chromatography (120 g silica column; hexane / ethyl acetate) to give 3.64 g of ethyl 2-(4-(trifluoromethyl)phenyl)butanoate as an off-white solid.

[0169] This material was dissolved in tetrahydrofuran, and lithium hydroxide hydrate (1.18 g, 28 mmol) was added. Water was added to the suspension until the solid was almost dissolved, and then the reaction was stirred at room temperature overnight. The reaction was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to give the title compound as a white solid (3.14 g). TIFF2025517991000303.tif18143

[0170] Step (2): 4-(Methoxycarbonyl)-3-methyl-5-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-2-carboxylic acid TIFF2025517991000304.tif241282 - (4-(Trifluoromethyl)phenyl)butanoic acid (3.14 g, 13.6 mmol) was dissolved in anhydrous dichloromethane, and then oxalyl chloride (2.0 M in dichloromethane, 6.78 mL, 13.6 mmol) and dimethylformamide (5 drops, catalytic amount) were added. After 2 hours at room temperature, the reaction was concentrated in vacuo. The residue was dissolved in anhydrous pyridine (25 mL), and 5-amino-3-methylthiophene-2,4-dicarboxylic acid 2-(tert-butyl) 4-methyl (3.68 g, 13.6 mmol) was added. The mixture was stirred at room temperature for 3 days, then diluted with brine and extracted with ethyl acetate. The extract was concentrated and then dissolved in 4N hydrogen chloride in dioxane (75 mL). The reaction was stirred at room temperature overnight, then concentrated and subjected to chromatography (120 g silica column; hexane / ethyl acetate) to give the title compound as an off-white solid (2.10 g). TIFF2025517991000305.tif17144

[0171] Step (3): Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate TIFF2025517991000306.tif241284 - (Methoxycarbonyl)-3-methyl-5-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-2-carboxylic acid (384 mg, 0.90 mmol) was dissolved in anhydrous dichloromethane, and then oxalyl chloride (2.0 M in dichloromethane, 0.450 mL, 0.90 mmol) and dimethylformamide (5 drops, catalytic amount) were added. After 1 hour, diisopropylethylamine (289 mg, 2.24 mmol) and tert-butyl (2-aminoethyl)carbamate (173 mg, 1.08 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was concentrated and subjected to chromatography (40 g silica column; hexane / ethyl acetate) to give methyl 5-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate (345 mg). This material was dissolved in 4N hydrochloric acid (20 mL) in dioxane and stirred overnight. The solution was lyophilized to give the hydrochloride salt of the title compound as a pale yellowish-brown solid (345 mg). TIFF2025517991000307.tif18142

[0172] With reference to the present disclosure and U.S. Patent Application No. 63 / 248,670, which is hereby incorporated by reference in its entirety, one of ordinary skill in synthetic chemistry would be able to prepare any of a number of alternative core intermediates, including, by way of non-limiting example, methyl 5-carbamoyl-4-methyl-2-(2-phenylbutanamido)thiophene-3-carboxylate (Figure 4).

[0173] Linked compound Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (1) TIFF2025517991000308.tif Methyl (2-(aminoethylcarbamoyl))-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate trifluoroacetate (250 mg, 0.47 mmol), N-Boc glycine (123 mg, 0.70 mmol), DIEA (245 μL, 1.41 mmol) and HATU (357 mg, 0.94 mmol) were dissolved in 2 mL of dimethylformamide. The reaction was stirred overnight at room temperature. Ethyl acetate was added and the mixture was then washed with water and brine. The solvent was removed in vacuo to give the crude product (260 mg), which was used in the next reaction without further purification. A 55 mg portion of the crude product was purified by preparative HPLC to give the title compound (42 mg). TIFF2025517991000309.tif24141

[0174] 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl (2) TIFF2025517991000310.tif Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate (260 mg, 0.45 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL), and the reaction was stirred for 1 hour. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as the trifluoroacetate salt (152 mg, 58% yield). TIFF2025517991000311.tif18145

[0175] 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl (3) TIFF2025517991000312.tif 221285 - ((2-(2 - aminoacetamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl trifluoroacetate (135 mg, 0.23 mmol), N - Boc glycine (51 mg, 0.29 mmol), diisopropylethylamine (120 μL, 0.69 mmol) and HATU (131 mg, 0.35 mmol) were dissolved in dimethylformamide (1 mL), and the reaction was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with water and brine. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (98 mg, 56% yield). TIFF2025517991000313.tif 24145

[0176] 5 - ((2 - ((S)-2 - amino - 3 - methylbutanamide)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl (4) TIFF2025517991000314.tif 241285 - ((2 - aminoethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl trifluoroacetate (230 mg, 0.43 mmol), N - Boc - L - valine (131 mg, 0.65 mmol), diisopropylethylamine (224 μL, 1.29 mmol) and HATU (327 mg, 0.86 mmol) were dissolved in 2 mL of dimethylformamide, and the reaction was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with water and brine. The solvent was removed under vacuum, and the crude material was purified by normal - phase column chromatography using a 0 - 10% (MeOH / dichloromethane elution gradient). Next, 260 mg of the isolated material was added to a 1:2 mixture of trifluoroacetic acid and dichloromethane (3 mL). The mixture was stirred for 1 hour, and the solvent was removed under vacuum. The material was purified by preparative HPLC to give the title compound as the trifluoroacetate salt (182 mg, 65% yield). TIFF2025517991000315.tif 24146

[0177] 5-(((6S,9S)-6,9-Diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylic acid methyl ester (5) TIFF2025517991000316.tif211285-((2-(2-Aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylic acid methyl ester trifluoroacetate (90 mg, 0.14 mmol), N-Boc-L-valine (43 mg, 0.21 mmol), diisopropylethylamine (73 μL, 0.42 mmol) and HATU (106 mg, 0.28 mmol) were dissolved in 2 mL of dimethylformamide and the reaction was stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water and brine. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to give the title compound (52 mg, 51% yield). TIFF2025517991000317.tif24141

[0178] 5-((2-(2-(2-Aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylic acid methyl ester (6) TIFF2025517991000318.tif241285-((2,2-Dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylic acid methyl ester (88 mg, 0.14 mmol) was dissolved in 2 mL of dichloromethane and 1 mL of trifluoroacetic acid and the reaction was stirred for 1 hour. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as the trifluoroacetate (80 mg, 86% yield). TIFF2025517991000319.tif18146

[0179] 5 - ((2 - ((S) - 2 - ((S) - 2 - Amino - 3 - methylbutanamide) - 3 - methylbutanamide)ethyl)carbamoyl) - 2 - (2 - (4 - fluorophenyl)butanamide) - 4 - methylthiophene - 3 - carboxylic acid methyl (7) TIFF2025517991000320.tif241285 - (((6S,9S) - 6,9 - Diisopropyl - 2,2 - dimethyl - 4,7,10 - trioxo - 3 - oxa - 5,8,11 - triazatridecane - 13 - yl)carbamoyl) - 2 - (2 - (4 - fluorophenyl)butanamide) - 4 - methylthiophene - 3 - carboxylic acid methyl (70 mg, 0.10 mmol) was dissolved in 1 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, and the reaction was stirred for 1 hour. The solvent was removed in vacuo and left under high vacuum overnight to give the title compound as the trifluoroacetate salt (75 mg, yield 93%). TIFF2025517991000321.tif24145

