Antibacterial compound

Abstract

The present invention relates to phenylenediamine derivatives having specific pharmacological properties resulting from the enhancement of epithelial barrier function and / or the blockade of bacterial translocation through the epithelial barrier. This compound is useful in the treatment of various conditions involving the translocation of pathogens from the gastrointestinal tract to underlying tissues and the vascular system, such as febrile neutropenia, intestinal tissue inflammation, bacteremia, and sepsis.

Description

【Technical Field】 【0001】 The present invention relates to phenylenediamine derivatives having specific pharmacological properties resulting from enhancement of the epithelial barrier function and / or blockade of bacterial translocation through the epithelial barrier. This compound is useful in the treatment of various conditions associated with translocation of pathogens from the gastrointestinal tract to underlying tissues and the vascular system, such as febrile neutropenia, intestinal tissue inflammation, bacteremia, and sepsis. 【Background Art】 【0002】 Damage to the epithelial barrier (mucosal barrier), such as damage to the epithelial barrier in the gastrointestinal tract, enables the translocation of pathogens through the barrier and can lead to diseases such as neutropenia, febrile neutropenia, intestinal tissue inflammation, bacteremia, and sepsis. 【0003】 The epithelial barrier can be damaged by multiple pathways, such as by chemical means after cancer treatment / chemotherapy, organ transplantation, and infections by enteric pathogens leading to dysbiosis of the natural microbiota (which may be caused by directly acting antibacterial agents), or mucositis. 【0004】 Damage to the epithelial barrier is particularly likely to be seen in subjects with low neutrophil counts (neutropenic), such as patients undergoing cytotoxic cancer treatment or patients being treated with immunosuppressive agents. The low neutrophil count resulting from cytotoxic chemotherapy is associated with an increased risk of severe bacterial and fungal infections. This is currently considered to be causally related to mucositis - cytotoxic damage to the inner layer of the gastrointestinal tract and other mucosae, and mucositis renders immunocompromised hosts vulnerable to invasion by infectious pathogens from their own microbiota. 【0005】 Damage to the epithelial barrier in patients with neutropenia can lead to febrile neutropenia. Febrile neutropenia is the most commonly seen (in about 1% of chemotherapy and radiotherapy patients), severe and life-threatening complication associated with patients undergoing cancer chemotherapy or who are immunosuppressed to avoid transplant rejection. Febrile neutropenia is often a limiting factor for treatment dosages, has a significant mortality rate of 5% - 50% in high-risk populations, with over 60,000 hospitalizations and over 4,000 deaths each year, costing over $2.8 billion (in 2012) in the United States alone, which is >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 for prophylaxis with fluoroquinolone broad-spectrum antibiotics is unpopular among oncologists not only because of drug toxicity, but also because the antibiotics lead to an increase in the occurrence of drug-resistant bacteria and dysbiosis of the gut microbiota, which further promotes colonization by opportunistic pathogens. This antibacterial approach is also fundamentally ineffective because it does not stop the migration of infectious organisms through the gastrointestinal wall into the underlying tissues and vascular system. 【0007】 International Publication No. WO 2015 / 063694 pamphlet (Akthelia) relates to benzoylated phenylenediamines and their use in the treatment of microbial infections. 【Prior Art Documents】 【Patent Documents】 【0008】 【Patent Document 1】 International Publication No. WO 2015 / 063694 pamphlet 【0009】 【Non-Patent Document 1】 Epidemiology, Volume 23, Issue 7, pages 1889 - 1893 【Summary of the Invention】 【Problems to be Solved by the Invention】 【0010】 Notwithstanding the above disclosure, it will be understood that the provision of a compound or combination of compounds for use in the treatment of diseases caused by or resulting from damage to the integrity of the epithelial barrier and / or translocation of bacteria through the epithelial barrier would provide a contribution to the art. 【Means for Solving the Problems】 【0011】 The inventors applied a treatment strategy based on their in - depth, field - leading expertise in cell biology to eliminate bacterial translocation and enhance the innate immune barrier resistance of the gastrointestinal tract. 【0012】 This was achieved, in part, by providing compounds that can up - regulate endogenous proteins naturally expressed within the epithelium and improve adherens junction signaling in the epithelial barrier. This epithelial barrier can act to contain the microbiota within the intestinal lumen in healthy individuals. 【0013】 The data disclosed herein show that the compounds of the invention unexpectedly and effectively knockdown pathogen translocation to multiple organs and systems in relevant mouse models, which suggests a reflective survival benefit. The inventors believe this may be achieved by the compounds of the invention that affect adherens junctions, for example, via cross - signaling pathways, resulting in a very efficient blockade of translocation and activation of the host defense system. 【0014】 As far as the inventors are aware, it was not previously known whether compounds capable of upregulating endogenous proteins could also separately block pathogen translocation. In fact, specific inducers of endogenous antimicrobial peptides have previously been shown to downregulate proteins essential for tight junctions of the epithelial barrier. See, for example, Yolanda M. Jacobo-Delgado et al.; Peptides, Volume 142, 2021, 170580, https: / / doi.org / 10.1016 / j.peptides.2021.170580; and Hatakeyama S et al., J Periodontal Res. April 2010;45(2):207-15. doi:10.1111 / j.1600-0765.2009.01219.x. 【0015】 The claimed invention enables a new standard treatment that has the potential to replace the prophylactic use of antibiotics and antifungals in patients at risk of febrile neutropenia, with a reduction in the risks of SAE, AMR, and microbiome dysbiosis. 【0016】 This highly differentiated approach has broad applicability, can assist in the treatment of the diseases described herein, and can address the growing threat of antibiotic bacterial resistance worldwide. 【0017】 Some of the advantages that may be shown by the claimed invention are as follows: (1) the combination of strengthening the epithelial barrier (tight junctions) and upregulating host defense peptides in epithelial cells and macrophages; (2) broad-spectrum therapy with a mode of action different from that of antibiotics - immunomodulation that induces the production of host defense peptides that attenuate bacteria; (3) the production of multiple host defense microbial factors is induced, so pathogens are less likely to become resistant. This is in contrast to antibiotics that act directly on microorganisms and thus rapidly select for resistant strains; (4) minimal impact on the natural microbiota. 【0018】 Accordingly, the present invention provides a compound effective for improving or restoring the epithelial barrier function of an animal and / or preventing (prophylaxis) or reducing microbial translocation through the epithelial barrier. In a preferred embodiment, the epithelial barrier is an intestinal barrier or a gastrointestinal barrier. This compound is a benzoylated phenylenediamine or a derivative or analog thereof, as described in more detail below. 【0019】 Preferred compounds are N-(2-aminophenyl)-4-{2-[(prop-2-yn-1-yl)oxy]acetamide}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-propanamidoethoxy)acetamide]methyl}benzamide (“Compound 2.2”), 4-[(2-aminophenyl)carbamoyl]phenyl hexa-5-ynoate (“Compound 2.3”), and pyridin-3-ylmethyl (4-((2-aminophenyl)-carbamoyl)benzyl)carbamate (“Entinostat”). 【0020】 The present invention provides the use of the compounds described herein for the treatment of the diseases disclosed herein. Preferred microbial targets and diseases targeted by the present invention are described below. 【0021】 This effectiveness of this class of compounds in preventing microbial translocation (such as bacterial translocation and / or fungal translocation etc.) through the epithelial barrier is unexpected, suggesting that these compounds and their analogs may act differently from some previous compounds that exclusively stimulate the innate antibacterial defense peptide system or may act through additional stimulatory mechanisms. 【0022】 Aspect of the present invention is a method of treating (including prophylaxis) the diseases described herein in an animal using the compounds described herein. 【0023】 The present invention further provides a compound as defined herein for use as a medicament for treating the diseases described herein in humans and other animals by improving or restoring the epithelial barrier function. 【0024】 In yet a further aspect, the present invention provides a pharmaceutical composition for use in the methods described herein, comprising an active ingredient which is at least one compound of the present invention and typically at least one pharmaceutically acceptable excipient. 【0025】 In yet a further aspect, the present invention provides the use of a compound of the present invention in the preparation of a medicament for use in the methods described herein. 【0026】 In one aspect, the present invention provides a compound of general 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 the epithelial barrier function, wherein administration of the compound improves, restores or maintains the epithelial barrier function in the animal, and the compound is defined by the following formula: 【Chemical formula】 In the formula, Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6, 【Chemical formula】 n is 0 or 1, L is -(CH2) m -, -C(=O)-, -(CH2) m -C(=O)-, -O-(CH2) m -C(=O)-, -O-C(=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)- selected from, m is an integer from 1 to 4, A 1 and A 2 together with the atom to which they are attached, may be substituted C 6~14 forms an aryl or heteroaryl group, A 3 when present, is selected from H and optionally substituted C 1~4 alkyl, R N is selected from H and optionally substituted 3 C 1~4 alkyl, B 1 B 2 B 3 B 4 and B 5 one of is a group of the formula -X-R X and the others are independently selected from H and R B , each -R B is 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 a covalent bond or C 1~3 selected from alkylene, R X is -H, R XX or R XY selected from, 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; R XY is of the formula -LX -R YY is a group, L X is selected from -NH-C(=O)-O-, -NH-C(=O)-NH-, -NH-C(=O)-, -NR-C(=O)-, -O-C(=O)-NH-, -O-C(=O)-O-, -O-(C=O)-, -C(=O)-NH-, -C(=O)-O-, -C(=O)-, R YY is C 1~4 alkyl, C 3~6 cycloalkyl, -C 6~14 aryl, -L Y -C 6~14 aryl, -L Y -O-C 6~14 aryl, -C 5~6 heteroaryl, -L Y -C 5~6 heteroaryl, -L Y -O-C 5~6 heteroaryl, -L Y -O-L Y -C≡N, -L Y -O-L Y -C≡R, -L Y -O-L Y -C≡CH, -L Y -O-L Y -NR N -C(=O)-R, -L Y -O-L Y -NH-C(=O)-R, -L Y -O-L Y -NR-C(=O)-R, -L Y -C≡N, -L Y -C≡R, -L Y is selected from -C≡CH, -L Y - is C 1~3 alkylene, and each of the above groups may be substituted, R L is halogen, -R LL , -CF3, -OH, -OR LL , -NO2, -NH2, -NHR LL , -NR2, -NH-C(=O)-R LL , -NH-C(=O)-O-R LLselected from, R LL is -C 1~4 alkyl, -C 3~6 cycloalkyl, -Ph, -L L -Ph, -C 5~6 heteroaryl, -L L -C 5~6 selected from heteroaryl, -L L - is C 1~3 alkylene, and each R is independently C 1~4 alkyl. 【0027】 In further aspects and embodiments, the present invention provides a compound of general formula (I) for use in a method of treating or preventing a disease or condition in an animal that benefits from preventing or reducing microbial translocation through the epithelial barrier of the animal, wherein administration of the compound prevents or reduces microbial translocation through the epithelial barrier of the animal. 【0028】 Diseases or conditions that benefit from preventing or reducing microbial translocation through the epithelial barrier of an animal, or that benefit from enhancing or restoring epithelial barrier function, include the specific diseases disclosed herein. 【0029】 In some particularly preferred embodiments, the compound follows formula (Ia). 【Chemical formula】 【0030】 From this, some aspects and embodiments of the present invention are described in more detail. 【Brief description of the drawings】 【0031】 【Figure 1(1)】 E. coli mouse infection model. CFU measured in tissues: colon, liver. Statistical analysis was performed using one-way ANOVA with Dunnett's post hoc test, comparing all conditions to the vehicle-treated group (*** p < 0.001, **** p < 0.0001, ns not significant). 【Figure 1(2)】 Escherichia coli (E. coli) mouse infection model. CFU measured in tissues: ileum, spleen. Statistical analysis was performed using one-way ANOVA with Dunnett's post hoc test, comparing all conditions to the vehicle-treated group (*** p < 0.001, **** p < 0.0001, ns not significant). 【Figure 2】 Induction assay. 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 after 24 hours. The corresponding concentrations of Compound 1 (2 - 128 μM) and entinostat (2.5 μM) were used as positive controls. Results are presented 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 to the corresponding vehicle control using two-way ANOVA with Dunnett's post hoc test. Only significant changes are shown, with ** p < 0.01, *** p < 0.001, **** p < 0.0001. Entinostat treatment (Entino) was compared to the control using a t-test (## p < 0.01). 【Figure 3】 Schematic protocol of the neutropenic mouse model. 【Figure 4(1)】 CFU measured in blood and liver in a mouse model of febrile neutropenia after administration of the listed compounds at the listed concentrations. 【Figure 4(2)】 CFU measured in kidney and spleen in a mouse model of febrile neutropenia after administration of the listed compounds at the listed concentrations. 