Molluscum contagiosum infection inhibitors and methods of use thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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, which is incorporated herein by reference in its entirety.

[0003] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0004] 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 this invention. Background Art

[0005] Molluscum contagiosum (MC) is a skin disease caused by the poxvirus molluscum contagiosum virus (MCV). MC manifests as skin lesions that can last for months to years before resolving. MC lesions occur in the skin of children, adults, and immunosuppressed individuals. MCV is spread by direct skin contact, sexual contact, autoinoculation from scratch injuries, and indirect inoculation from contaminated fomites (formites). Lesions may cause pain after receiving treatment designed to reduce spread. These lesions are also psychologically painful, even more so when they result in scarring. MC occurs in 2-10% of the population worldwide, accounts for approximately 1% of all diagnosed skin diseases in the United States, and approaches 5% in children. In immunocompromised individuals, this infectious disease is both severe and persistent. Between 5% and 18% of HIV patients suffer from MC. Typically, severe MC disease in AIDS patients begins to resolve while receiving highly active antiretroviral therapy (HAART). However, there are documented cases in which MC lesions develop shortly after initiation of HAART, suggesting that immune reconstitution inflammatory syndrome (IRIS) may play a role in the reappearance of MCV.

[0006] Current treatments for MC typically employ physical therapy or chemotherapy, which are not consistently effective or safe, often fail to completely eliminate lesions, and may result in scarring. In addition, the broad-spectrum antiviral drug cidofovir (i.e., 1-(3-hydroxy-2-phosphonomethoxy)propyl)cytosine), a dCMP analog, has been effectively used as a topical or intravenous drug for MC in immunocompromised patients. However, this drug has side effects, including inflammation, erosion, and pain with topical treatment, and potential nephrotoxicity with systemic administration. To date, no antiviral therapeutic has been licensed for the specific treatment of MC. The development of such an effective and safe treatment has been primarily hampered by the inability of MCV to propagate in culture.

[0007] Processivity factors (PFs) are attractive targets for antiviral therapy. Their function is to tether the DNA polymerase (Pol) to the template to enable the synthesis of the extended strand. PFs are specific for their cognate DNA Pol and are essential for DNA synthesis. All DNA Pols from bacteriophages to humans function as a single cognate PF. However, poxviruses, including the prototype vaccinia virus (VV) and MCV, are somewhat unusual in that a heterodimer comprising 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 the E9 Pol. On the other hand, A20 binds to both E9 and D4, suggesting that it partially acts as a bridge to indirectly connect D4 to E9.

[0008] Since D4 is absolutely required for DNA synthesis in MCV and VV (prototype poxviruses), D4 is also an attractive antiviral target. Remarkably, MCV D4 (mD4) can equally replace VV D4 (vD4) in in vitro DNA synthesis reactions. This is consistent with the amino acid sequence identity of mD4 of 55% and the similarity with VV of 82%. In addition, the virtual 3-D structure of mD4 was superimposed on the known crystal structure of vD4.

[0009] Therefore, there is a need in the art for compounds and methods of use that can be used to treat, prevent and / or ameliorate human MC infection. The present disclosure addresses this need. Summary of the invention

[0010] In one aspect, the disclosure relates to a compound of formula (I), or a salt, solvate, enantiomer, diastereomer, geometric isomer, isotopologue or tautomer thereof:

[0011]

[0012] in:

[0013] T 1 Yes ---L 2 -L 1 -R 1 , and T 2 YesR 3 ,

[0014] or T 1 YesR 3 , T 2 Yes ---L 2 -L 1 -R 1 ;

[0015] R 1 Yes --- A 1 -A 2 -A 3 -A 4 ;

[0016] A1 is selected from and keys;

[0017] A2 is selected from and keys;

[0018] A3 is selected from and keys;

[0019] A4 is selected from and Y;

[0020] And 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 Each of m1, m2, m3, m4, X and Y are defined elsewhere herein.

[0021] In certain embodiments, the compound of formula (I) is a compound of formula (Ia):

[0022]

[0023] In certain embodiments, the compound of formula (I) is a compound of formula (Ib):

[0024]

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient.

[0026] In another aspect, the present 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 a therapeutically effective amount of at least one compound of Formula (I) or a pharmaceutical composition of the present disclosure.

[0027] In certain embodiments, the orthopoxvirus infection is caused by Molluscum contagiosum virus (MCV).

[0028] In certain embodiments, the compound or pharmaceutical composition of Formula (I) is administered topically. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The following detailed description of specific embodiments of the present disclosure will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present disclosure, specific embodiments are shown in the accompanying drawings. However, it should be understood that the present disclosure is not limited to the precise arrangements and means of the embodiments shown in the accompanying drawings.

[0030] Figure 1A-1B It was shown that D4 is a processivity factor (PF) that functions as a sliding clamp to keep E9-Pol tethered to the DNA template. Figure 1A : In the absence of mD4, E9 Pol cannot remain bound to the template, thus preventing it from synthesizing DNA. Figure 1B : When E9 Pol is complexed with D4 (via A20), it remains tethered to the template, enabling it to synthesize an extended DNA strand.

[0031] Figure 2 It was shown that by mutating the GFI region of D4 or by administering a small molecule inhibitor (ie, compound 6407), D4 folding and / or function was lost.

[0032] Figure 3 The chemical structure of compound 7269 is provided.

[0033] Figure 4 A schematic diagram showing the synthesis of non-limiting variable amino acid conjugate compounds of the present disclosure is provided, wherein: (1) known aminothiophene A is acylated with 2-(4-fluorophenyl)butyric acid to provide amide B; (2) the tert-butyl ester of compound B is deprotected and converted to the corresponding amide with a suitable linking moiety (e.g., diaminoethane) to provide compound C; and (3) the terminal amine of compound C is conjugated with any of a variety of suitable amino acids, polypeptides and / or functionalized derivatives thereof to provide compound D.

[0034] Figure 5 The chemical structure of Compound 9 (ie, TriValine-7269) is provided.

[0035] Figures 6A-6C Compound 9 was shown to prevent mD4-VV from replacing the virus in infecting cells ( Fig. 6A ), and blocked ongoing DNA synthesis in vitro by targeting mD4 ( Figure 6B ), whereas administration of TriValine peptide (i.e., (L-Val)3) alone showed no effect ( Figure 6C ); HSV was used as a negative control.

[0036] Figure 7 A cell viability dose response graph is provided, which shows that Compound 9 has no measurable cytotoxicity in the cell viability assay compared to Compound 4 (ie, MonoValine-7269).

[0037] Figure 8 Compounds 4, 7 and 9 (K) showing binding to mD4 using microthermophoresis are provided. D =2.84 μM).

[0038] Fig. 9 Non-limiting examples of analogs of compound 9 are provided wherein the linker is variable.

[0039] Fig.10 A schematic diagram showing the use of a non-limiting analog of compound 9 as a prodrug, wherein the linker comprises a sulfenamide moiety that can be cleaved by glutathione to generate compound 7269 is provided. DETAILED DESCRIPTION

[0040] The present disclosure relates, in part, to the unexpected discovery of novel inhibitors of human infection with Molluscum Contagiosum Virus (MCV). MCV infects only humans, and viral infection is limited to the skin, not the whole body. In certain embodiments, all inhibitors described herein also block vaccinia, the prototype poxvirus. In other embodiments, the compounds described herein can inhibit other poxviruses, such as, but not limited to, camelpox virus, cowpox virus, ectromelia virus, horsepox virus, monkeypox virus, raccoonpox virus, turkeypox virus, smallpox virus, Yokapox virus, deerpox virus, fowlpox virus, myxoma pox virus, sheeppox virus, swinepox virus, and Yaba-like disease virus.

[0041] In certain embodiments, the compounds of the present disclosure or any composition comprising the same treat, prevent and / or ameliorate MCV infection when applied to the skin of an infected person. In yet other embodiments, the compounds of the present disclosure or any composition comprising the same is applied to at least one MCV lesion on the skin of an infected person.

[0042] Processivity factors (PFs) are essential for viral growth. DNA polymerases (Pols) from viruses to mammals are unable to synthesize DNA in the absence of PFs. Viral PFs have no cellular homologs, making them specific drug targets. The catalytic efficiency of DNA Pols requires that they be processive (i.e., must be able to continuously incorporate nucleotides without dissociating from the template). The catalytic efficiency of the Pol is achieved by binding to its cognate PF, which tethers the Pol to the DNA such that the rate of Pol nucleotide incorporation exceeds the rate of Pol dissociation from the template. Tethering of poxvirus E9-Pol to the DNA template by the D4 processivity factor and the A20 bridging protein is essential for elongated DNA synthesis ( Figure 1A-1B ).

[0043] The crystal structure of D4 helps to decipher its role in processivity. Mutational and biophysical analyses revealed that three amino acids at the C-terminus of D4 (i.e., GFI) can direct self-folding by contacting amino acid residues located within its inner core. Point mutations and therapeutic interventions in GFI can disrupt D4 folding and inactivate processive DNA synthesis ( Figure 2 ).

[0044] U.S. Patent Application No. 63 / 248,670, the entire contents of which are incorporated herein by reference, describes the identification and development of a class of substituted heterocycles, including substituted thiophenes, which are capable of inhibiting the folding and / or processivity of D4 and are therefore useful for treating, preventing and / or ameliorating orthopoxviruses, including but not limited to molluscum contagiosum virus (MCV), camelpox virus, cowpox virus, mousepox virus, horsepox virus, monkeypox virus, raccoonpox virus, tanapox virus, variola virus or smallpox virus, Yokapox virus, cervidaepox virus (deerpox), avipox virus (fowlpox), capripox virus (goatpox), rabbitpox virus (myxoma pox virus), parapox virus (sheeppox virus), suispox virus (swine pox) and yatapoxvirus (Yaba-like disease virus).

[0045] Compound 6407 was shown to block mD4-dependent processive DNA synthesis in vitro (IC 50 =16.4 μM) and infection with the alternative virus mD4-VV (EC 50 =21 μM). Although 6407 showed specificity in preventing herpesvirus infection of cells, cytotoxicity (CC 50 =30 μM), which is the reason for its lower selectivity index (SI) (<2). Compound 6407 has a systematic change in the tetrasubstituted thiophene at each of its four positions and at the central thiophene ring itself, while compound 7269 ( Figure 3 ) emerged as a target for mD4, among which IC 50 =6.8 μM, EC 50 =13.2μM, and CC 50 =103.2 μM. Compound 7269 also showed specificity for the alternative virus mD4-VV. Although SI=7.8 was improved, CC of compound 7269 50 Showed similar toxicity to compound 6407.

[0046] Accordingly, the present disclosure is directed, in part, to the development of antiviral agents having improved and / or desirable pharmacological properties, including, but not limited to, lower toxicity, greater bioavailability, and / or greater efficacy compared to compounds known in the art.

[0047] definition

[0048] As used herein, each of the following terms has the meaning associated with it in this section.

[0049] 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 the present disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described.

[0050] Generally, the nomenclature used herein and the laboratory procedures in pharmaceutical and organic chemistry are those well known and commonly used in the art.

[0051] As used herein, the articles "a" and "an" refer to one or more (ie, at least one) of the grammatical objects of the article. For example, "an element" refers to one element or more than one element.

[0052] As used herein, the term "about" is understood by one of ordinary skill in the art and varies to some extent depending on the context in which it is used. As used herein, when referring to a measurable value such as an amount, duration, etc., the term "about" is meant to include variations of ±20% or ±10%, in certain other embodiments ±5%, in other embodiments ±1%, in yet other embodiments ±0.1% from the specified value, as such variations are suitable for performing the disclosed methods.

[0053] As used herein, the term "D4" refers to the D4 processivity factor. Further, as used herein, the term "mD4" refers to the molluscum D4 processivity factor.

[0054] As used herein, a "disease" is a state of health in a subject in which the subject is unable to maintain homeostasis and in which the subject's health status would continue to deteriorate if the disease were not improved.

[0055] As used herein, a "disorder" in a subject refers to a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is worse than in the absence of the disorder. If untreated, the disorder does not necessarily lead to a further decline in the subject's state of health.

[0056] As used herein, the term "ED 50 ” or “ED50” refers to the effective dose of a formulation that produces about 50% of the maximal effect in subjects to which the formulation is administered.

[0057] As used herein, an "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" of a compound refers to an amount of the compound sufficient to provide a beneficial effect to the subject to which the compound is administered.

[0058] As used herein, the term "instructional materials" includes publications, records, charts, or any other medium of expression that can be used to convey the usefulness of the compositions and / or compounds of the present disclosure in the kit. For example, the instructional materials of the kit can be attached to a container containing the compounds and / or compositions of the present disclosure, or shipped together with the container containing the compounds and / or compositions.

[0059] 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, cattle, pigs, dogs, cats, and mice. In certain other embodiments, the subject is a human.

[0060] As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful in the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

[0061] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compounds useful in the present disclosure and is relatively nontoxic, i.e., the material can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any component of the composition contained therein.

[0062] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, which involves carrying or transporting a useful compound in the present disclosure in or to a subject so that it can perform its intended function. Typically, such a structure is carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable", i.e., compatible with the other ingredients of the formulation (including the useful compounds in the present disclosure) and harmless to the subject. Some examples of materials that can be used 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; 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; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solutions; and other nontoxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, and absorption delaying agents that are compatible with the activity of the compounds useful in the present disclosure and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of compounds useful in the present disclosure. Other additional ingredients that may be included in pharmaceutical compositions used in the practice of the present disclosure are known and described in the art, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0063] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, organic bases, solvates, hydrates and clathrates thereof.

[0064] As used herein, the term "pharmaceutical composition" refers to a mixture of at least one compound useful in the present disclosure with other chemical components (such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). The pharmaceutical composition facilitates administration of the compound to an organism. Various techniques for administering the compound include, but are not limited to, intravenous, oral, spray, parenteral, ophthalmic, pulmonary, and topical administration.

[0065] As used herein, the terms "prevent," "preventing," or "prevention" refer to avoiding or delaying the onset of symptoms associated with a disease or condition in a subject who does not experience such symptoms when administration of an agent or compound is initiated. Disease, condition, and disorder are used interchangeably herein.