[0180] 2 - (2 - (4 - fluorophenyl)butanamide) - 4 - methyl - 5 - (((6S,9S,12S) - 6,9,12 - Triisopropyl - 2,2 - dimethyl - 4,7,10,13 - tetraoxo - 3 - oxa - 5,8,11,14 - tetraazapentadecane - 16 - yl)carbamoyl)thiophene - 3 - carboxylic acid methyl (8) TIFF2025517991000322.tif191285 - ((2 - ((S) - 2 - Amino - 3 - methylbutanamide)ethyl)carbamoyl) - 2 - (2 - (4 - fluorophenyl)butanamide) - 4 - methylthiophene - 3 - carboxylic acid methyl trifluoroacetate salt (90 mg, 0.14 mmol), N - Boc - L - Val - Val (66 mg, 0.21 mmol), diisopropylethylamine (73 μL, 0.42 mmol) and HATU (106 mg, 0.28 mmol) were dissolved in 1 mL of dimethylformamide, and the reaction was stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water and brine. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to give the title compound (30 mg, yield 26%). TIFF2025517991000323.tif24145

[0181] Methyl 5 - ((2 - ((S)-2 - ((S)-2 - ((S)-2 - amino - 3 - methylbutanamido)-3 - methylbutanamido)-3 - methylbutanamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamido)-4 - methylthiophene - 3 - carboxylate (9) Methyl 2-(2-(4 - fluorophenyl)butanamido)-4 - methyl - 5 - (((6S,9S,12S)-6,9,12 - triisopropyl - 2,2 - dimethyl - 4,7,10,13 - tetraoxo - 3 - oxa - 5,8,11,14 - tetraazadecane - 16 - yl)carbamoyl)thiophene - 3 - carboxylate (20 mg, 0.024 mmol) was dissolved in 1 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, and the reaction was stirred for 1 hour. The solvent was removed in vacuo, and the crude material was left under high vacuum overnight to give the title compound as the trifluoroacetate salt (18 mg, 95% yield). TIFF2025517991000325.tif18149

[0182] Methyl 5 - (((5S,8S,11S,14S)-14 - amino - 5,8,11 - triisopropyl - 15 - methyl - 4,7,10,13 - tetraoxo - 3,6,9,12 - tetraazadecyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamido)-4 - methylthiophene - 3 - carboxylate (10) TIFF2025517991000326.tif191285 - ((2 - ((S)-2 - ((S)-2 - amino - 3 - methylbutanamide)-3 - methylbutanamide)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl trifluoroacetate (150 mg, 0.2 mmol), N - Boc - L - val - val (80 mg, 0.25 mmol), diisopropylethylamine (174 μL, 1.0 mmol) and HATU (95 mg, 0.25 mmol) were dissolved in 2 mL of dimethylformamide, and the reaction was stirred at room temperature overnight. Water was added, and the product was filtered to obtain a crude intermediate (32 mg), which was added to a 1:2 mixture of trifluoroacetic acid / dichloromethane (2 mL). The mixture was stirred for 1 hour, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by preparative HPLC to obtain the title compound as the trifluoroacetate salt (18 mg, yield 10%). TIFF2025517991000327.tif25143

[0183] 5 - ((2,2 - dimethyl - 4,7,10,13 - tetraoxo - 3 - oxa - 5,8,11,14 - tetraazadecane - 16 - yl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl (11) TIFF2025517991000328.tif201285 - ((2-(2-(2 - aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl trifluoroacetate (80 mg, 0.12 mmol), N - Boc glycine (27 mg, 0.15 mmol), diisopropylethylamine (84 μL, 0.48 mmol) and HATU (57 mg, 0.15 mmol) were dissolved in 1 mL of dimethylformamide, and the reaction was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with water and brine. The solvent was removed in vacuo to obtain a crude product, which was purified by normal - phase chromatography using a 0 - 10% MeOH / dichloromethane eluent gradient to obtain the title compound (81 mg, yield 92%). TIFF2025517991000329.tif24146

[0184] Methyl 5 - ((2 - (2 - (2 - (2 - aminoacetamido)acetamido)acetamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylate (12) Methyl 5 - ((2,2 - dimethyl - 4,7,10,13 - tetraoxo - 3 - oxa - 5,8,11,14 - tetraazadecane - 16 - yl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylate (60 mg, 0.087 mmol) was dissolved in 1 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, and the reaction was stirred for 1 hour. The solvent was removed in vacuo and left under high vacuum overnight to obtain the title compound as the trifluoroacetate salt (65 mg, yield 86%). TIFF2025517991000331.tif18144

[0185] Methyl 5 - ((2,2 - dimethyl - 4,7,10,13,16 - pentaoxo - 3 - oxa - 5,8,11,14,17 - pentaazanonadecane - 19 - yl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylate (13) TIFF2025517991000332.tif171285 - ((2-(2-(2 - aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl trifluoroacetate (60 mg, 0.08 mmol), N - Boc glycine (18 mg, 0.10 mmol), diisopropylethylamine (56 μL, 0.32 mmol) and HATU (38 mg, 0.10 mmol) were dissolved in 1 mL of dimethylformamide, and the reaction was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with water and brine. The solvent was removed in vacuo, and the crude material was purified by preparative HPLC to give the title compound (30 mg, 50% yield). TIFF2025517991000333.tif24146

[0186] 5 - ((14 - amino - 4,7,10,13 - tetraoxo - 3,6,9,12 - tetraazatetradecyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl (14) TIFF2025517991000334.tif191285 - ((2,2 - dimethyl - 4,7,10,13,16 - pentaoxo - 3 - oxa - 5,8,11,14,17 - pentaazanonadecan - 19 - yl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl (21 mg, 0.028 mmol) was dissolved in 1 mL of dichloromethane and 0.5 mL of trifluoroacetic acid, and the reaction was stirred for 1 hour. The solvent was removed in vacuo, and the crude material was placed under high vacuum overnight to give the title compound as the trifluoroacetate salt (20 mg, 93% yield). TIFF2025517991000335.tif24143

[0187] 5 - ((2 - ((S)-2 - amino - 4 - methylpentanamide)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamide)-4 - methylthiophene - 3 - carboxylic acid methyl (15) TIFF2025517991000336.tif29128Boc-leucine (21 mg, 0.092 mmol), PyBop (48 mg, 0.092 mmol), and diisopropylethylamine (49 mg, 0.38 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes and then methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate hydrochloride (35 mg, 0.076 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and subjected to chromatography (12 g silica column, ethyl acetate / hexane) to give methyl 5-((2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (26 mg). This material was dissolved in 4N HCl (1 mL) in dioxane and stirred for 4 hours. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was concentrated and subjected to chromatography (4 g silica column, methanol / dichloromethane) to give a colorless oil. The oil was converted to its hydrochloride salt with 2N hydrogen chloride in diethyl ether, diluted with dioxane, and then lyophilized to give the hydrochloride salt of the title compound as a white powder (21 mg). TIFF2025517991000337.tif18142