【Figure 5】 Body weight measured in a mouse model of febrile neutropenia (relative to naive control) after administration of the listed compounds at the listed concentrations. 【Figure 6】 Amplification plot of samples from the RT-PCR example. 【Figure 7】 1H NMR spectrum of Compound 1. 【Figure 8(1)】 LC / MS of Compound 1. 【Figure 8(2)】 Continuation of Fig. 8(1). 【Figure 9】 1H NMR spectrum of Compound 2.1 【Figure 10(1)】 LC / MS of Compound 2.1 【Figure 10(2)】 Continuation of Fig. 10(1). 【Figure 11】 1H NMR spectrum of Compound 2.2 【Figure 12(1)】 LC / MS of Compound 2.2 【Figure 12(2)】 Continuation of Fig. 12(1). 【Figure 13】 1H NMR spectrum of Compound 2.3 【Figure 14(1)】 LC / MS of Compound 2.3 【Figure 14(2)】 Continuation of Fig. 14(1). 【Figure 14(3)】 Continuation of Fig. 14(1) and Fig. 14(2). 【Mode for Carrying Out the Invention】 【0032】 Treatment Method The compounds described herein may be novel per se. Accordingly, aspects of the present invention extend to those compounds themselves in addition to their use in the treatment methods described herein. The compounds may be used alone or as adjuvant therapy. 【0033】 The compounds of the present invention may treat and / or prevent the diseases described herein, either in any combination thereof or alone. 【0034】 As used herein in the context of treating a disorder, the term "treatment" generally refers to treatment and therapy, regardless of whether it is a human subject or another animal (e.g., a mammal), and includes achieving some desired therapeutic effect, e.g., inhibition of the progression of the disorder, and the desired therapeutic effects include reduction in the rate of progression, cessation of the rate of progression, alleviation of the symptoms of the disorder, improvement of the disorder, and cure of the disorder. 【0035】 The term "treatment" includes combination treatments and combination therapies in which two or more treatments or therapies are combined, for example, consecutively or simultaneously. 【0036】 Agents (i.e., one or more other agents in addition to the compounds described herein) may be administered continuously via different routes, either simultaneously or at individually varying dosage schedules. For example, when administered continuously, the agents can be administered at close intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 hours or more apart, or even longer periods apart if necessary), and the exact dosing regimen will correspond to the properties of the therapeutic agents described herein, including the synergistic effects of the agents. 【0037】 Treatment as a prophylactic measure (i.e., prevention) is also included. For example, use in patients who have not yet developed a disorder but are at risk of developing that disorder is encompassed by the term "treatment". 【0038】 "Prevention" in the context of this specification should not be understood to be limited to complete success, i.e., complete protection or complete prevention. Rather, prevention in this context refers to measures taken for the purpose of preserving health by helping to delay, mitigate, or avoid a particular condition prior to the detection of symptomatic states. 【0039】 It is understood that the methods and compositions of the present invention are also useful in aquaculture applications, veterinary applications, and livestock applications for companion animals, livestock, and ranch animals. These applications include, but are not limited to, treating, preventing, or neutralizing diseases and conditions caused by microorganisms in fish, dogs, cats, cows, horses, deer, and poultry (including chickens, turkeys, ducks, geese), as well as in household pets such as birds and rodents. In the case of large animals, appropriate dosages may be more than the amounts approved for humans. 【0040】 The compounds described herein can act by improving or restoring epithelial barrier function, i.e., by strengthening the epithelial barrier, and thus can treat diseases and conditions from which benefit can be derived therefrom. As far as the inventors are aware, this is achieved by one or more of the following: promoting the maintenance of tight junctions between epithelial cells; neutralizing inflammation; and inducing the expression of antimicrobial peptides / proteins in epithelial cells. 【0041】 Epithelial cells form an important barrier separating the external environment from the internal tissue environment and have specific adaptations related to their functions. The monolayer 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. Prominent functions of the intestinal epithelium include, in addition to nutrient uptake, functioning as an active barrier that prevents the movement of bacteria to the underlying tissue and secretes antimicrobial compounds. 【0042】 The activity of epithelial cells is essential for maintaining the separation between host tissue and microorganisms and preserving host-microbial homeostasis. Epithelial cells are covered by a mucus protein layer containing antimicrobial effectors. The paracellular space between adjacent epithelial cells is sealed by a junctional complex interconnected with tight junctions composed of claudin / occludin. Thus, a decrease in epithelial barrier function may, in some embodiments, manifest 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 occludins. 【0043】 Improvement or restoration of epithelial barrier function and / or reduction or prevention of microbial translocation can be determined, for example, by measuring the number of colony-forming units (CFUs) in the basal tissue, circulation, and / or viscera in an in vivo animal model. Examples of viscera relevant to the present invention include highly vascularized organs including the kidney, liver, and spleen. 【0044】 Improvement or restoration of the epithelial barrier function can also be determined by the effect on the tight junction function, and the tight junction function itself can be determined by measuring the trans-epithelial electrical resistance (TEER), or by analyzing the levels of tight junction proteins such as occludin and claudin-1 by Western blot analysis. Those skilled in the art will know additional methods in the art for measuring these properties. 【0045】 In a particularly preferred embodiment, the epithelial barrier is an intestinal epithelial barrier or a gastrointestinal epithelial barrier. 【0046】 The gastrointestinal (GI) tract of a mammal is covered by a continuous sheet of epithelial cells (enterocytes) that are folded into villi projections and crypts. Stem cells of the GI tract can be found in the crypts, and within the base of those crypts are special granule cells called Paneth cells. Both enterocytes and Paneth cells produce antimicrobial peptides. Enterocytes synthesize antimicrobial peptides and secrete them into the intestinal lumen both constitutively and upon induction. Paneth cells at the base of the intestinal crypts secrete α-defensins into the crypt lumen, resulting in concentrations estimated at the mg / mL level, and the α-defensins ultimately flow out into the intestinal lumen. Furthermore, it is known that fixed macrophages, when activated, also secrete antimicrobial peptides into the intestinal lumen and additional tissue sites. 【0047】 Other epithelial surfaces of the mammalian body, including but not limited to the cornea, lung, kidney, and skin, also have such host defense secretory systems (see also WO 2012 / 140504 pamphlet). 【0048】 Stimulation of macrophages, epithelial cells, and Paneth cells in the gastrointestinal tract and other epithelial surfaces of humans and other animals secretes a large number of naturally occurring broad-spectrum antibacterial agents, including defensins, HMP1-4, LL-37, antibacterial peptides such as HBD1-4, and antibacterial proteins such as lysozyme, transferrin, lactoferrin, phospholipase, and SLPI (secretory leukocyte protease inhibitor). Substances stored by Paneth cells are active against a wide range of infectious pathogens, including bacteria, protozoa, viruses, and fungi. 【0049】 In doing so, the compounds of the present invention act to confine the microbiota within the intestinal lumen, as in healthy individuals. The natural microbiome is adapted to an environment containing antibacterial peptides, especially those that bind to bacteria and disrupt their membrane function. These commensal bacteria produce modified lipopolysaccharides (endotoxins) that do not bind strongly to positively charged antibacterial peptides and thus require higher concentrations of peptides for their bacteriostatic effects. In situations such as neutropenia, the concentration of antibacterial peptides is lower and the effect is less. Also, as can be seen from in vivo infection studies (Figure 1), Compound 1 does not eliminate pathogens but completely inhibits their translocation, strongly suggesting that epithelial integrity is maintained. 【0050】 The epithelial cells targeted by the present invention can be any of the epithelial cells in, for example, the oral cavity, lungs, trachea, urinary tract or kidneys, stomach, upper gastrointestinal tract (e.g., ileum) and lower gastrointestinal tract (e.g., jejunum), and colon. However, preferably, the present invention is used for the treatment of diseases involving the barrier function of the gastrointestinal tract. 【0051】 As described above, an important aspect of the present invention provides a method for treating, preventing or neutralizing a microbial infection or any of the described diseases by administering a medicament 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. The observable progression of a human infection can be monitored by performing, in addition to fever and swelling, culturing of blood samples, blood cell counting, and / or testing for bacterial products such as endotoxin. 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 evaluated by an intestinal permeability (IP) test, also called the "intestinal wall leak" test, which measures the levels of mannitol and lactulose ingested in urine samples. 【0052】 Therefore, in some embodiments, the compound can prevent the translocation of microorganisms from the intestine of an animal to further sites of the body, such as the basement tissue, the circulatory system, or other internal organs such as the kidney, liver or spleen, and the vascular bed via the circulatory system. 【0053】 The observable progression of a human infection can be monitored by performing, in addition to fever and swelling, culturing of blood samples, blood cell counting, and / or testing for bacterial products such as endotoxin. 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 evaluated by an intestinal permeability (IP) test, also called the "intestinal wall leak" test, which measures the levels of mannitol and lactulose ingested in urine samples. 【0054】 The compounds described herein may be used for the treatment of febrile neutropenia. Febrile neutropenia may be defined by an absolute neutrophil count (ANC) of <500 cells / microliter, or an ANC that is expected to decrease to <500 cells / microliter over the next 48 hours, with a single oral temperature measurement of >38.3°C (>101°F) or a temperature of ≥38.0°C (≥100.4°F) maintained for 1 hour. See, for example, StatPearls [Internet], Treasure Island (FL): StatPearls Publishing; January 2022, Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia. [Updated February 10, 2022], available from https: / / www.ncbi.nlm.nih.gov / books / NBK541102 / . 【0055】 Accordingly, in a preferred embodiment, the compounds described herein are useful for treating patients with low neutrophil counts, e.g., patients with an ANC of <500 cells / microliter, <450 cells / microliter, <400 cells / microliter, <350 cells / microliter, <300 cells / microliter, <250 cells / microliter, <200 cells / microliter, <150 cells / microliter, <100 cells / microliter, or <50 cells / microliter. 【0056】 In some embodiments, the febrile neutropenia is chemotherapy-induced febrile neutropenia. The risk of developing febrile neutropenia depends on many patient factors including the degree and duration of chemotherapy-induced febrile neutropenia and age, comorbidities, and serum albumin levels (Bodey et al., 1966; Meza et al., 2002; Lyman et al., 2005; Aapro et al., 2006). Thus, febrile neutropenia can be induced by any chemotherapeutic agent known in the art. A patient being treated according to the present invention may still be taking a chemotherapeutic agent. A patient being treated according to the present invention may have been treated with a chemotherapeutic agent in the past, for example, one week ago, one month ago, two months ago, three months ago, four months ago, five months ago, six months ago, one year ago, two years ago, three years ago, four years ago, or five years ago, or any amount of time in between. 【0057】 Therefore, in some embodiments, the compounds described herein are useful in the treatment of patients who have been treated for or are being treated for cancer. The cancer treatment of those patients may be ongoing or may have been administered in the past, for example, one week ago, one month ago, two months ago, three months ago, four months ago, five months ago, six months ago, one year ago, two years ago, three years ago, four years ago, or five years ago, or any amount of time in between. 【0058】 Febrile neutropenia can also be the result of organ transplantation where the patient is administered an immunosuppressive agent known in the art that causes a lower white blood cell count or impairs its function. Many immunosuppressive agents also affect epithelial cells through the integrated function of the immune system with the epithelial cell layer exposed to microorganisms (https: / / doi.org / 10.1038 / s12276-018-0126-x). Immunosuppressive agents also alter the gut microbiota, and this change can lead to an increased risk of infection (doi:10.1097 / QCO.0b013e3283630dd3). 