[0066] As used herein, the term "solvate" refers to a compound formed by solvation, which is the process by which solvent molecules attract and bind to solute molecules or ions. When molecules or ions of a solute are dissolved in a solvent, they diffuse and are surrounded by solvent molecules.

[0067] As used herein, the terms "treat," "treating" or "treatment" refer to 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.

[0068] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a alkyl radical having the specified number of carbon atoms (i.e., C1-C 10 The term "alkyl" refers to a straight or branched hydrocarbon having one to ten carbon atoms) and includes straight, branched or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl and cyclopropylmethyl. Most preferred are (C1-C6)alkyl groups such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.

[0069] As used herein, unless otherwise indicated, the term "alkylene" by itself or as part of another substituent refers to a group having the specified number of carbon atoms (i.e., C1-C 10 The term "alkyl" refers to a straight or branched hydrocarbon group of one to ten carbon atoms) and includes straight, branched or cyclic substituents wherein the group has two open valences. Examples include methylene, 1,2-ethylene, 1,1-ethylene, 1,1-propylene, 1,2-propylene and 1,3-propylene.

[0070] As used herein, unless otherwise indicated, the term "cycloalkyl" by itself or as part of another substituent refers to a cyclic hydrocarbon chain having a specified number of carbon atoms (i.e., C3-C6 refers to a cyclic group containing a ring consisting of three to six carbon atoms), and includes straight chain, branched or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Most preferred are (C3-C6) cycloalkyls, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0071] As used herein, unless otherwise indicated, the term "alkenyl" used alone or in combination with other terms refers to a stable monounsaturated or di-unsaturated straight or branched hydrocarbon group having the stated 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 exemplified by -CH2-CH=CH2.

[0072] As used herein, unless otherwise specified, the term "alkynyl" used alone or in combination with other terms refers to a stable straight or branched hydrocarbon group with a triple carbon-carbon bond with the number of carbon atoms. Non-limiting examples include ethynyl and propynyl, as well as higher homologues and isomers. The term "propargyl" refers to a group exemplified by -CH2-C≡CH. The term "high propargyl" refers to a group exemplified by -CH2CH2-C≡CH. The term "substituted propargyl" refers to a group exemplified by -CR2-C≡CR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, provided that at least one R group is not hydrogen. The term "substituted high propargyl" refers to a group exemplified by -CR2CR2-C≡CR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, provided that at least one R group is not hydrogen.

[0073] As used herein, unless otherwise stated, the term "alkenylene," employed alone or in combination with other terms, refers to a stable monounsaturated or diunsaturated straight or branched chain hydrocarbon radical having the stated number of carbon atoms, wherein the radical has two open valences.

[0074] As used herein, and unless otherwise stated, the term "alkynylene," employed alone or in combination with other terms, refers to a stable straight or branched chain hydrocarbon radical with a triple carbon-carbon bond having the stated number of carbon atoms, wherein the radical has two open valencies.

[0075] 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" refer to alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl or heterocycloalkyl as defined above substituted with one, two or three substituents selected from the group consisting of: C1-C 10 Alkyl, halogen, perhaloakyl, =O, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)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(C1-C4)alkyl, -C(=O)NH2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SO2NH2, -C(=NH)NH2 and -NO2, which preferably contain one or two substituents selected from the following: halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2 and -C(=O)OH, more preferably selected from halogen, alkoxy and -OH. Examples of substituted alkyl groups include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl. Further, the definition of a particular "substituted" moiety may be defined elsewhere herein.

[0076] As used herein, unless otherwise indicated, the term "alkoxy", used alone or in combination with other terms, refers to an alkyl group as defined above having a specified number of carbon atoms attached to the remainder of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred are (C1-C3) alkoxy groups, such as, but not limited to, ethoxy and methoxy.

[0077] As used herein, unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0078] As used herein, unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl consisting of the stated number of carbon atoms and one or two heteroatoms selected from O, N and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom may be positioned at any position of the heteroalkyl, including between the remainder of the heteroalkyl and the fragment to which it is attached, and connected to the carbon atom at the farthest end of the heteroalkyl. Examples include: -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3 and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 or -CH2-CH2-SS-CH3.

[0079] As used herein, unless otherwise indicated, the term "heteroalkenyl" by itself or in combination with another term refers to a stable straight or branched monounsaturated or diunsaturated hydrocarbon radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from O, N and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CHC-N(CH3)-CH3 and -CH2-CH=CH-CH2-SH.

[0080] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, ie, having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0081] As used herein, unless otherwise indicated, the term "aryl" used alone or in combination with other terms refers to a carbocyclic aromatic system containing one or more rings (usually one, two or three rings), wherein the rings may be attached together in a pendant manner, such as biphenyl, or may be fused, such as naphthyl. Examples include phenyl, anthracenyl and naphthyl. Phenyl and naphthyl are preferred, and phenyl is most preferred.

[0082] As used herein, the term "aryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to an aryl group, for example, -CH2CH2-phenyl or -CH2-phenyl(benzyl). Preferred are aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C3)alkyl" refers to an aryl-(C1-C3)alkyl functional group in which the aryl group is substituted. Preferred are substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to a heteroaryl group, for example, -CH2CH2-pyridyl. Preferred are heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C3)alkyl" refers to a heteroaryl-(C1-C3)alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl -(CH2)-.

[0083] As used herein, unless otherwise indicated, the term "heterocycle" or "heterocyclyl" by itself or as part of another substituent refers to an unsubstituted or substituted, stable, monocyclic or polycyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom selected from N, O and S, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Unless otherwise indicated, the heterocyclic ring system may be attached to any heteroatom or carbon atom that provides a stable structure. The heterocycle may be aromatic or non-aromatic in nature (e.g., heterocycloalkyl). In certain other embodiments, the heterocycle is a heteroaryl.

[0084] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic characteristics. Polycyclic heteroaryl groups may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuran.

[0085] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiol, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, tetrahydrothiophene, 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-dioxepane (dioxepin) and hexamethylene oxide.

[0086] Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2-pyrimidinyl and 4-pyrimidinyl), pyridazinyl, thienyl, furanyl, 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.

[0087] Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), dihydroindolinyl, 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, coumarinyl, dihydrocoumarinyl, 1,5-naphthyridinyl, benzofuranyl (such as, but not limited to, 3-, 4-, 5-, benzothiophenyl (such as, but not limited to, 3-, -4-, 5-, -6- and 7-benzothiophenyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl and quinolizidinyl.

[0088] The foregoing lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0089] As used herein, the term "substituted" refers to an atom or a group of atoms replacing a hydrogen as a substituent attached to another group. Non-limiting examples of "substituted" groups include C1-C 10 Alkyl, halogen, perhaloalkyl, =O, -OH, alkoxy, -NH2, -N(CH3)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(C1-C4)alkyl, -C(=O)NH2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SO2NH2, -C(=NH)NH2 and -NO2.

[0090] For aryl, aryl-(C1-C3)alkyl and heterocyclyl, the term "substituted" applied to the rings of these groups refers to any degree of substitution, i.e., mono-, di-, tri-, tetra- or penta-substitution, as long as such substitution is permitted. Substituents are independently selected, and substitution can be at any chemically accessible position. In certain other embodiments, the number of substituents varies between 1 and 4. In other embodiments, the number of substituents varies between 1 and 3. In yet other embodiments, the number of substituents varies between 1 and 2. In yet other embodiments, the substituents are independently selected from C 1-6 Alkyl, -OH, C 1-6 Alkoxy, halo, amino, acetamido and nitro. As used herein, when the substituent is an alkyl or alkoxy group, the carbon chain can be branched, straight or cyclic, wherein a straight chain is preferred. The terms "substituted heterocycle" and "substituted heteroaryl" used herein refer to a heterocycle or heteroaryl having one or more substituents, the one or more substituents including: halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, carboxyalkyl (C (O) O alkyl), trifluoroalkyl such as CF3, aryloxy, alkoxy, aryl or heteroaryl. The substituted heterocycle or heteroaryl can have 1, 2, 3 or 4 substituents.

[0091] Throughout the present disclosure, various aspects of the present disclosure can be presented in a range format. It should be understood that the description of the range format is only for convenience and brevity, and should not be interpreted as an inflexible limitation on the scope of the present disclosure. Therefore, the description of the range should be considered to have specifically disclosed all possible sub-ranges and each numerical value in the range, and disclose the partial integer of the numerical value in the range when appropriate. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and each numeral in the range, for example, 1, 2, 2.7, 3, 4, 5, 5.3 and 6. Regardless of the breadth of the scope, this applies.

[0092] Compounds and compositions

[0093] The present invention provides a compound of formula (I), or a salt, solvate, enantiomer, diastereomer, geometric isomer, isotopomer or tautomer thereof:

[0094]

[0095] in:

[0096] T 1 Yes ---L 2 -L 1 -R 1 , and T 2YesR 3 ,

[0097] or T 1 YesR 3 , and T 2 Yes ---L 2 -L 1 -R 1 ;

[0098] R 1 Yes --- A 1 -A 2 -A 3 -A 4 ;

[0099] A 1 Selected from and keys;

[0100] A 2 Selected from and keys;

[0101] A 3 Selected from and keys; and

[0102] A 4 Selected from

[0103] L 1 Selected from bonds, -N(R a )(Optionally substituted C1-C6 alkylene)N(R b )-、-N(R a )S(optionally substituted C1-C6 alkylene)N(R b )-、-N(R a )(optionally substituted C1-C6 heteroalkylene)N(R b )、-N(R a )S(optionally substituted C1-C6 heteroalkylene)N(R b )-、-N(R a )(Optionally substituted C3-C8 cycloalkylene)N(R b )-、-N(R a )S(optionally substituted C3-C8 cycloalkylene)N(R b )-、-N(R a )(Optionally substituted C2-C6 heterocyclylene)N(R b )-、-N(R a )S(optionally substituted C2-C6 heterocyclylene)N(R b )-、-N(R a )(Optionally substituted C1-C6 alkylene)C(=O)-, -N(R a)S(optionally substituted C1-C6 alkylene)C(=O)-, optionally substituted C1-C6 alkylene, -N(R a )(optionally substituted phenylene)N(R b )- and -N(R a )S(optionally substituted phenylene)N(R b )-;

[0104] L 2 Selected from -C(=O)-, N(R 6 ) and keys;

[0105] Y is selected from N(R 5e )(R 5f ) and OR 5e ,

[0106] Among them A 1 , A 2 , A 3 , A 4 , L 1 , L 2 and Y are chosen such that:

[0107] Selected from A 1 , A 2 , A 3 and A 4 Any substituent selected from A 1 , A 2 , A3, A 4 , L 1 and L 2 The bond between any substituents (if any) is a CN bond, and

[0108] Y and selected from A 1 , A 2 , A 3 and A 4 The bond between any substituents (if any) is a CN or CO bond; R 2 Selected from N(R a )C(═O)(optionally substituted C1-C6 alkyl), N(R a )C(=O)(optionally substituted C3-C8 cycloalkyl), N(C(=O)(optionally substituted C3-C8 cycloalkyl)2, N(R a )C(=O)O(optionally substituted phenyl), N(R a )C(=O)(optionally substituted C2-C8 heterocyclyl), N(R a )C(=O)N(R b )(optionally substituted C1-C6 alkyl), C(=O)OR a and C(=O)N(Ra )C(═O)(optionally substituted C1-C6 alkyl);

[0109] R 3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted phenyl, CN, NO2, C(=O)OR a and C(=O)NR a R b ; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted heterocyclyl, and optionally substituted phenyl;

[0110] R 5a , R 5b , R 5c , R 5d , R 5e and R 5f Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, C(=O)R a and C(=O)OR a ,

[0111] Or choose 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 adjacent substituents of may optionally combine with the atoms to which they are bound to form an optionally substituted C4-C8 heterocycloalkyl;

[0112] R 6 is selected from H and optionally substituted C1-C6 alkyl;

[0113] X is selected from CR 6 and N;

[0114] m1, m2, m3 and m4 are each independently an integer selected from 1, 2, 3 and 4;

[0115] R a and R b Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl,

[0116] Or with R a and R b The groups may be optionally combined with the atoms to which they are attached to form an optionally substituted C2-C8 heterocyclyl.

[0117] Those skilled in the art will understand that unless otherwise stated herein or implied from the specific context herein, the A 1 , A 2 and A 3 The definition of has no implicit directional meaning. The same applies to A 1 , A 2 and A 3 Any specific example of, as shown elsewhere herein. In non-limiting examples, Can correspond to In another non-limiting example, Can correspond to In another non-limiting example, Can correspond to In another non-limiting example, Can correspond to

[0118] In certain embodiments, the compound of formula (I) is a compound of formula (Ia):

[0119]

[0120] In certain embodiments, the compound of formula (I) is a compound of formula (Ib):

[0121]

[0122] In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted phenylene, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted haloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl (if present) is independently optionally substituted with at least one substituent selected from C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, 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)2N(R I )(R II )、N(RI)C(=O)R II 、N(R I )C(=NR II )N(R III )(RIV), N(R I )S(=O)2R II , an optionally substituted C2-C8 heterocyclyl, and an optionally substituted phenyl, wherein R I , R II , R III and R IV Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and optionally substituted phenyl.

[0123] In certain embodiments, each occurrence of optionally substituted phenyl and optionally substituted heterocyclyl (if present) is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, 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)2N(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)2R ii , C2-C8 heterocyclic group and phenyl group, wherein R i , R ii , R iii and R iv Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl.

[0124] In certain embodiments, A 4 yes AND one of the following applies:

[0125] (i)A 1 , A 2 and A 3 None of them are keys.

[0126] (ii)A 1 , A 2 and A 3 One of them is the key,

[0127] (iii)A 1 , A 2 and A 3 Two of them are keys, and

[0128] (iv)A 1 , A 2 and A 3 Each of is a key.

[0129] In certain embodiments, A 1 yes A 4 yes AND one of the following applies:

[0130] (i)A 2 and A 3 None of them are keys.

[0131] (ii)A 2 and A 3 One of them is the key, and

[0132] (iii)A 2 and A 3 They are all keys.

[0133] In certain embodiments, A1 yes A 4 is Y, and one of the following applies:

[0134] (i)A 2 and A 3 None of them are keys.