[0188] Methyl 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (16) TIFF2025517991000338.tif29128Boc-leucine (8 mg, 0.034 mmol), PyBop (18 mg, 0.034 mmol), and diisopropylethylamine (11 mg, 0.084 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes and then 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl hydrochloride (16 mg, 0.028 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and subjected to chromatography (12 g silica column, ethyl acetate / hexane) to give 5-((2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl (17 mg). This substance was dissolved in 4N HCl (1 mL) in dioxane and stirred for 3 hours. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was concentrated and subjected to chromatography (4 g silica column, dichloromethane / methanol / ammonium hydroxide) to give a colorless oil. The oil was converted to its hydrochloride salt with 4N HCl in dioxane and lyophilized to give the hydrochloride salt of the title compound as a white powder (17 mg). TIFF2025517991000339.tif24143

[0189] Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (17) TIFF2025517991000340.tif25128Boc-leucine (7 mg, 0.030 mmol), PyBop (16 mg, 0.030 mmol), and diisopropylethylamine (10 mg, 0.075 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes and then 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl hydrochloride (17 mg, 0.025 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and subjected to chromatography (12 g silica column, ethyl acetate / hexane) to give 5-(((6S,9S)-6,9-diisobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl (13 mg). This substance was dissolved in 4N hydrogen chloride in dioxane (1 mL) and stirred overnight. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated and subjected to chromatography (4 g silica column, methanol / dichloromethane / ammonium hydroxide) to give a colorless oil. The oil was converted to its hydrochloride salt with 4N hydrogen chloride in dioxane and then lyophilized to give the hydrochloride salt of the title compound as a white powder (11 mg). TIFF2025517991000341.tif24142

[0190] 5-((2-((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl (18) TIFF2025517991000342.tif24128The hydrochloride salt of the title compound was prepared as described for Compound 4, except that Boc-D-valine was used instead of Boc-L-valine. TIFF2025517991000343.tif24144

[0191] Methyl 5 - ((2 - ((R)-2 - ((R)-2 - amino - 3 - methylbutanamido)-3 - methylbutanamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamido)-4 - methylthiophene - 3 - carboxylate (19) The hydrochloride of the title compound was prepared as described for Compound 7, except that Boc - D - valine was used instead of Boc - L - valine. TIFF2025517991000344.tif24128 TIFF2025517991000345.tif25144

[0192] Methyl 5 - ((2 - ((R)-2 - ((R)-2 - ((R)-2 - amino - 3 - methylbutanamido)-3 - methylbutanamido)-3 - methylbutanamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamido)-4 - methylthiophene - 3 - carboxylate (20) The hydrochloride of the title compound was prepared as described for Compound 9, except that Boc - D - valine was used instead of Boc - L - valine. TIFF2025517991000346.tif21128 TIFF2025517991000347.tif24144

[0193] Methyl 5 - ((2 - ((S)-2 - ((S)-2 - ((S)-2 - amino - 3 - phenylpropanamido)-3 - methylbutanamido)-3 - methylbutanamido)ethyl)carbamoyl)-2-(2-(4 - fluorophenyl)butanamido)-4 - methylthiophene - 3 - carboxylate (21) TIFF2025517991000348.tif2712813 mg (0.050 mmol) of Boc-phenylalanine was suspended in 1 mL of dichloromethane. Oxalyl chloride (2 M in dichloromethane, 0.025 mL, 0.063 mmol) and dimethylformamide (0.010 mL) were added. The mixture was stirred at room temperature for 1 hour. Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (26 mg, 0.042 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was concentrated and subjected to chromatography (4 g silica column; hexane / ethyl acetate) to give methyl 5-(((6S,9S,12S)-6-benzyl-9,12-diisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate as a colorless oil. The oil was dissolved in 1 mL of 4 N hydrogen chloride in dioxane and stirred at room temperature overnight. The solution was lyophilized to give the hydrochloride of the title compound as a white solid (6 mg). TIFF2025517991000349.tif18140

[0194] Methyl 5-((2-((S)-2-((S)-2-(2-aminoacetamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (22) TIFF2025517991000350.tif21128Boc-glycine (11 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL), then oxalyl chloride (2 M in dichloromethane, 0.032 mL, 0.063 mol) and dimethylformamide (0.010 mL) were added. The mixture was stirred at room temperature for 1 h. Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (25 mg, 0.042 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was concentrated and subjected to chromatography (4 g silica column; hexane / ethyl acetate) to give methyl 5-(((9S,12S)-9,12-diisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate as a colorless oil. The oil was dissolved in 4 N hydrogen chloride in dioxane (1 mL) and stirred at room temperature overnight. The solution was lyophilized to give the hydrochloride salt of the title compound as a white solid (9 mg). TIFF2025517991000351.tif18144

[0195] Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate (23) TIFF2025517991000352.tif 21128 Boc-Val-Val-OH (191 mg, 0.603 mmol), PyBOP (314 mg, 0.603 mmol), and diisopropylethylamine (156 mg, 1.21 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes and then 5-(2-aminoethylcarbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamide)-4-methylthiophene-3-carboxylic acid methyl.HCl (204 mg, 0.402 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and subjected to chromatography (12 g silica column, ethyl acetate / hexane) to obtain the title compound as a white solid (240 mg). TIFF2025517991000353.tif 24145

[0196] 5-((2-((S)-2-((S)-2-Amino-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylic acid methyl (24) TIFF2025517991000354.tif 23128 5-(((6S,9S)-6,9-Diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylic acid methyl (230 mg, 0.299 mmol) was dissolved in 4N hydrogen chloride in dioxane (10 mL) and stirred overnight. The solution was lyophilized to obtain the hydrochloride salt of the title compound as a white solid (204 mg). TIFF2025517991000355.tif 11137

[0197] Methyl 4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)thiophene-3-carboxylate (25) TIFF2025517991000356.tif19128Boc-Val-OH (16 mg, 0.074 mmol), PyBOP (30 mg, 0.074 mmol), and diisopropylethylamine (22 mg, 0.17 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes and then methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate (40 mg, 0.057 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and subjected to chromatography (12 g silica column, ethyl acetate / hexane) to give the title compound as a white solid (17 mg). TIFF2025517991000357.tif25147

[0198] Methyl 4-methyl-5-(((6S,9S,12S,15S)-6,9,12,15-tetraisopropyl-2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecane-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate (26) TIFF2025517991000358.tif17128Boc-Val-Val-OH (23 mg, 0.074 mmol), PyBOP (30 mg, 0.074 mmol), and diisopropylethylamine (22 mg, 0.17 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes and then 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl (40 mg, 0.057 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and subjected to chromatography (12 g silica column, ethyl acetate / hexane) to obtain the title compound as a white solid (31 mg). TIFF2025517991000359.tif18148

[0199] Compounds 27 - 93 can be prepared according to the synthetic routes described elsewhere in this specification and / or methods known to those skilled in the art with reference to the teachings provided elsewhere in this specification.

[0200] Example 2: Trivaline - 7269 - conjugate (i.e., Compound 9) targets mD4 and blocks the infection of mD4 substitute In certain embodiments, cellular processes such as uptake or metabolic stability can be useful starting points for the optimization of Compound 7269 and its analogs. As a means to enhance the bioavailability of Compound 7269, short peptide bond analogs of Compound 7269 were prepared as described elsewhere in this specification.

[0201] In certain embodiments, valine peptides were conjugated to Compound 7269 to increase lipophilicity. First, Compound 7269 was conjugated to mono, di, tri, tetravaline amino acids and / or peptides respectively, and in certain embodiments, the conjugated moiety was incorporated.

