Antimicrobial compounds

Abstract

The present invention relates to phenylenediamine derivatives having certain pharmacological properties resulting from enhancing the epithelial barrier function and / or preventing bacterial translocation through the epithelial barrier. The compounds are useful in the treatment of various conditions, including conditions involving the displacement of pathogens from the gastrointestinal tract to the lower tissue and blood vessels, such as fever neutropenia, intestinal tissue inflammation, bacteremia, and sepsis.

Description

Technical Field

[0001] The present invention relates to phenylenediamine derivatives having certain pharmacological properties resulting from enhancement of epithelial barrier function and / or prevention of bacterial translocation across the epithelial barrier. These compounds can be used to treat a variety of conditions, including those involving translocation of pathogens from the gastrointestinal tract to the underlying tissues and vasculature, such as febrile neutropenia, intestinal tissue inflammation, bacteremia and sepsis. Background Art

[0002] Damage to the epithelial barrier (mucosal barrier), such as in the gastrointestinal tract, can allow pathogens to translocate across the barrier, leading to diseases such as neutropenia, febrile neutropenia, intestinal tissue inflammation, bacteremia, and sepsis.

[0003] The epithelial barrier can be compromised in a variety of ways, such as by chemotherapeutic approaches following cancer treatment / chemotherapy, organ transplantation and infection with enteric pathogens, leading to dysbiosis of the native microbiota (which can be caused by direct-acting antimicrobial agents) or mucositis.

[0004] Epithelial barrier damage may be particularly common in patients with low neutrophil counts (neutropenia), such as those undergoing cytotoxic cancer therapy or treated with immunosuppressants. Low neutrophil counts caused by cytotoxic chemotherapy are associated with an increased risk of serious bacterial and fungal infections. This is now causally linked to mucositis (cytotoxic damage to the lining of the gastrointestinal tract and other mucosa), which renders the immunocompromised host vulnerable to infectious pathogens from its own microbiota.

[0005] Impairment of the epithelial barrier in patients with neutropenia can lead to febrile neutropenia. Febrile neutropenia is the most common (~1% of patients undergoing chemotherapy and radiation therapy) and a serious, life-threatening complication associated with immunocompromised patients receiving cancer chemotherapy or to avoid transplant rejection. Febrile neutropenia is often the limiting factor in therapeutic doses, and it has a significant mortality rate - 5% to 50% in high-risk populations, with >60,000 hospitalizations and >4,000 deaths per year in the United States alone, costing ~$2.8B (2012), accounting for >8% of all cancer-related hospitalization costs (see original article Epidemiology | Volume 23, Issue 7, Pages 1889-1893, July 1, 2012).

[0006] The current treatment paradigm of prophylaxis with broad-spectrum fluoroquinolone antibiotics is unpopular among oncologists not only because of drug toxicity but also because it leads to an increase in the emergence of drug-resistant bacteria and dysbiosis of the gut microbiota, which further encourages colonization by opportunistic pathogens. The antimicrobial approach is also fundamentally ineffective because it does not prevent the translocation of infectious organisms across the gastrointestinal wall into the underlying tissues and vasculature.

[0007] WO2015063694 (Akthelia) relates to benzoylated phenylenediamines and their use in treating microbial infections.

[0008] Notwithstanding the above disclosure, it will be appreciated that a contribution to the art would be to provide compounds or combinations of compounds useful for treating diseases caused or resulting from impaired epithelial barrier integrity and / or bacterial translocation across the epithelial barrier. Summary of the invention

[0009] The inventors applied a therapeutic strategy based on field-leading deep cell biology expertise to abrogate bacterial translocation and enhance innate immune barrier resistance in the gastrointestinal tract.

[0010] This is achieved in part by delivering compounds that upregulate endogenous proteins naturally expressed within epithelial cells and improve tight junction signaling in the epithelial barrier. This may serve to contain the microbiota within the intestinal lumen in healthy individuals.

[0011] The data disclosed herein show that the compounds of the invention unexpectedly and effectively knock down pathogen translocation to multiple organs and systems in relevant mouse models, indicating transferable survival benefits. The inventors believe that this can be achieved by the compounds of the invention acting on tight junctions, for example, by cross-signaling pathways, resulting in very effective prevention of translocation, as well as activation of host defense systems.

[0012] To the best of the inventors' knowledge, it was not previously known whether compounds that can upregulate endogenous proteins can also block pathogen translocation alone. In fact, inducers of certain endogenous antimicrobial peptides have previously been shown to downregulate proteins essential in the tight junctions of the epithelial barrier. See, e.g., Yolanda M. Jacobo-Delgado et al.; Peptides, Vol. 142, 2021, 170580, https: / / doi.org / 10.1016 / j.peptides.2021.170580 ; and Hatakeyama S et al., J Periodontal Res. 2010 Apr;45(2):207-15. doi: 10.1111 / j.1600-0765.2009.01219.x.)

[0013] The claimed invention allows for a new standard of care treatment with the potential to replace the prophylactic use of antibiotics and antifungals in patients at risk for febrile neutropenia, with reduced risk of SAEs, AMR, and microbiome dysbiosis.

[0014] This highly differentiated approach has broad applications and could help treat the diseases described here, as well as address the growing threat of antibiotic bacterial resistance worldwide.

[0015] Some of the advantages that may be exhibited by the claimed invention are as follows: (1) Combined strengthening of the epithelial barrier (tight junctions) and upregulation of host defense peptides in epithelial cells and macrophages; (2) Broad spectrum therapy with a different mode of action than antibiotics - immunomodulation induces the production of host defense peptides, thereby weakening bacteria; (3) Pathogens are less likely to develop resistance because the production of multiple host defense microbial factors is induced. This is in contrast to antibiotics that act directly on microorganisms, thereby rapidly selecting for resistant strains; (4) Minimal impact on the natural microbiome.

[0016] ***

[0017] Therefore, the present invention provides compounds that are effective in improving or restoring epithelial barrier function and / or preventing or reducing microbial translocation across an animal epithelial barrier. In a preferred embodiment, the epithelial barrier is an intestinal or gastrointestinal barrier. The compound is a benzoylated phenylenediamine or a derivative or analog thereof, as described in more detail below.

[0018] Preferred compounds are N-(2-aminophenyl)-4-{2-[(prop-2-yn-1-yl)oxy]acetamido}benzamide ("Compound 1"), N-(2-aminophenyl)-4-[(methyl{[(prop-2-yn-1-yl)oxy]acetyl}amino)methyl]benzamide ("Compound 2.1"), N-(2-aminophenyl)-4-{[N-methyl-2-(2-propionamidoethoxy)acetamido]methyl}benzamide ("Compound 2.2"), 4-[(2-aminophenyl)carbamoyl]phenyl hex-5-ynoate ("Compound 2.3") and (4-((2-aminophenyl)-carbamoyl)benzyl)carbamic acid pyridin-3-ylmethyl ester ("Entinostat").

[0019] The present invention provides the use of the compounds described herein for treating the diseases disclosed herein.Preferred microbial targets and diseases targeted by the present invention are described below.

[0020] The effectiveness of this class of compounds in preventing microbial translocation (e.g., bacterial translocation and / or fungal translocation) across the epithelial barrier was unexpected and suggests that these compounds and their analogs may act through a different or additional stimulatory mechanism than certain previous compounds, which, for example, simply stimulated the innate antimicrobial defense peptide system.

[0021] Aspects of the invention are methods of using the compounds described herein to treat (including prevent) the diseases described herein in animals.

[0022] The invention further provides compounds as defined herein for use as medicaments for treating the diseases described herein in humans and other animals by improving or restoring epithelial barrier function.

[0023] In a still further aspect, the invention provides pharmaceutical compositions for use in the methods described herein, comprising an active ingredient (at least one compound of the invention) and typically at least one pharmaceutically acceptable excipient.

[0024] In a yet further aspect, the invention provides the use of a compound of the invention in the preparation of a medicament for use in the methods described herein.

[0025] ***

[0026] In one aspect, the present invention provides a compound of formula (I) for use in a method of treating or preventing a disease or condition in an animal that would benefit from enhancement or restoration of epithelial barrier function, wherein administration of the compound improves, restores or maintains the epithelial barrier function of the animal, wherein the compound is defined by the following formula:

[0027] (I)

[0028] in:

[0029] Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0030] ;

[0031] n is 0 or 1;

[0032] L is selected from –(CH2) m -、-C(=O)-、-(CH2) m -C(=O)-, -O-(CH2) m -C(=O)-, -OC(=O)-(CH2) m -(C=O)-, -NH-C(=O)-, -NR-C(=O)-, -NH-(CH2) m -C(=O)-、-NR-(CH2)m -C(=O)-, -NH-C(=O)-(CH2) m -C(=O)-, -NR-C(=O)-(CH2) m -C(=O)-, -C(=O)-NH-(CH2) m -C(=O)- and -(CH2) m -(CHR L )-C(=O)-, wherein m is an integer from 1 to 4;

[0033] A 1 and A 2 Together with the atoms to which they are attached, they form an optionally substituted C 6-14 an aryl or heteroaryl group;

[0034] If there is A 3 , which is selected from H and optionally substituted C 1-4 alkyl;

[0035] R N is selected from H and optionally substituted 3 C 1-4 alkyl;

[0036] B 1 , B 2 , B 3 , B 4 and B 5 One of them is of formula –XR X group, and the others are independently selected from H and R B ;

[0037] Each of these -R B independently selected from halogen, -CF3, -R, -OH, -OR, -OCF3, -C(=O)OH, -C(=O)OR, -C(=O)R, -OC(=O)R, -NH2, -NHR, -NR2, -NO2, -C(=O)NH2, -C(=O)NHR, C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2 or -CN;

[0038] X is selected from a covalent bond or C 1-3 Alkylene;

[0039] R X Selected from –H, R XX or R XY ;

[0040] in:

[0041] R XXis halogen, -CF3, -OH, -OR, -OCF3, -C(=O)OH, -NO2, -NH2, -NHR, -NR2, -C(=O)NH2, -C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2, or -CN; and

[0042] R XY Is the formula –L X -R YY ;

[0043] Where L X Selected from:

[0044] -NH-C(=O)-O-, -NH-C(=O)-NH-, -NH-C(=O)-, -NR-C(=O)-, -OC(=O)-NH-, -OC(=O)-O-, -O-(C=O)-, -C(=O)-NH-, -C(=O)-O-, -C(=O)-;

[0045] And R YY Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 6-14 Aryl, -L Y -C 6-14 Aryl, -L Y -OC 6-14 Aryl, -C 5-6 Heteroaryl, -L Y -C 5-6 Heteroaryl, -L Y -OC 5-6 Heteroaryl, -L Y -OL Y -C≡N, -L Y -OL Y -C≡R, -L Y -OL Y -C≡CH, -L Y -OL Y -NR N -C(=O)-R, -L Y -OL Y -NH-C(=O)-R, -L Y -OL Y -NR-C(=O)-R、-L Y -C≡N, -L Y -C≡R, -L Y -C≡CH,

[0046] Where -L Y - for C 1-3alkylene, and wherein each of said groups is optionally substituted;

[0047] R L Selected from halogen, -R LL 、-CF3、-OH、-OR LL 、-NO2、-NH2、-NHR LL 、-NR2、-NH-C(=O)-R LL 、-NH-C(=O)-OR LL , where R LL Selected from -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -Ph, -L L -Ph, -C 5-6 Heteroaryl, -L L -C 5-6 Heteroaryl, wherein -L L - for C 1-3 Alkylene.

[0048] and each R is independently C 1-4 alkyl.

[0049] In further aspects and embodiments, the present invention provides compounds of formula (I) for use in a method for treating or preventing a disease or condition in an animal that would benefit from preventing or reducing the translocation of microorganisms across the animal's epithelial barrier, wherein administration of the compound prevents or reduces the translocation of microorganisms across the animal's epithelial barrier.

[0050] Diseases or disorders that would benefit from preventing or reducing the translocation of microorganisms across an animal's epithelial barrier, or would benefit from enhancing or restoring epithelial barrier function, include the specific diseases disclosed herein.

[0051] In some particularly preferred embodiments, the compound is according to formula (Ia):

[0052] .

[0053] Certain aspects and embodiments of the invention will now be described in more detail.

[0054] Further description and preferred

[0055] Treatment

[0056] The compounds described herein may themselves be novel. Therefore, in addition to the use of these compounds in the methods of treatment described herein, aspects of the present invention also extend to these compounds themselves. These compounds can be used alone or as an adjunct therapy.

[0057] The compounds of the present invention may be used in any combination or alone to treat and / or prevent the diseases described herein.

[0058] As used herein in the context of treating a disorder, the term "treat" generally refers to treatment and therapy, whether of a human subject or another animal (e.g., a mammal), in which some desired therapeutic effect is achieved, e.g., inhibiting the progression of the disorder, and includes reducing the rate of progression, halting the rate of progression, alleviating the symptoms of the disorder, ameliorating the disorder, and curing the disorder.

[0059] The term "treatment" includes combination treatments and therapies in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.

[0060] The agents (i.e., the compounds described herein plus one or more other agents) can be administered simultaneously or sequentially, and can be administered in individually variable dosage regimens and by different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., within a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods of time when desired), the precise dosing regimen being commensurate with the properties of the therapeutic agents described herein, including their synergistic effects.

[0061] Also included is treatment as a prophylactic measure (ie, prevention).For example, the term "treatment" encompasses use in a patient who has not yet developed a disorder but is at risk of developing a disorder.

[0062] "Prevention" in the context of this specification should not be understood as limiting complete success, i.e., complete protection or complete prevention. Rather, prevention in the present context refers to measures administered before symptomatic disease is detected, with the goal of maintaining health by helping to delay, alleviate or avoid a particular disease.