[0135] (ii)A 2 and A 3 One of them is the key, and

[0136] (iii)A 2 and A 3 They are all keys.

[0137] In certain embodiments, A 1 Selected from In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes

[0138] In certain embodiments, A 2 Selected from In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes

[0139] In certain embodiments, A 3 Selected from In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes

[0140] In certain embodiments, A 4 Selected from In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments. 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes

[0141] In certain embodiments, R 4a is H, methyl. In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4a yes In certain embodiments, R 4ayes In certain embodiments, R 4a yes In certain embodiments, R 4a yes

[0142] In certain embodiments, R 4b is H, methyl. In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes In certain embodiments, R 4b yes

[0143] In certain embodiments, R 4c is H, methyl. In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes In certain embodiments, R 4c yes

[0144] In certain embodiments, R 4d is H, methyl. In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes In certain embodiments, R 4d yes

[0145] In certain embodiments, R 4e is H, methyl. In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes In certain embodiments, R 4e yes

[0146] In certain embodiments, R 4f is H, methyl. In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes In certain embodiments, R 4f yes

[0147] In certain embodiments, R 4g is H, methyl. In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes In certain embodiments, R 4g yes

[0148] In certain embodiments, R 4h is H, methyl. In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for In certain embodiments, R 4h for

[0149] In certain embodiments, R 4a and R 4b At least one of is H. In certain embodiments, R 4c and R 4dAt 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 them is H.

[0150] 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(CH3)3). In certain embodiments, R 5f is H. In certain embodiments, R 5f It is C(=O)O(C(CH3)3).

[0151] In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes

[0152] In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes In certain embodiments, A 2 yes

[0153] In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes In certain embodiments, A 3 yes

[0154] In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes In certain embodiments, A 4 yes

[0155] In certain embodiments, R 1 is NH2. In certain embodiments, R 1 is Ot-Bu. In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes In certain embodiments, R 1 yes

[0156] In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes

[0157] In certain embodiments, R 3 It's H.

[0158] In certain embodiments, L 1 Selected from

[0159] in:

[0160] R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are each independently selected from H and C1-C6 alkyl; and

[0161] R 8a , R 8b , R 8c and R 8d Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C6 alkoxy, halogen, CN and NO2.

[0162] In certain embodiments, R 7a , R 7b , R 7c , R 7d , R7e, R7f , 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 7hEach of them is H.

[0163] 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 Each of them is H.

[0164] In certain embodiments, L 1 yes In certain embodiments, L 1 yes In certain embodiments, L 1 yes In certain embodiments, L 1 yes

[0165] In certain embodiments, L 2 It is -C(=O)-.

[0166] In certain embodiments, X is C(CH3).

[0167] In certain embodiments, the compound is selected from: methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate;

[0168] 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0169] 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0170] 5-((2-(((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0171] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0172] 5-((2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0173] 5-((2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0174] 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0175] 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-carboxylic acid methyl ester;

[0176] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0177] 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0178] 5-((2-(2-(-2-(2-aminoacetamido)acetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0179] 5-((2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecyl-19-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0180] 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0181] 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0182] 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyrylamino)-4-methylthiophene-3-carboxylic acid methyl ester;

[0183] 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-carboxylic acid methyl ester;

[0184] 5-((2-(((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0185] 5-((2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0186] 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-carboxylic acid methyl ester;

[0187] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropionamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido-4-methylthiophene-3-carboxylic acid methyl ester;

[0188] 5-((2-(S)-2-((S)-2-(2-aminoacetylamino)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0189] 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)butyramido)thiophene-3-carboxylic acid methyl ester;

[0190] 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 ester;

[0191] 4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0192] 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-pentaazanonadecan-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester;

[0193] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester;

[0194] 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)butanamido)thiophene-3-carboxylic acid methyl ester;

[0195] 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-carboxylic acid methyl ester;

[0196] 5-((2-((S)-2-((S)-2-aminopropylamino)propionamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester;

[0197] 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(piperazine-1-carbonyl)thiophene-3-carboxylic acid methyl ester;

[0198] tert-Butyl (2-(5-carbamoyl-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxamido)ethyl)carbamate;

[0199] 5-(4-((tert-Butyloxycarbonyl)-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0200] 5-(4-(L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; N 4 -(2-aminoethyl)-5-(2-(4-fluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxamide;

[0201] tert-butyl (2S)-1-((2S)-1-(2-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxamido)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;

[0202] N 4 -(2-((S)-2-((S)-2-amino-3-methylbutyrylamino)-3-methylbutyramido)ethyl)-5-(2-(4-fluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxamide;

[0203] 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((5S,8S,11S)-5,8,11-triisopropyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0204] 5-(4-(L-valyl-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0205] tert-Butyl ((7S,10S,13S)-1-(5-carbamoyl-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophen-3-yl)-7,10-diisopropyl-14-methyl-1,6,9,12-tetraoxo-2,5,8,11-tetraazapentadecan-13-yl)carbamate;

[0206] 5-((3-((tert-Butyloxycarbonyl)amino)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0207] 5-((3-aminopropyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0208] Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate;

[0209] 2-(2-(4-fluorophenyl)butyramido)-5-((6S,9S)-6-isopropyl-2,2,9-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-4-methylthiophene-3-carboxylic acid methyl ester;

[0210] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)propionamido)ethyl)carbamoyl)-2-(-2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0211] 5-(((6S,9S,12S)-6,9-diisopropyl-2,2,12-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0212] 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3,14-dioxa-5,8,11-triazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0213] 5-((3-(S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0214] 5-((2-(2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0215] 2-(2-(Benzo[d][1,3]dioxol-5-yl)butanamido)-5-carbamoyl-4-methylthiophene-3-carboxylic acid methyl ester;

[0216] 2-(tert-butyl) 4-methyl 5-(2-(benzo[d][1,3]dioxol-5-yl)butanamido)-3-methylthiophene-2,4-dicarboxylate;

[0217] 2-(tert-butyl)4-methyl 5-(2-(3,5-difluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxylate;

[0218] 5-Carbamoyl-2-(2-(3,5-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0219] 5-Carbamoyl-2-(2-(4-cyanophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0220] 5-((2-aminoethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0221] 2-(2-(Benzo[d][1,3]dioxol-5-yl)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-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0222] 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)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0223] 5-((2-aminoethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0224] 2-(2-(3,5-difluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0225] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0226] Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(4-cyanophenyl)butyramido)-4-methylthiophene-3-carboxylate;

[0227] 2-(2-(4-cyanophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0228] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0229] 2-(2-(4-fluorophenyl)butyramido)-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-carboxylic acid methyl ester;

[0230] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0231] 2-(tert-butyl)4-methyl 5-(2-(3,4-difluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxylate;

[0232] 2-(tert-butyl)4-methyl-3-methyl-5-(2-(m-tolyl)butyramido)thiophene-2,4-dicarboxylate;

[0233] 2-(tert-butyl)4-methyl-3-methyl-5-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-2,4-dicarboxylate;

[0234] 5-Carbamoyl-2-(2-(3,4-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0235] 5-Carbamoyl-4-methyl-2-(2-(m-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0236] 5-Carbamoyl-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0237] 5-((2-aminoethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0238] 2-(2-(3,4-difluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0239] 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-carboxylic acid methyl ester;

[0240] 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0241] 4-methyl-2-(2-(m-tolyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0242] 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-carboxylic acid methyl ester;

[0243] Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylate;

[0244] 4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0245] 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-carboxylic acid methyl ester;

[0246] 5-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0247] (5-(2-(4-fluorophenyl)butyramido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valine;

[0248] 2-(tert-butyl)4-methyl 3-methyl-5-(2-(o-tolyl)butyramido)thiophene-2,4-dicarboxylate;

[0249] 5-Carbamoyl-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0250] 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0251] 4-methyl-2-(2-(o-tolyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,4-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0252] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0253] 2-(tert-butyl)4-methyl 3-methyl-5-(2-(2-(trifluoromethyl)phenyl)butyramido)thiophene-2,4-dicarboxylate;

[0254] 5-Carbamoyl-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0255] 4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0256] 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-carboxylic acid methyl ester;

[0257] 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-carboxylic acid methyl ester; and

[0258] (5-(2-(4-fluorophenyl)butyramido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valyl-D-valine.

[0259] Table 1

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] The compounds described herein can form salts with acids and / or bases, and these salts are included in the present disclosure. In certain other embodiments, the salt is a pharmaceutically acceptable salt. The term "salt" includes addition salts of free acids and / or bases useful in the methods of the present disclosure. However, pharmaceutically unacceptable salts may have properties such as high crystallinity, which are useful in the practice of the present disclosure, such as, for example, in the synthesis, purification or formulation of compounds useful in the methods of the present disclosure.

[0278] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include sulfates, bisulfates, hemisulfates, 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 aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include 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, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactonic acid, galacturonic acid, glycerophosphonic acid and saccharin (e.g., saccharinate, sucrate).

[0279] Suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include, for example, metal salts, including alkali metal salts, alkaline earth metal salts and transition metal salts, such as, for example, calcium salts, magnesium salts, potassium salts, sodium salts and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, ammonium, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0280] All of these salts can be prepared from the corresponding compounds by, for example, reacting an appropriate acid or base with the compound. Relative to any compound of the present disclosure, the salt can be composed of less than one molar equivalent, one molar equivalent, or more than one molar equivalent of the acid or base moiety. In certain other embodiments, at least one compound of the present disclosure is a component of a pharmaceutical composition that further comprises at least one pharmaceutically acceptable carrier.

[0281] The compounds of the present disclosure may have one or more stereocenters, and each stereocenter may exist independently in the (R) or (S) configuration. In certain other embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein include racemic, optically active, regioisomers and stereoisomeric forms having therapeutically useful properties as described herein, or combinations thereof. The preparation of optically active forms may be achieved in any suitable manner, including (non-limiting examples) by resolving the racemic form with recrystallization techniques, synthesizing from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain other embodiments, a mixture of one or more isomers is used as a therapeutic compound as described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds may be prepared in any manner, including stereoselective synthesis, enantioselective synthesis and / or separation of enantiomers and / or diastereomeric mixtures. The separation of compounds and their isomers may be achieved in any manner, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.

[0282] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also referred to as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having any compound structure of the present disclosure, as well as metabolites and active metabolites of these compounds having the same active type. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, and the like. In certain other embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated forms.

[0283] In certain other embodiments, the compounds of the present disclosure exist in the form of tautomers. All tautomers are included within the scope of the compounds described herein.

[0284] In certain other embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" is a pharmaceutical agent that is converted into a parent drug in vivo. In certain other embodiments, after in vivo administration, the prodrug is chemically converted into a biological, pharmaceutical or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutical or therapeutically active form of the compound by one or more steps or processes.

[0285] In certain other embodiments, for example, sites on the aromatic ring portion of the compounds of the present disclosure are susceptible to various metabolic reactions. Introducing appropriate substituents on the aromatic ring structure can reduce, minimize or eliminate such metabolic pathways. In certain other embodiments, by way of example only, appropriate substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are deuterium, halogen or alkyl.

[0286] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to 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. In certain other embodiments, isotope-labeled compounds can be used for drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium can provide greater metabolic stability (e.g., increase in vivo half-life or reduce dosage requirements). In yet other embodiments, substitution with positron emitting isotopes (such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process by using an appropriate isotopically labeled agent in place of the unlabeled agent otherwise employed.

[0287] In certain other embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0288] The compounds described herein and other related compounds with various substituents are synthesized using the techniques and materials described herein and in the art. The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein.

[0289] synthesis

[0290] The present disclosure further provides methods for preparing the compounds of the present disclosure. The compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates according to the steps outlined herein by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or standard textbooks in the field.

[0291] It should be understood that where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by conventional optimization procedures by those skilled in the art. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps set forth may be altered in order to optimize the formation of the compounds described herein.

[0292] The processes described herein can be monitored by any suitable method known in the art. For example, product formation 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-Vis), mass spectrometry, or monitoring by chromatography, such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0293] The preparation of compounds may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemical properties of protecting groups can be found 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.

[0294] The reactions or processes described herein can be carried out in a suitable solvent that can be easily selected by a technician in the field of organic synthesis. Suitable solvents are generally substantially unreactive with reactants, intermediates and / or products at the temperature at which the reaction is carried out, i.e., within the temperature range from the solvent freezing temperature to the solvent boiling temperature. A given reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction steps, a suitable solvent for a specific reaction step can be selected.

[0295] Pharmaceutical composition

[0296] 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.

[0297] method

[0298] The present disclosure includes methods for treating, ameliorating and / or preventing an orthopoxvirus infection 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 cowpox 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 raccoonpox virus. In certain embodiments, the orthopoxvirus infection is caused by tanapox virus. In certain embodiments, the orthopoxvirus infection is caused by variola virus (smallpox virus). In certain embodiments, the orthopoxvirus infection is caused by Yokapox virus. In certain embodiments, the orthopoxvirus infection is caused by Cervidae pox virus (deerpox). In certain embodiments, the orthopoxvirus infection is caused by avianpox virus (fowlpox). In certain embodiments, the orthopoxvirus infection is caused by capripox virus (goatpox). In certain embodiments, the orthopoxvirus infection is caused by rabbitpoxvirus (myxoma virus). In certain embodiments, the orthopoxvirus infection is caused by parapoxvirus (sob virus). In certain embodiments, the orthopoxvirus infection is caused by suidpoxvirus (swinepox). 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.

[0299] In some embodiments, the folding and / or function of the processivity factor mD4 in the virus is inhibited. In some embodiments, the processivity of the DNA polymerase in the virus is disrupted.

[0300] In certain embodiments, the orthopoxvirus infection is caused by MCV.

[0301] In certain embodiments, wherein the subject is a mammal. In certain embodiments, the mammal is a human.

[0302] In certain embodiments, at least one compound and / or pharmaceutical composition is administered topically.