[0202] When their ability to block the infection of the surrogate virus mD4-VV was evaluated, it was demonstrated that all of the mono-, di-, and tetravalin conjugates of compound 7269 were cytotoxic.

[0203] In sharp contrast, compound 9, a trivalin-7269 conjugate (Figure 5), not only could block the infection of the mD4-VV surrogate virus, but also blocked it with 6.3-fold the potency (EC 50 = 2.1 μM) of compound 7269 (Figure 6A). Compound 9 also specifically targeted mD4 with an IC 50 = 5.0 μM in an in vitro mechanism assay (Figure 6B), which was only slightly improved compared to the unbound compound 7269 (IC 50 = 6.8 μM). The unbound trivalin peptide (i.e., ((L)-Val) 3 ) was ineffective (Figure 6C).

[0204] These results indicate that the trivalin moiety does not affect the mechanism by which the 7269 moiety directly targets mD4 (IC 50 ). Without wishing to be bound by theory, these results suggest that the increase in antiviral potency (EC 50 ) in the infection assay (Figure 6A) is derived from the trivalin moiety, supporting the advantage of integrating the individual properties of the peptide and the small molecule.

[0205] Notably, compound 9 showed no measurable toxicity (CC 50 > 100 μM) when tested in a 3-day cell viability assay (Figure 7). This is in contrast to the unbound compound 7269, which was close to the toxicity limit (CC 50 = 103.2 μM) as described above. Finally, as confirmed by microscale thermophoresis, compound 9 binds to the mD4 viral target (K D = 2.84 μM) (Figure 8).

[0206] The present disclosure further provides exemplary mD4 anti-processivity data (Table 2) and / or antiviral mD4 / VV activity data (Table 3) for selected compounds.

[0207] Table 2 provides mD4 anti-processivity activity data for exemplary compounds.

[0208] Table 3 provides data for exemplary compounds having activity measurable in the antiviral mD4 / VV assay.

[0209] (Table 2) mD4 anti-processivity activity for selected compounds TIFF2025517991000360.tif28146

[0210] (Table 3) Antiviral mD4 / VV activity for selected compounds TIFF2025517991000361.tif90148

[0211] Example 3: Linker and / or linking amino acid modifications In certain embodiments, the length and shape of the linker can vary with any of a number of alternative divalent species (e.g., -NH(CH 2 ) 2 NH-, -NH(CH 2 ) 3 NH-, -NH(CH 2 ) 4 NH-, -NH(CH 2 ) 2 O(CH 2 ) 2 NH-, 1,4-piperazinyl, 1,2-diaminophenyl, 1,3-diaminophenyl, 1,4-diaminophenyl) (Figure 9). In certain embodiments, non-natural amino acids (e.g., D-amino acids, substituted L-amino acids, and / or homologated D- and / or L-amino acids) can be utilized. In certain embodiments, non-natural amino acids can enable the use of alternative linking moieties and / or provide favorable metabolic profiles and / or pharmacokinetics.

[0212] For example, as an example, cleavage of the amino acid attached to compound 7269 in compound 9 (e.g., by glutathione) can provide 7269 substituted with an aminoethyl linker rather than compound 7269. Thus, in certain embodiments, the linker can include a sulfenamide derivative. In such embodiments, the sulfenamide linker can enable prodrug activity of the compounds of the present disclosure (Figure 10).

[0213] Numbered embodiments The following exemplary embodiments are provided, but their numbering is not to be construed as indicating importance.

[0214] Embodiment 1 provides the following: A compound of formula (I), or a salt, solvate, enantiomer, diastereoisomer, geometric isomer, isotopologue, or tautomer thereof: TIFF2025517991000362.tif16128 wherein T 1 is TIFF2025517991000363.tif4128 and T 2 is R 3 or or T 1 is R 3 and T 2 is TIFF2025517991000364.tif4128; R 1 is TIFF2025517991000365.tif4128; A 1 is TIFF2025517991000366.tif18128 and selected from the group consisting of bonds; A 2 is TIFF2025517991000367.tif15128 and selected from the group consisting of bonds; A 3 is selected from the group consisting of TIFF2025517991000368.tif15128 and a bond; A 4 is selected from the group consisting of TIFF2025517991000369.tif17128 and Y; L 1 is a bond, -N(R a )(optionally substituted C 1 ~C 6 alkylenyl)N(R b )-, -N(R a )(optionally substituted C 1 ~C 6 alkylenyl)N(R b )-, -N(R a )(optionally substituted C 1 ~C 6 heteroalkylenyl)N(R b )-, -N(R a )(optionally substituted C 1 ~C 6 heteroalkylenyl)N(R b )-, -N(R a )(optionally substituted C 3 ~C 8 cycloalkylenyl)N(R b )-, -N(R a )S(optionally substituted C 3 ~C 8 cycloalkylenyl)N(R b )-, -N(R a )(optionally substituted C 2 ~C 6 heterocyclirenyl)N(R b )-, -N(R a )S(optionally substituted C 2 ~C 6 heterocyclirenyl)N(R b )-, -N(R a )(optionally substituted C 1 ~C 6 alkylenyl)C(=O)-, -N(R a )S(optionally substituted C 1 ~C 6(Alkenylenyl)C(=O)-, optionally substituted C 1 ~C 6 alkenylenyl, -N(R a )(optionally substituted phenylenyl)N(R b )-, and -N(R a )S(optionally substituted phenylenyl)N(R b )-; selected from the group consisting of L 2 is selected from the group consisting of -C(=O)-, N(R 6 ), and a bond Y is N(R 5e )(R 5f ), OR 5e and R 5e ; selected from the group consisting of wherein A 1 , A 2 , A 3 , A 4 , L 1 , L 2 , and Y are A 1 , A 2 , A 3 , and A 4 ; any substituent selected from the group consisting of A 1 , A 2 , A 3 , A 4 , L 1 , and L 2 ; the bond between any substituent selected from the group consisting of A Y and any substituent selected from the group consisting of A 1 , A 2 , A 3 , and A 4 ; when present, is a C-N bond selected such that R 2 is N(R a )C(=O)(optionally substituted C 1 ~C 6 alkyl), N(R a )C(=O)(optionally substituted C 3 ~C 8(cycloalkyl), N(C(=O)(optionally substituted C 3 ~C 8 (cycloalkyl)) 2 , N(R a )C(=O)O(optionally substituted phenyl), N(R a )C(=O)(optionally substituted C 2 ~C 8 (heterocyclyl), N(R a )C(=O)N(R b )(optionally substituted C 1 ~C 6 (alkyl), C(=O)OR a , and C(=O)N(R a )C(=O)(optionally substituted C 1 ~C 6 (alkyl) and is selected from the group consisting of; R 3 is H, optionally substituted C 1 ~C 6 (alkyl), optionally substituted phenyl, CN, NO 2 , C(=O)OR a , and C(=O)NR a R b and is selected from the group consisting of; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , and R 4h each occurrence is independently H, optionally substituted C 1 ~C 6 (alkyl), optionally substituted C 3 ~C 6 (cycloalkyl), optionally substituted C 2 ~C 6 (heteroalkyl), optionally substituted C 2 ~C 6 (alkenyl), optionally substituted C 2 ~C 6 (alkynyl), optionally substituted heterocyclyl, and optionally substituted phenyl and is selected from the group consisting of; R5a , R 5b , R 5c , R 5d , R 5e , and R 5f is, each time it appears, independently, H, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 3 ~C 8 cycloalkyl, optionally substituted phenyl, C(=O)R a , and C(=O)OR a selected from the group consisting of, or or R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4i , R 4j , R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f two vicinal substituents selected from the group consisting of and R 4 ~C 8 may form a optionally substituted C R 6 is selected from the group consisting of H and optionally substituted C 1 ~C 6 alkyl; X is selected from the group consisting of CR 6 and N; m1, m2, m3, and m4 are each independently an integer selected from the group consisting of 1, 2, 3, and 4; R a and R b is, each time it appears, independently, H, optionally substituted C 1 ~C 6 alkyl, optionally substituted C 3 ~C 8 cycloalkyl, optionally substituted C 1 ~C6 Haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 ~C 8 selected from the group consisting of heterocyclyl, or geminal R a and R b together with the atom to which they are attached may form an optionally substituted C 2 ~C 8 heterocyclyl.