【0059】 Therefore, in some embodiments, the compounds described herein are useful for the treatment of patients receiving immunosuppressive agents who are recipients of organ transplants. In some preferred cases, the transplant may be a bone marrow transplant or a kidney transplant. The organ transplant may have been performed in the past, for example, 1 week ago, 1 month ago, 2 months ago, 3 months ago, 4 months ago, 5 months ago, 6 months ago, 1 year ago, 2 years ago, 3 years ago, 4 years ago or 5 years ago, or any amount of time in between. The patient may be immunocompromised. The patient being treated according to the invention may still be taking immunosuppressive drugs. The patient being treated according to the invention may have been treated with immunosuppressive drugs in the past, for example, 1 week ago, 1 month ago, 2 months ago, 3 months ago, 4 months ago, 5 months ago, 6 months ago, 1 year ago, 2 years ago, 3 years ago, 4 years ago or 5 years ago, or any amount of time in between. 【0060】 The compounds described may be used in the treatment of sepsis in animals. Sepsis is generally defined as life-threatening organ dysfunction caused by dysregulation of the host response to infection (JAMA. Feb 23, 2016; 315(8):801-810). Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis (Shock, July 2016; 46(1):52-59). Observational studies have shown evidence of increased intestinal permeability in critically ill patients in general (Semin Respir Crit Care Med. 2011;32:626-638), particularly in sepsis patients (Biochem Med(Zagreb) 2013;23:107-111). Thus, the compounds of the invention may be useful for treating sepsis by strengthening the epithelial barrier and controlling intestinal permeability. 【0061】 The described compounds may be used in the treatment of bacteremia in animals. Bacteremia is the presence of bacteria in the blood. This can be caused in patients with weakened epithelial barrier function (e.g., patients who have received cancer treatment or organ transplantation) where pathogens from the gastrointestinal tract can pass into the bloodstream. Thus, the compounds of the present invention may be useful in treating sepsis by strengthening the epithelial barrier and controlling intestinal permeability. 【0062】 The described compounds may be used in the treatment of mucositis in animals. Mucositis is typically a painful inflammation and ulceration of the mucosa on the inner surface of the gastrointestinal tract as a harmful effect of chemotherapy and radiotherapy treatments for cancer (Ridge JA, Glisson BS, Lango MN et al., “Head and Neck Tumors”, Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (eds) Cancer Management: A Multidisciplinary Approach. 11th Edition, 2008). Thus, the compounds of the present invention may be useful in treating mucositis by repairing the mucosa on the inner surface of the gastrointestinal tract. 【0063】 The described compounds may be used in the treatment of microbiome dysbiosis in animals. Dysbiosis is characterized by a decrease in microbial diversity and an increase in inflammation-inducing species. This disrupted microbiota cannot protect against pathogenic organisms that can induce inflammation and produce genotoxins or carcinogenic metabolites (Precision Medicine for Investigators, Practitioners and Providers, 2020). Dysbiosis can be brought about by direct-acting antibacterial agents. When combined with a decrease in epithelial barrier function, dysbiosis can lead to the further diseases described herein by the translocation of the dysbiotic microbiota through the epithelial barrier. Thus, the compounds of the present invention may be useful in treating mucositis by repairing the mucosa on the inner surface of the gastrointestinal tract and causing the restoration of the normal function of the intestinal microbiota. 【0064】 Additional diseases that may be treated by the compounds of the present invention include atopic dermatitis, asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, meningitis, COPD, periodontitis, bronchitis, eczema, inflammatory bowel disease, celiac disease, intestinal permeability 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, and intestinal tissue inflammation. 【0065】 The compounds of the present invention may also be useful in travel medicine and in the treatment of travel-related diseases. Traveler's diseases include diarrhea, which is a gastrointestinal disorder that usually causes loose stools and abdominal cramps (e.g., traveler's diarrhea). This is caused by eating contaminated food or drinking contaminated water. Bacteria are the most common cause of traveler's diarrhea. The most commonly identified pathogens are enterotoxigenic Escherichia coli, followed by Campylobacter jejuni, Shigella species, and Salmonella species. These bacteria invade the epithelial lining and cause an inflammatory response, which manifests as diarrhea. Although not desired by physicians, antibiotics are very commonly used to relieve this discomfort. The side effects of antibiotic use are the emergence of AMR bacteria and dysbiosis. The most commonly used antibiotic is rifaximin, which is a poorly absorbed antibiotic that does not distribute systemically. Rifaximin relieves the symptoms of intestinal infections but often does not eradicate the pathogen. There are few preventive measures available to prevent bacterial invasion of the epithelial lining by these pathogens. Therefore, in some embodiments, the compounds of the present invention can be taken before exposure to the pathogens that cause traveler's diarrhea and may be used as a prophylactic to prevent infection. 【0066】 Other diseases that may be treated by the compounds of the present invention include non-alcoholic fatty liver disease and necrotizing enteritis. 【0067】 The compounds of the present invention are particularly useful against infections by bacterial strains that are resistant to conventional antibiotics. Bacterial species include, but are not limited to, strains of the genera Yersenia, Salmonella, Shigella, Campylobacter, Clostridium, Heliobacter, Mycobacterium, Pseudomonas, Haemophilus, Moraxella, Escherichia, Neisseria, and Staphylococcus. Targeting of viruses including HIV, RSV, herpes virus, hepatitis virus, and influenza virus is also included, and these are also thought to be targets of the antibacterial peptides stimulated by the present invention. The virus may be a DNA virus or an RNA virus. 【0068】 In some preferred embodiments, the compounds of the present invention may be used for treating HIV infection. In some preferred embodiments, the compounds of the present invention may be used for treating AIDS. In some preferred embodiments, the compounds of the present invention may be used in the long-term treatment of AIDS relapse patients, particularly those patients who may die early due to epithelial barrier dysfunction. In some preferred embodiments, the compounds of the present invention may be used for treating patients diagnosed with HIV infection and / or AIDS, who are further suffering from intestinal epithelial barrier dysfunction, or a condition or disease caused by intestinal epithelial barrier dysfunction, or a condition or disease that may be treated by improving or restoring epithelial barrier function. In some embodiments, the compounds of the present invention may be used for treating patients with a history of HIV infection and AIDS suppressed by antiretroviral therapy (ART). The patient may be suffering from AIDS or may have been previously diagnosed and / or treated as AIDS. In some embodiments, the compounds of the present invention may treat premature aging and may improve the morbidity and mortality rates in HIV patients treated with ART. 【0069】 The compounds of the present invention are also particularly useful against or in preventing microbial infections caused by Klebsiella pneumonia, Escherichia coli, Enterobacter species, Serratia species, Proteus species, Providencia species, Morganella species, Enterococcus faecium, Staphylococcus aureus, Helicobacter pylori, Acinetobacter baumannii, Pseudomonas aeruginosa, Campylobacter (e.g., Campylobacter jejuni), Salmonella species, Neisseria gonorrhoeae, Streptococcus pneumoniae, Haemophilus influenzae, Shigella species. In some embodiments, the compounds are effective against or in preventing microbial infections caused by Nairovirus, Marburg virus, Ebola virus, Coronaviridae, Mammarenavirus, Henipavirus, Phlebovirus, Chikungunya virus, Alphavirus (Togavirus), Zika virus, and Dengue virus and other Flavivirus. 【0070】 Infectious diseases, conditions and disorders treatable in accordance with the present invention include bacterial dysentery, endemic diarrhea, dysentery, viral gastroenteritis, parasitic enteritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, pre-cancerous conditions of the gastrointestinal tract, cancer of the gastrointestinal tract, diverticulitis, diarrhea after administration of antibiotics, 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, Eye infections that may be selected from conjunctivitis, hordeolum, blepharitis, orbital cellulitis of the eye, keratitis, corneal ulcer, trachoma, uveitis, canaliculitis and dacryocystitis, Urinary tract and genital infections that may be selected from pyelonephritis, cystitis, gonorrhea and urethritis, Respiratory infections that may be selected from bronchitis, pneumonia, rhinosinusitis, paranasal sinusitis, pharyngitis / tonsillitis, laryngitis and influenza, Tuberculosis, Skin infections that may be selected from boils, carbuncles, furuncles, cellulitis, abscesses, impetigo, and erysipelas are also included, but are not limited thereto. 【0071】 In some embodiments, the compounds of the present invention are effective against bacterial strains that are resistant to direct-acting antibiotics, i.e., antibiotics that exert their effect by direct interaction with microbial species. 【0072】 The compound of the present invention may be a HDAC inhibitor (「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 for any one of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10, and HDAC11. The compound may be a class 3 selective HDACi, a class 2A selective HDACi, or a class 2B HDACi. 【0073】 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. 【0074】 In some embodiments, the compound inhibits the above HDAC 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. 【0075】 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. 【0076】 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. 【0077】 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. 【0078】 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. 【0079】 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. 【0080】 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. 【0081】 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. 【0082】 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. 【0083】 The IC50 may be measured by an in-vitro enzyme assay such as those described in the Examples. 【0084】 Therefore, in some embodiments, the compounds of the invention may be useful in the treatment of diseases ameliorated by the inhibition of HDAC activity, such as cancer and cardiovascular diseases. 【0085】 In some embodiments, the compounds of the present invention may be useful for the treatment of acute lung injury. In some embodiments, the compounds of the present invention may be useful for the treatment of acute respiratory distress syndrome. In some embodiments, the compounds of the present invention may be useful for the treatment of respiratory fever. In some embodiments, the compounds of the present invention may be useful for the treatment of septic acute lung injury. In some embodiments, the compounds of the present invention may be useful for the treatment of septic acute respiratory distress syndrome. In some embodiments, the compounds of the present invention may be useful for the treatment of septic respiratory failure. Septic acute lung injury or other induced acute lung injury may, in some cases, deteriorate into acute respiratory distress syndrome and respiratory failure. In some particularly preferred embodiments, the compounds of the present invention are HDAC3 inhibitors for use in the treatment of these diseases. 【0086】 Route of administration The agents (i.e., one or more other agents in addition to the compounds described herein) may be formulated together in a single dosage form, or the individual agents may be formulated separately and presented together in the form of a kit, which may be accompanied by instructions for their use. 【0087】 For example, the compounds described herein may, in any aspect and embodiment, be used in combination therapy, for example, in combination with other agents. Such agents may be as follows. 【0088】 Butyrate and PBA Sodium phenylbutyrate is a known drug. For example, sodium phenylbutyrate is marketed under the trade name Buphenyl by Ucyclyd Pharma (Hunt Valley, USA) and as Ammonaps by Swedish Orphan Biovitrum AB (Sweden). It is used to treat urea cycle disorders (Batshaw et al. (2001) J. Pediatr. 138(1 Suppl):S46-54; discussion S54-5). Scandinavian Formulas, Inc., Sellersville, Pennsylvania, supplies sodium phenylbutyrate worldwide for clinical trials. Sodium phenylbutyrate is also being studied for the treatment of some sickle cell disorders (Blood Products Plasma Expanders and Haemostatics), as well as for potential use as a differentiation inducer in malignant glioma and acute myeloid leukemia. Sodium phenylbutyrate has also been studied in relation to cystic fibrosis pathology due to its ability to transport the DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR) to the cell membrane and restore CFTR chloride function in the plasma membrane of CF lung cells in vitro and in vivo (Roque et al., J Pharmacol Exp Ther. September 2008;326(3):949-56. Epub June 23, 2008). Sodium phenylbutyrate is thought in the literature to be a prodrug that is metabolized in the body by β-oxidation to phenylacetic acid. 