[0303] Administration / dosage / formulation

[0304] The administration regimen will affect what constitutes an effective dose. The therapeutic formulation may be administered to the subject before or after the onset of the disease or disorder contemplated in the present disclosure. Further, several divided doses and staggered doses may be administered daily or sequentially, or the dose may be infused continuously, or may be a single injection. Further, the dose of the therapeutic formulation may be proportionally increased or decreased according to the exigencies of the therapeutic or preventive situation.

[0305] The compositions of the present disclosure can be administered to a patient, preferably a mammal, more preferably a human, at a dosage and time period effective to treat the disease or disorder contemplated in the present disclosure using known procedures. The effective amount of the therapeutic compound necessary to achieve a therapeutic effect can vary depending on factors such as the disease or disorder state of the patient; the age, sex and weight of the patient; and the ability of the therapeutic compound to treat the disease or condition contemplated in the present disclosure. The dosage regimen can be adjusted to provide the best therapeutic response. For example, several separate doses can be administered daily, or the dose can be reduced proportionally according to the urgency of the treatment situation. A non-limiting example of an effective dosage range for the therapeutic compound of the present disclosure is about 1 to 5000 mg / kg body weight / day. The pharmaceutical composition that can be used to implement the present disclosure can be administered at a dosage of 1 ng / kg / day to 100 mg / kg / day. One of ordinary skill in the art will be able to study the relevant factors and determine the effective amount of the therapeutic compound without undue experimentation.

[0306] A physician, e.g., a physician or veterinarian, having ordinary skills in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of the present disclosure used 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.

[0307] In certain embodiments, it is advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages 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 carrier.

[0308] In certain other embodiments, the compositions of the present disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In other embodiments, 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 other embodiments, the compound of the present disclosure is the only bioactive agent in the composition (i.e., capable of treating, improving and / or preventing diseases and disorders discussed herein). In yet other embodiments, the compound of the present disclosure is the only bioactive agent in the composition (i.e., capable of treating, improving and / or preventing diseases and disorders discussed herein).

[0309] In certain other embodiments, the compositions of the present disclosure are administered to the patient at a dosage of 1 to 5 times or more per day. In other embodiments, the compositions of the present disclosure are administered to the patient at a dosage range including, but not limited to, once a day, once every two days, once every three days to a week, and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various combination compositions of the present disclosure varies from individual to individual, depending on many factors, including, but not limited to, age, disease or disorder to be treated, sex, overall health, and other factors. Therefore, the present disclosure should not be construed as being limited to any specific dosage regimen, and the precise dosage and composition to be administered to any patient is determined by the attending physician after considering all other factors of the patient.

[0310] The compounds of the present disclosure for administration may be administered in an amount 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 any and all whole or partial increments therebetween.

[0311] In certain embodiments, the dose of the compound of the present disclosure is from about 1 mg to about 2,500 mg. In certain embodiments, the dose of the compound 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 dose 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.

[0312] In certain other embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the present disclosure, alone or in combination with a second agent; and instructions for using the compound to treat, prevent, or alleviate one or more symptoms of a disease or disorder contemplated in the present disclosure.

[0313] The preparation can be used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier materials suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral or any other suitable administration known in the art. The pharmaceutical preparation can be sterilized and, if necessary, can be mixed with adjuvants, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure buffers, coloring agents, flavoring agents and / or aromatic substances, etc. They can also be combined with other active agents as required.

[0314] The administration route of any composition of the present disclosure includes intravitreal, oral, nasal, rectal, vaginal, parenteral, buccal, sublingual or topical. The compound used in the present disclosure can be formulated to be administered by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (through) buccal, (through) urethra, vagina (e.g., vaginal and perivaginal), nasal (intra) and (through) rectal, intravitreal, intravesical, intrapulmonary, intraduodenal, intragastrointestinal, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration.

[0315] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, slurries, lozenges, creams, pastes, plasters, emulsions, disks, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions useful in the present disclosure are not limited to the specific formulations and compositions described herein.

[0316] As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical disruption of a subject's tissue and administration of the pharmaceutical composition through a rupture in the tissue. Thus, parenteral administration includes, but is not limited to, administration of the pharmaceutical composition by injection of the composition, administration of the composition through a surgical incision, administration of the composition through tissue penetration of a non-surgical wound, and the like. In particular, parenteral administration includes, but is not limited to, subcutaneous, intravenous, intravitreal, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

[0317] Topical application

[0318] One obstacle to topical drug administration is the epidermal stratum corneum. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids and various other lipids, including cornified cells and living cells. One of the factors that limit the penetration rate (flux) of compounds through the stratum corneum is the amount of active substance that can be loaded or applied to the skin surface. The greater the amount of active substance applied per unit skin area, the greater the concentration gradient between the skin surface and the lower layer of the skin, and the greater the diffusion force of the active substance through the skin. Therefore, all other conditions being equal, preparations containing higher concentrations of active substances are more likely to cause the active substance to penetrate the skin, and the penetration rate is more stable, compared with preparations with lower concentrations.

[0319] Preparations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations, such as liniments, emulsions, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes, and solutions or suspensions. Topical preparations may, for example, contain 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. Preparations for topical administration may also contain one or more other ingredients described herein.

[0320] Penetration enhancers can be used. These materials increase the rate of skin penetration of the drug. Typical enhancers in the art include ethanol, laurin, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, etc. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0321] An acceptable carrier for topical delivery of some compositions of the present disclosure may contain liposomes. The composition of liposomes and their use are known in the art (eg, see US Pat. No. 6,323,219).

[0322] In alternative embodiments, the topically active pharmaceutical composition may optionally be combined with other ingredients, such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, tackifiers, buffers, preservatives, etc. In another embodiment, a permeation or penetration enhancer is included in the composition, and the percutaneous penetration of the active ingredient into the stratum corneum is effectively improved relative to a composition lacking a permeation enhancer. Various permeation enhancers are known to those skilled in the art, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In another aspect, the composition may also include a hydrotrope, which acts to increase the disorder of the stratum corneum structure, thereby increasing transport through the stratum corneum. Various hydrotropes are known to those skilled in the art, such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate.

[0323] The amount of topically active pharmaceutical composition applied should be effective to achieve the desired change. As used herein, "effective amount" refers to an amount sufficient to cover the skin surface area to be changed. The active compound should be present in an amount of about 0.0001 wt.% to about 15 wt.% of the volume of the composition. More preferably, it should be present in an amount of about 0.0005 wt.% to about 5 wt.% of the composition; most preferably, it should be present in an amount of about 0.001 wt.% to about 1 wt.% of the composition. Such compounds can be synthetic or naturally derived.

[0324] Oral administration

[0325] The pharmaceutical compositions of the present disclosure may be prepared, packaged or sold in formulations suitable for oral administration. For example, such formulations may be in the form of tablets or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) of active ingredients, the remainder comprising an orally soluble or degradable composition, and optionally one or more other ingredients described herein. Alternatively, formulations suitable for oral administration may include a powder or an aerosolized or atomized solution or suspension containing the active ingredient. Such powdered, aerosolized or atomized formulations, when dispersed, preferably have an average particle size or droplet size of about 0.1 to about 200 nm, and may also include one or more other ingredients described herein. The formulation examples described herein are not exhaustive, and it should be understood that the present disclosure includes additional changes to these and other formulations not described herein but known to those skilled in the art.

[0326] Controlled release formulations and drug delivery systems

[0327] In certain other embodiments, the formulations of the present disclosure may be, but are not limited to, short-term, rapid replenishment, and controlled release formulations, such as sustained release, delayed release, and pulsed release formulations.

[0328] The term sustained release in its traditional sense refers to a pharmaceutical formulation that provides a gradual release of a drug over a long period of time and may (although not necessarily) result in a substantially constant blood level of the drug over a long period of time. The time period may be as long as one month or longer and should be a longer release than the same amount of a medicament administered in a bolus form. In certain embodiments, the compounds of the present disclosure may be formulated to be sustained release within 3-12 months.

[0329] For sustained release, the compounds may be formulated with suitable polymers or hydrophobic materials that provide sustained release properties to the compound.Thus, the compounds useful in the methods of the present disclosure may be administered in microparticle form, for example by injection, or in the form of wafers or discs by implantation.

[0330] In one embodiment of the disclosure, a compound of the disclosure is administered to a patient alone or in combination with another pharmaceutical agent using a sustained release formulation.

[0331] As used herein, the term delayed release refers in its conventional sense to a drug formulation that provides initial release of the drug after a delay after administration and may, but does not necessarily, include a delay of about 10 minutes to about 12 hours.

[0332] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in a manner that produces a pulsatile plasma profile of the drug following administration.

[0333] The term immediate release in its traditional sense refers to a pharmaceutical formulation that releases the drug immediately after administration.

[0334] As used herein, short-term refers to any time period up to and including 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, as well as any or all full or partial increments after administration.

[0335] As used herein, rapid replenishment refers to any time period after administration up to and including 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, and any and all full or partial increments thereof.

[0336] dose

[0337] The therapeutically effective amount or dosage of the disclosed compounds depends on the age, sex and weight of the patient, the patient's current medical condition and the progression of the disease or disorder anticipated in the disclosure. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

[0338] The suitable dosage of the compound of the present disclosure can be in the range of about 0.01 mg to about 5000 mg per day, such as about 0.1 mg to about 1000 mg per day, for example, about 1 mg to about 500 mg, such as about 5 mg to about 250 mg. The dosage can be administered in a single or multiple times, for example 1 to 5 times or more per day. When multiple doses are used, the amount of each dose can be the same or different. For example, a dosage of 1 mg per day can be administered in two 0.5 mg doses, with an interval of about 12 hours between the two doses.

[0339] It is to be understood that, in non-limiting examples, the amount of compound administered daily may be administered every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.

[0340] In the event that the patient's condition does improve, the administration of the inhibitor of the present disclosure may optionally be continued, at the physician's discretion; optionally, the drug dosage may be temporarily reduced or suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including, by way of example only, 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. Dose reductions during a drug holiday include 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0341] Once the patient's condition has improved, a maintenance dose may be administered as necessary. Subsequently, depending on the disease or disorder, the dose or frequency of administration, or both, is reduced to a level that maintains the improved disease. In certain other embodiments, patients require long-term intermittent treatment when symptoms and / or infections recur.

[0342] The compounds used in the methods of the present disclosure can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit doses for patients receiving treatment, each unit containing a predetermined amount of active substance, which can be calculated to produce the desired therapeutic effect, optionally used in combination with a suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or one of multiple daily doses (e.g., about 1 to 5 times or more per day). When multiple daily doses are used, the unit dosage form of each dose can be the same or different.

[0343] The toxicity and therapeutic efficacy of such treatment regimens are optionally determined in cell culture or experimental animals, including but not limited to LD 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as LD 50 and ED 50 The data obtained from cell culture assays and animal studies can optionally be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the least toxic ED 50 The dosage may optionally vary within this range depending upon the dosage form employed and the route of administration utilized.

[0344] Those skilled in the art will recognize, or be able to determine using only routine experimentation, many equivalents to the specific steps, embodiments, claims, and examples described herein. These equivalents are considered to be within the scope of the present disclosure and are covered by the appended claims. For example, it should be understood that changes in reaction conditions, including but not limited to reaction time, reaction size / volume, and experimental reagents (such as solvents), catalysts, pressures, atmospheric conditions (such as nitrogen atmospheres), and reducing agents / oxidants, as well as art-recognized alternatives, and using only routine experimentation, are within the scope of the present application.

[0345] The following examples further illustrate aspects of the present disclosure. However, they are in no way limiting to the teachings or disclosures of the present disclosure as described herein.

[0346] Example

[0347] The present disclosure is now 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 includes all variations that are obvious as a result of the teaching provided herein.

[0348] Example 1: Compound Synthesis

[0349] Synthesis of core intermediate(s)

[0350] 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester

[0351]

[0352] Step (1): 2-(4-(trifluoromethyl)phenyl)butanoic acid

[0353]

[0354] Diisopropylamine (1.95g, 19.3mmol) is dissolved in anhydrous tetrahydrofuran. The solution is cooled to -78°C using a dry ice / acetone bath, and n-butyl lithium (2.5M hexane solution, 7.70mL, 19.3mmol) is slowly added. The solution is stirred for 1h at -78°C. 4-(trifluoromethyl)phenylethyl acetate (4.47g, 19.3mmol) is added. The solution is stirred for 1h at -78°C, and then iodoethane (3.00g, 19.3mmol) is added. The cooling bath is removed, and the reactant is warmed to room temperature and stirred overnight. The reaction is then diluted with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The extract is concentrated and chromatographed (120g silica gel column; hexane / ethyl acetate) to obtain 3.64g of 2-(4-(trifluoromethyl)phenyl)butyric acid ethyl ester as an off-white solid.

[0355] The material was dissolved in tetrahydrofuran and lithium hydroxide hydrate (1.18 g, 28 mmol) was added. Water was added to the suspension until most of the solid was dissolved, and the reaction was stirred at room temperature overnight. The reaction was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to give the title compound (3.14 g) as a white solid. 1 H NMR (300MHz, CDCl3) δ: 7.35 (2H, d, J=8.6Hz), 7.20 (2H, d, J=8.6Hz), 3.90 (1H, t, J=7.6Hz), 1.69-1.84 (m, 2H), 0.91 (3H, t, J=7.6Hz).

[0356] Step (2): 4-(Methoxycarbonyl)-3-methyl-5-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-2-carboxylic acid

[0357] 2-(4-(Trifluoromethyl)phenyl)butanoic acid (3.14 g, 13.6 mmol) was dissolved in anhydrous dichloromethane, followed by the addition of oxalyl chloride (2.0 M in dichloromethane, 6.78 mL, 13.6 mmol) and dimethylformamide (5 drops, catalytic). 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 ester (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 a 4N solution of hydrogen chloride in dioxane (75 mL). The reaction was stirred at room temperature overnight, then concentrated and chromatographed (120 g silica gel column; hexane / ethyl acetate) to give the title compound (2.10 g) as an off-white solid. MS m / z 430.42 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.11 (s, 1H), 7.22 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 6.23 (br s, 1H), 4.81 (m, 1H), 3.43 (s, 3H), 1.81 (m, 2H), 0.95 (m, 3H).