[0063] It will be appreciated that the methods and compositions of the present invention may also be used in aquaculture, veterinary and animal husbandry applications for companion animals, farm animals and ranch animals. These applications include, but are not limited to, treatment, prevention or resistance to microbial diseases and conditions in fish, dogs, cats, cattle, horses, deer and poultry (including hens, turkeys, ducks, geese) and domestic pets (e.g., birds and rodents). For large animals, suitable dosages may be greater than the amounts approved for humans.

[0064] ***

[0065] Compounds described herein can work by improving or restoring epithelial barrier function (i.e., strengthening epithelial barrier), and therefore can treat diseases and conditions that will benefit therefrom. As far as the inventors know, this is achieved by one or more of the following: promoting the maintenance of tight junctions between epithelial cells; resisting inflammation; and inducing the expression of antimicrobial peptides / proteins in epithelial cells.

[0066] Epithelial cells constitute an important barrier separating the external environment from the internal tissue environment and have specific adaptations related to their functions. The single layer of polarized epithelial cells in the intestine separates the internal tissue from the lumen of the gastrointestinal tract (which contains a large number of microorganisms, especially in the colon). In addition to absorbing nutrients, the prominent functions of intestinal epithelial cells also involve their role as an active barrier to prevent bacterial migration into the underlying tissue and secretion of antimicrobial compounds.

[0067] The activity of epithelial cells is essential for maintaining the separation between host tissues and microorganisms and maintaining host-microorganism homeostasis. Epithelial cells are covered by a layer of mucus proteins containing antimicrobial effectors. The paracellular gaps between adjacent epithelial cells are sealed by interconnected junctional complexes, which have tight junctions and are composed of claudins / occludin. Therefore, in some embodiments, a decrease in epithelial barrier function can be manifested as a decrease in tight junction function, a decrease in junctional complex function, a decrease in claudin function, a decrease in occludin function, a decrease in the number of claudins, or a decrease in the number of occludin.

[0068] Improvement or restoration of epithelial barrier function and / or prevention or reduction of microbial translocation can be determined, for example, by measuring colony forming unit (CFU) counts in basal tissues, circulation and / or internal organs in an in vivo animal model. Examples of visceral organs relevant to the present invention include highly vascularized organs, including kidneys, liver and spleen.

[0069] Improvement or restoration of epithelial barrier function can also be determined by the effect on tight junction function, which itself can be determined by measuring transepithelial electrical resistance (TEER), or by analyzing the levels of tight junction proteins (e.g., occluding and claudin-1) by Western blot analysis. Those skilled in the art will recognize other methods in the art for measuring these properties.

[0070] In particularly preferred embodiments, the epithelial barrier is an intestinal epithelial barrier or a gastrointestinal epithelial barrier.

[0071] The gastrointestinal tract (GI tract) of mammals is covered by a continuous sheet of epithelial cells (enterocytes) that are folded into villus projections and crypts. Within the bottom of the crypts, where the stem cells of the gastrointestinal tract can be found, there are specialized granular cells, called Paneth cells. Both enterocytes and Paneth cells produce antimicrobial peptides. Enterocytes synthesize and secrete antimicrobial peptides into the intestinal lumen both constitutively and when induced. Paneth cells at the bottom of the intestinal crypts secrete α-defensins into the crypt pores, producing concentrations estimated at mg / mL levels, which are eventually flushed into the intestinal lumen. In addition, fixed macrophages are also known to secrete antimicrobial peptides into the intestinal lumen and other tissue sites when activated.

[0072] Other epithelial surfaces of the mammalian body also possess such host defense secretion systems, including but not limited to the cornea, lungs, kidneys, and skin (see also WO 2012 / 140504).

[0073] Macrophages and epithelial cells and Paneth cells of the gastrointestinal tract and other epithelial surfaces of humans and other animals are stimulated to secrete a large number of naturally occurring broad-spectrum antimicrobial agents, including antimicrobial peptides (e.g., defensins, HMP 1-4, LL-37, HBD1-4) and antimicrobial proteins (e.g., lysozyme, transferrin, lactoferrin, phospholipases, and SLPI (secretory leukocyte protease inhibitor). Paneth cell stored substances exhibit activity against a wide range of infectious pathogens including bacteria, protozoa, viruses, and fungi.

[0074] In doing so, the compounds of the invention can contain the microbiota within the intestinal lumen as they would in a healthy individual. The natural microbiota has adapted to an environment containing antimicrobial peptides, especially those that bind to bacteria and disrupt their membrane function. These commensal bacteria produce modified lipopolysaccharides (endotoxins) that do not bind aggressively to the positively charged antimicrobial peptides, thus requiring higher concentrations of the peptides for their bacteriostatic effects. In conditions such as neutropenia, the concentrations of antimicrobial peptides are lower and less effective. In addition, from in vivo infection studies ( Figure 1 ), compound 1 did not eliminate the pathogen but completely inhibited its translocation, strongly suggesting that epithelial integrity was maintained.

[0075] The epithelial cells targeted by the present invention may be any of these (e.g. oral cavity, lung, trachea, urinary tract or kidney, stomach, upper gastrointestinal tract (e.g. ileum) and lower gastrointestinal tract (e.g. jejunum) and colon). However, the present invention is preferably used to treat diseases involving gastrointestinal barrier function.

[0076] As described above, an important aspect of the present invention provides a method for treating, preventing or resisting microbial infection or any of the diseases, for example, by administering a drug comprising an effective amount of at least one compound of the present invention, thereby improving or restoring epithelial barrier function and / or preventing or reducing microbial translocation. In addition to fever and swelling, the observable progress of human infection can be monitored by culturing blood samples, counting blood cells and / or detecting bacterial products (e.g., endotoxins). In addition, measurable plasma proteins that are upregulated in infection include C-reactive protein, procalcitonin and inflammatory cytokines. The integrity of the intestinal epithelial layer can be assessed by an intestinal permeability (IP) test (also known as a "leaky gut" test), which measures the levels of mannitol and lactulose ingested in urine samples.

[0077] Thus, in some embodiments, the compound is capable of preventing the translocation of a microorganism from the intestine of an animal to other locations in the body, such as the basal tissue, circulatory system, or other internal organs, such as the kidney, liver, or spleen, and through the circulatory system to the vascular bed.

[0078] In addition to fever and swelling, observable progression of infection in humans can be monitored by performing blood sample cultures, blood cell counts, and / or testing for bacterial products (e.g., endotoxins). Additionally, measurable plasma proteins upregulated in infection include C-reactive protein, procalcitonin, and inflammatory cytokines. The integrity of the intestinal epithelial lining can be assessed by an intestinal permeability (IP) test (also known as a "leaky gut" test), which measures ingested mannitol and lactulose levels in urine samples.

[0079] ***

[0080] The compounds described herein can be used to treat febrile neutropenia. Febrile neutropenia can be defined as a single oral temperature measurement of >38.3°C (>101°F) or a temperature of ≥38.0°C (≥100.4°F) for more than 1 hour, an absolute neutrophil count (ANC) of <500 cells / microliter, or an ANC expected to drop to <500 cells / microliter within the next 48 hours. See, e.g., Punnapuzha S, Edemobi PK, Elmoheen A. FebrileNeutropenia. [Updated February 10, 2022]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Obtained from: https: / / www.ncbi.nlm.nih.gov / books / NBK541102 / .

[0081] Thus, in preferred embodiments, the compounds described herein are useful for treating patients with low neutrophil counts, e.g., patients with an ANC of <500 cells / μl, <450 cells / μl, <400 cells / μl, <350 cells / μl, <300 cells / μl, <250 cells / μl, <200 cells / μl, <150 cells / μl, <100 cells / μl, or <50 cells / μl.

[0082] In some embodiments, febrile neutropenia is chemotherapy-induced febrile neutropenia. The risk of febrile neutropenia depends on the degree and duration of chemotherapy-induced neutropenia and many patient factors, including age, comorbidities and serum albumin levels (Bodey et al., 1966; Meza et al., 2002; Lyman et al., 2005; Aapro et al., 2006). Therefore, febrile neutropenia can be induced by any chemotherapeutic drug known in the art. The patient treated by the present invention may still be taking chemotherapeutic drugs. The patient to be treated by the present invention may have been treated with chemotherapeutic drugs in the past (e.g., 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years or 5 years ago, or any time between the two).

[0083] Thus, in some embodiments, the compounds described herein can be used to treat patients who have received or are currently receiving cancer treatment. Their cancer treatment may be ongoing, or may have been administered in the past, for example, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years ago, or any time in between.

[0084] Febrile neutropenia may also be a consequence of organ transplantation in which the patient is administered immunosuppressive drugs known in the art to reduce the number of white blood cells or inhibit their function. Many immunosuppressive drugs also affect epithelial cells due to the integrated function of the immune system with the epithelial cell layer that is exposed to microorganisms (https: / / doi.org / 10.1038 / s12276-018-0126-x). Immunosuppressants also alter the gut microbiota which can lead to an increased risk of infection (doi:10.1097 / QCO.0b013e3283630dd3).

[0085] In some embodiments, the compounds described herein can therefore be used to treat patients who receive immunosuppressants (the patients have received organ transplants). In some preferred cases, the transplant can be a bone marrow transplant or a kidney transplant. The organ transplant can be performed in the past, for example 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years or 5 years ago, or any time in between. The patient may be immunocompromised. The patient to be treated by the present invention may still be taking immunosuppressant drugs. The patient to be treated by the present invention may also have been treated with immunosuppressant drugs in the past (for example 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years or 5 years ago, or any time in between).

[0086] ***

[0087] The compounds described can be used to treat sepsis in animals. Sepsis is generally defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (JAMA. 2016 Feb 23; 315(8): 801–810). Intestinal barrier dysfunction is thought to be a cause of the development of multiple organ dysfunction syndrome in sepsis (Shock. 2016 Jul; 46(1): 52–59). Observational studies have shown signs of intestinal hyperpermeability in critically ill patients in general (Semin Respir Crit Care Med. 2011; 32: 626–638) and in sepsis patients in particular (Biochem Med (Zagreb) 2013; 23: 107–111). Therefore, the compounds of the present invention can treat sepsis by strengthening the epithelial barrier and controlling intestinal permeability.

[0088] The compounds described are useful for treating bacteremia in animals. Bacteremia refers to the presence of bacteria in the blood. It can occur in patients with reduced epithelial barrier function (e.g., patients who have undergone cancer treatment or organ transplantation), where pathogens from the gastrointestinal tract can enter the blood. Therefore, the compounds of the invention can be used to treat sepsis by strengthening the epithelial barrier and controlling intestinal permeability.

[0089] The compounds described can be used to treat mucositis in animals. Mucositis is a painful inflammation and ulceration of the mucous membrane lining the digestive tract, which is usually an adverse reaction to cancer chemotherapy and radiotherapy (Ridge JA, Glisson BS, Lango MN, et al. "Head and Neck Tumors" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.). Therefore, the compounds of the present invention can treat mucositis by repairing the mucous membrane that lines the digestive tract.

[0090] The compounds described can be used to treat microbial imbalance in animals. The imbalance is characterized by reduced microbial diversity and increased pro-inflammatory species. This unbalanced microbiome cannot protect against pathogenic organisms that trigger inflammation and produce genotoxins or carcinogenic metabolites (Precision Medicine for Investigators, Practitioners and Providers, 2020). It can be caused by direct-acting antimicrobial agents. In combination with decreased epithelial barrier function, it can cause further diseases described by the displacement of dysbiotic microbiota through the epithelial barrier. Therefore, the compounds of the present invention can be used to treat mucositis by repairing the mucosa lining the digestive tract and causing the normal function of the intestinal microbiota to be restored.

[0091] ***

[0092] Further diseases that may be treated by the compounds of the invention include atopic dermatitis, asthma, allergic rhinitis, chronic sinusitis, eosinophilic esophagitis, meningitis, COPD, periodontitis, bronchitis, eczema, inflammatory bowel disease, celiac disease, leaky gut syndrome, Alzheimer's disease, Parkinson's disease, chronic depression, autism, diabetes, obesity, nonalcoholic steatohepatitis, autoimmune hepatitis, cirrhosis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, and inflammation of intestinal tissue.

[0093] The compounds of the present invention can also be used in travel medicine and treatment of travel-related diseases. Traveler diseases include diarrhea (e.g., traveler's diarrhea), which is a digestive tract disorder that usually causes loose stools and abdominal cramps. It is caused by eating contaminated food or drinking contaminated water. Bacteria are the most common cause of traveler's diarrhea. The most common pathogens identified are enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella, and Salmonella. These bacteria penetrate the epithelial lining and cause an inflammatory response, which manifests as diarrhea. Although doctors do not encourage it, antibiotics are very commonly used to alleviate this pain. The side effects of using antibiotics are the emergence of AMR bacteria and dysbiosis. The most commonly used antibiotic is rifaximin, which is a poorly absorbed antibiotic that is non-systemically distributed. Rifaximin can alleviate the symptoms of intestinal infections, but it usually does not eradicate the pathogen. There is a lack of preventive treatments that can be used to prevent these pathogenic bacteria from infiltrating the epithelial lining. Therefore, in some embodiments, the compounds of the present invention can be used as a preventive agent that can be ingested before exposure to pathogens that cause traveler's diarrhea, thereby preventing infection.

[0094] Other diseases treatable by the compounds of the invention include nonalcoholic fatty liver disease and necrotizing enterocolitis.