[0215] Aspect 2 provides the following: A compound of Aspect 1 selected from the group consisting of TIFF2025517991000370.tif15128.

[0216] Aspect 3 provides the following: Optionally substituted alkyl, optionally substituted alkenylenyl, optionally substituted cycloalkenylenyl, optionally substituted heterocyclylenyl, optionally substituted phenylenyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted haloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl are each independently, when they appear, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, C 1 ~C 3 haloalkoxy, phenoxy, halogen, CN, NO 2 、OR I 、N(R I )(R II )、SR I 、C(=O)R I 、C(=O)OR I 、OC(=O)OR I 、C(=O)N(R I )(R II )、S(=O) 2 N(RI )(R II )、N(R I )C(=O)R II 、N(R I )C(=NR II )N(R III )(R IV 、N(R I )S(=O) 2 R II 、optionally substituted C 2 ~C 8 heterocyclyl, and optionally substituted phenyl, and is optionally substituted with at least one substituent selected from the group consisting of, where R I , R II , R III , and R IV is, each time it appears, independently, H, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, benzyl, and optionally substituted phenyl, a compound of embodiment 1 or 2.

[0217] Embodiment 4 provides the following: Optionally substituted phenyl and optionally substituted heterocyclyl are, each time they appear, independently, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, C 1 ~C 3 haloalkoxy, phenoxy, halogen, CN, NO 2 , OR i , N(R i )(R ii ), SR i , C(=O)R i , C(=O)OR i , OC(=O)OR i , C(=O)N(R i )(R ii ), S(=O) 2 N(Ri )(R ii )、N(R i )C(=O)R ii 、N(R i )C(=NR ii )N(R iii )(R iv )、N(R i )S(=O) 2 R ii 、C 2 ~C 8 optionally substituted with at least one substituent selected from the group consisting of heterocyclyl and phenyl, wherein R i 、R ii 、R iii 、and R iv is, in each occurrence, independently, H, C 1 ~C 6 alkyl, C 3 ~C 8 cycloalkyl, C 1 ~C 6 haloalkyl, benzyl, and phenyl, a compound of any one of Aspects 1 to 3.

[0218] Aspect 5 provides: A compound of any one of Aspects 1 to 4, wherein one of the following applies: (a)A 4 is TIFF2025517991000371.tif16128, and (i)none of A 1 、A 2 and A 3 is a bond, (ii)one of A 1 、A 2 and A 3 is a bond, (iii)two of A 1 、A 2 and A 3 are bonds, and (iv)A 1 、A 2 and A 3 are each bonds one of which applies; (b) A 1 is TIFF2025517991000372.tif17128, and A 4 is TIFF2025517991000373.tif16128, and (i) Neither A 2 nor A 3 is a bond; (ii) One of A 2 and A 3 is a bond, and (iii) Both A 2 and A 3 are bonds One of which applies; or (c) A 1 is TIFF2025517991000374.tif17128, A 4 is Y, and (i) Neither A 2 nor A 3 is a bond; (ii) One of A 2 and A 3 is a bond, and (iii) Both A 2 and A 3 are bonds One of which applies.

[0219] Aspect 6 provides the following: At least one of the following compounds of any one of Aspects 1 - 5 applies: (a) A 1 is selected from the group consisting of TIFF2025517991000375.tif16128 and a bond; (b) A 2 is selected from the group consisting of TIFF2025517991000376.tif16128 and a bond; (c) A 3 is TIFF2025517991000377.tif16128 and selected from the group consisting of; and (d)A 4 is selected from the group consisting of TIFF2025517991000378.tif16128 and Y.

[0220] Aspect 7 provides the following: R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g 、and R 4h when present, are each independently H, methyl, a compound of any one of Aspects 1 - 6 selected from the group consisting of TIFF2025517991000379.tif48132.

[0221] Aspect 8 provides the following: a compound of any one of Aspects 1 - 7, where at least one of the following applies: (a)At least one of R 4a and R 4b is H; (b)At least one of R 4c and R 4d is H; (c)At least one of R 4e and R 4f is H; and (d)At least one of R 4g and R 4h is H.

[0222] Aspect 9 provides the following: a compound of any one of Aspects 1 - 8, where at least one of the following applies: (a)At least one selected from the group consisting of A 1 、A 2 、and A 3 is Selected from the group consisting of TIFF2025517991000380.tif41128; (b)A 4 is Selected from the group consisting of TIFF2025517991000381.tif61138.

[0223] Aspect 10 provides the following: R 1 is NH 2 , Ot-Bu, C(=O)Ot-Bu, A compound of any one of Aspects 1 to 9 selected from the group consisting of TIFF2025517991000382.tif56137 TIFF2025517991000383.tif183145.

[0224] Aspect 11 provides the following: R 2 is A compound of any one of Aspects 1 to 10 selected from the group consisting of TIFF2025517991000384.tif67144.

[0225] Aspect 12 provides the following: R 3 is H, C(=O)OMe, and C(=O)NH 2 Selected from the group consisting of a compound of any one of Aspects 1 to 11.

[0226] Aspect 13 provides the following: L 1 is Selected from the group consisting of TIFF2025517991000385.tif87128, a compound of any one of Aspects 1 to 12: Wherein R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are each independently H and C 1 ~C 6selected from the group consisting of alkyl; R 8a 、R 8b 、R 8c 、and R 8d are each independently H, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 3 haloalkyl, C 1 ~C 6 alkoxy, halogen, CN, and NO 2 selected from the group consisting of.

[0227] Aspect 14 provides the following: A compound of Aspect 13, where at least one of the following applies: (a) At least one of R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、and R 7h is H; (b) At least two of R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、and R 7h are H; (c) At least three of R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、and R 7h are H; (d) At least four of R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、and R 7h are H; (e)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least five of the are H; (f)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least six of the are H; (g)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least seven of them are H; (h)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h are H, respectively; (i)R 8a , R 8b , R 8c , and R 8d at least one of is H; (j)R 8a , R 8b , R 8c , and R 8d at least two of are H; (k)R 8a , R 8b , R 8c , and R 8d at least three of are H; and (l)R 8a , R 8b , R 8c , and R 8d are H, respectively.