[0358] Step (3): 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester

[0359]

[0360] 4-(Methoxycarbonyl)-3-methyl-5-(2-(4-(trifluoromethyl)phenyl)butyramido)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) were added. After one 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 solution and extracted with dichloromethane. The extract was concentrated and chromatographed (40 g silica gel 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). The material was dissolved in 4N hydrochloric acid in dioxane (20 mL) and stirred overnight. The solution was lyophilized to give the hydrochloride salt of the title compound as a light brown solid (345 mg). MS m / z 472.42 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.23 (s, 1H), 8.22 (br s, 2H), 7.80 (br s,1H), 7.45-7.60(m,2H), 7.38-7.41(m,2H), 3.20-7.95(m,8H), 2.12-2.47(m,4H), 0.68-0.90(m,3H).

[0361] In view of the present disclosure and U.S. Patent Application No. 63 / 248,670 (the entire contents of which are incorporated herein by reference), one skilled in the art of synthetic chemistry will be able to prepare any of a variety of alternative core intermediates, including but not limited to 5-carbamoyl-4-methyl-2-(2-phenylbutyramido)thiophene-3-carboxylic acid methyl ester ( Figure 4 ).

[0362] Conjugated compounds

[0363] 5-((2-(2-((tert-Butyloxycarbonyl)amino)acetylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (1)

[0364]

[0365] 5-(2-aminoethylcarbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid 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 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 a crude product (260 mg) which was used in subsequent reactions without further purification. A 55 mg portion of the crude product was purified by preparative HPLC to give the title compound (42 mg). MS m / z 579.73 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.39 (dd, J = 5.6, 8.5 Hz, 2H), 7.20-7.01 (m, 2H), 3.84 (s, 3H), 3.79-3.61 (m, 4H), 3.48-3.35 (m, 4H), 2.52 (s, 3H), 2.21 (quintet, J = 7.3, 14.1 Hz, 1H), 1.97-1.76 (m, 1H), 1.41 (s, 9H), 0.91 (t, J = 7.3 Hz, 3H). 5-((2-(2-aminoacetylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (2)

[0366]

[0367] Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-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 hr. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as a trifluoroacetate salt (152 mg, 58% yield). MS m / z 479.62 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.54-7.28 (m, 2H), 7.22-6.96 (m, 2H), 3.85 (s, 3H), 3.78-3.70 (m, 1H), 3.65 (d, J = 1.2 Hz, 3H), 3.45 (d, J = 2.3 Hz, 4H), 2.53 (s, 3H), 2.20 (dd, J = 7.0, 14.1 Hz, 1H), 2.01-1.77 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H).

[0368] 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (3)

[0369]

[0370] Methyl 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate 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). MS m / z 636.78 (M+H). 1 H NMR (300MHz, methanol-d4) δ: 7.40 (dd, J=5.6, 8.5Hz, 2H), 7.11 (t, J=8.5Hz, 2H), 3.84 (s, 5H), 3.78-3.70 (m, 3H), 3.65 (s, 2H ), 3.42 (dd, J=3.8, 9.1Hz, 4H), 2.52 (s, 3H), 2.33-2.09 (m, 1H), 2.03-1.78 (m, 1H), 1.42 (s, 9H), 0.91 (t, J=7.6Hz, 3H). 5-((2-(((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (4)

[0371]

[0372] 5-((2-aminoethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramide)-4-methylthiophene-3-carboxylic acid trifluoroacetic acid methyl ester (230mg, 0.43mmol), N-Boc-L-valine (131mg, 0.65mmol), diisopropylethylamine (224μL, 1.29mmol) and HATU (327mg, 0.86mmol) were dissolved in 2mL 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 normal phase column chromatography using a 0-10% (MeOH / dichloromethane) eluent gradient. Next, 260mg of the separated material was added to a 1:2 mixture (3mL) of trifluoroacetic acid and dichloromethane. The mixture was stirred for 1hr, and the solvent was removed in vacuo. The substance was purified by preparative HPLC to obtain the title compound (182mg, 65% yield) as a trifluoroacetate. MS m / z 521.65 (M+H). 1 H NMR (300MHz, methanol-d4) δ: 7.53-7.25 (m, 2H), 7.21-7.01 (m, 2H), 3.85 (s, 3H), 3.74 (s, 1H), 3.59 (d, J=5.3Hz, 1H), 3.5 7-3.36 (m, 4H), 2.54 (s, 3H), 2.28-2.11 (m, 2H),, 2.02-1.74 (m, 1H), 1.03 (t, J=7.6Hz, 6H), 0.91 (t, J=7.3Hz, 3H).

[0373] 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (5)

[0374]

[0375] Methyl 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate 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). MS m / z 720.91 (M+H). 1 H NMR (300MHz, methanol-d4) δ: 7.40 (dd, J=5.3, 8.8Hz, 2H), 7.11 (t, J=8.8Hz, 2H), 4.09 (s, 1H), 3.88-3.83 (m, 4H) , 3.78-3.63(m, 2H), 3.49-3.35(m, 4H), 2.53(s, 3H), 2.36-1.75(m, 4H), 1.42(s, 9H), 1.01-0.78(m, 16H).

[0376] 5-((2-(2-aminoacetylamino)acetylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (6)

[0377]

[0378] 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramide)-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 stirred for 1 hr. The solvent was removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as a trifluoroacetate salt (80 mg, 86% yield). MS m / z 536.68 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.40 (dd, J = 5.3, 8.8 Hz, 2H), 7.11 (t, J = 8.8 Hz, 2H), 3.94-3.81 (m, 5H), 3.76 (s, 3H), 3.43 (dd, J = 5.3, 12.9 Hz, 4H), 2.53 (s, 3H), 2.29-2.09 (m, 1H), 2.04-1.77 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H).

[0379] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (7)

[0380]

[0381] Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (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 hr. The solvent was removed in vacuo and placed under high vacuum overnight to give the title compound as the trifluoroacetate salt (75 mg, 93% yield). MS m / z 620.57 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.40 (dd, J = 5.6, 8.5 Hz, 2H), 7.11 (t, J = 8.8 Hz, 2H), 4.20-4.04 (m, 1H), 3.85 (s, 3H), 3.80-3.60 (m, 4H), 3.51-3.34 (m, 4H), 2.54 (s, 3H), 2.33-1.96 (m, 3H), 1.95-1.77 (m, 1H), 1.05-0.78 (m, 15H).

[0382] 2-(2-(4-Fluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester (8)

[0383]

[0384] Methyl 5-((2-((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate trifluoroacetate (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, 26% yield). MS m / z 819.92 (M+H). 1 H NMR (300MHz, methanol-d4) δ: 7.40 (dd, J=5.3, 8.8Hz, 2H), 7.19-6.99 (m, 2H), 4.23-4.01 (m, 2H), 3.90-3.79 (m, 4H), 3.78-3.6 2 (m, 2H), 3.42 (d, J=5.3Hz, 4H), 2.53 (s, 3H), 2.29-2.11 (m, 1H), 2.09-1.75 (m, 4H), 1.43 (s, 10H), 0.99-0.80 (m, 21H).

[0385] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (9)

[0386]

[0387] Methyl 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-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 hr. The solvent was removed in vacuo and the crude material was placed under high vacuum overnight to give the title compound as a trifluoroacetate salt (18 mg, 95% yield). 1H NMR (300 MHz, methanol-d4) δ: 7.45-7.26 (m, 2H), 7.19-6.94 (m, 2H), 4.25-3.95 (m, 2H), 3.86-3.75 (m, 3H), 3.68 (d, J=6.4 Hz, 2H), 3.35 (d, J=4.1 Hz, 3H), 2.60-2.42 (m, 3H), 2.29-1.67 (m, 5H), 1.05-0.74 (m, 19H).

[0388] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (10)

[0389]

[0390] 5-((2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid 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 give 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 hr and the solvent was removed in vacuo to give a crude product. The crude product was purified by preparative HPLC to give the title compound as a trifluoroacetate salt (18 mg, 10% yield). MS m / z 818.83 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.36 (dd, J = 5.6, 8.5 Hz, 2H), 7.20-6.96 (m, 2H), 4.26-4.13 (m, 2H), 4.06 (t, J = 8.2 Hz, 1H), 3.81 (s, 3H), 3.77-3.64 (m, 2H), 3.46-3.30 (m, 4H), 2.49 (s, 3H), 2.27-1.77 (m, 7H), 1.39-1.39 (m, 1H), 1.08-0.69 (m, 27H).

[0391] 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (11)

[0392]

[0393] Methyl 5-((2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate 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 the crude product, which was purified by normal phase chromatography using a 0-10% MeOH / dichloromethane elution gradient to give the title compound (81 mg, 92% yield). MS m / z 693.68 (M+H). 1 H NMR (300MHz, methanol-d4) δ: 7.50-7.32(m, 2H), 7.20-7.05(m, 2H), 3.90(s, 2H), 3.85(s, 5H), 3.78-3.68(m, 4H), 3.50-3.35(m, 4H), 2.53(s, 3H) , 2.20 (dd, J=7.0, 14.1Hz, 1H), 1.88 (td, J=7.8, 13.6Hz, 1H), 1.47-1.47 (m, 1H), 1.44-1.43 (m, 1H), 1.47-1.39 (m, 11H), 0.98-0.84 (m, 3H).

[0394] 5-((2-(2-(-2-(2-aminoacetamido)acetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (12)

[0395]

[0396] Methyl 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-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 hr. The solvent was removed in vacuo and placed under high vacuum overnight to give the title compound as a trifluoroacetate salt (65 mg, 86% yield). MS m / z 593.53 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.49-7.30 (m, 2H), 7.23-7.03 (m, 2H), 3.98 (s, 2H), 3.87-3.84 (m, 5H), 3.76 (s, 3H), 3.43 (dd, J=5.3, 11.7 Hz, 4H), 2.53 (s, 3H), 2.30-2.12 (m, 1H), 1.97-1.78 (m, 1H), 0.97-0.85 (m, 3H).

[0397] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (13)

[0398]

[0399] Methyl 5-((2-(2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate 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). MS m / z 750.69 (M+H). 1HNMR (300MHz, methanol-d4) δ: 7.41 (br.s., 2H), 7.12 (br.s., 2H), 3.95-3.82 (m, 9H), 3.76 (br.s., 3H), 3.45 (d, J =7.6Hz, 4H), 2.54 (br.s., 3H), 2.34-2.12 (m, 1H), 2.04-1.80 (m, 1H), 1.44 (br.s., 8H), 1.02-0.81 (m, 3H).

[0400] 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (14)

[0401]

[0402] 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)butanamido)-4-methylthiophene-3-carboxylate (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 hr. The solvent was removed in vacuo and the crude material was placed under high vacuum overnight to give the title compound as a trifluoroacetate salt (20 mg, 93% yield). MS m / z 650.67 (m+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.48-7.31 (m, 2H), 7.24-6.97 (m, 2H), 4.07-3.66 (m, 13H), 3.43 (dd, J=5.0, 11.4 Hz, 4H), 2.53 (s, 3H), 2.21 (td, J=7.0, 14.1 Hz, 1H), 1.92 (d, J=8.2 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

[0403] 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (15)

[0404]

[0405] Boc-leucine (21mg, 0.092mmol), PyBop (48mg, 0.092mmol) and diisopropylethylamine (49mg, 0.38mmol) are mixed in anhydrous dimethylformamide (1mL). The mixture is stirred for 15 minutes, and then 5-((2-aminoethyl) formamyl)-2-(2-(4-fluorophenyl) butyramide)-4-methylthiophene-3-carboxylic acid methyl esters hydrochloride (35mg, 0.076mmol) is added. The reaction is stirred at room temperature overnight, and then diluted with saline. The mixture is extracted with ethyl acetate, concentrated and chromatographically separated (12g silica gel column, ethyl acetate / hexane), 5-((2-((S)-2-((tert-butyloxycarbonyl) amino)-4-methylpentanamide) ethyl) formamyl)-2-(2-(4-fluorophenyl) butyramide)-4-methylthiophene-3-carboxylic acid methyl esters (26mg) are obtained. The substance was dissolved in 4N HCl dioxane (1mL) solution and stirred for 4hr. The reaction was then diluted with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The extract was concentrated and chromatographed (4g silica gel column, methanol / dichloromethane) to obtain a colorless oil. The oil was converted into its hydrochloride with 2N hydrogen chloride in ether, diluted with dioxane, and then freeze-dried to obtain the hydrochloride (21mg) of the title compound as a white powder. MS m / z 535.22 (M+H). 1 H NMR (300 MHz, CDCl3) δ: 11.41 (s, 1H), 7.84 (br s, 1H), 7.24-7.28 (m, 2H), 6.98-7.17 (m, 2H), 6.69 (br s, 1H), 3.83 (s, 3H), 3.35-3.58 (m, 7H), 2.49 (s, 3H), 1.2-2.3 (m, 6H), 0.82-0.98 (m, 9H). 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyrylamino)-4-methylthiophene-3-carboxylic acid methyl ester (16)

[0406]

[0407] Boc-leucine (8 mg, 0.034 mmol), PyBop (18 mg, 0.034 mol) and diisopropylethylamine (11 mg, 0.084 mmol) were mixed in anhydrous dimethylformamide (1 mL). The mixture was stirred for 15 minutes, then 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester hydrochloride (16 mg, 0.028 mmol) was added. The reaction was stirred at room temperature overnight, then diluted with brine. The mixture was extracted with ethyl acetate, concentrated and chromatographed (12 g silica gel column, ethyl acetate / hexanes) to give methyl 5-((2-((S)-2-((tert-butyloxycarbonyl)amino)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate (17 mg). The material was dissolved in 4N HCl in dioxane (1 mL) and stirred for 3 hr. The reaction was then diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was concentrated and chromatographed (4 g silica gel column, dichloromethane / methanol / ammonium hydroxide) to give a colorless oil. The oil was converted to its hydrochloride with 4N HCl in dioxane and lyophilized to give the hydrochloride of the title compound as a white powder (17 mg). MS m / z 648.71 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.42 (s, 1H), 7.81 (br s, 1H), 7.31-7.38 (m, 2H), 6.99-7.13 (m, 2H), 6.75 (br s, 1H), 4.30-4.4.0 (m, 1H), 3.83 (s, 3H), 3.16-3.57 (m, 6H), 2.57 (s, 3H), 2.04-2.26 (m, 4H), 1.05-1.90 (m, 7H), 0.80-1.10 (m, 15H).