[0095] ***

[0096] Compounds of the present invention are particularly useful in resisting bacterial strains that are tolerant to conventional antibiotics. Bacterial species include but are not limited to Yersinia, Salmonella, Shigella, Campylobacter, Clostridium, Helicobacter, Mycobacterium, Pseudomonas, Haemophilus, Moraxella, Escherichia, Neisseria and Staphylococcus strains. Targeted viruses are also included, including HIV, RSV, herpes, hepatitis and influenza viruses, which are also considered to be the targets of the antimicrobial peptides stimulated by the present invention. Viruses can be DNA or RNA viruses.

[0097] In some preferred embodiments, the compounds of the present invention can be used to treat HIV infection. In some preferred embodiments, the compounds of the present invention can be used to treat AIDS. In some preferred embodiments, the compounds of the present invention can be used for long-term treatment of patients with recurrent AIDS, particularly those who may die prematurely due to epithelial barrier dysfunction. In some preferred embodiments, the compounds of the present invention can be used to treat patients diagnosed with HIV infection and / or AIDS, who also suffer from intestinal epithelial barrier dysfunction or a condition or disease caused by intestinal epithelial barrier dysfunction, or a condition or disease that can be treated by improving or restoring epithelial barrier function. In some embodiments, the compounds of the present invention can be used to treat patients with a history of HIV infection and AIDS suppressed by antiretroviral therapy (ART). The patient may have AIDS, or may have been previously diagnosed with AIDS and / or received AIDS treatment. In some embodiments, the compounds of the present invention can treat premature aging and improve the morbidity and mortality of HIV patients who have been treated with ART.

[0098] The compounds of the present invention are also particularly useful for combating or preventing microbial infections caused by Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., Morganella spp., Enterococcus faecium, Staphylococcus aureus, Helicobacter pylori, Acinetobacter baumannii, Pseudomonas aeruginosa, Campylobacter (e.g., Campylobacter jejuni), Salmonella spp., Neisseria gonorrhoeae, Streptococcus pneumoniae, Haemophilus influenzae, Shigella spp. In some embodiments, the compounds are effective against or prevent infections caused by microorganisms such as Nairovirus, Marburg, Ebola, Coronaviridae, Mammarenavirus, Henipavirus, Phlebovirus, Chikungunya, Alphavirus (Enveloped Virus), Zika, and Dengue, as well as other Flaviviruses.

[0099] Infections, disorders and diseases treatable according to the present invention also include, but are not limited to:

[0100] Shigellosis, endemic diarrhea, dysentery, viral gastroenteritis, parasitic enteritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, precancerous conditions of the gastrointestinal tract, cancer of the gastrointestinal tract, diverticulitis, post-antibiotic diarrhea, Clostridium difficile colitis, lactose intolerance, flatulence, gastritis, esophagitis, heartburn, gastric ulcer, ulcer associated with Helicobacter pylori, duodenal ulcer, short bowel syndrome, dumping syndrome, gluten enteropathy;

[0101] ocular infection is optionally selected from conjunctivitis, sty, blepharitis, ocular cellulitis, keratitis, corneal ulcer, granular conjunctivitis, uveitis, canaliculitis, and dacryocystitis;

[0102] Urinary tract and genital infections are optionally selected from pyelonephritis, cystitis, gonorrhea and urethritis;

[0103] Infection of the respiratory system is optionally selected from bronchitis, pneumonia, sinusitis, sinusitis, pharyngitis / tonsillitis, laryngitis and influenza; tuberculosis;

[0104] The skin infection is optionally selected from boils, carbuncles, furuncles, cellulitis, abscesses, impetigo and erysipelas.

[0105] In some embodiments, the compounds of the invention are effective against bacterial strains that are resistant to direct-acting antibiotics (ie, antibiotics that exert their effects by directly interacting with the microbial species).

[0106] ***

[0107] The compounds of the present invention can also be HDAC inhibitors ("HDACi"). In some embodiments, the compound is a selective HDACi. In some preferred embodiments, the compound is a class 1 selective HDACi. In some embodiments, the compound is a class 2 selective HDACi. In some embodiments, the compound is a class 4 selective HDACi. In some embodiments, the compound is a selective HDACi of any one of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10, and HDAC11. The compound can also be a class 3 selective HDACi, a class 2A selective HDACi, or a class 2B HDACi.

[0108] In some embodiments, the compound is a selective HDACi for HDAC1. In some embodiments, the compound is a selective HDACi for HDAC2. In some embodiments, the compound is a selective HDACi for HDAC3. In some embodiments, the compound is a selective HDACi for HDAC1 and HDAC2. In some embodiments, the compound is a selective HDACi for HDAC1 and HDAC3. In some embodiments, the compound is a selective HDACi for HDAC2 and HDAC3. In some embodiments, the compound is a selective HDACi for HDAC1, HDAC2 and HDAC3.

[0109] In some embodiments, the compound inhibits the above HDACs with an IC50 of less than 500 μM, less than 450 μM, less than 400 μM, less than 350 μM, less than 300 μM, less than 250 μM, less than 200 μM, less than 150 μM, less than 100 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, less than 20 μM, less than 15 μM, less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM or less than 0.1 μM.

[0110] In some embodiments, the compound inhibits Class 1 HDAC with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0111] In some embodiments, the compound inhibits HDAC1 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0112] In some embodiments, the compound inhibits HDAC2 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0113] In some embodiments, the compound inhibits HDAC3 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0114] In some embodiments, the compound inhibits HDAC1 and HDAC2 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0115] In some embodiments, the compound inhibits HDAC1 and HDAC3 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0116] In some embodiments, the compound inhibits HDAC2 and HDAC3 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0117] In some embodiments, the compound inhibits HDAC1, HDAC2, and HDAC3 with an IC50 of less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1.5 μM, less than 1.4 μM, less than 1.3 μM, less than 1.2 μM, less than 1.1 μM, less than 1.0 μM, less than 0.9 μM, less than 0.8 μM, less than 0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.2 μM, or less than 0.1 μM.

[0118] IC50 can be measured by an in vitro enzymatic assay, such as the assay described in the Examples.

[0119] Thus, in some embodiments, the compounds of the invention may be used to treat diseases that are ameliorated by inhibition of HDAC activity, such as cancer and cardiovascular disease.

[0120] In some embodiments, the compounds of the present invention can be used to treat acute lung injury. In some embodiments, the compounds of the present invention can be used to treat acute respiratory distress syndrome. In some embodiments, the compounds of the present invention can be used to treat respiratory fever. In some embodiments, the compounds of the present invention can be used to treat acute lung injury induced by sepsis. In some embodiments, the compounds of the present invention can be used to treat acute respiratory distress syndrome induced by sepsis. In some embodiments, the compounds of the present invention can be used to treat respiratory failure induced by sepsis. In some cases, acute lung injury induced by sepsis or otherwise induced may deteriorate into acute respiratory distress syndrome and respiratory failure. In some particularly preferred embodiments, the compounds of the present invention are HDAC3 inhibitors for the treatment of these diseases.

[0121] Application method

[0122] The agents (ie, a compound described herein, plus one or more other agents) can be formulated together in a single dosage form, or the separate agents can be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

[0123] For example, the compounds described herein in any aspect and embodiment may also be used in combination therapy, for example in combination with other agents. Such agents may be the following:

[0124] Butyrate and PBA

[0125] Sodium phenylbutyrate is a known drug. For example, it is sold by Ucyclyd Pharma (Hunt Valley, USA) under the trade name Buphenyl and by Swedish Orphan Biovitrum AB (Sweden) as Ammonaps. The drug has been used to treat urea cycle disorders (Batshaw et al. (2001) J. Pediatr. 138 (1 Suppl): S46–54; discussion S54–5). Scandinavian Formulas, Inc. Sellersville, PA provides sodium phenylbutyrate for global clinical trials. Sodium phenylbutyrate is also being studied for use in the treatment of certain sickle cell disorders (blood product plasma expander and hemostatic) and as a potential differentiation inducer for malignant gliomas and acute myeloid leukemia. It has also been studied in cystic fibrosis pathology due to its ability to transport DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR) to the cell membrane and restore CFTR chloride function at the plasma membrane of CF lung cells in vitro and in vivo (Roque et al. J Pharmacol Exp Ther. 2008 Sep;326(3):949-56. Epub 2008 Jun 23). Phenylbutyric acid is considered in the literature to be a prodrug that is metabolized to phenyl acetate in vivo by β-oxidation.

[0126] Vitamin D

[0127] This new class of compounds acts synergistically with vitamin D, as shown by (4-((2-aminophenyl)carbamoyl)benzyl)carbamic acid pyridin-3-ylmethyl ester. Vitamin D-type compounds are discussed in US20080038374 or WO / 2008 / 073174. When the term "vitamin D" is used herein, it is used in a broad sense to cover vitamin D3 (or "1,25 D3") and its hormonally active forms, thereby including compounds that are structurally similar to vitamin D3. Many such compounds have been recognized and include a large number of natural precursors, metabolites, and synthetic analogs of the hormonally active 1,25-dihydroxyvitamin D3 (1α25 (OH)2D3). The expression is intended to include vitamin D3 or its analogs at any stage of its metabolism, as well as mixtures of vitamin D3 or its analogs in different metabolic forms.

[0128] antibiotic

[0129] The compounds of the invention are particularly useful for combating infection by bacterial strains that are resistant to conventional antibiotics. However, the use of the compounds described herein in combination with conventional antibiotics, especially narrow spectrum antibiotics, may be preferred and forms part of the present invention.

[0130] Example antibiotics include penicillin, penicillin G, phenoxymethyl-penicillin, flucloxacillin, amoxicillin, metronidazole, cefuroxime, Augmentin, pivmecillin, acetomycin, ciprofloxacin and erythromycin. When these specific antibiotics are named, it should be understood that common analogs can be used. As mentioned above, in some aspects, it may be preferred to use the compounds described herein in combination with known antibiotics, as shown below:

[0131] (1) acutely administering antibiotics to a patient, preferably for 1 or 2 days, with or without a compound of formula (I) or (Ia); subsequently,

[0132] (2) administering an effective amount of a compound of Formula (I) or (Ia) to the patient for an additional 2, 3, 4, 5 or more days.

[0133] Such a regimen may be beneficial in minimizing the development of antibiotic resistance in the targeted pathogens.

[0134] Isoleucine and related compounds

[0135] The amino acid L-isoleucine upregulates the expression of β-defensins in cow epithelial cells (18). US2002-0076393 (Fehlbaum et al.); US2003-0109582 (Zasloff); US7311925 (Zasloff) also relate to the use of isoleucine, its active isomers and its active analogs, in each case for stimulating the innate antimicrobial defense system.

[0136] All of these references are expressly incorporated herein by cross-reference for their disclosure of these compounds, their definitions and provisions.

[0137] Also provided are pharmaceutical compositions which, in addition to one or more compounds of the invention, contain vitamin D or one of the above compounds as a further ingredient. Such compositions may be formulated into any of the above formulations and dosage forms.

[0138] As described below, oral or inhaled dosage forms are preferred.

[0139] dose

[0140] In a particular aspect of the invention, there is provided a method of treating, preventing or combating a disease described herein in a patient in need thereof by administering to the patient an effective amount of a compound of the invention as described herein.

[0141] As used herein, the term "therapeutically effective amount" relates to that amount of a compound, or a material, composition or dosage form containing a compound, which, when administered according to the desired treatment regimen, is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0142] Thus, an effective amount in the context of the present invention will be an amount sufficient to demonstrate improvement or restoration of epithelial barrier function and / or reduction or prevention of bacterial translocation, or to achieve a clinical endpoint of a disease of interest. In some cases, an effective amount will be an amount sufficient to demonstrate antimicrobial activity in vivo, for example by stimulating (e.g., inhibiting or counteracting downregulation caused by several pathogens) the synthesis of the antimicrobial peptide LL-37 or other naturally occurring antibiotic peptides or proteins (e.g., defensins). The stimulation may be close to, equal to, or above basal levels (i.e., normal levels in the absence of infection and / or normal levels of epithelial barrier function).

[0143] As used herein, the term "antimicrobial activity" refers to the ability to inhibit the growth of a microbial population or actually kill a microbial population, which may be a bacterium, virus, protozoa or fungal microorganism. Therefore, "antimicrobial activity" should be interpreted as microbial inhibition (microbiostatic) and microbicidal activity. Antimicrobial activity should also be interpreted as including compounds that can inhibit infection (i.e., the pathogenicity of microorganisms). In general, the purposes of the present invention are therefore, for example, to cause the secretion of related peptides onto the epithelial surface.

[0144] ***

[0145] Preferred dosages and dosage forms are described in more detail below.

[0146] Preferred dosages of Form I compounds may be: between 25 μg and 2000 mg; more preferably 0.05 mg to 500 mg; more preferably 0.1 to 250 mg; more preferably about 0.2 to 100 mg; more preferably less than or equal to about 50 mg / day.

[0147] Another preferred dose of a compound of the invention is a dose of at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg or at least 100 mg / kg.

[0148] Another preferred dosage of the compounds of the invention is a dosage of at least 50 mg / kg.

[0149] Another preferred dose of the compounds of the invention is a dose of less than 200 mg / kg, less than 190 mg / kg, less than 180 mg / kg, less than 170 mg / kg, less than 160 mg / kg, less than 150 mg / kg, less than 140 mg / kg, less than 130 mg / kg, less than 120 mg / kg or less than 110 mg / kg.

[0150] Further preferred dosages of the invention are ranges having a starting point including at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg or at least 100 mg / kg, and an endpoint of less than 200 mg / kg, less than 190 mg / kg, less than 180 mg / kg, less than 170 mg / kg, less than 160 mg / kg, less than 150 mg / kg, less than 140 mg / kg, less than 130 mg / kg, less than 120 mg / kg or less than 110 mg / kg.