【0089】 Vitamin D This new class of compounds acts synergistically with vitamin D as represented by pyridin-3-ylmethyl (4-((2-aminophenyl)carbamoyl)benzyl)carbamate. Vitamin D type compounds are discussed in U.S. Patent Application Publication No. 20080038374 or International Publication No. 2008 / 073174 pamphlet. When the term "vitamin D" is used herein, this term includes vitamin D3 (or "1,25D3") and its hormonally active forms and is used broadly to include compounds structurally similar to vitamin D3. Many of these compounds are recognized and include a number of natural precursors, metabolites, and synthetic analogs of the hormonally active 1,25-dihydroxyvitamin D3 (1α25(OH)2D3). This term is intended to include vitamin D3 or its analogs at any stage of the metabolism of vitamin D3, as well as mixtures of different metabolic forms of vitamin D3 or its analogs. 【0090】 Antibiotics The compounds of the present invention are particularly useful against infections by bacterial strains that are resistant to conventional antibiotics. Nevertheless, the use of the compounds described herein in combination with conventional antibiotics, especially narrow-spectrum antibiotics, may be preferred in some cases and forms part of one aspect of the present invention. 【0091】 Exemplary antibiotics include penicillin, penicillin G, phenoxymethyl-penicillin, flucloxacillin, amoxicillin, metronidazole, cefuroxime, augmentin, pivmecillinam, acetomycin, ciprofloxacin, and erythromycin. It will be understood that generally available analogs may be used if these particular antibiotics are mentioned. As noted above, in certain embodiments, it may be preferred to use the compounds described herein in combination with the following known antibiotics. (1) With or without the compound of formula (I) or (Ia), preferably acute administration of the antibiotic to the patient for one or two days, followed by (2) Further administration to the patient of an effective amount of a compound of formula (I) or (Ia) for 2, 3, 4, 5 or more additional days. 【0092】 Such regimens may have the benefit of minimizing the development of antibiotic resistance in the targeted pathogen. 【0093】 Isoleucine and related compounds The amino acid L-isoleucine up-regulates β-defensin expression in bovine epithelial cells (18). U.S. Patent Application Publication No. 2002-0076393 (Fehlbaum et al.); U.S. Patent Application Publication No. 2003-0109582 (Zasloff); U.S. Patent No. 7311925 (Zasloff), in each case relating to the use of isoleucine, its active isomers, and their active analogs for stimulation of the innate antibacterial defense system. 【0094】 The disclosures of all of these references regarding these compounds, their definitions, and their provision are specifically incorporated herein by reference. 【0095】 In addition to one or more of the compounds of the invention, pharmaceutical compositions are also provided that contain vitamin D or one of the other aforementioned compounds as a further component. Such compositions can be formulated into any of the above-described formulations and dosage forms. 【0096】 As described below, oral dosage forms or inhalation dosage forms are preferred. 【0097】 Dosage In certain embodiments of the invention, there is provided a method of treating, preventing or neutralizing a disease described herein in a patient in need thereof, by administering to the patient an effective amount of a compound of the invention described herein. 【0098】 As used herein, the term "therapeutically effective amount" relates to an amount of a compound, or a material, composition or dosage form containing a compound, that is effective to bring about some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired therapeutic regimen. 【0099】 Accordingly, an effective amount in this context would 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 related disease. In some cases, an effective amount would be an amount sufficient to demonstrate (show) antibacterial activity in vivo, for example, by stimulating the synthesis of cathelicidin LL-37 or other naturally occurring antibiotic peptides or proteins, such as defensins (e.g., suppressing or neutralizing downregulation caused by some pathogens). The stimulation may be towards, equal to, or above the basal level (i.e., the normal level in the absence of infection and / or the normal level of epithelial barrier function). 【0100】 As used herein, the term "antibacterial activity" means the ability to inhibit the growth of a population of microorganisms, which may be bacteria, viruses, protozoa or fungi, or to actually kill the microorganisms. Accordingly, "antibacterial activity" should be interpreted to mean both growth-inhibiting (microbistatic) activity and bactericidal activity. Antibacterial activity should also be interpreted to include compounds that can inhibit the ability of an infection, i.e., a microorganism's ability to cause disease. Generally, the use of the present invention is such that it results in the secretion of the relevant peptides onto the epithelial surface. 【0101】 Preferred dosages and dosage forms are described in more detail below. 【0102】 Preferred dosages of type I compounds may be from 25 μg to 2000 mg per day, more preferably from 0.05 mg to 500 mg, more preferably from 0.1 to 250 mg, more preferably from about 0.2 to 100 mg, and more preferably may be about 50 mg or less. 【0103】 Another preferred dosage of the compound of the present invention is a dosage 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. 【0104】 Another preferred dosage of the compound of the present invention is a dosage of at least 50 mg / kg. 【0105】 Another preferred dosage of the compound of the present invention is a dosage 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. 【0106】 A more preferred dosage of the present invention is a range including a starting point 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 and an end point 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. 【0107】 In each case, the dosage can be divided into 1, 2, 3, 4, 5, 6 or 7 dosages per week, or 1, 2 or 3 dosages per day. For example, 1, 2 or 3 times of 3 mg, 5 mg or 10 mg / week, 1 or 2 times of 5 mg or 50 mg / day, or 2 times of 250 mg / week, etc. Preferred regimens are less than 3 times per day, for example, 1 or 3 times of 3 mg / week, 2 times of 1 mg / day or 2 times of 5 mg / week. 【0108】 Preferred dosages may be 0.1 mg to 100 mg, 0.2 mg to 50 mg, 0.2 mg to 20 mg, optionally with vitamin D3. The dosage of vitamin D may be on the order of 1000 to 10000 IU per day. 【0109】 Therefore, preferred dosages can be divided into dosages of 1, 2, 3 or 4 times per week or 1 or 2 times per day. For example, 1 or 3 times of 2 mg / week, 2 times of 0.5 mg / day, etc. 【0110】 The corresponding preferred weight / mole amounts of the other compounds of the present invention can be calculated by those skilled in the art based on the disclosure herein. 【0111】 Each of the amounts disclosed herein and above may be administered as a weekly dosage or a daily dosage. Each weekly dosage may be divided into dosages administered 1, 2 or 3 times, or 4 or more times. Each daily dosage may be divided into dosages administered 1, 2 or 3 times, or 4 or more times. The dosing schedules disclosed herein and above may include, or be consistent with, dosing for a total of 1, 2, 3, 4, 5, 6, 7 days, or a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 weeks. 【0112】 Dosage form The compounds of the present invention are preferably administered in oral dosage forms including, but not limited to, tablets, capsules, solutions, emulsions, suspensions, powders, pastes, elixirs, and syrups. Administration of the compounds can also include incorporation into nanoparticles or ultrafine particles composed of organic and inorganic biocompatible materials, having two- or three-dimensional lengths greater than 0.001 micrometers (1 nanometer) and less than about 0.1 micrometers (100 nanometers). 【0113】 Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as, for example, but not limited to, cellulose, hydroxypropylmethylcellulose, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with an oil such as, for example, but not limited to, arachidonic oil, glycerides, peanut oil, liquid paraffin or olive oil. 【0114】 Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as, for example, but not limited to, lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as, for example, but not limited to, corn starch or alginic acid, binders such as, for example, but not limited to, starch, lubricants such as, for example, but not limited to, magnesium stearate, stearic acid or talc, preservatives such as, for example, but not limited to, ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate, and antioxidants such as, for example, but not limited to, ascorbic acid. Tablets may or may not be coated and may be coated to modify the disintegration of the active ingredient in the gastrointestinal tract and subsequent absorption, or to improve its stability and / or appearance, in which case conventional coating agents and procedures well known in the art may be used, and enteric coating agents having various resistances to intestinal pH and enzymes may also be used. 【0115】 Other dosage forms are also useful and include, but are not limited to, topical dosage forms that are particularly useful for treating skin infections, including, for example, creams, oils, lotions, and ointments. Still further dosage forms include dosage forms for delivery to the respiratory system, including the lungs, such as aerosols and intranasal spray devices or rectal enemas. 【0116】 In some particularly preferred embodiments, the compounds of the present invention are administered as lozenges. Lozenges or troches are pharmaceutical dosage forms that may be particularly effective in treating conditions that affect the tissues and epithelial barriers contained within the oral cavity and larynx. A typical lozenge or troche is primarily composed of an inert vehicle, carrier, or diluent. The compounds of the present invention are dispersed within this carrier. Lozenges dissolve slowly when placed in the oral cavity, thereby releasing the pharmaceutical agent so that it can come into contact with the tissues of the mouth and throat. As used herein, the term "lozenge" encompasses dosage forms in which the product is formed by cooling a sugar-based or sugar alcohol-based (e.g., isomalt) molten mass containing the compound of the present invention. Preferably, the term "molten lozenge-forming composition" encompasses a sugar-based or sugar alcohol-based (e.g., isomalt) molten mass. Lozenges are solid dosage forms that are intended to be sucked by the patient. 【0117】 The compounds of the present invention The compounds of the present invention relate to compounds that can improve the barrier function or block microbial translocation and may induce antimicrobial peptides (AMPs) of the innate immune system. 【0118】 The compounds of the present invention are defined according to Formula I or Ia described herein. Specific preferred embodiments of the compounds are described below. 【0119】 Group Q In the compounds of formula (I) or (Ia), group Q is selected from Q1, Q2, Q3, Q4, Q5 and Q6, 【Chemical formula】 wherein B1 and B 2 (and when present, B 3 , B 4 and B 5 ) one of which is a group of the formula -X-R X and the others are, independently, H and R B selected from. In other words, each possible Q group contains one -X-R X substituent at an available position and the other available positions are either unsubstituted (-H) or substituted with a group -R B . 【0120】 In some preferred embodiments, Q is a phenyl group, Q1, 【Chemical formula】 wherein B 1 , B 2 , B 3 , B 4 and B 5 one of which is a group of the formula -X-R X and the others are, independently, H and R B selected from. 【0121】 In some embodiments, B 3 is a group of the formula -X-R X and B 1 , B 2 , B 4 and B 5 are, independently, H and R B selected from. In some embodiments, B 3 is a group of the formula -X-R X and B 1 , B 2 , B 4 and B 5 are H. Thus, in these embodiments, Q is a group of the following formula. 【Chemical formula】 【0122】 In other embodiments, B 2 is a group of the formula -X-RX is a radical of, B 1 , B 3 , B 4 and B 5 are, independently, H and R B selected from. In still further embodiments, B 1 is a radical of the formula -X-R X and B 2 , B 3 , B 4 and B 5 are, independently, H and R B selected from. 【0123】 In some embodiments, one of B 1 , B 2 , B 3 , B 4 and B 5 is a radical of the formula -X-R X and the others are, independently, H. 【0124】 In some embodiments, B 2 or B 3 is a radical of the formula -X-R X and the others are, independently, H. 【0125】 In some embodiments, B 3 is a radical of the formula -X-R X and the others are, independently, H. 【0126】 In some embodiments, Q is a pyridyl group Q2, Q3 or Q4, 【Chemical formula】 wherein, B 1 , B 2 , B 3 and B 4 one of which is a radical of the formula -X-R X and the others are, independently, H and R B selected from. 【0127】 In some embodiments, B 1 , B 2 , B3 and B 4 One of them is a group of the formula -X-R X and the others are independently H. In some of the above embodiments, X is a covalent bond and R X is -H. 【0128】 In some embodiments, Q is Q2. 【0129】 In some embodiments, Q is Q3. 【0130】 In some embodiments, Q is Q4. 【0131】 In some embodiments, Q is an imidazolyl group Q5, 【Chemical formula】 wherein B 1 and B 2 One of them is a group of the formula -X-R X and the other is selected from H and R B . 【0132】 In some embodiments, B 1 and B 2 One of them is a group of the formula -X-R X and the other is -H. In some of the above embodiments, X is a covalent bond and R X is -H. 【0133】 In some embodiments, Q is an indolyl group Q6, 【Chemical formula】 wherein B 1 , B 2 , B 3 , B 4 and B 5 One of them is a group of the formula -X-R X and the others are independently selected from H and R B . 【0134】 In some embodiments, B 1 , B 2 , B 3 , B 4 and B 4 one of which is a group of the formula -X-R X and the others are independently H. In some of the above embodiments, X is a covalent bond and R X is -H. 【0135】 When the group R B is present, each -R B group is 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. 【0136】 In some embodiments, -R B is selected from halogen (i.e., -F, -Cl, -Br, -I), -CF3, -R, -OH, -OR, -NH2, -NHR, -NR2, -NO2, and -CN. 