[0228] Aspect 15 provides the following: L 1 is a compound of any one of Aspects 1 to 14 selected from the group consisting of TIFF2025517991000386.tif11128.

[0229] Aspect 16 provides the following: L 2 is -C(=O)-, a compound of any one of Aspects 1 to 15.

[0230] Aspect 17 provides the following: X is C(CH 3 )), a compound of any one of Aspects 1 to 16.

[0231] Aspect 18 provides the following: Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-(((5S,8S,11S,14S)-14-amino-5,8,11-triisopropyl-15-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazadecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecan-19-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((R)-2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-(2-aminoacetamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 4-methyl-5-(((6S,9S,12S,15S)-6,9,12,15-tetraisopropyl-2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecane-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-(((5S,8S,11S,14S)-14-amino-5,8,11-triisopropyl-15-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazapentadecyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-5-(((6S,9S)-2,2,6,9-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-aminopropanamido)propanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamido)-4-methyl-5-(piperazine-1-carbonyl)thiophene-3-carboxylate; tert-Butyl 2-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxamido)ethyl)carbamate; Methyl 5-(4-((tert-butoxycarbonyl)-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-(4-(L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; N 4-(2-Aminoethyl)-5-(2-(4-fluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxamide; tert-Butyl ((2S)-1-(((2S)-1-((2-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxamide)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate; N 4 -(2-((S)-2-((S)-2-Amino-3-methylbutanamide)-3-methylbutanamide)ethyl)-5-(2-(4-fluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxamide; Methyl 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(((5S,8S,11S)-5,8,11-triisopropyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)thiophene-3-carboxylate; Methyl 5-(4-(L-valyl-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; tert-Butyl ((7S,10S,13S)-1-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-yl)-7,10-diisopropyl-14-methyl-1,6,9,12-tetraoxo-2,5,8,11-tetraazapentadecane-13-yl)carbamate; Methyl 5-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((3-aminopropyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamide)-5-(((6S,9S)-6-isopropyl-2,2,9-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-yl)carbamoyl)-4-methylthiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S,12S)-6,9-diisopropyl-2,2,12-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3,14-dioxa-5,8,11-triazapentadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((3-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-(2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-5-carbamoyl-4-methylthiophene-3-carboxylate; 5-(2-(Benzo[d][1,3]dioxol-5-yl)butanamide)-3-methylthiophene-2,4-dicarboxylic acid 2-(tert-butyl) 4-methyl; 5-(2-(3,5-Difluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxylic acid 2-(tert-butyl) 4-methyl; Methyl 5-carbamoyl-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-carbamoyl-2-(2-(4-cyanophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(3,5-difluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-cyanophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(4-fluorophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3,17-dioxa-5,8,11,14-tetraazanonadecane-19-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-(((8S,11S,14S)-14-amino-8,11-diisopropyl-15-methyl-7,10,13-trioxo-3-oxa-6,9,12-triazahexadecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; 2-(tert-Butyl)-4-methyl 5-(2-(3,4-difluorophenyl)butanamido)-3-methylthiophene-2,4-dicarboxylate; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(m-tolyl)butanamido)thiophene-2,4-dicarboxylate; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-2,4-dicarboxylate; Methyl 5-carbamoyl-2-(2-(3,4-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(m-tolyl)butanamido)thiophene-3-carboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 2-(2-(3,4-difluorophenyl)butanamido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(m-tolyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazadecane-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; (5-(2-(4-Fluorophenyl)butanamido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valine; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(o-tolyl)butanamido)thiophene-2,4-dicarboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(o-tolyl)butanamido)thiophene-3-carboxylate; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(o-tolyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadec-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butanamido)thiophene-3-carboxylate; 2-(tert-Butyl)-4-methyl 3-methyl-5-(2-(2-(trifluoromethyl)phenyl)butanamido)thiophene-2,4-dicarboxylate; Methyl 5-carbamoyl-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazapentadec-16-yl)carbamoyl)thiophene-3-carboxylate; Methyl 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate; Methyl 5-(((R)-1-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate; and (5-(2-(4-Fluorophenyl)butanamido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valyl-D-valine A compound of any one of embodiments 1 to 17 selected from the group consisting of

[0232] Embodiment 19 provides the following: A pharmaceutical composition comprising at least one compound of any one of embodiments 1 to 18 and at least one pharmaceutically acceptable excipient.

[0233] Embodiment 20 provides the following: A method of treating, ameliorating, and / or preventing orthopoxvirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 18 and / or the pharmaceutical composition of embodiment 19.

[0234] Embodiment 21 provides the following: The method of embodiment 20, wherein the orthopoxvirus is selected from the group consisting of molluscum contagiosum virus (MCV), camelpox virus, vaccinia virus, mousepox virus, horsepox virus, monkeypox virus, squirrelpox virus, tanapox virus, variola (smallpox) virus, yabapox virus, celipox virus (cowpox), avipox virus (fowlpox), capripox virus (goatpox), lepripox virus (myxoma virus), parapox virus (orf virus), suipox virus (swinepox), and yatapox virus (yaba-like disease virus).

[0235] Embodiment 22 provides the following: The method of embodiment 21, wherein the folding and / or function of the processivity factor mD4 is inhibited in the orthopoxvirus.

[0236] Embodiment 23 provides the following: The method of any one of embodiments 20 to 22, wherein the processivity of DNA polymerase is impaired in the orthopoxvirus.

[0237] Embodiment 24 provides the following: A method according to any one of aspects 20 to 23, wherein the orthopoxvirus infection is caused by MCV.

[0238] Aspect 25 provides the following: A method according to any one of aspects 20 to 24, wherein the subject is a mammal.

[0239] Aspect 26 provides the following: A method according to aspect 25, wherein the mammal is a human.

[0240] Aspect 27 provides the following: A method according to any one of aspects 20 to 26, wherein a compound according to any one of aspects 1 to 18 and / or a pharmaceutical composition according to aspect 19 is administered topically.

[0241] Aspect 28 provides the following: A method according to any one of aspects 20 to 27, wherein a compound according to any one of aspects 1 to 18 and / or a pharmaceutical composition according to aspect 19 is administered topically to at least one lesion associated with an orthopoxvirus infection.

[0242] The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. Although the disclosure has been described with reference to specific aspects, it will be apparent to other skilled artisans that other aspects and variations of the disclosure may be made without departing from the true spirit and scope of the disclosure. The appended claims are intended to cover all such aspects and equivalent variations.