[0151] In each case, the dosage may be divided into 1, 2, 3, 4, 5, 6 or 7 doses per week or 1, 2 or 3 doses per day. For example, 1, 2 or 3 x 3, 5 or 10 mg / week, 1 or 2 x 5 or 50 mg / day or 2 x 250 mg / week, etc. A preferred regimen is less than 3x per day, for example 1 or 3 x 3 mg / week, 2 x 1 mg / day or 2 x 5 mg / week.

[0152] Preferred dosages may be between 0.1 mg and 100 mg; between 0.2 mg and 50 mg; between 0.2 mg and 20 mg; optionally together with vitamin D3. The dosage of vitamin D may be of the order of 1000-10 000 IU per day.

[0153] Therefore, the preferred dosage may be divided into 1, 2, 3 or 4 doses per week or 1 or 2 doses per day, for example 1 or 3 x 2 mg / week, 2 x 0.5 mg / day, etc.

[0154] The corresponding preferred weight / molar amounts of other compounds of the present invention can be calculated by those skilled in the art based on the disclosure herein.

[0155] Each of the amounts disclosed herein and above can be administered as a weekly dose or a daily dose. Each weekly dose can be divided into doses administered 1, 2, or 3 times or more. Each daily dose can be divided into doses administered 1, 2, or 3 times or more. The dosage schedule disclosed herein and above may include or consist of 1, 2, 3, 4, 5, 6, 7 days of administration in total, or may include or consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 weeks of administration in total.

[0156] Dosage form

[0157] The compounds of the present invention are preferably administered in oral dosage forms, such as, but not limited to, tablets, capsules, solutions, emulsions, suspensions, powders, pastes, elixirs and syrups. Administration of the compounds may also include incorporation into nanoparticles or ultrafine particles composed of organic and inorganic biocompatible materials with a two-dimensional or three-dimensional length greater than 0.001 microns (1 nanometer) and less than about 0.1 microns (100 nanometers).

[0158] Compositions for oral use may be in the form of hard gelatin capsules where the active ingredient is mixed with an inert solid diluent such as, but not limited to, cellulose, hydroxypropylmethylcellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with an oil such as, but not limited to, arachidonic acid oil, glycerides, peanut oil, liquid paraffin or olive oil.

[0159] Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as, but not limited to, lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating agents and disintegrants such as, but not limited to, corn starch or alginic acid; binders such as, but not limited to, starch; lubricants such as, but not limited to, magnesium stearate, stearic acid or talc; preservatives such as, but not limited to, ethyl or propyl paraben, and antioxidants such as, but not limited to, ascorbic acid. Tablets may be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case, using conventional coating agents and procedures well known in the art, enteric coatings having various resistances to intestinal pH and enzymes.

[0160] Other administration forms are also useful, including, but not limited to, topical administration forms, particularly for combating skin infections, including, for example, creams, oils, lotions and ointments. Still further dosage forms include those for delivery to the respiratory system (including the lungs), such as aerosol and nasal spray devices or via rectal enema.

[0161] In some particularly preferred embodiments, the compounds of the present invention are administered as lozenges. Lozenges or lozenges are pharmaceutical dosage forms that can be particularly effective in treating diseases that affect tissues and epithelial barriers contained in the oral cavity and throat. Typical lozenges or lozenges are mainly composed of inert vehicles, carriers or diluents. The compounds of the present invention are dispersed in the carrier. The lozenges will slowly dissolve when placed in the oral cavity, thereby releasing the medicament so that it contacts the tissues of the oral cavity and throat. As used herein, the term "lozenge" includes dosage forms formed by cooling a molten material based on sugar or based on sugar alcohol (e.g., isomalt) containing the compounds of the present invention. Suitably, the term "molten lozenge forming composition" includes a molten material based on sugar or based on sugar alcohol (e.g., isomalt). Lozenges are solid dosage forms intended for sucking by patients.

[0162] Compounds of the present invention

[0163] The compounds of the present invention are able to improve barrier function or block microbial translocation and may also induce antimicrobial peptides (AMPs) of the innate immune system.

[0164] The compounds of the present invention are defined according to Formula I or Ia as described herein. Certain preferred embodiments of the compounds are now described.

[0165] Group Q

[0166] In the compounds of formula (I) or (Ia), the group Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6:

[0167]

[0168] Among them B 1 and B 2 (and B 3 , B 4 and B 5 , when present) is of the formula -XR X and the rest are independently selected from H and R B In other words, each possible Q group includes a –XR at an available position X Substituents, other available positions are unsubstituted (-H) or replaced by -R B replace.

[0169] In some preferred embodiments, Q is a phenyl group, Q1:

[0170]

[0171] Among them B 1 , B 2 , B 3 , B 4 and B 5 One of them is of formula –XR X group, and the rest are independently selected from H and R B .

[0172] In some embodiments, B 3 Formula – XR X group, and B 1 , B 2 , B 4 and B 5 Independently selected from H and R B In some embodiments, B 3 Formula – XR X group, and B 1 , B 2 , B 4 and B 5 is H. Thus, in these embodiments, Q is a group of the formula:

[0173]

[0174] In other embodiments, B 2 Formula – XR X group, and B 1 , B 3 , B 4 and B 5 Independently selected from H and R B In a further embodiment, B 1 Formula – XRX group, and B 2 , B 3 , B 4 and B 5 Independently selected from H and R B .

[0175] In some embodiments, B 1 , B 2 , B 3 , B 4 and B 5 One of them is of formula –XR X group, and the rest are independently H.

[0176] In some embodiments, B 2 or B 3 Formula – XR X group, and the rest are independently H.

[0177] In some embodiments, B 3 Formula – XR X group, and the rest are independently H.

[0178] In some embodiments, Q is a pyridyl group Q2, Q3 or Q4:

[0179]

[0180] Among them B 1 , B 2 , B 3 and B 4 One of them is of formula –XR X group, and the rest are independently selected from H and R B .

[0181] In some embodiments, B 1 , B 2 , B 3 and B 4 One of them is of formula –XR X group, and the rest are independently H. In some such embodiments, X is a covalent bond, and R X is –H.

[0182] In some embodiments, Q is Q2.

[0183] In some embodiments, Q is Q3.

[0184] In some embodiments, Q is Q4.

[0185] In some embodiments, Q is an imidazolyl group Q5:

[0186]

[0187] Among them B 1 and B 2 One of them is of formula –XR X group, and the other is selected from H and R B .

[0188] In some embodiments, B 1 and B 2 One of them is formula – XR X In some of the embodiments, X is a covalent bond, and R X Yes – H.

[0189] In some embodiments, Q is an indolyl group Q6:

[0190]

[0191] Among them B 1 , B 2 , B 3 , B 4 and B 5 One of them is of formula –XR X group, and the rest are independently selected from H and R B .

[0192] In some embodiments, B 1 , B 2 , B 3 , B 4 and B 4 One of them is of formula –XR X and the rest are independently H. In some of the embodiments, X is a covalent bond, and R X is –H.

[0193] Group R B

[0194] When present, each -R B The groups are independently selected from halogen, -CF3, -R, -OH, -OR, -OCF3, -C(=O)OH, -C(=O)OR, -C(=O)R, -OC(=O)R, -NH2, -NHR, -NR2, -NO2, -C(=O)NH2, -C(=O)NHR, C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2 or -CN.

[0195] In some embodiments, -R BSelected from halogen (i.e., -F, -Cl, -Br, -I), -CF3, -R, -OH, -OR, -NH2, -NHR, -NR2, -NO2 and -CN.

[0196] In some embodiments, -R B Selected from -OH, -OR, -NH2, -NHR and -NR2.

[0197] In some embodiments, -R B Selected from -OH or -OR.

[0198] In some embodiments, -R B It is -OR.

[0199] In some embodiments, -R B It is -OMe.

[0200] In some embodiments, -R B For -R.

[0201] In some embodiments, -R B For-Me.

[0202] Group XR X

[0203] In Group – XR X In the formula, X is selected from a covalent bond or C 1-3 Alkylene, and R X Selected from H, R XX or R XY .

[0204] In some embodiments, X is a covalent bond (ie, the group -XR X Formula –R X group).

[0205] In some embodiments, X is selected from C 1-3 Alkylene.

[0206] In some embodiments, X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH(CH2CH3)-.

[0207] In some embodiments, X is -CH2-.

[0208] In some embodiments, R X It's H.

[0209] In some embodiments, R X For R XX . RXX Selected from halogen, -CF3, -OH, -OR, -OCF3, -C(=O)OH, -NO2, -NH2, -NHR, -NR2, -C(=O)NH2, -C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2 and -CN.

[0210] In some embodiments, R XX Selected from -OH, -OR, -NO2, -NH2, NHR and NR2.

[0211] In some embodiments, R XX Selected from -OR, -NO2 and -NR2.

[0212] In some embodiments, R XX It is OMe-, -NO2 or -NMe2.

[0213] In some embodiments, R X For R XY , where R XY Formula –L X -R YY The group.

[0214] L X Selected from -NH-C(=O)-O-, -NH-C(=O)-NH-, -NH-C(=O)-, -NR-C(=O)-, -OC(=O)-NH-, -OC(=O)-O-, -O-(C=O)-, -C(=O)-NH-, -C(=O)-O- and -C(=O)-.

[0215] In some embodiments, L X is selected from -NH-C(=O)-O-, -NH-C(=O)- and -C(=O)-NH-. In some embodiments, L X is selected from -NH-C(=O)-O-, -NH-C(=O)-, NR-C(=O)- or -O-(C=O)-. In some embodiments, L X is selected from -NH-C(=O)- or -NH-C(=O)-O-.

[0216] In some embodiments, L X In some embodiments, L X is -NH-C(=O)-. In some embodiments, L X is NR-C(=O)-. In some embodiments, L X In some embodiments, L X It is -C(=O)-NH-.

[0217] R YY Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 6-14 Aryl, -L Y -C 6-14 Aryl, -L Y -OC 6-14 Aryl-C 5-6 Heteroaryl, -L Y -C 5-6 Heteroaryl, -L Y -C 5-6 Heteroaryl, -L Y -OC 5-6 Heteroaryl, L Y -OL Y -C≡N,L Y -OL Y -C≡R,L Y -OL Y -C≡CH, -L Y -OL Y -NR N -C(=O)-R、L Y -OL Y -NH-C(=O)-R、L Y -OL Y -NR-C(=O)-R、L Y -C≡N,L Y -C ≡ R and L Y -C≡CH, where -L Y - for C 1-3 alkylene, and wherein each of said R YY Groups are optionally substituted.

[0218] In some embodiments, R YY Independently: -C 6-14 Aryl, -L Y -C 6-14 Aryl, -C 5-6 Heteroaryl or -L Y -C 5-6 Heteroaryl, wherein the C 6-14 Aryl and C 5-6 Heteroaryl groups are optionally substituted.

[0219] In some embodiments, R YY Independently: -Ph, -L Y -Ph, C 5-6 Heteroaryl or -L Y -C 5-6heteroaryl, wherein the Ph and C 5-6 Heteroaryl groups are optionally substituted.

[0220] In some embodiments, R YY Independently: -L Y -Ph or -L Y -C 5-6 heteroaryl, wherein the Ph and C 5-6 Heteroaryl groups are optionally substituted.

[0221] In some embodiments, R YY Independently -L Y -C 6-14 Aryl, wherein the C 6-14 Aryl groups are optionally substituted.

[0222] In some embodiments, R YY Independently: -L Y -Ph, wherein said Ph is optionally substituted.

[0223] In some embodiments, R YY Independently: -L Y -C 5-6 Heteroaryl, L Y -OL Y -C≡CH,L Y -OL Y -NH-C(=O)-R、L Y -C≡R,L Y -C≡CH.

[0224] In some embodiments, -L Y - is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)- and -CH(CH2CH3)-.

[0225] In some embodiments, -L Y - is independently -CH2-.

[0226] In some embodiments, each of the R YY The group is optionally substituted by one or more substituents selected from the group consisting of -F, -Cl, -Br, -I, -R, -CF3, -OH, -OR, -OCF3, -NO2, -L YY -OH, -L YY -OR, -NH2, -NHR, -NR2, -L YY -NH2, -L YY -NHR, -LYY -NR2, -CO2H, -CO2R, -L YY -CO2H, -L YY -CO2R, -Ph and -L YY -Ph-, where L YY C 1-3 Alkylene.

[0227] In some embodiments, each of the R YY The group is optionally substituted by one or more substituents selected from: -OH, -OR, -L YY -OH, -L YY -OR, -NH2, -NHR, -NR2, -L YY -NH2, -L YY -NHR, -L YY -NR2, -L YY -CO2H, -L YY -CO2R, -Ph and -L YY -Ph-, where L YY C 1-3 Alkylene.

[0228] In some embodiments, each of the R YY The group is optionally substituted with one or more substituents selected from: -NH2, -NHR, -NR 2、 -L YY -CO2H and -L YY -CO2R, where L YY C 1-3 Alkylene.

[0229] In some embodiments, R YY Independently: -L Y -Ph, wherein the Ph is substituted by one or more substituents selected from the group consisting of: -OH, -OR, -L YY -OH, -L YY -OR, -NH2, -NHR, -NR2, -L YY -NH2, -L YY -NHR, -L YY -NR2, -L YY -CO2H, -L YY -CO2R, -Ph and -L YY -Ph-, where L YY C 1-3 Alkylene.