【0137】 In some embodiments, -R B is selected from -OH, -OR, -NH2, -NHR, and -NR2. 【0138】 In some embodiments, -R B is selected from -OH or -OR. 【0139】 In some embodiments, R B is -OR. 【0140】 In some embodiments, R B is -OMe. 【0141】 In some embodiments, R B is -R. 【0142】 In some embodiments, R B is -Me. 【0143】 The group X-R X The group -X-R X in which X is a covalent bond or C 1~3 selected from alkylene, and R X is H, R XX or R XY selected from. 【0144】 In some embodiments, X is a covalent bond (i.e., the group -X-R X is a group of the formula -R X ). 【0145】 In some embodiments, X is selected from C 1~3 alkylene. 【0146】 In some embodiments, X is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH(CH2CH3)-. 【0147】 In some embodiments, X is -CH2-. 【0148】 In some embodiments, R X is H. 【0149】 In some embodiments, R X is R XX . R XX is 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. 【0150】 In some embodiments, R XXis selected from -OH, -OR, -NO2, -NH2, NHR, and NR2. 【0151】 In some embodiments, R XX is selected from -OR, -NO2, and -NR2. 【0152】 In some embodiments, R XX is -OMe, -NO2, or -NMe2. 【0153】 In some embodiments, R X is R XY where R XY is the group of formula -L X -R YY is a group of the formula. 【0154】 L X is selected from -NH-C(=O)-O-, -NH-C(=O)-NH-, -NH-C(=O)-, -NR-C(=O)-, -O-C(=O)-NH-, -O-C(=O)-O-, -O-(C=O)-, -C(=O)-NH-, -C(=O)-O-, and -C(=O)-. 【0155】 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-. 【0156】 In some embodiments, L X is -NH-C(=O)-O-. In some embodiments, L X is -NH-C(=O)-. In some embodiments, L X is NR-C(=O)-. In some embodiments, L X is -O-(C=O)-. In some embodiments, LX is -C(=O)-NH-. 【0157】 R YY is C 1~4 alkyl, C 3~6 cycloalkyl, -C 6~14 aryl, -L Y -C 6~14 aryl, -L Y -O-C 6~14 aryl, -C 5~6 heteroaryl, -L Y -C 5~6 heteroaryl, -L Y -C 5~6 heteroaryl, -L Y -O-C 5~6 heteroaryl, L Y -O-L Y -C≡N, L Y -O-L Y -C≡R, L Y -O-L Y -C≡CH, -L Y -O-L Y -NR N -C(=O)-R, L Y -O-L Y -NH-C(=O)-R, L Y -O-L Y -NR-C(=O)-R, L Y -C≡N, L Y -C≡R, and L Y selected from -C≡CH, -L Y - is C 1~3 alkylene, and each of said R YY groups may be substituted. 【0158】 In some embodiments, R YY is independently -C 6~14 aryl, -L Y -C 6~14 aryl, -C 5~6 heteroaryl, or -L Y -C 5~6 heteroaryl, and said C 6~14 aryl group and C 5~6 heteroaryl group may be substituted. 【0159】 In some embodiments, R YY is, independently, -Ph, -L Y -Ph, C 5~6 heteroaryl, or -L Y -C 5~6 heteroaryl, and the Ph group and C 5~6 heteroaryl group may be substituted. 【0160】 In some embodiments, R YY is, independently, -L Y -Ph or -L Y -C 5~6 heteroaryl, and the Ph group and C 5~6 heteroaryl group may be substituted. 【0161】 In some embodiments, R YY is, independently -L Y -C 6~14 aryl, and the C 6~14 aryl may be substituted. 【0162】 In some embodiments, R YY is, independently -L Y -Ph, and the Ph may be substituted. 【0163】 In some embodiments, R YY is, independently, -L Y -C 5~6 heteroaryl, L Y -O-L Y -C≡CH, L Y -O-L Y -NH-C(=O)-R, L Y -C≡R, L Y -C≡CH. 【0164】 In some embodiments, -L Y- is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, and -CH(CH2CH3)-. 【0165】 In some embodiments, -L Y - is independently -CH2-. 【0166】 In some embodiments, each of said R YY groups is -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- and may be substituted with one or more substituents selected from, L YY is C 1~3 alkylene. 【0167】 In some embodiments, each of said R YY groups is -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- and may be substituted with one or more substituents selected from, L YY is C 1~3 alkylene. 【0168】 In some embodiments, each of said R YY groups is -NH2, -NHR, -NR2, -L YY -CO2H, and -L YYOptionally substituted with one or more substituents selected from -CO2R, L YY is C 1~3 alkylene. 【0169】 In some embodiments, R YY is independently -L Y -Ph, where said Ph is -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- and is substituted with one or more substituents selected therefrom, L YY is C 1~3 alkylene. 【0170】 In some embodiments, R YY is independently -L Y -Ph, where said Ph is substituted with one or more substituents selected from -NH2, -NHR, and -NR2. 【0171】 In some embodiments, R YY is independently -C 5~6 heteroaryl, where said C 5~6 heteroaryl is -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- and is substituted with one or more substituents selected therefrom, L YY is C 1~3 alkylene. 【0172】 In some embodiments, R YY is independently -C5~6 is heteroaryl, and said C 5~6 The heteroaryl is -L YY - is substituted with -CO2R. 【0173】 In some embodiments, -L YY - is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, and -CH(CH2CH3)-. 【0174】 In some embodiments, -L YY - is independently -CH2-. 【0175】 Linker L In the compound of formula (I) or (Ia), the linker group L is -(CH2) m -, -C(=O)-, -(CH2) m -C(=O)-, -O-(CH2) m -C(=O)-, -O-C(=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)-, and m is an integer from 1 to 4. 【0176】 In some embodiments, L is -(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)-selected from 【0177】 In some embodiments, L is -(CH2) m -, -C(=O)-, -NH-C(=O)-, and -NR-C(=O)-selected from 【0178】 In some embodiments, L is -C(=O)-. Accordingly, the compound may be a compound of formula (II). 【Chemical formula】 【0179】 In some embodiments, L is -C(=O)-NH-(CH2) m -C(=O)-. Accordingly, the compound may be a compound of formula (III). 【Chemical formula】 【0180】 In some embodiments, L is -(CH2) m -(CHR L )-C(=O)-, and R L is as defined herein. Accordingly, the compound may be a compound of formula (IV). 【Chemical formula】 【0181】 When the group R L is present, for example, in a compound of formula (Ic), the group R L is halogen, -R LL , -CF3, -OH, -OR LL , -NO2, -NH2, -NHR LL , -NR2, -NH-C(=O)-R LL , -NH-C(=O)-O-R LL selected from 【0182】 In some embodiments, R L is -NH2, -NHR LL , -NH-C(=O)-R LL and -NH-C(=O)-O-R LL is selected from, and R LL is as previously defined. 【0183】 In some embodiments, R L is NH2. 【0184】 In some embodiments, R L is -NHR LL is. 【0185】 In some embodiments, R L is -NH-C(=O)-O-R LL is. 【0186】 R LL is -C 1~4 alkyl, -C 3~6 cycloalkyl, -Ph, -L L -Ph, -C 5~6 heteroaryl, and -L L -C 5~6 heteroaryl is selected from, and -L L is C 1~3 alkylene, and the -Ph and -C 5~6 heteroaryl may be substituted. 【0187】 In some embodiments, the -Ph and -C 5~6 heteroaryl may be substituted with one or more groups selected from -F, -Cl, -Br, -I, -R, -CF3, -OH, -OR, -OCF3, -NO2, -NH2, -NHR, -NR2, -CO2H, -CO2R. 【0188】 In some embodiments, R LL is -Ph, -L L -Ph, -C 5~6 heteroaryl, and -L L -C 5~6It is selected from heteroaryl. 【0189】 In some embodiments, R LL is -L L -Ph and -L L -C 5~6 is selected from heteroaryl. 【0190】 In some embodiments, R LL is -L L -Ph. 【0191】 In some embodiments, R LL is -CH2-Ph(-Bn). 【0192】 L L is C 1~3 selected from alkylene. 【0193】 In some embodiments, L L is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH(CH2CH3)-. 【0194】 In some embodiments, L L is -CH2- or -CH2CH2. 【0195】 In some embodiments, L L is -CH2-. 【0196】 The group R N R N is selected from H and optionally substituted C 1~4 alkyl. 【0197】 In some embodiments, R N is H. 【0198】 In some embodiments, R N is C 1~4 alkyl. 【0199】 In some embodiments, R N is C 1~4 When the alkyl is alkyl, the C 1~4 alkyl may be substituted with one or more substituents R N1 , and each R N1 is independently selected from halogen, -CF3, -R, -OH, -OR, -OCF3, -NH2, -NHR, -NR2, -NO2 and -CN, and each R is independently C 1~4 alkyl. 【0200】 In some embodiments, R N1 is independently selected from -OH, -OR, -NH2, -NHR, -NR2. 【0201】 In some embodiments, R N1 is OH or NH2. 【0202】 In some embodiments, R N1 is NH2. 【0203】 In some embodiments, R N is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, and may be substituted. 【0204】 In some embodiments, R N is ethyl and may be substituted. 【0205】 In some embodiments, R N is ethyl substituted with at least one R N1 . 【0206】 In some embodiments, R N is -CH2CH2NH2. 【0207】 Group A 1 , A 2 , A 3 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form an optionally substituted C 6~14 aryl group. 【0208】 In some embodiments, said C 6~14 aryl group may be substituted with one or more substituents R A2 , and each R A2 is 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. 【0209】 In some embodiments, R A2 is independently selected from -R, -OH, -OR, -OCF3, -NO2, -NH2, -NHR, -NR2 and -CN. 【0210】 In certain embodiments, R A2 is independently -R. 【0211】 In certain embodiments, R A2 is independently methyl. 【0212】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form an optionally substituted phenyl group. Accordingly, the compound may be a compound of formula (V). 【Chemical formula】 【0213】 In some embodiments, A 1 and A 2Together with the atoms to which they are attached, they form an optionally substituted naphthalene group. Accordingly, the compound may be a compound of formula (VI). 【Chemical formula】 【0214】 In the compounds of formulas (V) and (VI), the phenyl ring and the naphthalene ring are optionally substituted with one or more of the substituents R A2 as defined above. 【0215】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form an unsubstituted phenyl group or naphthalene group. 【0216】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form an unsubstituted phenyl group. 【0217】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form a phenyl group substituted with one or more substituents R A2 as defined above. 【0218】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form a phenyl group substituted with two substituents R A2 as defined above. 【0219】 A 3 , when present, is selected from H and optionally substituted C 1~4 alkyl. 【0220】 In some embodiments, A 3 is H. 【0221】 In some embodiments, A3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 【0222】 In some embodiments, A 3 is methyl or ethyl. 【0223】 In some embodiments, A 3 is methyl. 【0224】 n is selected from 0 and 1. When n is 0, A 3 (and the atom to which it is attached) does not exist. In some embodiments, n is 0. In some embodiments, n is 1. 【0225】 Therefore, the compound may be a compound of formula (VII). 【Chemical formula】 【0226】 Group R Each "R" used throughout these definitions is independently a C 1~4 alkyl group. 【0227】 In some embodiments, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. 【0228】 In some embodiments, R is methyl or ethyl. 【0229】 In some embodiments, R is methyl. 【0230】 Certain preferred embodiments In some embodiments, A 1 and A 2 , together with the atom to which they are attached, have one or more substituents R A2which may form a phenyl ring optionally substituted with n is 0, R N is H. 【0231】 Therefore, the compound is a compound of formula (VIII), 【Chemical formula】 wherein Q, L and R A2 are as defined hereinbefore. 【0232】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached, form a phenyl ring optionally substituted with one or more substituents R A2 n is 0, R is H, N and L is C(=O). 【0233】 Therefore, the compound is a compound of formula (IX), 【Chemical formula】 wherein Q and R A2 are as defined hereinbefore. 【0234】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached, form a phenyl ring optionally substituted with one or more substituents R A2 n is 0, R is H, N L is C(=O), Q is Q1, and B 3 is X-R X 【0235】 Therefore, the compound is a compound of formula (X),​​​ 【Chem.】 In the formula, X, R X , B 1 , B 2 , B 4 , B 5 and R A2 are as defined heretofore. 【0236】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form a phenyl ring, n is 0, R N is H, L is C(=O), Q is Q1, and B 3 is X-R X , B 1 , B 2 , B 4 and B 5 are all H. 【0237】 Therefore, the compound is a compound of formula (XI), 【Chem.】 In the formula, X and R X are as defined heretofore. 【0238】 In some embodiments, A 1 and A 2 together with the atoms to which they are attached form a phenyl ring, n is 0, R N is H, and Q is Q1. 【0239】 Therefore, the compound is a compound of formula (XII), 【Chem.】 In the formula, B 1 、B 2 、B 3 、B 4 、B 5 and L are as defined heretofore. 【0240】 In some embodiments, A 1 and A 2 together with the atom to which they are attached form a phenyl ring, n is 0, R N is H, Q is Q1, and B 3 is X-R X and B 1 、B 2 、B 4 and B 5 are all H. 【0241】 Therefore, the compound is a compound of formula (XIII), 【Chemical formula】 In the formula, X, R X and L are as defined heretofore. 【0242】 Specific compounds In some embodiments, the compound is selected from the following. 【0243】 【Table 1】 【0244】 Definition As used herein, the term "alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a saturated aliphatic hydrocarbon compound, which may be linear or branched, preferably a monovalent moiety obtained by removing a hydrogen atom from a saturated aliphatic hydrocarbon compound having 1 to 4 carbon atoms ("C 1~4 alkyl"). 【0245】 C 1~4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain examples, a methyl group or an ethyl group may be preferred. 【0246】 Similarly, the term "alkylene" refers to a divalent moiety obtained by removing two hydrogen atoms from a saturated aliphatic hydrocarbon compound, which may be linear or branched, preferably a divalent moiety obtained by removing two hydrogen atoms from a saturated aliphatic hydrocarbon compound having 1 to 3 carbon atoms ("C 1~3 alkylene"). 【0247】 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)-. 【0248】 As used herein, the term "cycloalkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a saturated alicyclic hydrocarbon compound, preferably a monovalent moiety obtained by removing a hydrogen atom from a saturated alicyclic hydrocarbon compound having 3 to 6 ring atoms ("C 3~6 cycloalkyl"). 【0249】 C 3~6 Examples of cycloalkyl groups include 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, but are not limited thereto. 【0250】 The term "C 6~14"Aryl", as used herein, C 6~14 is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, said compound having one ring, or two or more rings (e.g., fused), having 6 to 14 ring atoms, and at least one of said rings being an aromatic ring. Preferably, each ring has 6 to 10 ring atoms. The term "C 6~14 aromatic ring" may also be used and should be construed in the same manner, which may refer to a polyvalent moiety. 