[0408] 5-((2-((S)-2-((S)-2-((S)-4-methylpentanamido)-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)4-methylthiophene-3-carboxylic acid methyl ester (17)

[0409]

[0410] Boc-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, then 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyrylamino)-4-methylthiophene-3-carboxylic acid methyl ester hydrochloride (17 mg, 0.025 mmol) was added. The reaction was stirred at room temperature overnight, then diluted with brine. The mixture was extracted with ethyl acetate, concentrated and chromatographed (12 g silica gel column, ethyl acetate / hexanes) to give methyl 5-(((6S,9S)-6,9-diisobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate (13 mg). The material 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 chromatographed (4 g silica gel column, methanol / dichloromethane / ammonium hydroxide) to give a colorless oil. The oil was converted to the 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). MS m / z 761.78 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.42 (s, 1H), 7.81-7.88 (m, 1H), 7.28-7.36 (m, 2H), 6.97-7.10 (m, 2H), 6.78 -6.82 (m, 1H), 4.17-4.44 (m, 2H), 3.81 (s, 3H), 3.00-3.75 (m, 12H), 2.59 (s, 3H), 0.88-1.97 (m, 30H).

[0411] 5-((2-((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (18)

[0412]

[0413] The 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. MS m / z 521.77 (M+H). 1H NMR (300MHz, methanol-d4) δ: 7.53-7.25 (m, 2H), 7.21-7.01 (m, 2H), 3.85 (s, 3H), 3.74 (s, 1H), 3.59 (d, J=5.3Hz, 1H), 3. 57-3.36 (m, 4H), 2.54 (s, 3H), 2.28-2.11 (m, 2H), 2.02-1.74 (m, 1H), 1.03 (t, J=7.6Hz, 6H), 0.91 (t, J=7.3Hz, 3H).

[0414] 5-((2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (19)

[0415]

[0416] The hydrochloride salt of the title compound was prepared as described for compound 7, except that Boc-D-valine was used instead of Boc-L-valine. MS m / z 620.78 (M+H). 1 H NMR (300 MHz, methanol-d4) δ: 7.40 (dd, J = 5.6, 8.5 Hz, 2H), 7.11 (t, J = 8.8 Hz, 2H), 4.20-4.04 (m, 1H), 3.85 (s, 3H), 3.80-3.60 (m, 4H), 3.51-3.34 (m, 4H), 2.54 (s, 3H), 2.33-1.96 (m, 3H), 1.95-1.77 (m, 1H), 1.05-0.78 (m, 15H).

[0417] 5-((2-((R)-2-((R)-2-((R)-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (20)

[0418]

[0419] The hydrochloride salt of the title compound was prepared as described for compound 9, except that Boc-D-valine was used instead of Boc-L-valine. MS m / z 719.86 (M+H). 1H NMR (300 MHz, methanol-d4) δ: 7.45-7.26 (m, 2H), 7.19-6.94 (m, 32H), 4.25-3.95 (m, 2H), 3.86-3.75 (m, 3H), 3.68 (d, J=6.4 Hz, 2H), 3.35 (d, J=4.1 Hz, 3H), 2.60-2.42 (m, 3H), 2.29-1.67 (m, 5H), 1.05-0.74 (m, 19H).

[0420] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropionamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (21)

[0421]

[0422] Boc-phenylalanine (13 mg, 0.050 mmol) was suspended in dichloromethane (1 mL). Oxalyl chloride (2M in dichloromethane, 0.025 mL, 0.063 mol) and dimethylformamide (0.010 mL) were added. The mixture was stirred at room temperature for 1 hr. 5-((2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester (26 mg, 0.042 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was then diluted with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The extract was concentrated and chromatographed (4 g silica gel 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-tetraazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate as a colorless oil. The oil was dissolved in 4N hydrochloric acid 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 (6 mg). MS m / z 768.01 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.43 (s, 1H), 6.9-7.8 (m, 11H), 3.81 (s, 3H), 3.03-3.81 (m, 12H), 2.56 (s, 3H), 0.86-2.03 (m, 21H).

[0423] 5-((2-((S)-2-((S)-2-(2-aminoacetylamino)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester (22)

[0424]

[0425] Boc-glycine (11 mg, 0.063 mmol) was dissolved in dichloromethane (1 mL), followed by addition of oxalyl chloride (2 M dichloromethane solution, 0.032 mL, 0.063 mol) and dimethylformamide (0.010 mL). The mixture was stirred at room temperature for 1 hour. Add 5-((2-((S)-2-((S)-2-amino-3-methylbutyrylamide)-3-methylbutyrylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyrylamide)-4-methylthiophene-3-carboxylic acid methyl ester (25 mg, 0.042 mmol), and the reaction was stirred at room temperature overnight. The reaction was then diluted with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The extract was concentrated and chromatographed (4 g silica gel 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-tetraazahexadecane-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylate as a colorless oil. The oil was dissolved in 4N hydrochloric acid 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). MS m / z 677.91 (M+H). 1 H NMR (300 MHz, CDCl3) δ: 11.40 (s, 1H), 7.80 (br s, 1H), 7.29-7.40 (m, 2H), 7.02-7.21 (m, 3H), 3.83 (s, 3H), 3.03-3.81 (m, 14H), 2.54 (s, 3H), 0.86-2.03 (m, 18H). 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester (23)

[0426]

[0427] 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, then 5-(2-aminoethylcarbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butyramide)-4-methylthiophene-3-carboxylic acid methyl ester HCl (204 mg, 0.402 mmol) was added. The reaction was stirred at room temperature overnight, then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and chromatographed (12 g silica gel column, ethyl acetate / hexane) to give the title compound (240 mg) as a white solid. MS m / z 770.54 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.22 (s, 1H), 7.99 (s, 3H), 7.45 (d, 2H, J = 8.8Hz), 7.42 (d, 2H, J = 8.8Hz), 4.2 (m , 2H), 3.80 (s, 3H), 3.4-3.6 (m, 3H), 2.48 (s, 3H), 1.8-2.3 (m, 7H), 1.36-1.40 (m, 9H), 0.8-1.0 (m, 15H).

[0428] 5-((2-((S)-2-((S-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester (24)

[0429]

[0430] Methyl 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13yl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylate (230 mg, 0.299 mmol) was dissolved in 4N hydrogen chloride dioxane (10 mL) solution and stirred overnight. The solution was lyophilized to give the hydrochloride salt of the title compound as a white solid (204 mg). MS m / z 670.57 (M+H). 1 H NMR (300MHz, DMSO-d6) δ: 11.2 (s, 1H), 7.99 (br s, 1H, 7.65 (d, 2H, J=8.8Hz), 7.45 (d, 2H, J=8.8Hz), 3.0-4.0 (m, 21H), 0.8-1.0 (m, 15H).

[0431] 4-Methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)-5-((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester (25)

[0432]

[0433] Boc-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 5-((2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester (40 mg, 0.057 mmol) was added. The reaction was stirred at room temperature overnight and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and chromatographed (12 g silica gel column, ethyl acetate / hexane) to give the title compound (17 mg) as a white solid. MS m / z 869.68 (m+H). 1 HNMR (300MHz, CDCl3) δ: 11.65 (s, 1H), 8.02 (s, 1H), 7.55-7.65 (m, 2H), 7.43-7.55 (m, 2H), 7.0-7.4 (m, 2H), 5.24-5.45 (m, 2H), 4.0-4 .5(4H), 3.78-3.82(m, 3H), 3.3-3.6(m, 4H), 2.8-3.0(m, 6H), 2.45-2.6(m, 2H), 1.8-2.4(m, 6H), 1.2-1.5(m, 10H), 0.75-1.0(m, 21H).

[0434] 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-pentaazanonadecan-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester (26)

[0435]

[0436] Boc-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-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester (40 mg, 0.057 mmol) was added. The reaction was stirred at room temperature overnight and then diluted with brine. The mixture was extracted with ethyl acetate, concentrated, and chromatographed (12 g silica gel column, ethyl acetate / hexane) to give the title compound (31 mg) as a white solid. MS m / z 968.81 (M+H). 1 H NMR (300MHz, CDCl3) δ: 11.43-11.60 (m, 1H), 8.0-8.2 (m, 2H), 7.70 (d, 2H), 7.50 (d, 2H), 3.9-4.4 (m, 2H), 3.83 (s, 3H), 3.3-3.6(m, 4H), 2.8-3.0(m, 10H), 2.45-2.60(m, 2H), 1.7-2.3(m, 8H), 1.2-1.5(m, 10H), 0.75-1.1(m, 27H).

[0437] Compounds 27-93 can be prepared according to the synthetic routes described elsewhere herein and / or methods known to those skilled in the art in view of the teachings provided elsewhere herein.

[0438] Example 2: Trivaline-7269 conjugate (ie, compound 9) targets mD4 and blocks infection by mD4 replacement

[0439] In certain embodiments, cellular processes, such as uptake or metabolic stability, can serve as a useful starting point for optimizing compound 7269 and its analogs. As a means of improving the bioavailability of compound 7269, short peptide conjugated analogs of compound 7269 were prepared as described elsewhere herein.

[0440] In certain embodiments, valine peptides are conjugated to compound 7269 to increase lipophilicity. Initially, compound 7269 is conjugated to monovaline, divaline, trivaline, and tetravaline of amino acids and / or peptides, respectively, wherein in certain embodiments, a linking moiety is attached.

[0441] When evaluated for their ability to block infection by the surrogate virus mD4-VV, monovaline, divaline, and tetravaline conjugates of compound 7269 were all shown to be cytotoxic.

[0442] In contrast, the trivaline-7269 conjugate, compound 9 ( Figure 5 ) can not only block the infection of mD4-VV replacement virus, but also its efficacy (EC 50 =2.1 μM) is 6.3 times that of compound 7269 ( Fig. 6A Compound 9 also specifically targeted mD4 in an in vitro mechanistic assay, with IC 50 =5.0μM( Figure 6B ), which is only slightly higher than the unconjugated compound 7269 (IC 50 =6.8 μM). Unconjugated tri-valine peptide (ie, (L)-Val)3) had no effect ( Figure 6C ).

[0443] These results suggest that the trivaline 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 antiviral efficacy (EC 50 ) Fig. 6A ) is derived from the trivaline moiety, supporting the benefits of integrating the individual properties of peptides with those of small molecules.

[0444] Notably, compound 9 showed no measurable toxicity when tested in a 3-day cell viability assay (CC 50 >100μM)( Figure 7 This is in contrast to the unconjugated compound 7269, which, as described above, is marginally toxic (CC 50 =103.2 μM). Finally, as confirmed by microscale thermoelectrophoresis, compound 9 bound to the mD4 viral target (K D =2.84 μM)( Figure 8 ).

[0445] The present disclosure further provides exemplary mD4 anti-processivity data (Table 2) and / or antiviral mD4 / VV activity data (Table 3) for selected compounds.

[0446] Table 2 provides mD4 anti-processivity activity data for exemplary compounds.

[0447] Table 3 provides data for exemplary compounds with measurable activity in the antiviral mD4 / VV assay.

[0448] Table 2. mD4 anti-processivity activity of selected compounds

[0449]

[0450] Table 3. Antiviral mD4 / VV activity of selected compounds

[0451]

[0452] Example 3: Linker and / or conjugated amino acid modifications

[0453] In certain embodiments, the length and geometry of the linker can be altered by using any of a variety of alternative divalent species (e.g., -NH(CH2)2NH-, -NH(CH2)3NH-, -NH(CH2)4NH-, -NH(CH2)2O(CH2)2NH-, 1,4-piperazinyl, 1,2-diaminophenyl, 1,3-diaminophenyl, and 1,4-diaminophenyl) ( Fig. 9 In some embodiments, non-natural amino acids (e.g., D-amino acids, substituted L-amino acids, and / or homologous D- and / or L-amino acids) can be used. In some embodiments, non-natural amino acids can allow the use of alternative linking moieties and / or can provide favorable metabolic characteristics and / or pharmacokinetics.

[0454] For example, in contrast to compound 7269, for example, in compound 9, cleavage of the amino acid conjugated to compound 7269 (e.g., by glutathione) can provide 7269 substituted with an aminoethyl linker. Thus, in certain embodiments, the linker can comprise a sulfenamide derivative. In these embodiments, the sulfenamide linker can allow for the prodrug activity of the compounds of the present disclosure ( Fig.10 ).