[0230] In some embodiments, R YY Independently: -L Y-Ph, wherein said Ph is substituted with one or more substituents selected from the group consisting of -NH2, -NHR and -NR2.

[0231] In some embodiments, R YY Independently: -C 5-6 Heteroaryl, wherein the C 5-6 The heteroaryl group is substituted with one or more substituents selected from: -OH, -OR, -L YY -OH, -L YY -OR, -NH2, -NHR, -NR2, -L YY -NH2, -L YY -NHR, -L YY -NR2, -L YY -CO2H, -L YY -CO2R, -Ph and -L YY -Ph-, where L YY C 1-3 Alkylene.

[0232] In some embodiments, R YY Independently: -C 5-6 Heteroaryl, wherein the C 5-6 Heteroaryl is -L YY -CO2R replacement.

[0233] In some embodiments, -L YY - is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)- and -CH(CH2CH3)-.

[0234] In some embodiments, -L YY - is independently -CH2-.

[0235] Linking base L

[0236] In the compounds of formula (I) or (Ia), the linker group L is selected from -(CH2) m -、-C(=O)-、-(CH2) m -C(=O)-, -O-(CH2) m -C(=O)-, -OC(=O)-(CH2) m -(C=O)-, -NH-C(=O)-, -NR-C(=O)-, -NH-(CH2) m -C(=O)-、-NR-(CH2) m -C(=O)-, -NH-C(=O)-(CH2)m -C(=O)-, -NR-C(=O)-(CH2) m -C(=O)-, -C(=O)-NH-(CH2) m -C(=O)- and -(CH2) m -(CHR L )-C(=O)-, wherein m is an integer from 1 to 4.

[0237] In some embodiments, L is selected from -(CH2) m -、-C(=O)-、-(CH2) m -C(=O)-, -NH-C(=O)-, -NR-C(=O)-, -NH-C(=O)-(CH2) m -C(=O)-, -C(=O)-NH-(CH2) m -C(=O)- and -(CH2) m -(CHR L )-C(=O)-.

[0238] In some embodiments, L is selected from -(CH2) m -, -C(=O)-, -NH-C(=O)- and -NR-C(=O)-.

[0239] In some embodiments, L is -C(=O)-. Thus, the compound may be a compound of formula (II):

[0240] (II)

[0241] In some embodiments, L is -C(=O)-NH-(CH2) m -C(=O)-. Therefore, the compound may be a compound of formula (III):

[0242] (III)

[0243] In some embodiments, L is -(CH2) m -(CHR L )-C(=O)-, where R L As defined herein. Thus, the compound may be a compound of formula (IV):

[0244] (IV)

[0245] Group R L

[0246] When present, for example in compounds of formula (Ic), the group R L Selected from halogen, -RLL 、-CF3、-OH、-OR LL 、-NO2、-NH2、-NHR LL 、-NR2、-NH-C(=O)-R LL 、-NH-C(=O)-OR LL .

[0247] In some embodiments, R L Selected from -NH2, -NHR LL 、-NH-C(=O)-R LL and -NH-C(=O)-OR LL , where R LL As defined previously.

[0248] In some embodiments, R L is NH2.

[0249] In some embodiments, R L NHR LL .

[0250] In some embodiments, R L -NH-C(=O)-OR LL .

[0251] R LL Selected from -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -Ph, -L L -Ph, -C 5-6 Heteroaryl and –L L -C 5-6 Heteroaryl, where –L L - for C 1-3 Alkylene, wherein the -Ph and -C 5-6 Heteroaryl groups are optionally substituted.

[0252] In some embodiments, the -Ph and -C 5-6 The heteroaryl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R, -CF3, -OH, -OR, -OCF3, -NO2, -NH2, -NHR, -NR2, -CO2H, -CO2R.

[0253] In some embodiments, R LL Selected from -Ph, -L L -Ph, -C 5-6 Heteroaryl and -L L -C 5-6 Heteroaryl.

[0254] In some embodiments, R LL Selected from -L L -Ph and -L L -C 5-6 Heteroaryl.

[0255] In some embodiments, R LL For -L L -Ph.

[0256] In some embodiments, R LL is -CH2-Ph (-Bn).

[0257] L L Selected from C 1-3 Alkylene.

[0258] In some embodiments, L L Selected from: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)- or -CH(CH2CH3)-.

[0259] In some embodiments, L L It is -CH2- or CH2CH2-.

[0260] In some embodiments, L L It is -CH2-.

[0261] Group R N

[0262] R N is selected from H and optionally substituted C 1-4 alkyl.

[0263] In some embodiments, R N For H.

[0264] In some embodiments, R N C 1-4 alkyl.

[0265] In some embodiments, when R N C 1-4 When the C 1-4 The alkyl group is optionally substituted by one or more substituents R N1 Substitute, where each R N1 independently selected from halogen, -CF3, -R, -OH, -OR, -OCF3, -NH2, -NHR, -NR2, -NO2 and -CN, wherein each R is independently C 1-4 alkyl.

[0266] In some embodiments, RN1 Independently selected from -OH, -OR, -NH2, -NHR, -NR2.

[0267] In some embodiments, R N1 It is OH or NH2.

[0268] In some embodiments, R N1 is NH2.

[0269] In some embodiments, R N is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl and is optionally substituted.

[0270] In some embodiments, R N is ethyl and is optionally substituted.

[0271] In some embodiments, R N is an ethyl group, which is occupied by at least one R N1 replace.

[0272] In some embodiments, R N It is –CH2CH2NH2.

[0273] Group A 1 , A 2 , A 3

[0274] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached, they form an optionally substituted C 6-14 Aryl group.

[0275] In some embodiments, the C 6-14 The aryl group is optionally substituted by one or more substituents R A2 Substitute, where each R A2 Independently selected from halogen, -CF3, -R, -OH, -OR, -OCF3, -NO2, -C(=O)OH, -C(=O)OR, -C(=O)R, -OC(=O)R, -NH2, -NHR, -NR2, -C(=O)NH2, -C(=O)NHR, -C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2 and -CN.

[0276] In some embodiments, R A2 Independently selected from -R, -OH, -OR, -OCF3, -NO2, -NH2, -NHR, -NR2 and -CN.

[0277] In some embodiments, R A2 Independently -R.

[0278] In some embodiments, R A2 are independently methyl.

[0279] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached, they form an optionally substituted phenyl group. Thus, the compound may be of formula (V):

[0280] (V)

[0281] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached, they form an optionally substituted naphthyl group. Thus, the compound may be a compound of formula (VI):

[0282] (VI)

[0283] In the compounds of formula (V) and (VI), the phenyl and naphthalene rings may be optionally substituted by one or more substituents R as defined above. A2 replace.

[0284] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached they form an unsubstituted phenyl or naphthyl group.

[0285] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached they form an unsubstituted phenyl group.

[0286] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached, they form a A2 Substituted phenyl.

[0287] In some embodiments, A 1 and A 2 Together with the atoms to which they are attached, they form a A2 Substituted phenyl.

[0288] A 3 (if present) selected from H and optionally substituted C 1-4 alkyl.

[0289] In some embodiments, A 3 For H.

[0290] In some embodiments, A 3is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0291] In some embodiments, A 3 It is methyl or ethyl.

[0292] In some embodiments, A 3 It is methyl.

[0293] n is selected from 0 and 1. When n is 0, A 3 (and the atom to which it is attached) is absent. In some embodiments, n is 0. In some embodiments, n is 1.

[0294] Thus, the compound may be a compound of formula (VII):

[0295] (VII)

[0296] Group R

[0297] As used throughout these definitions, each 'R' is independently C 1-4 Alkyl group.

[0298] In some embodiments, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0299] In some embodiments, R is methyl or ethyl.

[0300] In some embodiments, R is methyl.

[0301] Some preferred embodiments

[0302] In some embodiments:

[0303] A 1 and A 2 Together with the atoms to which they are attached, they form a phenyl ring, optionally substituted by one or more substituents R A2 replace;

[0304] n is 0;

[0305] R N For H.

[0306] Therefore, the compound is a compound of formula (VIII):

[0307] (VIII)

[0308] Where Q, L and R A2 As defined above.

[0309] In some embodiments:

[0310] A 1 and A 2 Together with the atoms to which they are attached, they form a phenyl ring, optionally substituted by one or more substituents R A2 replace;

[0311] n is 0;

[0312] R N is H;

[0313] L is C(=O).

[0314] Therefore, the compound is a compound of formula (IX):

[0315] (IX)

[0316] Where Q and R A2 As defined above.

[0317] In some embodiments:

[0318] A 1 and A 2 Together with the atoms to which they are attached, they form a phenyl ring, optionally substituted by one or more substituents R A2 replace;

[0319] n is 0;

[0320] R N is H;

[0321] L is C(=O);

[0322] Q is Q1, where B 3 For XR X .

[0323] Therefore, the compound is a compound of formula (X):

[0324] (X)

[0325] Among them, X, R X , B 1 , B 2 , B 4 , B 5 and R A2 As defined above.

[0326] In some embodiments:

[0327] A 1 and A 2 Together with the atoms to which they are bound, they form a phenyl ring;

[0328] n is 0;

[0329] R N is H;

[0330] L is C(=O);

[0331] Q is Q1, where B 3 For XR X And B 1 , B 2 , B 4 and B 5 Both are H.

[0332] Therefore, the compound is a compound of formula (XI):

[0333] (XI)

[0334] Where X and R X As defined above.

[0335] In some embodiments:

[0336] A 1 and A 2 Together with the atoms to which they are bound, they form a phenyl ring;

[0337] n is 0;

[0338] R N is H;

[0339] Q is Q1.

[0340] Therefore, the compound is a compound of formula (XII):

[0341] (XII)

[0342] Among them B 1 , B 2 , B 3 , B 4 , B 5 and L are as defined above.

[0343] In some embodiments:

[0344] A 1 and A 2 Together with the atoms to which they are bound, they form a phenyl ring;

[0345] n is 0;

[0346] R N is H;

[0347] Q is Q1, where B 3 For XR X, and B 1 , B 2 , B 4 and B 5 Both are H.

[0348] Therefore, the compound is a compound of formula (XIII):

[0349] (XIII)

[0350] Among them, X, R X and L are as defined above.

[0351] Specific compounds

[0352] In some embodiments, the compound is selected from:

[0353]

[0354] definition

[0355] As used herein, the term "alkyl" refers to a monovalent moiety derived from a saturated aliphatic hydrocarbon compound by removing a hydrogen atom, preferably having 1 to 4 carbon atoms ("C 1-4 "alkyl"), which may be straight chain or branched.

[0356] C 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. In some cases, methyl or ethyl groups may be preferred.

[0357] Similarly, the term "alkylene" refers to a divalent moiety derived from a saturated aliphatic hydrocarbon compound by removing two hydrogen atoms, preferably having 1 to 3 carbon atoms ("C 1-3 "alkylene"), which may be straight chain or branched.

[0358] C 1-3 Examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH(CH2CH3)-.

[0359] As used herein, the term "cycloalkyl" refers to a monovalent moiety derived from a saturated alicyclic hydrocarbon compound by removing a hydrogen atom, preferably having 3 to 6 ring atoms ("C 3-6 "cycloalkyl").

[0360] C 3-6Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and substituted groups (e.g., groups containing such groups) such as methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropylmethyl, and cyclohexylmethyl.

[0361] As used herein, the term “C 6-14 "Aryl" means a C 6-14 A monovalent moiety derived from an aromatic ring atom of an aromatic compound by removing a hydrogen atom, the compound having one ring, two or more rings (e.g., fused), and having 6 to 14 ring atoms, and wherein at least one of the rings is aromatic. Preferably, each ring has 6 to 10 ring atoms. The term "C 6-14 "Aromatic ring" may also be used and should be interpreted accordingly; this may refer to a multivalent moiety.

[0362] The ring atoms may all be carbon atoms, such as a "carboaryl group", in which case the group may conveniently be referred to as a "C 6-14 "Carboaryl" group.

[0363] C 6-14 Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C6), naphthalene (C 10 ), anthracene (C 14 ) and Phi (C 14 )

[0364] Examples of aryl groups containing fused rings (one of which is not aromatic) include, but are not limited to, groups derived from indene and fluorene, such as:

[0365] (Indene) (Fluorene)

[0366] As used herein, the term 'heteroaryl' refers to a monovalent moiety derived from an aromatic ring atom of a heteroaromatic compound by removing a hydrogen atom, i.e., a compound containing at least one aromatic ring, wherein the ring atoms include at least one heteroatom. Possible heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur. Preferably, the aromatic ring has 5 to 6 ring atoms, of which 0 to 4 are ring heteroatoms. In this case, the group is referred to as 'C 5-6 Heteroaryl' group, where 'C 5-6 ' represents a ring atom, whether a carbon atom or a heteroatom.

[0367] C 5-6Examples of heteroaryl groups include, but are not limited to, C5 heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1,3-oxadiazole), pyrazole (1,2-oxadiazole), triazole (1,2,3-triazole, 1,2,4-triazole), oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and oxatriazole; and C6 heteroaryl groups derived from isoxazine, pyridine (azine), pyridazine (1,2-oxadiazines), pyrimidine (1,3-oxadiazines; e.g., cytosine, thymine, uracil), pyrazine (1,4-oxadiazines), triazines, tetrazoles, and oxadiazoles (furazans).

[0368] The term "halo" or "halogen" refers to -F, -Cl, -Br, and -I substituents. Fluorine (-F) and chlorine (-Cl) substituents are generally preferred.