【0251】 The ring atoms may all be carbon atoms, as in the case of a "carboaryl group", in which case this group may be conveniently referred to as a "C 6~14 carboaryl" group. 【0252】 C 6~14 Examples of carboaryl groups include those derived from benzene (i.e., phenyl) (C6), those derived from naphthalene (C 10 ), those derived from anthracene (C 14 ), and those derived from phenanthrene (C 14 ), but are not limited thereto. 【0253】 Examples of aryl groups containing a fused ring where one of the fused rings is not an aromatic ring include groups derived from indene and fluorene, such as 【Chemical formula】 but are not limited thereto. 【0254】 The term "heteroaryl", as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a heteroaromatic compound, i.e., a compound containing at least one aromatic ring having at least one heteroatom in the ring atoms. Possible heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur. Preferably, the aromatic ring has 5 to 6 ring atoms, 0 to 4 of which are ring heteroatoms. In this case, this group is a "C5~6 referred to as a "heteroaryl" group, and "C" 5~6 ", whether a carbon atom or a heteroatom, represents a ring atom. 【0255】 C 5~6 Examples of heteroaryl groups include C5 heteroaryl groups derived from furan (oxole), thiophene (thiole), pyrrole (azole), imidazole (1,3-diazole), pyrazole (1,2-diazole), 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-diazine), pyrimidine (1,3-diazine, such as cytosine, thymine, uracil), pyrazine (1,4-diazine), triazine, tetrazole, and oxadiazole (furazan), but are not limited thereto. 【0256】 The term "halo" or "halogen" refers to -F, -Cl, -Br, and -I substituents. Fluoro (-F) and chloro (-Cl) substituents are usually preferred. 【0257】 Isomers, salts, solvates, and protected forms A particular compound may exist as one or more specific geometric isomers, optical isomers, enantiomers, diastereomers, epimers, stereoisomers, tautomers, conformational isomers, or anomeric forms, including but not limited to cis and trans isomers, E and Z isomers, c, t and r isomers, endo and exo isomers, R, S and meso isomers, D and L isomers, d and l isomers, (+) and (-) isomers, keto, enol, and enolate isomers, syn and anti isomers; synclinal and anticlinal isomers, α and β isomers, axial and equatorial forms, boat, chair, twist, envelope, and half-chair forms, and combinations thereof, which are collectively referred to hereinafter as "isomers" (or "isomeric forms"). 【0258】 It should be noted that, except where tautomers are discussed below, structural (or constitutional) isomers (i.e., isomers that differ not merely in the position of atoms in space but in the connections between atoms) are specifically excluded from the term "isomers" as used herein. For example, reference to a methoxy group, -OCH3, should not be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl. However, reference to a class of structures may include structurally isomeric forms that fall within that class (e.g., C 1~7 Alkyl includes n-propyl and isopropyl, butyl includes n-butyl, iso, sec-butyl and tert-butyl, and methoxyphenyl includes ortho-methoxyphenyl, meta-methoxyphenyl and para-methoxyphenyl). 【0259】 The above exclusions are not related to tautomeric forms, such as keto forms, enol forms, and enolate forms, for example, in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro. 【Chemical formula】 【0260】 It should be noted that the term "isomer" specifically includes compounds having one or more isotope substitutions. For example, H can be 1 H, 2 H(D), and 3 H(T) in any isotopic form, C can be 12 C, 13 C, and 14 C in any isotopic form, O can be 16 O and 18 O in any isotopic form, and so on. 【0261】 Unless otherwise specified, references to a particular compound include all such isomeric forms, including (fully or partially) racemates and other mixtures. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are known in the art or can be readily obtained by adapting known methods in a known manner or by methods taught herein. 【0262】 Unless otherwise specified, references to a particular compound also include its ionic forms, salt forms, solvate forms, and protected forms, as discussed, for example, below. 【0263】 It may be convenient or desirable to prepare, purify, and / or handle the corresponding salts of the active compound, for example, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., J. Pharm. Sci., 66, 1-19 (1977). 【0264】 For example, if the compound is anionic or has a functional group that may be anionic (e.g., -COOH may be -COO - ), a salt may be formed with a suitable cation. Examples of suitable inorganic cations include alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ , but are not limited thereto. Examples of suitable organic cations include ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + , NH2R2 + , NHR3 + , NR4 + ), but are not limited thereto. Examples of some 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 + . 【0265】 If the compound is cationic or has a functional group that may be cationic (e.g., NH2 may be -NH3 +When it has (it may also be), an appropriate anion and a salt may be formed. 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, phenylsulfonic 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 polymeric (macromolecular) anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. 【0266】 It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvates of the active compound. The term "solvate" is used herein in its conventional meaning to refer to a complex of a solute (e.g., an active compound, a salt of an active compound) and a solvent. When the solvent is water, the solvate may be conveniently referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc. 【0267】 It may be convenient or desirable to prepare, purify, and / or handle the active compound in a chemically protected form. As used herein, the term "chemically protected form" refers to a compound in which one or more reactive functional groups are protected from unwanted chemical reactions, i.e., in the form of a protected group or protecting group (also known as a masked group or masking group, or a blocked group or blocking group). By protecting the reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group, and the protecting group can usually be removed in a subsequent step without substantially affecting the other parts of the molecule. See, e.g., Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1999). 【0268】 For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), e.g., as a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc). 【0269】 For example, an aldehyde group or a ketone group may each be protected as an acetal or a ketal, respectively, where the carbonyl group (>C=O) is converted to a diether (>C(OR)2), e.g., by reaction with 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. 【0270】 For example, an amino group may be protected as an amide or urethane, such as methylamide (-NHCO-CH3); benzyloxyamide (-NHCO-OCH2C6H5, -NH-Cbz); t-butoxyamide (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc); 9-fluorenylmethoxyamide (-NH-Fmoc); 6-nitroveratryloxyamide (-NH-Nvoc); 2-trimethylsilylethyloxyamide (-NH-Teoc); 2,2,2-trichloroethyloxyamide (-NH-Troc); allyloxyamide (-NH-Alloc); 2-(phenylsulfonyl)ethyloxyamide (-NH-Psec); or, where appropriate, as an N-oxide (>N-O·). 【0271】 For example, a carboxylic acid group may be protected as an ester, such as a C 1~7 alkyl ester (e.g., methyl ester, t-butyl ester), a C 1~7 haloalkyl ester (e.g., a C 1~7 trihaloalkyl ester), a tri-C 1~7 alkylsilyl-C 1~7 alkyl ester, or a C 5~20 aryl-C 1~7 alkyl ester (e.g., benzyl ester, nitrobenzyl ester), or as an amide, such as methylamide. 【0272】 For example, a thiol group may be protected as a thioether (-SR), such as benzyl thioether; acetamidomethyl ether (-S-CH2NHC(=O)CH3). 【0273】 Any subheadings in this specification are included for convenience only and should in no way be construed as limiting the disclosure. 【0274】 The present invention will now be further described with reference to the following non-limiting figures and examples. Other embodiments of the invention will be apparent to those skilled in the art in light of these. 【0275】 To the extent that the disclosures of all references cited herein may be used by those skilled in the art to practice the present invention, the disclosures of all references cited herein are specifically incorporated herein by cross-reference. 【Example】 【0276】 Methods and Materials MN8CampLuc cells were treated according to Nylen et al., except for the following exceptions when pre-differentiation of the cells was induced prior to treatment. 【0277】 Glucose, which is known to promote differentiation in colonic epithelial cells (Pinto, M., M.D. Appay, P. Simon-Assman, G. Chevalier, N. Dracopoli, J. Fogh, and A. Zweibaum, 1982, Biol. Cell., 44:193-196), was replaced with galactose (5 mg / ml) and the cells were seeded in the medium. The cells were then grown for 72 hours and then stimulated with the test compound. 【0278】 RT-PCR experiments were performed according to Nylen et al. (Nylen 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.). 【0279】 RT-PCR experiments on the expression of marker genes for autophagy in HEK-293 cells were measured by real-time PCR. The data were normalized by the expression of the 18s rRNA housekeeping gene. For immunofluorescence spectroscopy experiments, HEK-293 cells were fixed after treatment with inducer or control. The cells were then stained with DAPI to visualize the nucleus (blue), immunolabeled with anti-LC3, and subsequently Alexa-fluor488 (green) was added. Scale bar = 10 μm. 【0280】 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 ( 1 400 MHz for H and 13 101 MHz for C), with the residual solvent signal as the chemical shift reference. Mass spectra were recorded on a Micromass LCT (ESI-TOF) mass spectrometer. Pyridin-3-ylmethyl (4-((2-aminophenyl)carbamoyl)benzyl)carbamate (5, enzastaurin) and N1-hydroxy-N8-phenyloctanediamide (12, vorinostat) were purchased from LC laboratories (Woburn, Massachusetts, USA), N-(4-methoxybenzyl)-1,2-benzenediamine (16) was purchased from Fluorochem Ltd (Hadfield, UK), and trichostatin A (19) was purchased from Sigma-Aldrich Sweden AB (Stockholm, Sweden). 【0281】 Example 1. Synthesis of the compounds according to the invention Exemplary syntheses are provided below. The compounds of the invention may also be synthesized by other methods known in the art. 【0282】 Compound 1 may be synthesized as follows. 【Chemical formula】 Step A: To a solution of 2 (1 eq) in acetonitrile, CDI (1.2 eq) was added. The reaction mixture was stirred at room temperature for 40 minutes, 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. Purification of the residue by column chromatography on silica gel gave 3. 【0283】 Step B: To a solution of 3 in dichloromethane, TFA (10 eq) was added. The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was crystallized from hexane to give 4. 【0284】 Step C: To a solution of 4 in DMF, triethylamine (2 eq) and HATU (1.1 eq) were added, 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. 【0285】 Step D: To a solution of 6 in dichloromethane, TFA (10 eq) was added. 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 about 8 with an aqueous solution of sodium bicarbonate. The precipitated product was isolated by simple filtration, washed with water, and dried to give Compound 1. 【0286】 The analytical data of Compound 1 are shown in Figures 7 and 8. 【0287】 Compound 2.1 may be synthesized as follows. 【Chemical Structure】 Procedure F: To a solution of 6 (3 g, 26.3 mmol) in dry DMF (50 mL) were 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 minutes. 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 solution (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give crude 7. After column chromatography (H:EA = 1:1), pure ester 7 was obtained (5.55 g, 76%). 【0288】 Procedure 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 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 pure acid 8 (4.65 g, 88%). 【0289】 Procedure H: To a solution of 8 (4.65 g, 17.8 mmol) in dry THF (50 mL) were 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 minutes. 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 give crude 10. After column chromatography (H:EA = 1:4), pure ester 10 was obtained (5.6 g, 70%). 【0290】 Procedure I: To a solution of 10 (5.6 g, 12.4 mmol) in dry dioxane (60 mL) was added HCl / dioxane (60 mL), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with MTBE (100 mL), the solid was filtered off and dried under reduced pressure to give Compound 2.1 as the HCl salt. 【0291】 Procedure J: Compound 2.1 HCl salt (2 g) was dissolved in an aqueous NaHCO3 solution (50 mL) and extracted with DCM (3×30 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give Compound 2.1. 【0292】 The analytical data of Compound 2.1 are shown in Figures 9 and 10. 【0293】 Compound 2.2 may be synthesized as follows. 【Chemical formula】 Procedure K: To a solution of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetic acid (3 g, 13.7 mmol) in dry DMF (50 mL) were 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 minutes. 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, 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 product 11. After column chromatography (H:EA = 1:1), pure ester 11 was obtained (3 g, 57.5%). 【0294】 Procedure L: To a solution of 11 (3 g, 7.89 mmol) in dry 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 off and dried under reduced pressure to give 12 as the HCl salt. 【0295】 Procedure M: To a suspension of 12 (1.8 g, 5.7 mmol) in dry 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%). 【0296】 Procedure 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 pure acid 14 (0.4 g, 25%). 【0297】 Procedure O: To a solution of 14 (0.4 g, 1.2 mmol) in dry THF (10 mL) were 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 minutes. 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 (10%, 100 mL), and aqueous NaHCO3 (100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give pure 15 (0.5 g, 75%). 