[0455] Examples of implementation methods

[0456] The following exemplary embodiments are provided, the numbering of which should not be construed as designating a level of importance:

[0457] Embodiment 1 provides a compound of formula (I) or a salt, solvate, enantiomer, diastereomer, geometric isomer, isotopomer or tautomer thereof:

[0458]

[0459] in:

[0460] T 1 Yes ---L 2 -L 1 -R 1 , and T 2 YesR 3 ,

[0461] or T 1 YesR 3 , and T 2 Yes ---L2 -L 1 -R 1 ;

[0462] R 1 Yes --- A 1 -A 2 -A 3 -A 4 ;

[0463] A 1 Selected from and keys;

[0464] A 2 Selected from and keys;

[0465] A 3 Selected from and keys; and

[0466] A 4 Selected from and Y;

[0467] L 1 Selected from bonds, -N(R a )(Optionally substituted C1-C6 alkylene)N(R b )-、-N(R a )S(optionally substituted C1-C6 alkylene)N(R b )-、-N(R a )(optionally substituted C1-C6 heteroalkylene)N(R b )、-N(R a )S(optionally substituted C1-C6 heteroalkylene)N(R b )-、-N(R a )(Optionally substituted C3-C8 cycloalkylene)N(R b )-、-N(R a )S(optionally substituted C3-C8 cycloalkylene)N(R b )-、-N(R a )(Optionally substituted C2-C6 heterocyclylene)N(R b )-、-N(R a )S(optionally substituted C2-C6 heterocyclylene)N(R b )-、-N(R a )(Optionally substituted C1-C6 alkylene)C(=O)-, -N(R a )S(optionally substituted C1-C6 alkylene)C(=O)-, optionally substituted C1-C6 alkylene, -N(R a )(optionally substituted phenylene)N(R b )- and -N(Ra )S(optionally substituted phenylene)N(R b )-;

[0468] L 2 Selected from -C(=O)-, N(R 6 ) and keys;

[0469] Y is selected from N(R 5e )(R 5f ), OR 5e and R 5e ,

[0470] Among them A 1 , A 2 , A 3 , A 4 , L 1 , L 2 and Y are chosen such that:

[0471] Selected from A 1 , A 2 , A 3 and A 4 Any substituent selected from A 1 , A 2 , A3, A 4 , L 1 and L 2 The bond between any substituents (if any) is a CN bond, and

[0472] Y and selected from A 1 , A 2 , A 3 and A 4 The bond between any substituents (if any) is a CN or CO bond;

[0473] R 2 Selected from N(R a )C(=O)(optionally substituted C1-C6 alkyl), N(R a )C(=O)(optionally substituted C3-C8 cycloalkyl), N(C(=O)(optionally substituted C3-C8 cycloalkyl)2, N(R a )C(=O)O(optionally substituted phenyl), N(R a )C(=O)(optionally substituted C2-C8 heterocyclyl), N(R a )C(=O)N(R b )(optionally substituted C1-C6 alkyl), C(=O)OR a and C(=O)N(R a )C(═O)(optionally substituted C1-C6 alkyl);

[0474] R3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted phenyl, CN, NO2, C(=O)OR a and C(=O)NR a R b ;

[0475] R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted heterocyclyl, and optionally substituted phenyl;

[0476] R 5a , R 5b , R 5c , R 5d , R 5e and R 5f Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, C(=O)R a and C(=O)OR a ,

[0477] Or choose 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 adjacent substituents of may optionally combine with the atoms to which they are bound to form an optionally substituted C4-C8 heterocycloalkyl;

[0478] R 6 is selected from H and optionally substituted C1-C6 alkyl;

[0479] X is selected from CR 6 and N;

[0480] m1, m2, m3 and m4 are each independently an integer selected from 1, 2, 3 and 4;

[0481] R a and R b Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl,

[0482] Or with R a and R b The groups may be optionally combined with the atoms to which they are attached to form an optionally substituted C2-C8 heterocyclyl.

[0483] Embodiment 2 provides a compound of embodiment 1 selected from the following:

[0484]

[0485] Embodiment 3 provides a compound of embodiment 1 or 2, wherein each occurrence of optionally substituted alkyl, optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted phenylene, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted haloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, 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)2N(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)2R II , an optionally substituted C2-C8 heterocyclyl, and an optionally substituted phenyl, wherein R I , R II , R III and RIV Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and optionally substituted phenyl.

[0486] Embodiment 4 provides a compound of any one of embodiments 1-3, wherein each occurrence of optionally substituted phenyl and optionally substituted heterocyclyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, 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)2N(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)2R ii , C2-C8 heterocyclic and phenyl, wherein R i , R ii , R iii and R iv Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl.

[0487] Embodiment 5 provides compounds of any one of embodiments 1-4, wherein one of the following is applicable:

[0488] (a)A 4 yes AND one of the following applies:

[0489] (i)A 1 , A 2 and A 3 None of them are keys.

[0490] (ii)A 1 , A 2 and A 3 One of them is the key,

[0491] (iii)A1 , A 2 and A 3 Two of them are keys, and

[0492] (iv)A 1 , A 2 and A 3 Each of is a key;

[0493] (b)A 1 yes A 4 yes AND one of the following applies:

[0494] (i)A 2 and A 3 None of them are keys.

[0495] (ii)A 2 and A 3 One of them is the key, and

[0496] (iii)A 2 and A 3 are all keys; or

[0497] (c)A 1 yes A 4 is Y, and one of the following applies:

[0498] (i)A 2 and A 3 None of them are keys.

[0499] (ii)A 2 and A 3 One of them is the key, and

[0500] (iii)A 2 and A 3 They are all keys.

[0501] Embodiment 6 provides compounds of any one of embodiments 1-5, wherein at least one of the following applies:

[0502] (a)A 1 Selected from and keys;

[0503] (b)A 2 Selected from and keys;

[0504] (c)A 3 Selected from and keys; and

[0505] (d)A 4 Selected from and Y.

[0506] Embodiment 7 provides a compound of any one of embodiments 1-6, wherein R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h (if present) are each independently selected from H, methyl,

[0507] Embodiment 8 provides compounds of any one of embodiments 1-7, wherein at least one of the following applies:

[0508] (a)R 4a and R 4b At least one of them is H;

[0509] (b)R 4c and R 4d At least one of them is H;

[0510] (c)R 4e and R 4f At least one of is H; and

[0511] (d) R 4g and R 4h At least one of them is H.

[0512] Embodiment 9 provides compounds of any one of embodiments 1-8, wherein at least one of the following applies:

[0513] (a) Selected from A 1 , A 2 and A 3 At least one of

[0514] (b)A 4 Selected from

[0515] Embodiment 10 provides compounds of any one of embodiments 1-9, wherein R 1 Selected from NH2, Ot-Bu, C(=O)Ot-Bu,

[0516]

[0517] Embodiment 11 provides compounds of any one of embodiments 1-10, wherein R2 Selected from

[0518] Embodiment 12 provides compounds of any one of embodiments 1-11, wherein R 3 Selected from H, C(═O)OMe and C(═O)NH 2 .

[0519] Embodiment 13 provides the compound of any one of Embodiments 1-12, wherein L 1 Selected from

[0520] in:

[0521] R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are each independently selected from H and C1-C6 alkyl; and R 8a , R 8b , R 8c and R 8d Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C6 alkoxy, halogen, CN and NO2.

[0522] Embodiment 14 provides compounds of embodiment 13, wherein at least one of the following applies:

[0523] (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;

[0524] (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;

[0525] (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;

[0526] (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;

[0527] (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;

[0528] (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;

[0529] (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;

[0530] (h)R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h Each of is H;

[0531] (i)R 8a , R 8b , R 8c and R 8d At least one of them is H;

[0532] (j)R 8a , R8b , R 8c and R 8d At least two of them are H;

[0533] (k)R 8a , R 8b , R 8c and R 8d At least three of them are H; and

[0534] (l)R 8a , R 8b , R 8c and R 8d Each of them is H.

[0535] Embodiment 15 provides compounds of any one of embodiments 1-14, wherein L 1 Selected from

[0536] Embodiment 16 provides compounds of any one of embodiments 1-15, wherein L 2 It is -C(=O)-.

[0537] Embodiment 17 provides compounds of any one of embodiments 1-16, wherein X is C(CH3).

[0538] Embodiment 18 provides a compound of any one of embodiments 1-17 selected from:

[0539] Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate;

[0540] 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0541] 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0542] 5-((2-(((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0543] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0544] 5-((2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0545] 5-((2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0546] 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0547] 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-carboxylic acid methyl ester;

[0548] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0549] 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0550] 5-((2-(2-(-2-(2-aminoacetamido)acetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0551] 5-((2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecyl-19-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0552] 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0553] 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0554] 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyrylamino)-4-methylthiophene-3-carboxylic acid methyl ester;

[0555] 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-carboxylic acid methyl ester;

[0556] 5-((2-(((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0557] 5-((2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0558] 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-carboxylic acid methyl ester;

[0559] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropionamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido-4-methylthiophene-3-carboxylic acid methyl ester;

[0560] 5-((2-(S)-2-((S)-2-(2-aminoacetylamino)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0561] 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)butyramido)thiophene-3-carboxylic acid methyl ester;

[0562] 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 ester;

[0563] 4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0564] 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-pentaazanonadecan-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester;

[0565] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester;

[0566] 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)butanamido)thiophene-3-carboxylic acid methyl ester;

[0567] 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-carboxylic acid methyl ester;

[0568] 5-((2-((S)-2-((S)-2-aminopropylamino)propionamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester;

[0569] 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(piperazine-1-carbonyl)thiophene-3-carboxylic acid methyl ester;

[0570] tert-Butyl (2-(5-carbamoyl-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxamido)ethyl)carbamate;

[0571] 5-(4-((tert-Butyloxycarbonyl)-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0572] 5-(4-(L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; N 4 -(2-aminoethyl)-5-(2-(4-fluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxamide;

[0573] tert-butyl (2S)-1-((2S)-1-(2-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxamido)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate;

[0574] N 4 -(2-((S)-2-((S)-2-amino-3-methylbutyrylamino)-3-methylbutyramido)ethyl)-5-(2-(4-fluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxamide;

[0575] 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((5S,8S,11S)-5,8,11-triisopropyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0576] 5-(4-(L-valyl-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0577] tert-Butyl ((7S,10S,13S)-1-(5-carbamoyl-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophen-3-yl)-7,10-diisopropyl-14-methyl-1,6,9,12-tetraoxo-2,5,8,11-tetraazapentadecan-13-yl)carbamate;

[0578] 5-((3-((tert-Butyloxycarbonyl)amino)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0579] 5-((3-aminopropyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0580] Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate;

[0581] 2-(2-(4-fluorophenyl)butyramido)-5-((6S,9S)-6-isopropyl-2,2,9-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-4-methylthiophene-3-carboxylic acid methyl ester;

[0582] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)propionamido)ethyl)carbamoyl)-2-(-2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0583] 5-(((6S,9S,12S)-6,9-diisopropyl-2,2,12-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0584] 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3,14-dioxa-5,8,11-triazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0585] 5-((3-(S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0586] 5-((2-(2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0587] 2-(2-(Benzo[d][1,3]dioxol-5-yl)butanamido)-5-carbamoyl-4-methylthiophene-3-carboxylic acid methyl ester;

[0588] 2-(tert-butyl) 4-methyl 5-(2-(benzo[d][1,3]dioxol-5-yl)butanamido)-3-methylthiophene-2,4-dicarboxylate;

[0589] 2-(tert-butyl)4-methyl 5-(2-(3,5-difluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxylate;

[0590] 5-Carbamoyl-2-(2-(3,5-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0591] 5-Carbamoyl-2-(2-(4-cyanophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0592] 5-((2-aminoethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0593] 2-(2-(Benzo[d][1,3]dioxol-5-yl)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-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0594] 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)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0595] 5-((2-aminoethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0596] 2-(2-(3,5-difluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0597] 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0598] Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(4-cyanophenyl)butyramido)-4-methylthiophene-3-carboxylate;

[0599] 2-(2-(4-cyanophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0600] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0601] 2-(2-(4-fluorophenyl)butyramido)-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-carboxylic acid methyl ester;

[0602] 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0603] 2-(tert-butyl)4-methyl 5-(2-(3,4-difluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxylate;

[0604] 2-(tert-butyl)4-methyl 3-methyl-5-(2-(m-tolyl)butyramido)thiophene-2,4-dicarboxylate;

[0605] 2-(tert-butyl)4-methyl 3-methyl-5-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-2,4-dicarboxylate;

[0606] 5-Carbamoyl-2-(2-(3,4-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0607] 5-Carbamoyl-4-methyl-2-(2-(m-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0608] 5-Carbamoyl-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0609] 5-((2-aminoethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0610] 2-(2-(3,4-difluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0611] 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-carboxylic acid methyl ester;

[0612] 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0613] 4-methyl-2-(2-(m-tolyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0614] 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-carboxylic acid methyl ester;

[0615] Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylate;

[0616] 4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0617] 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-carboxylic acid methyl ester;

[0618] 5-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester;

[0619] (5-(2-(4-fluorophenyl)butyramido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valine;

[0620] 2-(tert-butyl)4-methyl 3-methyl-5-(2-(o-tolyl)butyramido)thiophene-2,4-dicarboxylate;

[0621] 5-Carbamoyl-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0622] 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0623] 4-methyl-2-(2-(o-tolyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,4-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0624] 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0625] 2-(tert-butyl)4-methyl 3-methyl-5-(2-(2-(trifluoromethyl)phenyl)butyramido)thiophene-2,4-dicarboxylate;

[0626] 5-Carbamoyl-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester;

[0627] 4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester;

[0628] 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-carboxylic acid methyl ester;

[0629] 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-carboxylic acid methyl ester; and

[0630] (5-(2-(4-fluorophenyl)butyramido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valyl-D-valine.

[0631] Embodiment 19 provides a pharmaceutical composition comprising at least one compound of any one of embodiments 1-18 and at least one pharmaceutically acceptable excipient.

[0632] Embodiment 20 provides a method for 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 1-18 and / or a pharmaceutical composition of Embodiment 19.

[0633] Embodiment 21 provides the method of embodiment 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, Tanapox virus, smallpox virus, Yokapox virus, Cervidaepox virus (deerpox), Avipox virus (fowlpox), Capripox virus (goatpox), Leporipox virus (myxomapox virus), Parapox virus (sheeppox virus), Suopox virus (swinepox) and Yatapox virus (Yaba-like disease virus).

[0634] Embodiment 22 provides the method of embodiment 21, wherein the folding and / or function of the processivity factor mD4 is inhibited in the orthopoxvirus.

[0635] Embodiment 23 provides the method of any one of embodiments 20-22, wherein DNA polymerase processivity is disrupted in the orthopoxvirus.

[0636] Embodiment 24 provides the method of any one of embodiments 20-23, wherein the orthopoxvirus infection is caused by MCV.

[0637] Embodiment 25 provides the method of any one of embodiments 20-24, wherein the subject is a mammal.

[0638] Embodiment 26 provides the method of embodiment 25, wherein the mammal is a human.

[0639] Embodiment 27 provides the method of any one of embodiments 20-26, wherein the compound of any one of embodiments 1-18 and / or the pharmaceutical composition of embodiment 19 is administered topically.

[0640] Embodiment 28 provides the method of any one of embodiments 20-27, wherein the compound of any one of embodiments 1-18 and / or the pharmaceutical composition of embodiment 19 is topically administered to at least one lesion associated with orthopoxvirus infection.