[0369] Isomers, salts, solvates and protected forms

[0370] Certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis- and trans- forms; E- and Z- forms; c-, t- and r- forms; endo- and exo- forms; R-, S- and meso forms; D- and L- forms; d- and l- forms; (+) and (-) forms; keto-, enol- and enolate- forms; syn- and anti- forms; syncline and anticline forms; α- and β- forms; axial and equatorial forms; boat, chair, twist, envelope and half-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomers").

[0371] Note that, in addition to the tautomeric forms discussed below, specifically excluded from the term "isomers" as used herein are structural (or compositional) isomers (i.e., isomers that differ in the connectivity between the atoms rather than merely the position of the atoms in space). For example, reference to a methoxy group -OCH3 should not be construed as a reference to its structural isomer, the hydroxymethyl group -CH2OH. Similarly, reference to o-chlorophenyl should not be construed as a reference to its structural isomer, m-chlorophenyl. However, reference to a class of structures is likely to include structurally isomeric forms belonging to that class (e.g., C 1-7 The alkyl group includes n-propyl and isopropyl; the butyl group includes n-butyl, isobutyl, sec-butyl and tert-butyl; the methoxyphenyl group includes o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl).

[0372] The above exclusion does not relate to tautomeric forms, such as keto-, enol- and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (described below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thione / enethiol, N-nitroso / hydroxyazo and nitro / nitroso alcohol (aci-nitrol).

[0373]

[0374] Note that specifically included in the term "isomers" are compounds having one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; etc.

[0375] Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including (whole or partial) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic methods) of such isomeric forms are known in the art or can be readily obtained in a known manner by adopting the methods taught herein or known methods.

[0376] Unless otherwise stated, a reference to a particular compound also includes its ionic, salt, solvate, and protected forms, such as discussed below.

[0377] It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt (e.g., a pharmaceutically acceptable salt) of the active compound. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0378] For example, if the compound is anionic, or has a functional group that can be anionic (e.g., -COOH can be COO - ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na + and K + ), alkaline earth metal cations (such as Ca 2+ and Mg 2+ ) and other cations (such as Al 3+ Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R + NH2R2 + 、NHR3 + 、NR4 + ). Some examples of suitable substituted ammonium ions are those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, and amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0379] If the compound is a cationic group, or has a functional group that can be a cationic group (e.g., -NH2 can be -NH3 + ), then it can form salts with suitable anions. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, palmitic acid, lactic acid, malic acid, pamoic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, aspartic acid, benzoic acid, cinnamic acid, pyruvic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, oxalic acid, pantothenic acid, isethionic acid, valeric acid, lactobionic acid and gluconic acid. Examples of suitable polymer anions include, but are not limited to, those derived from the following polymer acids: tannic acid, carboxymethyl cellulose.

[0380] It may be convenient or desirable to prepare, purify and / or handle the corresponding solvate of the active compound. The term "solvate" is used in the conventional sense herein to refer to a complex of a solute (e.g., an active compound, a salt of an active compound) and a solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, such as a monohydrate, a dihydrate, a trihydrate, etc.

[0381] It may be convenient or desirable to prepare, purify and / or handle chemically protected forms of active compounds. As used herein, the term "chemically protected form" refers to compounds in which one or more reactive functional groups are protected to prevent undesirable chemical reactions, i.e., in the form of a protected or protected group (also referred to as a masked or masked group or a blocked or blocked group). By protecting the reactive functional groups, reactions involving other unprotected reactive functional groups can be carried out without affecting the protecting groups; the protecting groups can usually be removed in subsequent steps without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1999).

[0382] For example, a hydroxy group can be protected as an ether (-OR) or an ester (-OC(=O)R), such as: tert-butyl ether; benzyl, diphenylmethyl (diphenylmethyl) or triphenylmethyl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).

[0383] For example, an aldehyde or ketone group can be protected as an acetal or ketal, respectively, in which the carbonyl group (>C=0) is converted into a diether (>C(OR)2) by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of an acid.

[0384] For example, the amine group can be protected, for example, as an amide or carbamate, for example as: methylamide (-NHCO-CH3); benzyloxyamide (-NHCO-OCH2C6H5, -NH-Cbz); as tert-butoxyamide (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as 9-fluorenylmethoxyamide (-NH-Fmoc), as 6-nitrovarachnyloxyamide (-NH-Nvoc), as 2-trimethylsilylethoxyamide (-NH-Teoc), as 2,2,2-trichloroethoxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), as 2(-phenylsulfonyl)ethoxyamide (-NH-Psec); or, where appropriate, as an N-oxide (>NO•).

[0385] For example, a carboxylic acid group may be protected as an ester, for example as: C 1-7 Alkyl esters (e.g. methyl ester, tert-butyl ester); C 1-7 Haloalkyl esters (e.g., C 1-7 trihaloalkyl ester); triC1-7 Alkylsilyl-C 1-7 Alkyl ester; or C 5-20 Aryl-C 1-7 Alkyl esters (eg benzyl esters; nitrobenzyl esters); or as amides, for example as methyl amides.

[0386] For example, a thiol group can be protected as a thioether (-SR), for example: benzyl thioether; acetamidomethyl ether (-S-CH2NHC(=O)CH3).

[0387] ***

[0388] Any sub-headings herein are included for convenience only and should not be construed as limiting the disclosure in any way.

[0389] The invention will now be further described with reference to the following non-limiting figures and examples.In view of these, other embodiments of the invention will occur to those skilled in the art.

[0390] The disclosures of all references cited herein are hereby specifically incorporated herein by cross-reference insofar as they can be used by one skilled in the art to practice the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0391] Figure 1 : E. coli mouse infection model. CFU measured in tissues: colon, ileum, liver, spleen. Statistical analysis was performed by comparing all conditions to the vehicle-treated group using one-way ANOVA with Dunnett's post hoc test, ***p<0.001, ****p<0.0001, ns not significant.

[0392] Figure 2 : Induction assay. After 24 h, compounds 2.1, 2.2 and 2.3 induced the expression of ProLL-37-luciferase fusion protein in the HT-29 CampLuc MN8 reporter cell line. Corresponding concentrations of compound 1 (2-128 µM) and Entinostat (2.5 µM) were used as positive controls. The results are expressed as the mean ± SD of the luminescence signal relative to the control (untreated cells; value 1) from three independent experiments. Statistical analysis was performed by comparing each compound treatment condition with the corresponding vehicle control using a two-way ANOVA with Dunnett's post hoc test. Only significant changes are indicated, **p<0.01, ***p<0.001, ****p<0.0001. Entinostat treatment (Entino) was compared with the control by using a t-test, ##p<0.01.

[0393] Figure 3 : Schematic representation of the protocol for the neutropenia mouse model.

[0394] Figure 4 : CFU measured in blood, liver, kidney and spleen following administration of the listed compounds at the listed concentrations in a mouse model of febrile neutropenia.

[0395] Figure 5 : Body weight measured after administration of compound at the listed concentrations in a mouse model of febrile neutropenia (referenced to naïve controls).

[0396] Figure 6 : Amplification plots of samples from the RT-PCR example.

[0397] Figure 7 :Compound 1 1 H NMR spectrum.

[0398] Figure 8 : LC / MS of compound 1.

[0399] Fig. 9 :Compound 2.1 1 H NMR spectrum.

[0400] Fig.10 : LC / MS of compound 2.1.

[0401] Fig.11 :Compound 2.2 1 H NMR spectrum.

[0402] Fig.12 : LC / MS of compound 2.2.

[0403] Fig.13 :Compound 2.3 1 H NMR spectrum.

[0404] Fig.14 : LC / MS of compound 2.3. Example

[0405] Methods and Materials

[0406] MN8CampLuc cells were treated as described by Nylén et al. with the following exceptions when predifferentiating the cells prior to induction:

[0407] Cells were plated in medium in which galactose (5 mg / ml) replaced glucose, which is known to promote differentiation of colonic epithelial cells (Pinto, M., MD Appay, P. Simon-Assman, G. Chevalier, N. Dracopoli, J. Fogh, and A. Zweibaum, 1982, Biol. Cell., 44:193-196). Cells were then grown for 72 hours before being stimulated with test compounds.

[0408] RT-PCR experiments were performed according to Nylen et al. (Nylén F, Miraglia E, Cederlund A, Ottosson H, Stromberg R, Gudmundsson GH, Agerberth B. 2013. Boosting innate immunity: Development and validation of a cell-based screening assay to identify LL-37 inducers. Innate Immun.).

[0409] RT-PCR experiments measuring the expression of autophagy marker genes in HEK-293 cells by real-time PCR. Data were normalized by the expression of the 18srRNA housekeeping gene. For immunofluorescence spectroscopy experiments, HEK-293 cells were fixed after treatment with inducers or controls. Cells were then stained with DAPI to visualize nuclei (blue) and immunolabeled with anti-LC3 followed by the addition of Alexa-fluor 488 (green). Scale bar = 10 μM.

[0410] All reagents and solvents (analytical grade) were purchased from commercial sources and used without further purification. NMR spectra were collected on a Bruker DRX-400 spectrometer ( 1 H is 400 MHz, and 13C at 101 MHz) with the residual solvent signal as chemical shift reference. Mass spectra were recorded on a Micromass LCT (ESI-TOF) mass spectrometer. (4-((2-aminophenyl)carbamoyl)benzyl)carbamic acid pyridin-3-ylmethyl ester (5, entinostat) and N1-hydroxy-N8-phenyloctanediamide (12, vorinostat) were purchased from LC Laboratories (Woburn, MA, USA), N-(4-methoxybenzyl)-1,2-phenylenediamine (16) from Fluorochem Ltd (Hadfield, UK), and trichostatin A (19) from Sigma-Aldrich Sweden AB (Stockholm, Sweden).

[0411] Example 1. Synthesis of compounds related to the present invention

[0412] An exemplary synthesis is provided below. The compounds of the present invention may also be synthesized by other methods known in the art.

[0413] Compound 1 can be synthesized as follows:

[0414]

[0415] Step A: To a solution of 2 (1 eq.) in acetonitrile was added CDI (1.2 eq.). The reaction mixture was stirred at room temperature for 40 min, and 1 (1 eq.) was added. The resulting mixture was stirred at 40 °C overnight, evaporated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3.

[0416] Step B: To a solution of 3 in dichloromethane was added TFA (10 eq.) and the reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was crystallized from hexane to give 4.

[0417] Step C: To a solution of 4 in DMF were added triethylamine (2 eq.) and HATU (1.1 eq.), followed by 5 (1 eq.). The reaction mixture was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 6, which was used in the next step without further purification.

[0418] Step D: To a solution of 6 in dichloromethane was added TFA (10 equivalents), and the reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was diluted with water and the pH was adjusted to ~8 with aqueous sodium bicarbonate. The precipitated product was isolated by simple filtration, washed with water and dried to give compound 1.

[0419] The analytical data of compound 1 are shown in Figure 7 and Figure 8 middle.

[0420] ***

[0421] Compound 2.1 can be synthesized as follows:

[0422]

[0423] Step F: To a solution of 6 (3 g, 26.3 mmol) in anhydrous DMF (50 mL) was added HATU (10.9 g, 28.6 mmol) and DIPEA (11.1 g, 85.8 mmol), and the mixture was stirred at room temperature for 30 min. Then 5 (6.16 g, 28.6 mmol, HCl salt) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in EtOAc (100 mL) and washed with water (100 mL), aqueous citric acid solution (10%, 100 mL) and aqueous NaHCO3 (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain crude 7. Pure ester 7 (5.55 g, 76%) was obtained after column chromatography (H:EA=1:1).

[0424] Step G: To a solution of 7 (5.55 g, 20.2 mmol) in MeOH (100 mL) was added NaOH (1.2 g, 30 mmol) in water (5 mL), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was diluted with water, acidified by citric acid, and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give pure acid 8 (4.65 g, 88%).

[0425] Step H: To a solution of 8 (4.65 g, 17.8 mmol) in anhydrous THF (50 mL) was added HATU (7.45 g, 19.6 mmol) and DIPEA (7.6 g, 58.7 mmol), and the mixture was stirred at room temperature for 30 min. Then 9 (4.1 g, 19.6 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in EtOAc (100 mL) and washed with water (100 mL), aqueous citric acid solution (10%, 100 mL) and aqueous NaHCO3 solution (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain crude 10. Pure ester 10 (5.6 g, 70%) was obtained after column chromatography (H:EA=1:4).

[0426] Step I: To a solution of 10 (5.6 g, 12.4 mmol) in anhydrous dioxane (60 mL) was added HCl\dioxane (60 mL) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then diluted with MTBE (100 mL), the solid was filtered and dried under reduced pressure to give compound 2.1 as an HCl salt.

[0427] Step J: The hydrochloride salt of compound 2.1 (2 g) was dissolved in aqueous NaHCO3 solution (50 mL) and extracted with DCM (3 x 30 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give compound 2.1.

[0428] The analytical data of compound 2.1 are shown in Fig. 9 and Fig.10 middle.

[0429] ***

[0430] Compound 2.2 can be synthesized as follows:

[0431]

[0432] Step K: To a solution of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetic acid (3 g, 13.7 mmol) in anhydrous DMF (50 mL) was added HATU (5.7 g, 15 mmol) and DIPEA (5.8 g, 45.2 mmol) and the mixture was stirred at room temperature for 30 min. Then 5 (3.23 g, 15 mmol, HCl salt) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc (100 mL) and washed with water (100 mL), aqueous citric acid solution (10%, 100 mL) and aqueous NaHCO3 solution (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude 11. Pure ester 11 (3 g, 57.5%) was obtained after column chromatography (H:EA=1:1).