【0298】 Procedure P: To a solution of 15 (0.5 g, 0.98 mmol) in dry dioxane (10 mL) was added HCl / dioxane (10 mL), and the reaction mixture was stirred at room temperature overnight. Then the resulting mixture was diluted with MTBE (100 mL), the solid was filtered off, and dried under reduced pressure to give compound 2.2 as the HCl salt. 【0299】 The analytical data of Compound 2.2 are shown in Figures 11 and 12. 【0300】 Compound 2.3 may be synthesized as follows. 【Chemical formula】 Step A: To a solution of 2 (3 g, 21.7 mmol) in dry THF (50 mL) were 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 minutes. Then, tert-butyl (2-aminophenyl) carbamate (1) (5 g, 23.9 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Thereafter, 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 (2.65 g) of crude product 3. After column chromatography (H:EA = 1:1), pure 3 was obtained (2.65 g). 【0301】 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 dry DMF (30 mL) was added DCC (2.43 g, 12 mmol), and the reaction mixture was stirred at room temperature overnight. Then, the resulting mixture was quenched with water and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with aqueous NaHCO3 solution and brine. Then, it was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (CHCl3:MeOH = 24:1) to obtain pure 5 (1.5 g). 【0302】 Procedure C: To a solution of 5 (1.5 g, 3.55 mmol) in dry dioxane (10 mL) was added HCl / dioxane (20 mL), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was then diluted with MTBE (50 mL), the solid was filtered off and dried under reduced pressure to give compound 2.3 as the 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 give compound 2.3. 【0303】 The analytical data of compound 2.3 are shown in Figures 13 and 14. 【0304】 Example 2. Escherichia coli mouse infection model Compound 1 was orally administered to a mouse model of Escherichia coli infection at 25 mg / kg, 73.5 mk / kg and 50 mg / kg. Compound 1 achieved the research goal of reducing the number of colony-forming units in colonic tissue by 3 log 10 times compared to vehicle-treated animals. 【0305】 Unexpectedly, 1) the number of colony-forming units in the liver and spleen was found to be higher than expected (on the order of 2 - 3 log 10 ), and 2) compound 1 was found to have the unexpected effect of completely knocking out the translocation of bacteria to these organs. 【0306】 Example 3: Evaluation of further compounds of the present invention Further compounds were newly designed (compounds 2.1, 2.2 and 2.3), and variants of compound 1 were synthesized. 【0307】 Compounds 2.1, 2.2 and 2.3 were tested for the induction of antimicrobial peptides in human cell lines. The experiments resulted in a dose-dependent induction fold for the expression of the CAMP gene (encoding human cathelicidin), as shown in Figure 2. 【0308】 Example 4: Comparison of compound 1 with HO13 and HO56 After comparison with HO53 and HO56 (Myszor, I.T., Parveen, Z., Ottosson, H. et al., Novel aroylated phenylenediamine compounds enhance antimicrobial defense and maintain airway epithelial barrier integrity. Sci Rep 9, 7114 (2019). https: / / doi.org / 10.1038 / s41598-019-43350-z), Compound 1 was selected as a particularly preferred embodiment of the present invention. [Chemical formula] 【0309】 Table 1 below shows the comparison data of the above three compounds. An important feature of Compound 1 versus HO53 and HO56 is that Compound 1 exhibits unexpectedly high affinity (permeability) in Caco-2 cell studies. Caco-2 cells are used as a model of the intestinal epithelial barrier. Therefore, this result indicates that the compounds of the present invention are particularly beneficial for treating diseases that can be treated by improving or restoring gastrointestinal barrier function and / or preventing or reducing microbial translocation through the gastrointestinal barrier. 【0310】 [Table 2] 【0311】 Example 5: Results of the mouse model A mouse model was prepared to mimic chemically induced febrile neutropenia. A schematic diagram of the experimental model is shown in Figure 3. 【0312】 The results of this experiment are shown in Tables 2-7 and Figures 4 and 5. Specific observations include the following. · The animals were clearly normal in the naive and Compound 1 and enchinostat treatment groups. Vehicle control animals were observed to be lethargic on day 7. · Clinical symptoms were consistent with efficacy. · The CFU load in the blood was below the limit of quantification (BLOQ) in all groups on days 5 and 6. · Compound 1 showed a significant dose-dependent antibacterial effect in the liver and blood on day 7 when compared to their corresponding vehicle controls (p < 0.05). · Bacteria were below the limit of quantification (BLOQ) in animals treated with enoxacin and compound 1 (50 mg / kg) on day 7. · Colonies recovered from the plates were confirmed for enterotoxigenic E. coli by RT-PCR. 【0313】 【Table 3】 【0314】 【Table 4(1)】 【Table 4(2)】 【0315】 【Table 5】 【0316】 【Table 6】 【0317】 【Table 7】 【0318】 【Table 8】 【0319】 Example 6: RT-PCR data: RNA extraction: RNA was extracted from representative bacterial colonies on the plate using the Nucleo-pore® RNASure® Mini Kit. The final volume of the eluted RNA was 30 μl. Furthermore, these sample RNAs were processed for qRT-PCR. 【0320】 Quantitative real-time polymerase chain reaction (qRT-PCR): The obtained equal-volume RNAs were used for the qRT-PCR reaction setup, and the RNA-direct™ SYBR® Green Realtime PCR Master Mix kit was used. Additional samples were analyzed on a QuantStudio™ 3 real-time PCR system. 【0321】 Results: As shown in Table 8 and Figure 6, the RT-PCR data confirm that the colonies recovered from the plate are enterotoxigenic Escherichia coli. 【0322】 【Table 9】 【0323】 Example 7: Overview of the experiment · Oral administration of a vancomycin-resistant pathogenic strain of Escherichia coli to infect mice simplified the process of determining the mechanism by which Compound 1 exerts its effect on the pathogenic process. All bacteria that grew and were detected in these experiments are not commensal bacteria because they die and do not grow on bacterial plates with vancomycin. 【0324】 · Compound 1 does not act as an antibiotic, nor does it stimulate the production of these natural antibacterial agents to the extent that the natural antibacterial agents function as general antibiotics. This is demonstrated by the fact that viable vancomycin-resistant Escherichia coli present in the colon and ileum at the end of the experiment still exist (Figure 1). The Escherichia coli load in the intestine decreased by nearly 3 logs compared to the control, indicating that the growth of Escherichia coli is attenuated, perhaps through stimulation of natural antibacterial peptide production. This is supported by in vitro data demonstrating that Compound 1 is not toxic to bacteria in culture and that natural antibacterial peptides function like general antibiotics only at supra-physiological concentrations. 【0325】 · Figure 1 also shows that the inhibition of the translocation of vancomycin-resistant Escherichia coli to the liver and spleen is not dose-dependent for Compound 1. In contrast, Compound 1 shows dose-dependence in attenuating Escherichia coli growth in the colon and ileum. Therefore, it is unlikely that Compound 1 inhibits the translocation of Escherichia coli to these organs solely due to its ability to stimulate the production of antibacterial peptides. The most likely explanation is the ability of Compound 1 and related compounds to stimulate and enhance cell-cell contact, as demonstrated by in vitro cell culture experiments. This is supported by the data shown in Figure 4. This experiment was carried out in the presence of cyclophosphamide, which is known to cause febrile neutropenia due to the translocation of bacteria to vital organs. In Figure 4, lower concentrations of Compound 1 (5 mg / kg) have little to no effect on bacterial translocation, while higher concentrations (50 mg / kg) completely inhibit bacterial translocation. 【0326】 · In summary, these data suggest that two cooperating but distinct mechanisms are responsible for the action of Compound 1 against Escherichia coli pathogenicity in the intestine. First, the ability of Compound 1 to weaken bacterial growth, and second, the ability of Compound 1 to inhibit bacterial translocation. 【0327】 Example 8: HDAC Inhibition Data The objective of this study is to determine the effect of Compound 1 on the enzymatic activities of recombinant human HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 using in vitro enzyme assays. 【0328】 The materials were as follows. HDAC Assay Buffer (BPS catalog number 50031) HDAC Assay Developer (BPS catalog number 50030) HDAC Substrate 3 (BPS number 50037) HDAC Class 2a Substrate 1 (BPS number 50040) TSA was purchased from Selleck (Houston, Texas, catalog number S1045) SAHA was purchased from Cayman Chemicals (Ann Arbor, Michigan, catalog number 10009929) 【0329】 The compounds were as follows. 【Table 10】 * Reference compound 【0330】 The experimental conditions were as follows. 【Table 11】 【0331】 The assay conditions were as follows. 【0332】 All compounds were dissolved in DMSO. A series of dilutions of the compounds were prepared in 10% DMSO in HDAC assay buffer, and 5 μl of the dilution was added to 50 μl of the reaction to make the final concentration of DMSO 1% in all reactions. The compounds were pre-incubated in duplicate for 30 minutes at room temperature in a mixture containing HDAC assay buffer, 5 μg of BSA, HDAC enzyme and the test compound. After 30 minutes, the enzyme reaction was initiated by adding the HDAC substrate to a final concentration of 20 μM or 2 μM. The enzyme reaction was allowed to proceed at 37 °C for 30 minutes. After the enzyme reaction, 50 μl of 2× HDAC Developer was added to each well for the HDAC enzyme, and the plate was incubated at room temperature for an additional 15 minutes. Fluorescence intensity was measured at an excitation of 360 nm and emission of 460 nm using a Tecan Infinite M1000 microplate reader. 【0333】 Data analysis was as follows. 【0334】 The HDAC activity assay was performed twice at each concentration. Fluorescence intensity data were analyzed using computer software, Graphpad Prism. The fluorescence intensity (Ft) in each data set in the absence of the compound was defined as 100% activity. The fluorescence intensity (Fb) in each data set in the absence of HDAC was defined as 0% activity. The percent activity 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 the compound). Then, the values of % activity for the series of compound concentrations were plotted using non-linear regression analysis of a sigmoid dose-response curve generated using the formula Y = B + (T - B) / 1 + 10^((LogEC50 - X) × Hill slope) (where Y = percent activity, B = minimum percent activity, T = maximum percent activity, X = logarithm of the compound, and Hill slope = slope coefficient or Hill coefficient). The IC50 value was determined by the concentration that caused the maximum half percent activity. 【0335】 A summary of the effect of the compounds on HDAC activity is as follows. 【0336】 【Table 12】 【0337】 References 1. Original Articles Epidemiology | Volume 23, Issue 7, pp. 1889 - 1893, July 1, 2012 2. International Publication No. WO 2015 / 063694 Pamphlet 3. Yolanda M. Jacobo - Delgado et al., Peptides, Volume 142, 2021, 170580, https: / / doi.org / 10.1016 / j.peptides.2021.170580 4. Hatakeyama S et al., J Periodontal Res. April 2010;45(2):207 - 15. doi:10.1111 / j.1600 - 0765.2009.01219.x 5. International Publication No. WO 2012 / 140504 Pamphlet 6. StatPearls[Internet]. Treasure Island (FL): StatPearls Publishing; Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia. In: StatPearls [Updated February 10, 2022]. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK541102 / 7. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. February 1966;64(2):328 - 40. doi:10.7326 / 0003 - 4819 - 64 - 2 - 328. PMID:5216294 8. Meza L, Baselga J, Holmes FA, Liang B, Breddy J, Pegfilgrastim Study Group (2002) Incidence of febrile neutropenia (FN) is directly related to duration of sever neutropenia (DSN) after myelosuppressive chemotherapy. Proc Am Soc Clin Oncol 21:Abstract 2840 9. Lyman GH, Lyman CH, Agboola O, ANC Study Group (2005) Risk models for predicting chemotherapy-induced neutropenia. Oncologist 10:427-437 10. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, 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 to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 42:2433-2453 11. Chelakkot, C., Ghim, J., & Ryu, S. H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 50, 1 - 9 (2018). https: / / doi.org / 10.1038 / s12276-018-0126-x 12. Taur Y, Pamer EG. The intestinal microbiota and susceptibility to infection in immunocompromised patients. Curr Opin Infect Dis. August 2013;26(4):332 - 7. doi:10.1097 / QCO.0b013e3283630dd3. PMID:23806896; PMCID:PMC4485384. 13. JAMA. February 23, 2016;315(8):801 - 810 14. Shock. July 2016;46(1):52 - 59 15. Crit Care Med. 2011;32:626 - 638) 16. Biochem Med (Zagreb) 2013;23:107 - 111 17. Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (eds) Cancer Management: A Multidisciplinary Approach. In Ridge JA, Glisson BS, Lango MN et al., "Head and Neck Tumors" in the 11th Edition 2008 18. Precision Medicine for Investigators, Practitioners and Providers, 2020 19. Batshaw et al. (2001) J. Pediatr. 138(1 Suppl):S46 - 54; discussion S54 - 5 20. Roque et al., J Pharmacol Exp Ther. September 2008;326(3):949-56. Epub June 23, 2008 21. US Patent Application Publication No. 20080038374 22. International Publication No. WO 2008 / 073174 Pamphlet 23. US Patent Application Publication No. 2002-0076393 24. US Patent Application Publication No. 2003-0109582 25. US Patent No. 7311925 26. Berge et al., J.Pharm.Sci., 66, 1-19(1977). 27. Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1999) 28. Pinto, M., M.D. Appay, P. Simon-Assman, G. Chevalier, N. Dracopoli, J. Fogh and A. Zweibaum, 1982, Biol.Cell., 44:193-196 29. Nylen 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.