Claims

1. Compounds of formula (I), or their salts, solvates, enantiomers, diastereoisomers, geometric isomers, isotopologs, or tautomers: During the ceremony T 1 teeth And, T 2 is R 3 Is it, or T 1 is R 3 And, T 2 teeth And; R 1 teeth And; A 1 teeth Selected from the group consisting of and combinations; A 2 is Selected from the group consisting of and combinations; A 3 teeth Selected from the group consisting of and combinations; A 4 teeth Selected from the group consisting of and Y; L 1 This is a bond, -N(R a )(C may be replaced) 1 ~C 6 Alkyrenyl)N(R b )-,-N(R a )S (C may be substituted) 1 ~C 6 Alkyrenyl)N(R b )-,-N(R a )(C may be replaced) 1 ~C 6 Heteroalkylenyl)N(R b ), -N(R a )S (C may be substituted) 1 ~C 6 Heteroalkylenyl)N(R b )-,-N(R a )(C may be replaced) 3 ~C 8 Cycloalkylenyl)N(R b )-,-N(R a )S (C may be substituted) 3 ~C 8 Cycloalkylenyl)N(R b )-,-N(R a )(C may be replaced) 2 ~C 6 Heterocyclinyl)N(R b )-,-N(R a )S (C may be substituted) 2 ~C 6 Heterocyclinyl)N(R b )-,-N(R a )(C may be replaced) 1 ~C 6 Alkyrenyl)C(=O)-, -N(R a )S (C may be substituted) 1 ~C 6 Alkyrenyl)C(=O)-, even if substituted, C may still be present. 1 ~C 6 Alkyrenyl, -N(R a )(phenylenyl which may be substituted)N(R b )-, and -N(R a )S (phenylenyl which may be substituted)N(R b Selected from the group consisting of )-; L 2 is -C(=O)-, N(R 6 Selected from the group consisting of ), and combinations; Y is N(R) 5e )(R 5f ), OR 5e and R 5e Selected from the group consisting of, Here, A 1 , A 2 , A 3 , A 4 , L 1 , L 2 , and Y are, A 1 , A 2 , A 3 , and A 4 A substituent selected from the group consisting of and 1 , A 2 , A 3 , A 4 , L 1 , and L 2 If a bond exists between any substituent selected from the group consisting of the above, it is a CN bond. Y and A 1 , A 2 , A 3 , and A 4 If a bond exists between any substituent selected from the group consisting of the above, it is a CN or CO bond. Selected to do so; R 2 is N(R a )C(=O)(optionally substituted C 1 -C 6 alkyl), N(R a )C(=O)(optionally substituted C 3 -C 8 cycloalkyl), N(C(=O)(optionally substituted C 3 -C 8 cycloalkyl)) 2 , N(R a )C(=O)O(optionally substituted phenyl), N(R a )C(=O)(optionally substituted C 2 -C 8 heterocyclyl), N(R a )C(=O)N(R b )(optionally substituted C 1 -C 6 alkyl), C(=O)OR a , and C(=O)N(R a )C(=O)(optionally substituted C 1 -C 6 alkyl) selected from the group consisting of; R 3 H, and C may be substituted. 1 ~C 6 Alkyl, optionally substituted phenyl, CN, NO 2 , C(=O)OR a , and C(=O)NR a R b Selected from the group consisting of; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , and R 4h Each instance of H may be independently substituted for C. 1 ~C 6 Alkyl, possibly substituted C 3 ~C 6 Cycloalkyl, may be substituted C 2 ~C 6 Heteroalkyl, possibly substituted C 2 ~C 6 Alkenyl, C may be substituted 2 ~C 6 Selected from the group consisting of alkynyl, optionally substituted heterocyclyl, and optionally substituted phenyl; R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f Each instance of H may be independently substituted for C. 1 ~C 6 Alkyl, possibly substituted C 3 ~C 8 Cycloalkyl, optionally substituted phenyl, C(=O)R a , and C(=O)OR a Selected from the group consisting of, or R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4i , R 4j , R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f Two vicinal substituents selected from the group consisting of the following may be substituted together with the atom to which they are bonded: C 4 ~C 8 They may also form heterocycloalkyl groups; R 6 H and C may be substituted. 1 ~C 6 Selected from the group consisting of alkyl groups; X is CR 6 Selected from the group consisting of and N; m1, m2, m3, and m4 are each an integer independently selected from the group consisting of 1, 2, 3, and 4; R a and R b Each instance of H may be independently substituted for C. 1 ~C 6 Alkyl, possibly substituted C 3 ~C 8 Cycloalkyl, may be substituted C 1 ~C 6 Haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 ~C 8 Selected from a group consisting of heterocyclines, Or Geminal R a and R b These, together with the atoms to which they are bonded, may be substituted C 2 ~C 8 They may form heterocyclines.

2. A compound according to claim 1, selected from the group consisting of

2. .

3. When each optionally substituted alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclenyl, optionally substituted phenylenyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted haloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl appear, independently, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 3 Haloalkoxy, phenoxy, halogen, CN, NO 2 , OR I , N(R I )(R II ), SR I , C(=O)R I , C(=O)OR I , OC(=O)OR I , C(=O)N(R I )(R II ), S(=O) 2 N(R I )(R II ), N(R I )C(=O)R II , N(R I )C(=NR II )N(R III )(R IV ), N(R I )S(=O) 2 R II , C which may be substituted 2 ~C 8 R may be substituted with at least one substituent selected from the group consisting of heterocyclyls and optionally substituted phenyls, where R I , R II , R III , and R IV Each instance of occurrence is independently H and C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 The compound according to claim 1, selected from the group consisting of haloalkyl, benzyl, and optionally substituted phenyl.

4. In each instance, an optionally substituted phenyl and an optionally substituted heterocycline are independently C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 3 Haloalkoxy, phenoxy, halogen, CN, NO 2 , OR i , N(R i )(R ii ), SR i , C(=O)R i , C(=O)OR i , OC(=O)OR i , C(=O)N(R i )(R ii ), S(=O) 2 N(R i )(R ii ), N(R i )C(=O)R ii , N(R i )C(=NR ii )N(R iii )(R iv ), N(R i )S(=O) 2 R ii , C 2 ~C 8 It may be substituted with at least one substituent selected from the group consisting of heterocyclyl and phenyl, where R i , R ii , R iii , and R iv Each instance of occurrence is independently H and C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 A compound according to claim 1, selected from the group consisting of haloalkyl, benzyl, and phenyl.

5. The compound according to claim 1, wherein one of the following applies: (a)A 4 but And, (i)A 1 , A 2 and A 3 None of these are combinations. (ii)A 1 , A 2 and A 3 One of them is joining. (iii) A 1 , A 2 and A 3 Two of them are combinations, and (iv)A 1 , A 2 and A 3 Each is a combination. One of these applies; (b) A 1 but A 4 but And, (i)A 2 and A 3 None of these are combinations. (ii)A 2 and A 3 One of them is a combination, and (iii) A 2 and A 3 Both are combinations. One of the following applies; or (c)A 1 but A 4 Y is, (i)A 2 and A 3 None of these are combinations. (ii)A 2 and A 3 One of them is a combination, and (iii) A 2 and A 3 Both are combinations. One of them is applicable.

6. The compound according to claim 1, wherein at least one of the following applies: (a)A 1 teeth Selected from the group consisting of and combinations; (b) A 2 teeth Selected from the group consisting of and combinations; (c)A 3 teeth and selected from the group consisting of combinations; and (d)A 4 teeth The group is selected from the group consisting of and Y.

7. R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , and R 4h However, if present, H, methyl, A compound according to claim 1, selected from the group consisting of the following.

8. The compound according to claim 1, wherein at least one of the following applies: (a)R 4a and R 4b At least one of them is H; (b)R 4c and R 4d At least one of them is H; (c)R 4e and R 4f At least one of them is H; and (d)R 4g and R 4h At least one of them is H.