[0433] Step L: To a solution of 11 (3 g, 7.89 mmol) in anhydrous dioxane (30 mL) was added HCl\dioxane (30 mL) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with MTBE (100 mL), the solid was filtered and dried under reduced pressure to obtain 12 as HCl salt.

[0434] Step M: To a suspension of 12 (1.8 g, 5.7 mmol) in anhydrous THF (30 mL) was added TEA (2.3 g, 22.8 mmol), and the mixture was cooled to 0 ° C. Then propionyl chloride (0.63 g, 6.8 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM (50 mL) and washed with citric acid. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give pure 13 (1.9 g, 90%).

[0435] Step N: To a solution of 13 (1.9 g, 5.7 mmol) in MeOH (30 mL) was added NaOH (0.34 g, 8.5 mmol) in water (1 mL), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was diluted with water, acidified with citric acid, and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give the pure acid 14 (0.4 g, 25%).

[0436] Step O: To a solution of 14 (0.4 g, 1.2 mmol) in anhydrous THF (10 mL) was added HATU (0.5 g, 1.3 mmol) and DIPEA (0.52 g, 4 mmol), and the mixture was stirred at room temperature for 30 min. Then 9 (see 9 in the synthesis of compound 2.1) (0.27 g, 1.3 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in EtOAc (100 mL) and washed with water (100 mL), aqueous citric acid solution (10%, 100 mL) and aqueous NaHCO solution 3 (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give pure 15 (0.5 g, 75%).

[0437] Step P: To a solution of 15 (0.5 g, 0.98 mmol) in anhydrous dioxane (10 mL) was added HCl\dioxane (10 mL) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then diluted with MTBE (100 mL), the solid was filtered and dried under reduced pressure to give compound 2.2 as an HCl salt.

[0438] The analytical data of compound 2.2 are shown in Fig.11 and 12 middle.

[0439] ***

[0440] Compound 2.3 can be synthesized as follows:

[0441]

[0442] Step A: To a solution of 2 (3 g, 21.7 mmol) in anhydrous THF (50 mL) was added HATU (9.1 g, 23.9 mmol) and DIPEA (9.3 g, 71.6 mmol), and the mixture was stirred at room temperature for 30 min. Then tert-butyl (2-aminophenyl)carbamate (1) (5 g, 23.9 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After this, the solvent was evaporated, and the residue was dissolved in EtOAc (100 mL) and washed with water (100 mL), ag. citric acid (10%, 100 mL) and NaHCO3 aqueous solution (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure (2.65 g) to give crude 3. Pure 3 (2.65 g) was obtained after column chromatography (H:EA=1:1).

[0443] Step B: To a solution of 3 (2.65 g, 8 mmol), 4 (1.32 g, 12 mmol) and DMAP (0.72 g, 5.9 mmol) in anhydrous DMF (30 mL) was added DCC (2.43 g, 12 mmol), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then quenched with water and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with aqueous NaHCO3 solution and brine. Then dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (CHCl3:MeOH=24:1) to give pure 5 (1.5 g).

[0444] Step C: To a solution of 5 (1.5 g, 3.55 mmol) in anhydrous dioxane (10 mL) was added HCl\dioxane (20 mL), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then diluted with MTBE (50 mL), the solid was filtered and dried under reduced pressure to give compound 2.3 as an HCl salt. The solid was dissolved in aqueous NaHCO3 and extracted with DCM (3×30 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain compound 2.3.

[0445] The analytical data of compound 2.3 are shown in Fig.13 and 14 middle.

[0446] Example 2. Escherichia coli mouse infection model.

[0447] Compound 1 was orally administered at 25 mg / kg, 73.5 mg / kg, and 50 mg / kg to a mouse model of E. coli infection. Compound 1 achieved a 3 log reduction in colony forming unit counts in colon tissue compared to vehicle-treated animals. 10 The research objective of the coefficient.

[0448] Unexpectedly, the study found that: 1) CFU counts in the liver and spleen were higher than expected (2-3 log 10 level), and 2) Compound 1 had the unexpected effect of completely blocking bacterial translocation to these organs.

[0449] Example 3: Evaluation of further compounds of the invention

[0450] Further compounds were newly designed (compounds 2.1, 2.2 and 2.3) and were synthetic variants of compound 1.

[0451] Compounds 2.1, 2.2 and 2.3 were tested for their ability to induce antimicrobial peptides in human cell lines. Dose-dependent fold induction of the expression of the CAMP gene (encoding a human antimicrobial peptide) was obtained, as Figure 2 shown.

[0452] Example 4. Comparison of Compound 1 with HO13 and HO56

[0453] In comparison with HO53 and HO56 (Myszor, IT, Parveen, Z., Ottosson, H. et al. Novelaroylated phenylenediamine compounds enhance antimicrobial defense andmaintain airway epithelial barrier integrity. Sci Rep 9, 7114 (2019). https: / / doi.org / 10.1038 / s41598-019-43350-z ) after comparison, compound 1 was selected as a particularly preferred embodiment of the present invention:

[0454]

[0455]

[0456] Table 1 below describes the comparative data for these three compounds. An important feature of compound 1 relative to HO53 and HO56 is that it unexpectedly exhibits high affinity (permeability) in Caco-2 cell studies. Caco-2 cells are used as a model of the intestinal epithelial barrier. Therefore, the results indicate that the compounds of the present invention are particularly useful for treating diseases that can be treated by improving or restoring gastrointestinal barrier function and / or preventing or reducing microbial translocation across the gastrointestinal barrier.

[0457] Table 1

[0458]

[0459]

[0460] Example 5: Mouse Model Results

[0461] A mouse model was prepared to mimic chemically induced febrile neutropenia. A schematic diagram of the experimental model is described in Figure 3 middle.

[0462] The results of this experiment are shown in Tables 2-7 and Figure 4 and Figure 5 Some observations include:

[0463] - Animals in the Naïve and Compound 1 and Entinostat treated groups were apparently normal. Lethargy was observed in animals in the vehicle control on day 7

[0464] -Clinical symptoms are consistent with efficacy.

[0465] - CFU burden in blood was BLOQ in all groups on days 5 and 6

[0466] - On day 7, compound 1 exhibited significant dose-dependent antibacterial effects in liver and blood when compared to its corresponding vehicle control (p<0.05)

[0467] - In animals treated with entinostat and compound 1 (50 mg / kg) on ​​day 7, bacteria were BLOQ

[0468] -Confirmation by RT-PCR that colonies recovered from the plates are enterotoxigenic E. coli.

[0469] Table 2: Efficacy of Compound 1 against intestinal bacterial translocation of enterotoxigenic Escherichia coli (ETEC) (ATCC® 35401™, H10407) in a neutropenic mouse model.

[0470]

[0471] Table 3: Clinical observations following administration of the listed compounds at the listed concentrations in a mouse model of febrile neutropenia (referenced to untreated controls).

[0472]

[0473]

[0474] Table 4: Liver - Raw data on vancomycin (32 μg / ml) plates, Log10 CFU / g

[0475]

[0476] Table 5: Spleen - Raw data on vancomycin (32 μg / ml) plates, Log10 CFU / g

[0477]

[0478] Table 6: Kidney - Raw data on vancomycin (32 μg / ml) plates, Log10 CFU / g

[0479]

[0480] Table 7: Blood - Raw data on vancomycin (32 μg / ml) plates, Log10 CFU / g – Day 7 PI

[0481]

[0482] Example 6: RT-PCR data:

[0483] RNA extraction: RNA from representative bacterial colonies on the plate was extracted using the Nucleo-pore® RNASure® Mini Kit. The final RNA elution volume was 30µl. Further, these sample RNAs were processed for qRT-PCR.

[0484] Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR): Equal volumes of RNA obtained were used to set up qRT-PCR reactions using RNA-direct™ SYBR® Green Real-Time PCR Master Mix Kit. Further, samples were analyzed on the QuantStudio™ 3 Real-Time PCR System.

[0485] Results: As shown in Table 8 and Figure 6 As shown in , RT-PCR data confirmed that the colonies recovered from the plates were enterotoxigenic E. coli.

[0486] Table 8

[0487]

[0488] Example 7: Summary of Experiments

[0489] - Infection of mice with vancomycin-resistant pathogenic strains of E. coli by oral administration simplified the process of determining the mechanism by which compound 1 exerts its effects on the pathogenic process. All bacteria grown and detected in these experiments were not commensal bacteria, as they were killed and would not grow on bacterial plates with vancomycin.

[0490] - Compound 1 does not act as an antibiotic, nor does it stimulate the production of innate antimicrobial agents to the extent that they act as general antibiotics. By the end of the experiment, viable vancomycin-resistant E. coli ( Figure 1 This was supported by the fact that compound 1 was not toxic to bacteria in culture and that innate antimicrobial peptides acted like general antibiotics only at supraphysiological concentrations.

[0491] - Figure 1 It was also shown that the inhibition of vancomycin-resistant E. coli translocation to the liver and spleen was not dose-dependent for compound 1. In contrast, compound 1 showed a dose-dependent reduction in E. coli growth in the colon and ileum. Therefore, it is unlikely that compound 1 inhibits E. coli translocation to these organs simply because it can stimulate the production of antimicrobial peptides. The most likely explanation is that compound 1 and related compounds can stimulate and enhance cell-cell contacts, as demonstrated by in vitro cell culture experiments. Figure 4 This is supported by data presented in . The experiment was performed in the presence of cyclophosphamide, which is known to cause febrile neutropenia due to bacterial translocation to vital organs. Figure 4 In the experiments, the lower concentration of compound 1 (5 mg / kg) had almost no effect on bacterial translocation, while the higher concentration (50 mg / kg) completely inhibited bacterial translocation.

[0492] - Taken together, these data suggest that two cooperative but separate mechanisms are responsible for the effects of compound 1 on the pathogenicity of E. coli in the intestine. The first is the ability of compound 1 to attenuate bacterial growth, and the second is its ability to inhibit bacterial translocation.

[0493] Example 8: HDAC inhibition data

[0494] The objective of the study was to determine the effect of Compound 1 on the enzymatic activity of recombinant human HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 using an in vitro enzymatic assay.

[0495] The materials are as follows:

[0496] HDAC Assay Buffer (BPS Cat. No. 50031)

[0497] HDAC Assay Developer (BPS Cat. No. 50030)

[0498] HDAC substrate 3 (BPS No. 50037)

[0499] HDAC 2a class substrate 1 (BPS No. 50040)

[0500] TSA was purchased from Selleck (Houston, TX, catalog number S1045)

[0501] SAHA was purchased from Cayman Chemicals (Ann Arbor, MI, catalog number 10009929)

[0502] The compounds are as follows:

[0503]

[0504] The experimental conditions are as follows:

[0505]

[0506] The test conditions are as follows:

[0507] All compounds were dissolved in DMSO. A series of dilutions of the compounds were prepared with 10% DMSO in HDAC assay buffer and 5 µl of the dilutions were added to 50 µl reactions so that the final concentration of DMSO was 1% in all reactions. Compounds were pre-incubated in duplicate at RT for 30 minutes in a mixture containing HDAC assay buffer, 5 µg BSA, HDAC enzyme and test compound. After 30 minutes, the enzymatic reaction was initiated by adding HDAC substrate to a final concentration of 20 μM or 2 μM. The enzymatic reaction was performed at 37ºC for 30 minutes. After the enzymatic reaction, 50 μl of 2 x HDAC developer for HDAC enzyme was added to each well and the plate was incubated for another 15 minutes at room temperature. Fluorescence intensity was measured using a Tecan Infinite M1000 microplate reader at excitation at 360 nm and emission at 460 nm.

[0508] The data analysis is as follows:

[0509] HDAC activity determination was performed in duplicate at each concentration. Fluorescence intensity data were analyzed using computer software Graphpad Prism. In the absence of compound, the fluorescence intensity (Ft) in each data set was defined as 100% activity. In the absence of HDAC, the fluorescence intensity (Fb) in each data set was defined as 0% activity. The activity percentage in the presence of each compound was calculated according to the following formula: activity%=(F-Fb) / (Ft-Fb), where F=fluorescence intensity in the presence of compound. The nonlinear regression analysis of the S-shaped dose-response curve was then used to plot the value of activity% relative to a series of compound concentrations, and the S-shaped dose-response curve was generated using the following formula: Y=B+(TB) / 1+10^((LogEC50-X)×Hill slope), where Y=activity percentage, B=minimum activity percentage, T=maximum activity percentage, X=logarithm of compound, and Hill slope=slope factor or Hill coefficient. IC50 values ​​are determined by the concentration that results in half the maximum activity percentage.

[0510] The effects of the compounds on HDAC activity are summarized as follows:

[0511]

[0512] References

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[0514] 2. WO2015063694

[0515] 3. Yolanda M. Jacobo-Delgado et al; Peptides, Volume 142, 2021,170580, https: / / doi.org / 10.1016 / j.peptides.2021.170580

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[0517] 5. WO2012 / 140504.