Claims

[Claim 1] A pharmaceutical product comprising a compound of formula (I) as an active ingredient for use in a method of treating a disease or condition in animals that can be treated by improving or restoring epithelial barrier function, wherein the compound is defined by the following formula: 【Chemistry 1】 During the ceremony, Q is selected from Q1, Q2, Q3, Q4, Q5, and Q6. 【Chemistry 2】 n is either 0 or 1, L is -(CH ｍ , ｍ , ２ , ｍ , ｍ , ｍ , ｍ , ｍ , ｍ , ｍ ), ｍ -, -C(=O)-, -(CH ２ ), ｍ -C(=O)-, -O-(CH ２ ), ｍ -C(=O)-, -O-C(=O)-(CH ２ ), ｍ -(C=O)-, -NH-C(=O)-, -NR-C(=O)-, -NH-(CH ２ ), ｍ -C(=O)-, -NR-(CH ２ ), ｍ -C(=O)-, -NH-C(=O)-(CH ２ ), ｍ -C(=O)-, -NR-C(=O)-(CH ２ ), ｍ -C(=O)-, -C(=O)-NH-(CH ２ ), ｍ -C(=O)-, and -(CH ２ ), ｍ -(CHR Ｌ )-C(=O)-, where m is an integer from 1 to 4, A １ and A ２ These, along with the atoms to which they are bonded, may be substituted C ６～１４ Forming an aryl group, A ３ If present, H and possibly substituted C １～４ Selected from alkyl groups, R Ｎ H and possibly substituted C １～４ Selected from alkyl groups, B １ , B ２ , B ３ , B ４ , and B ５ One of them is formula -X-R Ｘ It is the basis of, and the others are, independently, H and R Ｂ Selected from, Each -R Ｂ These are, independently, halogen, -CF ３ , -R, -OH, -OR, -OCF ３ , -C(=O)OH, -C(=O)OR, -C(=O)R, -OC(=O)R, -NH ２ -NHR, -NR ２ , -NO ２ , -C(=O)NH ２ , -C(=O)NHR, C(=O)NR ２ , -S(=O)R, -S(=O) ２ R, -S (=O) ２ NR ２ Selected from , or -CN, X is covalent or C １～３ Selected from alkylenes, R Ｘ -H, R ＸＸ or R ＸＹ Selected from, R ＸＸ is halogen, -CF ３ , -OH, -OR, -OCF ３ , -C(=O)OH, -NO ２ , -NH ２ -NHR, -NR ２ , -C(=O)NH ２ , -C(=O)NR ２ , -S(=O)R, -S(=O) ２ R, -S (=O) ２ NR ２ , or -CN, R ＸＹ is equation -L Ｘ -R ＹＹ It is the basis of, L Ｘ is selected from -NH-C(=O)-O-, -NH-C(=O)-NH-, -NH-C(=O)-, -NR-C(=O)-, -O-C(=O)-NH-, -O-C(=O)-O-, -O-(C=O)-, -C(=O)-NH-, -C(=O)-O-, and -C(=O)-, R ＹＹ is C １～４ alkyl, C ３～６ cycloalkyl, -C ６～１４ aryl, -L Ｙ -C ６～１４ aryl, -L Ｙ -O-C ６～１４ aryl, -C ５～６ heteroaryl, -L Ｙ -C ５～６ heteroaryl, -L Ｙ -O-C ５～６ heteroaryl, -L Ｙ -O-L Ｙ -C≡N, -L Ｙ -O-L Ｙ -C≡R, -L Ｙ -O-L Ｙ -C≡CH, -L Ｙ -O-L Ｙ -NR Ｎ -C(=O)-R, -L Ｙ -O-L Ｙ -NH-C(=O)-R, -L Ｙ -O-L Ｙ -NR-C(=O)-R, -L Ｙ -C≡N, and -L Ｙ -C≡R, -L Ｙ selected from -C≡CH, -L Ｙ - is C １～３ It is an alkylene, and each of the aforementioned groups may be substituted. R Ｌ is halogen, -R ＬＬ , -CF ３ , -OH, -OR ＬＬ , -NO ２ , -NH ２ , -NHR ＬＬ , -NR ２ , -NH-C(=O)-R ＬＬ , -NH-C(=O)-O-R ＬＬ selected from, R ＬＬ is -C １～４ alkyl, -C ３～６ cycloalkyl, -Ph, -L Ｌ -Ph, -C ５～６ heteroaryl, -L Ｌ -C ５～６ heteroaryl selected from, -L Ｌ - is C １～３ alkylene, Each R is independent of C １～４ Alkyl, a pharmaceutical product. [Claim 2] The pharmaceutical product according to claim 1, wherein the disease or condition is febrile neutropenia, mucositis, or microbial infection. [Claim 3] The aforementioned compound is defined by the following formula: 【Transformation 3】 During the ceremony, Each R that may be substituted Ａ２ These are, independently, halogen, -CF ３ , -R, -OH, -OR, -OCF ３ , -NO ２ , -C(=O)OH, -C(=O)OR, -C(=O)R, -OC(=O)R, -NH ２ -NHR, -NR ２ , -C(=O)NH ２ , -C(=O)NHR, -C(=O)NR ２ , -S(=O)R, -S(=O) ２ R, -S (=O) ２ NR ２ Selected from , and -CN, B １ , B ２ , B ４ , and B ５ H and R are independent of each other. Ｂ Selected from, R Ｘ is equation -L Ｘ -R ＹＹ It is the basis of, L Ｘ This is selected from -NH-C(=O)-, -NR-C(=O)-, and -C(=O)-, R ＹＹ is, -L Ｙ -O-L Ｙ -C≡CH, -L Ｙ -O-L Ｙ -NH-C(=O)-R, and -L Ｙ - Selected from C≡CH, R Ｂ , X, -L Ｌ - and R are as defined in claim 1. The pharmaceutical product according to claim 1. [Claim 4] The pharmaceutical product according to claim 1, for use in a method for treating a disease or condition in an animal that can be treated by preventing or reducing microbial migration across the epithelial barrier. [Claim 5] The pharmaceutical product according to claim 1, wherein the epithelial barrier is an intestinal epithelial barrier. [Claim 6] The pharmaceutical product according to claim 5, wherein the intestinal epithelial barrier is a gastrointestinal epithelial barrier. [Claim 7] The pharmaceutical product according to any one of claims 1 to 6, wherein the animal has been treated for cancer or is currently being treated for cancer. [Claim 8] The pharmaceutical product according to any one of claims 1 to 6, wherein the animal is a recipient of an organ transplant, and the animal may be in an immunodeficient state. [Claim 9] The animal has a low neutrophil count. The pharmaceutical product according to any one of claims 1 to 6. [Claim 10] The pharmaceutical product according to any one of claims 1 to 6, wherein administration of the compound improves or restores the epithelial barrier function in the animal and / or prevents or reduces the migration of microorganisms through the epithelial barrier in the animal. [Claim 11] The pharmaceutical product according to claim 10, wherein the compound can prevent the migration of microorganisms from the intestines of the animal to the kidneys, liver, spleen or other organs and to the vascular bed via the circulatory system. [Claim 12] The pharmaceutical product according to claim 10, wherein the compound can improve, restore, or maintain the tight bonding function of the epithelial barrier of the animal. [Claim 13] For use in methods of treating and / or preventing microbial infections selected from the group consisting of bacterial infections, viral infections, prion infections, protozoan infections and fungal infections, wherein (i) the microbial infection is caused by a microbial species of a genera selected from the group consisting of Yersinia, Salmonella, Shigella, Campylobacter, Clostridium, Helicobacter, Mycobacterium, Pseudomonas, Haemophilus, Moraxella, Escherichia coli, Neisseria, Streptococcus, Staphylococcus, and norovirus, or (ii) the microbial infection is caused by Klebsiella pneumoniae, Escherichia coli, Enterobacter species, Serratia species, Proteus species, Providencia species, Morganella species, Enterococcus faecium (iii) The microbial infection is caused by Staphylococcus aureus, Helicobacter pylori, Acinetobacter baumannii, Pseudomonas erginosa, Campylobacter (e.g., Campylobacter jejuni), Salmonella species, Neisseria gonorea, Streptococcus pneumoniae, Haemophilus influenzae, Shigella species, or (iii) the microbial infection is caused by Nairovirus, Marburg virus, Ebola virus, Coronaviridae, Mamma Arenavirus, Henipavirus, Phlebovirus, Chikungunya virus, Alphavirus (Togavirus), Zika virus, and Dengue virus or other Flavivirus, or (iv) the microbial infection is caused by Yersinia enterocolitica The pharmaceutical product according to any one of claims 1 to 6, wherein the microbial infection is caused by (v) a bacterial strain resistant to direct-acting antibiotic treatment. [Claim 14] B １ , B ２ , B ４ and B ５ The pharmaceutical product according to any one of claims 1 to 6, wherein all of the elements are H. [Claim 15] X is C １～３ It is an alkylene, and X is optional, -CH ２ - The pharmaceutical product according to any one of claims 1 to 6. [Claim 16] The aforementioned compound, 【Chemistry 4】 and pyridine-3-ylmethyl (4-((2-aminophenyl)-carbamoyl)benzyl)carbamate (entinostat): 【Transformation 5】 A pharmaceutical product according to any one of claims 1 to 6, selected from among them. [Claim 17] The method comprises administering the compound to the animal in an effective amount of the compound, wherein the weekly or daily dose of the compound is 10 μg to about 1 g, and the dose may be divided into one, two or three doses, optionally (i) the dose is 0.025 mg to 500 mg, and optionally the dose is 0.1 mg to 250 mg, or (ii) the compound is 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 The pharmacopoeia according to any one of claims 1 to 6, administered in a dose of 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 optionally further administered in a dose of at least 50 mg / kg, or (iii) administered in a dose of less than 150 mg / kg. [Claim 18] (i) The treatment is a combination therapy comprising the compound and one or more of the following: an antibiotic, isoleucine or an active isomer or analog thereof, and / or a vitamin D compound. (ii) A compound comprising at least one pharmaceutically acceptable excipient and the compound as an active ingredient, A pharmaceutical composition comprising the pharmaceutical product described in any one of claims 1 to 6. [Claim 19] The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is formulated as an oral dosage form. [Claim 20] A compound selected from the following: 【Transformation 6】 [Claim 21] A pharmaceutical composition comprising a compound represented by the following formula and at least one pharmaceutically acceptable excipient. 【Transformation 7】 [Claim 22] A pharmaceutical product comprising a compound represented by the following formula as an active ingredient. 【Transformation 8】 [Claim 23] A pharmaceutical product comprising a compound represented by the following formula as an active ingredient, for use in a method of treating a disease or symptom in an animal. 【Chemistry 9】

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