9. The compound according to claim 1, wherein at least one of the following applies: (a)A 1 , A 2 , and A 3 At least one selected from the group consisting of is Selected from the group consisting of; (b) A 4 teeth Selected from the group consisting of

10. R 1 がNH 2 Ot-Bu C(=O)Ot-Bu A compound according to claim 1, selected from the group consisting of the following.

11. R 2 but A compound according to claim 1, selected from the group consisting of the following.

12. R 3 H, C(=O)OMe, and C(=O)NH 2 A compound according to claim 1, selected from the group consisting of the following.

13. L 1 but A compound according to claim 1, selected from the group consisting of: During the ceremony R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h These are H and C, respectively, independently. 1 ~C 6 Selected from the group consisting of alkyl groups; R 8a , R 8b , R 8c , and R 8d These are H and C, respectively, independently. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 6 Alkoxy, halogens, CN, and NO 2 Selected from the group consisting of

14. The compound according to claim 13, wherein at least one of the following applies: (a)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least one of them is H; (b)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least two of them are H; (c)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least three of them are H; (d)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least four of them are H; (e)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least five of them are H; (f)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least six of them are H; (g)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h At least seven of them are H; (h)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , and R 7h These are H, respectively; (i)R 8a , R 8b , R 8c , and R 8d At least one of them is H; (j)R 8a , R 8b , R 8c , and R 8d At least two of them are H; (k)R 8a , R 8b , R 8c , and R 8d At least three of them are H; and (l)R 8a , R 8b , R 8c , and R 8d These are H.

15. L 1 but A compound according to claim 1, selected from the group consisting of the following.

16. L 2 The compound according to claim 1, wherein is -C(=O)-.

17. X is C(CH 3 The compound according to claim 1, which is the compound described in claim 1.

18. 5-((2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-amino-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-(2-(2-aminoacetamide)acetamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(((5S,8S,11S,14S)-14-amino-5,8,11-triisopropyl-15-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-(2-(2-(2-aminoacetamide)acetamide)acetamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecane-19-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-amino-4-methylpentanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-amino-4-methylpentanamide)-4-methylpentanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-4-methylpentanamide)-4-methylpentanamide)-4-methylpentanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((R)-2-amino-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((R)-2-((R)-2-amino-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((R)-2-((R)-2-((R)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-(2-aminoacetamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 4-methyl-5-(((6S,9S,12S,15S)-6,9,12,15-tetraisopropyl-2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecane-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-(((5S,8S,11S,14S)-14-amino-5,8,11-triisopropyl-15-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 4-methyl-5-(((6S,9S)-2,2,6,9-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-aminopropanamide)propanamide)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(piperazine-1-carbonyl)thiophene-3-carboxylate methyl; 2-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxamide)ethyl) tert-butyl carbamate; 5-(4-((tert-butoxycarbonyl)-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(4-(L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; N 4 -(2-aminoethyl)-5-(2-(4-fluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxamide; ((2S)-1-(((2S)-1-(((2-(5-Carbamoyl-2-(2-(4-Fluorophenyl)butanamide)-4-Methylthiophene-3-Carboxamide)Ethyl)amino)-3-Methyl-1-Oxobutan-2-yl)amino)-3-Methyl-1-Oxobutan-2-yl)Carbamate tert-butyl; N 4 -(2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)ethyl)-5-(2-(4-fluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxamide; 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(((5S,8S,11S)-5,8,11-triisopropyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)thiophene-3-carboxylate methyl; 5-(4-(L-valyl-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; ((7S,10S,13S)-1-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophen-3-yl)-7,10-diisopropyl-14-methyl-1,6,9,12-tetraoxo-2,5,8,11-tetraazapentadecane-13-yl) tert-butyl carbamate; 5-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((3-aminopropyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(4-fluorophenyl)butanamide)-5-(((6S,9S)-6-isopropyl-2,2,9-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-4-methylthiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)propanamide)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(((6S,9S,12S)-6,9-diisopropyl-2,2,12-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3,14-dioxa-5,8,11-triazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((3-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-(2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-5-carbamoyl-4-methylthiophene-3-carboxylate methyl; 5-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-3-methylthiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 5-(2-(3,5-difluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 5-Carbamoyl-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-Carbamoyl-2-(2-(4-cyanophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(3,5-difluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(4-cyanophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(4-fluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3,17-dioxa-5,8,11,14-tetraazanonadecan-19-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-(((8S,11S,14S)-14-amino-8,11-diisopropyl-15-methyl-7,10,13-trioxo-3-oxa-6,9,12-triazahexadecyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-(2-(3,4-difluorophenyl)butanamide)-3-methylthiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 3-methyl-5-(2-(m-tolyl)butanamide)thiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 3-methyl-5-(2-(3-(trifluoromethyl)phenyl)butanamide)thiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 5-Carbamoyl-2-(2-(3,4-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-Carbamoyl-4-methyl-2-(2-(m-tolyl)butanamide)thiophene-3-carboxylate methyl; 5-Carbamoyl-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 2-(2-(3,4-difluorophenyl)butanamide)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butanamide)thiophene-3-carboxylate methyl; 4-Methyl-2-(2-(m-tolyl)butanamide)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butanamide)thiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamide)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; (5-(2-(4-fluorophenyl)butanamide)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valine; 3-methyl-5-(2-(o-tolyl)butanamide)thiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 5-Carbamoyl-4-methyl-2-(2-(o-tolyl)butanamide)thiophene-3-carboxylate methyl; 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butanamide)thiophene-3-carboxylate methyl; 4-Methyl-2-(2-(o-tolyl)butanamide)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butanamide)thiophene-3-carboxylate methyl; 3-methyl-5-(2-(2-(trifluoromethyl)phenyl)butanamide)thiophene-2,4-dicarboxylic acid 2-(tert-butyl)4-methyl; 5-Carbamoyl-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamide)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)thiophene-3-carboxylate methyl; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butanamide)thiophene-3-carboxylate methyl; 5-(((R)-1-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamide)-4-methylthiophene-3-carboxylate methyl; and (5-(2-(4-fluorophenyl)butanamide)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valyl-D-valine A compound according to claim 1, selected from the group consisting of the following.

19. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 18 and at least one pharmaceutically acceptable excipient.

20. A pharmaceutical composition for treating, improving, and / or preventing orthopoxvirus infection in a subject where such treatment is necessary, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 18.

21. The pharmaceutical composition according to claim 20, wherein the orthopoxvirus is selected from the group consisting of molluscum contagiosum virus (MCV), camelpox virus, cowpox virus, mousepox virus, horsepox virus, monkeypox virus, raccoonpox virus, pistachiovirus, smallpox virus, yocapoxvirus, servidopoxvirus (deerpox), avipoxvirus (fowlpox), capripoxvirus (goatpox), lepolipoxvirus (myxoma virus), parapoxvirus (aarf virus), sweetopoxvirus (swinepox), and yatapoxvirus (yaba-like disease virus).

22. The pharmaceutical composition according to claim 21, wherein the folding and / or function of the processivity factor mD4 is inhibited in orthopoxvirus.

23. The pharmaceutical composition according to claim 20, wherein the processing of DNA polymerase is inhibited in orthopoxvirus.

24. The pharmaceutical composition according to claim 20, wherein the orthopoxvirus infection is caused by MCV.

25. The pharmaceutical composition according to claim 20, wherein the subject is a mammal.

26. The pharmaceutical composition according to claim 25, wherein the mammal is a human.

27. ​​The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is administered topically.

28. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is administered topically to at least one lesion associated with orthopoxvirus infection.

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