[0641] The disclosure of each and every patent, patent application, and publication cited herein is incorporated herein by reference in its entirety. Although the present disclosure is disclosed with reference to specific embodiments, it is apparent that other persons skilled in the art may design other embodiments and variations of the present disclosure without departing from the true spirit and scope of the present disclosure. The appended claims are intended to be interpreted as including all such embodiments and equivalent variations.

Claims

1. A compound of formula (I) or a salt, solvate, enantiomer, diastereomer, geometric isomer, isotopomer or tautomer thereof: in: T 1 Yes ---L 2 -L 1 -R 1 , and T 2 YesR 3 , or T 1 YesR 3 , and T 2 Yes ---L 2 -L 1 -R 1 ; R 1 Yes---A 1 -A 2 -A 3 -A 4 ; A 1 Selected from and keys; A 2 Selected from and keys; A 3 Selected from and keys; and A 4 Selected from and Y; L 1 Selected from bonds, -N(R a )(Optionally substituted C1-C6 alkylene)N(R b )-、-N(R a )S(optionally substituted C1-C6 alkylene)N(R b )-、-N(R a )(optionally substituted C1-C6 heteroalkylene)N(R b )、-N(R a )S(optionally substituted C1-C6 heteroalkylene)N(R b )-、-N(R a )(Optionally substituted C3-C8 cycloalkylene)N(R b )-、-N(R a )S(optionally substituted C3-C8 cycloalkylene)N(R b )-、-N(R a )(Optionally substituted C2-C6 heterocyclylene)N(R b )-、-N(R a )S(optionally substituted C2-C6 heterocyclylene)N(R b )-、-N(R a )(Optionally substituted C1-C6 alkylene)C(=O)-, -N(R a )S(optionally substituted C1-C6 alkylene)C(=O)-, optionally substituted C1-C6 alkylene, -N(R a )(optionally substituted phenylene)N(R b )- and -N(R a )S(optionally substituted phenylene)N(R b )-;L 2 Selected from -C(=O)-, N(R 6 ) and keys; Y is selected from N(R 5e )(R 5f ), OR 5e and R 5e , Among them A 1 , A 2 , A 3 , A 4 , L 1 , L 2 and Y are chosen such that: Selected from A 1 , A 2 , A 3 and A 4 Any substituent selected from A 1 , A 2 , A 3 , A 4 , L 1 and L 2 The bond between any substituents, if any, is a CN bond, and Y and selected from A 1 , A 2 , A 3 and A 4 The bond between any substituents, if any, is a CN or CO bond; R 2 Selected from N(R a )C(=O)(optionally substituted C1-C6 alkyl), N(R a )C(=O)(optionally substituted C3-C8 cycloalkyl), N(C(=O)(optionally substituted C3-C8 cycloalkyl)2, N(R a )C(=O)O(optionally substituted phenyl), N(R a )C(=O)(optionally substituted C2-C8 heterocyclyl), N(R a )C(=O)N(R b )(optionally substituted C1-C6 alkyl), C(=O)OR a and C(=O)N(R a )C(═O)(optionally substituted C1-C6 alkyl); R 3 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted phenyl, CN, NO2, C(=O)OR a and C(=O)NR a R b ; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted heterocyclyl, and optionally substituted phenyl; R 5a , R 5b , R 5c , R 5d , R 5e and R 5f Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, C(=O)R a and C(=O)OR a , Or choose 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 adjacent substituents of may optionally combine with the atoms to which they are bound to form an optionally substituted C4-C8 heterocycloalkyl; R 6 is selected from H and optionally substituted C1-C6 alkyl; X is selected from CR 6 and N; m1, m2, m3 and m4 are each independently an integer selected from 1, 2, 3 and 4; R a and R b Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl, Or with R a and R b The groups may be optionally combined with the atoms to which they are attached to form an optionally substituted C2-C8 heterocyclyl.

2. The compound according to claim 1, which is selected from the following:

3. A compound according to claim 1 or 2, wherein each occurrence of optionally substituted alkyl, optionally substituted alkylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted phenylene, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted haloalkyl, optionally substituted alkenyl and optionally substituted alkynyl is independently optionally substituted by at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, 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)2N(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)2R II , an optionally substituted C2-C8 heterocyclyl, and an optionally substituted phenyl, wherein R I , R II , R III and R IV Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and optionally substituted phenyl.

4. A compound according to any one of claims 1 to 3, wherein each occurrence of the optionally substituted phenyl and the optionally substituted heterocyclyl is independently optionally substituted by at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, 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)2N(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)2R ii , C2-C8 heterocyclic group and phenyl group, wherein R i , R ii , R iii and R iv Each occurrence of is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl.

5. A compound according to any one of claims 1 to 4, wherein one of the following applies: (a)A 4 yes AND one of the following applies: (i)A 1 , A 2 and A 3 None of them are keys. (ii)A 1 , A 2 and A 3 One of them is the key, (iii)A 1 , A 2 and A 3 Two of them are keys, and (iv)A 1 , A 2 and A 3 Each of is a key; (b)A 1 yes A 4 yes AND one of the following applies: (i)A 2 and A 3 None of them are keys. (ii)A 2 and A 3 One of them is the key, and (iii)A 2 and A 3 are all keys; or (c)A 1 yes A 4 is Y, and one of the following applies: (i)A 2 and A 3 None of them are keys. (ii)A 2 and A 3 One of them is the key, and (iii)A 2 and A 3 They are all keys.

6. A compound according to any one of claims 1 to 5, wherein at least one of the following applies: (a)A 1 Selected from and keys; (b)A 2 Selected from and keys; (c)A 3 Selected from and keys; and (d)A 4 Selected from and Y.

7. A compound according to any one of claims 1 to 6, wherein R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h If present, each independently selected from H, methyl, 8. A compound according to any one of claims 1 to 7, 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 is H; and (d) R 4g and R 4h At least one of them is H.

9. A compound according to any one of claims 1 to 8, wherein at least one of the following applies: (a) Selected from A 1 , A 2 and A 3 At least one of (b)A 4 Selected from 10. A compound according to any one of claims 1 to 9, wherein R 1 Selected from NH2, Ot-Bu, C(=O)Ot-Bu, 11. A compound according to any one of claims 1 to 10, wherein R 2 Selected from 12. A compound according to any one of claims 1 to 11, wherein R 3 Selected from H, C(═O)OMe and C(═O)NH 2 .

13. A compound according to any one of claims 1 to 12, wherein L 1 Selected from in: R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g and R 7h are each independently selected from H and C1-C6 alkyl; and R 8a , R 8b , R 8c and R 8d Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C6 alkoxy, halogen, CN and NO2.

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 Each of is H; (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 Each of them is H.

15. A compound according to any one of claims 1 to 14, wherein L 1 Selected from 16. A compound according to any one of claims 1 to 15, wherein L 2 It is -C(=O)-.

17. A compound according to any one of claims 1 to 16, wherein X is C(CH3).

18. A compound according to any one of claims 1 to 17, selected from: Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)acetylamino)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate; 5-((2-(2-aminoacetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-(((S)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-(2-aminoacetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-(2-(-2-(2-aminoacetamido)acetamido)acetamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2,2-dimethyl-4,7,10,13,16-pentaoxo-3-oxa-5,8,11,14,17-pentaazanonadecyl-19-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((14-amino-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-amino-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-amino-4-methylpentanamido)-4-methylpentanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyrylamino)-4-methylthiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 5-((2-(((R)-2-amino-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-((R)-2-((R)-2-amino-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-phenylpropionamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-(S)-2-((S)-2-(2-aminoacetylamino)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 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)butyramido)thiophene-3-carboxylic acid methyl ester; 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 ester; 4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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-pentaazanonadecan-19-yl)carbamoyl)-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutanamido)-3-methylbutanamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester; 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)butanamido)thiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-aminopropylamino)propionamido)ethyl)carbamoyl)-4-methyl-2-(2-(4-(trifluoromethyl)phenyl)butanamido)thiophene-3-carboxylic acid methyl ester; 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(piperazine-1-carbonyl)thiophene-3-carboxylic acid methyl ester; tert-Butyl (2-(5-carbamoyl-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxamido)ethyl)carbamate; 5-(4-((tert-Butyloxycarbonyl)-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-(4-(L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; N 4 -(2-aminoethyl)-5-(2-(4-fluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxamide; tert-butyl (2S)-1-((2S)-1-(2-(5-carbamoyl-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxamido)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-methylbutyrylamino)-3-methylbutyramido)ethyl)-5-(2-(4-fluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxamide; 2-(2-(4-fluorophenyl)butyramido)-4-methyl-5-(((5S,8S,11S)-5,8,11-triisopropyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazatetradecyl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 5-(4-(L-valyl-L-valyl-L-valyl)piperazine-1-carbonyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; tert-Butyl ((7S,10S,13S)-1-(5-carbamoyl-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophen-3-yl)-7,10-diisopropyl-14-methyl-1,6,9,12-tetraoxo-2,5,8,11-tetraazapentadecan-13-yl)carbamate; Methyl 5-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate; 5-((3-aminopropyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; Methyl 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylate; 2-(2-(4-fluorophenyl)butyramido)-5-((6S,9S)-6-isopropyl-2,2,9-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridec-13-yl)carbamoyl)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-amino-3-methylbutanamido)propionamido)ethyl)carbamoyl)-2-(-2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-(((6S,9S,12S)-6,9-diisopropyl-2,2,12-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-(((6S,9S)-6,9-diisopropyl-2,2-dimethyl-4,7,10-trioxo-3,14-dioxa-5,8,11-triazahexadec-16-yl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((3-(S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)propyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-(2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)ethoxy)ethyl)carbamoyl)-2-(2-(4-fluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(2-(Benzo[d][1,3]dioxol-5-yl)butanamido)-5-carbamoyl-4-methylthiophene-3-carboxylic acid methyl ester; 2-(tert-butyl) 4-methyl 5-(2-(benzo[d][1,3]dioxol-5-yl)butanamido)-3-methylthiophene-2,4-dicarboxylate; 2-(tert-butyl)4-methyl 5-(2-(3,5-difluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxylate; 5-Carbamoyl-2-(2-(3,5-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-Carbamoyl-2-(2-(4-cyanophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-aminoethyl)carbamoyl)-2-(2-(benzo[d][1,3]dioxol-5-yl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(2-(Benzo[d][1,3]dioxol-5-yl)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-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-((2-aminoethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(2-(3,5-difluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(3,5-difluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; Methyl 5-((2-aminoethyl)carbamoyl)-2-(2-(4-cyanophenyl)butyramido)-4-methylthiophene-3-carboxylate; 2-(2-(4-cyanophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-methylbutanamide)-3-methylbutanamide)ethyl)carbamoyl)-2-(2-(4-cyanophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(2-(4-fluorophenyl)butyramido)-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-carboxylic acid methyl ester; 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)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(tert-butyl)4-methyl 5-(2-(3,4-difluorophenyl)butyramido)-3-methylthiophene-2,4-dicarboxylate; 2-(tert-butyl)4-methyl 3-methyl-5-(2-(m-tolyl)butyramido)thiophene-2,4-dicarboxylate; 2-(tert-butyl)4-methyl 3-methyl-5-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-2,4-dicarboxylate; 5-Carbamoyl-2-(2-(3,4-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 5-Carbamoyl-4-methyl-2-(2-(m-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester; 5-Carbamoyl-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester; 5-((2-aminoethyl)carbamoyl)-2-(2-(3,4-difluorophenyl)butyramido)-4-methylthiophene-3-carboxylic acid methyl ester; 2-(2-(3,4-difluorophenyl)butyramido)-4-methyl-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(m-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester; 4-methyl-2-(2-(m-tolyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; Methyl 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylate; 4-methyl-2-(2-(3-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 5-(((R)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)-2-(2-(4-fluorophenyl)butanamido)-4-methylthiophene-3-carboxylic acid methyl ester; (5-(2-(4-fluorophenyl)butyramido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valine; 2-(tert-butyl)4-methyl 3-methyl-5-(2-(o-tolyl)butyramido)thiophene-2,4-dicarboxylate; 5-Carbamoyl-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester; 5-((2-aminoethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester; 4-methyl-2-(2-(o-tolyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,4-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 5-((2-((S)-2-((S)-2-((S)-2-amino-3-methylbutyramido)-3-methylbutyramido)-3-methylbutyramido)ethyl)carbamoyl)-4-methyl-2-(2-(o-tolyl)butyramido)thiophene-3-carboxylic acid methyl ester; 2-(tert-butyl)4-methyl 3-methyl-5-(2-(2-(trifluoromethyl)phenyl)butyramido)thiophene-2,4-dicarboxylate; 5-Carbamoyl-4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butyramido)thiophene-3-carboxylic acid methyl ester; 4-methyl-2-(2-(2-(trifluoromethyl)phenyl)butyramido)-5-(((6S,9S,12S)-6,9,12-triisopropyl-2,2-dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadec-16-yl)carbamoyl)thiophene-3-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; 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-carboxylic acid methyl ester; and (5-(2-(4-fluorophenyl)butyramido)-4-(methoxycarbonyl)-3-methylthiophene-2-carbonyl)-D-valyl-D-valine.

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 method for treating, ameliorating and / or preventing an orthopoxvirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 18 and / or the pharmaceutical composition of claim 19.

21. The method of 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, Tanapox virus, smallpox virus, Yokapox virus, Cervidaepox virus (deerpox), Avipox virus (fowlpox), Capripox virus (goatpox), Leporipox virus (myxomapox virus), Parapox virus (sheeppox virus), Suopox virus (swinepox) and Yatapox virus (Yaba-like disease virus).

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

23. The method of any one of claims 20-22, wherein DNA polymerase processivity is disrupted in the orthopoxvirus.

24. The method of any one of claims 20-23, wherein the orthopoxvirus infection is caused by MCV.

25. The method of any one of claims 20-24, wherein the subject is a mammal.

26. The method of claim 25, wherein the mammal is a human.

27. The method according to any one of claims 20-26, wherein the compound according to any one of claims 1-18 and / or the pharmaceutical composition according to claim 19 is administered topically.

28. The method of any one of claims 20-27, wherein the compound of any one of claims 1-18 and / or the pharmaceutical composition of claim 19 is topically administered to at least one lesion associated with the orthopoxvirus infection.

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