[0518] 6. Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia.[Updated 2022 Feb 10]. In: StatPearls [Internet]. Treasure Island (FL):StatPearls Publishing; 2022 Jan-. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK541102 /

[0519] 7. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitativerelationships between circulating leukocytes and infection in patients withacute leukemia. Ann Intern Med. 1966 Feb;64(2):328-40. doi: 10.7326 / 0003-4819-64-2-328. PMID: 5216294

[0520] 8. Meza L, Baselga J, Holmes FA, Liang B, Breddy J, for thePegfilgrastim Study Group (2002) Incidence of febrile neutropenia (FN) isdirectly related to duration of sever neutropenia (DSN) aftermyelosuppressive chemotherapy. Proc Am Soc Clin Oncol 21: Abstract 2840

[0521] 9. Lyman GH, Lyman CH, Agboola O, for the ANC Study Group (2005) Riskmodels for predicting chemotherapy-induced neutropenia. Oncologist 10: 427–437

[0522] 10. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, EllisM, Kearney N, Lyman GH, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinskil C,European Organisation for Research and Treatment of Cancer (EORTC)Granulocyte Colony-Stimulating Factor (G-CSF) Guidelines Working Party (2006)EORTC guidelines for the use of granulocyte-colony stimulating factor toreduce the incidence of chemotherapy-induced febrile neutropenia in adultpatients with lymphomas and solid tumours. Eur J Cancer 42: 2433–2453

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Claims

1. A compound of formula (I) for use in a method for treating a disease or condition in an animal, wherein the disease or condition can be treated by improving or restoring the epithelial barrier function of the animal, wherein the compound is defined by the following formula: (I) in: Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6: ； n is 0 or 1; L is selected from –(CH2) m -、-C(=O)-、-(CH2) m -C(=O)-, -O-(CH2) m -C(=O)-, -OC(=O)-(CH2) m -(C=O)-, -NH-C(=O)-, -NR-C(=O)-, -NH-(CH2) m -C(=O)-、-NR-(CH2) m -C(=O)-, -NH-C(=O)-(CH2) m -C(=O)-, -NR-C(=O)-(CH2) m -C(=O)-, -C(=O)-NH-(CH2) m -C(=O)- and -(CH2) m -(CHR L )-C(=O)-, wherein m is an integer from 1 to 4; A 1 and A 2 Together with the atoms to which they are attached, they form an optionally substituted C 6-14 Aryl groups; If there is A 3 , which is selected from H and optionally substituted C 1-4 alkyl; R N is selected from H and optionally substituted C 1-4 alkyl; B 1 , B 2 , B 3 , B 4 and B 5 One of them is of formula –XR X and the rest are independently selected from H and R B ; Each of these -R B independently selected from halogen, -CF3, -R, -OH, -OR, -OCF3, -C(=O)OH, -C(=O)OR, -C(=O)R, -OC(=O)R, -NH2, -NHR, -NR2, -NO2, -C(=O)NH2, -C(=O)NHR, C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2 or -CN; X is selected from a covalent bond or C 1-3 Alkylene; R X Selected from –H, R XX or R XY ; in: R XX is halogen, -CF3, -OH, -OR, -OCF3, -C(=O)OH, -NO2, -NH2, -NHR, -NR2, -C(=O)NH2, -C(=O)NR2, -S(=O)R, -S(=O)2R, -S(=O)2NR2, or -CN; and R XY Is the formula –L X -R YY Groups; Where L X Selected from: -NH-C(=O)-O-, -NH-C(=O)-NH-, -NH-C(=O)-, -NR-C(=O)-, -OC(=O)-NH-, -OC(=O)-O-, -O-(C=O)-, -C(=O)-NH-, -C(=O)-O-, and -C(=O)-; And R YY Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 6-14 Aryl, -L Y -C 6-14 Aryl, -L Y -OC 6-14 Aryl, -C 5-6 Heteroaryl, -L Y -C 5-6 Heteroaryl, -L Y -OC 5-6 Heteroaryl, -L Y -OL Y -C≡N, -L Y -OL Y -C≡R, -L Y -OL Y -C≡CH, -L Y -OL Y -NR N -C(=O)-R 、-L Y -OL Y -NH-C(=O)-R, -L Y -OL Y -NR-C(=O)-R、-L Y -C≡N and -L Y -C≡R, -L Y -C≡CH, Where -L Y - for C 1-3 alkylene, and wherein each of said groups is optionally substituted; R L Selected from halogen, -R LL 、-CF3、-OH、-OR LL 、-NO2、-NH2、-NHR LL 、-NR2、-NH-C(=O)-R LL 、-NH-C(=O)-OR LL , where R LL Selected from -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -Ph, -L L -Ph, -C 5-6 Heteroaryl, -L L -C 5-6 Heteroaryl, wherein -L L - for C 1-3 Alkylene; and each R is independently C 1-4 alkyl.

2. A compound according to claim 1 for use in a method of treating a disease or condition in an animal that can be treated by preventing or reducing the translocation of microorganisms across the epithelial barrier of the animal.

3. The compound for use according to claim 1 or 2, wherein the epithelial barrier is a gastrointestinal epithelial barrier.

4. The compound for use according to claim 3, wherein the intestinal epithelial barrier is an intestinal epithelial barrier.

5. A compound as claimed in any one of the preceding claims for use in a method for the treatment and / or prevention of microbial infections in animals.

6. A compound as claimed in any one of the preceding claims for use in a method for the treatment and / or prevention of febrile neutropenia in an animal.

7. The compound for use as claimed in any one of the preceding claims, wherein the animal has been or is being treated for cancer.

8. The compound for use as claimed in any one of the preceding claims, wherein the animal is a recipient of an organ transplant, optionally wherein the animal is immunocompromised.

9. The compound for use as claimed in any one of the preceding claims, wherein the animal has a low neutrophil count.

10. A compound as claimed in any preceding claim for use in a method for the treatment and / or prevention of sepsis in an animal.

11. A compound as claimed in any one of the preceding claims for use in a method for the treatment and / or prevention of bacteremia or fungemia in an animal.

12. A compound as claimed in any one of the preceding claims for use in a method of treating and / or preventing mucositis in a subject.

13. A compound as claimed in any one of the preceding claims for use in a method for treating and / or preventing microbiome imbalance in an animal.

14. A compound as claimed in any one of the preceding claims for use in a method of treating and / or preventing a condition selected from atopic dermatitis, asthma, allergic rhinitis, chronic sinusitis, eosinophilic esophagitis, meningitis, COPD, periodontitis, bronchitis, eczema, inflammatory bowel disease, celiac disease, leaky gut syndrome, Alzheimer's disease, Parkinson's disease, chronic depression, autism, diabetes, obesity, non-alcoholic steatohepatitis, autoimmune hepatitis, cirrhosis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, inflammation of intestinal tissue, non-alcoholic fatty liver disease and necrotizing enterocolitis.

15. A compound as claimed in any preceding claim for use in a method for the treatment and / or prevention of diarrhoea, such as traveller's diarrhoea.

16. A compound for use according to any one of the preceding claims, wherein administration of the compound improves or restores epithelial barrier function in the animal, and / or prevents or reduces translocation of microorganisms across the epithelial barrier of the animal.

17. The compound for use according to claim 16, wherein the compound is capable of preventing the translocation of microorganisms from the intestine of the animal via the circulatory system to the kidney, liver, spleen or other organs and vascular beds.

18. The compound for use according to claim 16, wherein the compound is capable of improving, restoring or maintaining the tight junction function of the epithelial barrier of the animal.

19. A compound for use in a method of treating and / or preventing a microbial infection according to any one of the preceding claims, wherein the microbial infection is selected from bacterial infection, viral infection, prion infection, protozoan infection and fungal infection.

20. The compound for use according to claim 19, wherein the microbial infection is caused by a microbial species selected from the group consisting of Yersinia, Salmonella, Shigella, Campylobacter, Clostridium; Helicobacter; Mycobacterium, Pseudomonas, Haemophilus, Moraxella, Escherichia, Neisseria, Streptococcus, Staphylococcus and Norovirus.

21. The compound for use according to claim 19, wherein the microbial infection is caused by Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., Morganella spp., Enterococcus faecium, Staphylococcus aureus, Helicobacter pylori, Acinetobacter baumannii, Pseudomonas aeruginosa, Campylobacter (e.g., Campylobacter jejuni), Salmonella spp., Neisseria gonorrhoeae, Streptococcus pneumoniae, Haemophilus influenzae, Shigella spp.

22. The compound for use according to claim 19, wherein the microbial infection is caused by Nairovirus, Marburg virus, Ebola virus, Coronaviridae, mammalian arenavirus, Henipavirus, Phlebovirus, Chikungunya virus, Alphavirus (enveloped virus), Zika virus and Dengue virus or other flavivirus.

23. The compound for use according to claim 19, wherein the microbial infection is caused by Yersinia enterocolitica, Escherichia coli, Clostridium difficile, Helicobacter pylori, Mycobacterium tuberculosis, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus, Group A and Group B Streptococcus, HIV, RSV, influenza virus, herpes or hepatitis virus.

24. The compound for use according to claim 19, wherein the microbial infection is caused by a bacterial strain resistant to direct acting antibiotic treatment.

25. The compound for use according to any one of the preceding claims, wherein the compound is a compound according to formula (Ia): (It)。 26. A compound for use according to any one of the preceding claims, wherein A 1 and A 2 Together with the atoms to which they are attached they form an optionally substituted phenyl, naphthyl or heteroaryl group.

27. A compound for use according to any one of the preceding claims, wherein A 1 and A 2 Together with the atoms to which they are attached they form a phenyl group.

28. A compound for use according to any one of the preceding claims, wherein R N It's H.

29. The compound for use according to any one of the preceding claims, wherein n is 0.

30. The compound for use according to any one of the preceding claims, wherein Q is Q1.

31. A compound for use according to any one of the preceding claims, wherein B 3 Yes - XR X .

32. The compound for use according to claim 30 or claim 31, wherein B 1 , B 2 , B 4 and B 5 All are H.

33. A compound for use according to any one of the preceding claims, wherein L is selected from -(CH2) m -, -C(=O)-, -NH-C(=O)- and -NR-C(=O)-.

34. The compound for use according to claim 32, wherein L is -C(=O)-.

35. The compound for use according to any one of the preceding claims, wherein X is a covalent bond.

36. A compound for use according to any one of claims 1 to 34, wherein X is C 1-3 Alkylene.

37. The compound for use according to claim 36, wherein X is -CH2-.

38. A compound for use according to any one of the preceding claims, wherein R X Yes-R XY .

39. A compound for use according to any one of the preceding claims, wherein L X are independently: -NH-C(=O)-O-, -NH-C(=O)-, -NR-C(=O)- or -O-(C=O)-.

40. The compound for use according to claim 38, wherein L X are independently -NH-C(=O)- or -NH-C(=O)-O-.

41. A compound for use according to any one of the preceding claims, wherein R YY Independently: -L Y -OL Y -C≡H, -L Y -OL Y -NH-C(=O)-R or -L Y -C≡CH.

42. A compound for use according to any one of claims 1 to 40, wherein R YY Yes-L Y -C 5-6 Heteroaryl.

43. A compound for use according to any one of the preceding claims, wherein -L Y -is -CH2-.

44. A compound for use according to any one of claims 1 to 40, wherein R YY Substituted by one or more substituents selected from the following: -F, -Cl, -Br, -I, -R, -CF3, -OH, -OR, -OCF3, -NO2, -L YY -OH, -L YY -OR, -NH2, -NHR, -NR2, -L YY -NH2, -L YY -NHR, -L YY -NR2, -CO2H, -CO2R, -L YY -CO2H, -L YY -CO2R, -Ph and -L YY -Ph-, where L YY C 1-3 Alkylene.

45. A compound for use according to any one of the preceding claims, wherein the compound is selected from: ， and (4-((2-aminophenyl)-carbamoyl)benzyl)carbamic acid pyridin-3-ylmethyl ester (Entinostat): 。 46. ​​The compound for use according to any one of the above claims, wherein the method comprises administering to the animal the compound in an effective amount of the compound, wherein the weekly or daily dose is between 10 μg to about 1 g, optionally divided into doses given in 1, 2 or 3 times.

47. The compound for use according to claim 46, wherein the dosage is between 0.025 mg and 500 mg.

48. The compound for use according to claim 47, wherein the dosage is between 0.1 mg and 250 mg.

49. The compound for use according to any one of claims 46-48, wherein the compound is administered at a dose of at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg or at least 100 mg / kg.

50. The compound for use according to claim 49, wherein the compound is administered at a dose of at least 50 mg / kg.

51. The compound for use according to any one of claims 46-50, wherein the compound is administered at a dose of less than 150 mg / kg.

52. A compound for use according to any one of the preceding claims, wherein the treatment is a combination therapy, wherein the compound is used in combination with any one or more of the following: an antibiotic; isoleucine or an active isomer or analog thereof; a vitamin D-type compound.

53. The compound for use according to any one of the preceding claims, wherein the compound is present in a pharmaceutical composition comprising the compound as an active ingredient and at least one pharmaceutically acceptable excipient.

54. The compound for use according to claim 53, wherein the pharmaceutical composition is formulated as an oral dosage form.

55. The compound for use according to claim 54, wherein the oral dosage form is selected from the group consisting of tablets, capsules, solutions, suspensions, powders, pastes, elixirs, syrups and lozenges.

56. A compound for use according to claim 54 or claim 55, wherein the oral dosage form comprises the active ingredient in the range of about 0.01-1000 mg.

57. The compound for use according to claim 53, wherein the pharmaceutical composition is formulated as an inhalation dosage form.

58. A compound for use according to any one of the above claims, wherein the method comprises: (1) administering antibiotics to the animal for 1 or 2 days with or without the compound; Then (2) administering an effective amount of the compound to the animal for a further 2, 3, 4, 5 days or longer.

59. The method of treatment of any of the above claims.

60. Use of a compound as claimed in any one of the preceding claims for the preparation of a medicament for use in a method of treatment as claimed in any one of the preceding claims.

61. The compound, use or method of any preceding claim, wherein the animal is a mammal, preferably wherein the animal is a human.

62. The compound, use or method of any of the preceding claims, wherein the animal is selected from fish, dogs, cats, cattle, horses, deer and poultry including hens, turkeys, ducks, geese and household pets such as birds and rodents.

63. A compound selected from: 。

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