Combination of β-lactam compound, probenecid and valproic acid and its use

Abstract

The present disclosure relates to a combination of valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof. The present disclosure also relates to a method of using the combination for treating or preventing a disease.

Description

[0001] Related Applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 987,963, filed on March 11, 2020, the entire content of which is incorporated herein by reference in its entirety. Background Art

[0003] β-lactam compounds are a class of antibiotics that have a β-lactam ring in their molecular structure. β-lactam compounds have been used to treat diseases associated with Gram-positive and Gram-negative bacteria. Valproic acid (“VPA”) is a drug mainly used to treat patients with seizure disorders and less frequently used for other neurological disorders such as mania and migraine. The co-administration of valproic acid and β-lactam compounds (including penem antibiotics) may be necessary for the treatment of acute infections. It has been reported that the serum valproic acid concentration in patients receiving carbapenem antibiotics (such as ertapenem, imipenem, and meropenem, etc.) is clinically significantly reduced and may lead to loss of seizure control. The mechanism of this interaction is not very clear. Summary of the Invention

[0004] In some aspects, the present disclosure provides a method for treating or preventing a disease, comprising administering to a subject in need thereof:

[0005] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0006] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0007] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0008] In some aspects, the present disclosure provides a method for treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof:

[0009] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0010] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0011] In some aspects, the present disclosure provides a method for treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof:

[0012] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0013] In some aspects, the present disclosure provides a method for reducing or alleviating side effects in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof:

[0014] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0015] In some aspects, the present disclosure provides a combination for treating or preventing a disease, wherein the combination comprises:

[0016] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0017] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0018] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0019] In some aspects, the present disclosure provides a combination for treating or preventing a disease in a subject administered valproic acid or a pharmaceutically acceptable salt thereof, wherein the combination comprises:

[0020] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0021] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0022] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for treating or preventing a disease in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0023] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for reducing or alleviating side effects in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0024] In some aspects, the present disclosure provides a combination, which comprises:

[0025] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0026] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0027] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0028] In some aspects, the present disclosure provides a pharmaceutical kit, which comprises:

[0029] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0030] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0031] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0032] In some aspects, the present disclosure provides a pharmaceutical composition comprising:

[0033] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0034] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0035] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although those methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the following describes suitable methods and materials. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification (including definitions) shall prevail. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between the chemical structure and the name of the compounds disclosed herein, the chemical structure shall prevail.

[0037] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 A graph showing the mean (± standard deviation) plasma concentration (μg / ml) of valproic acid when administered alone and in combination with imipenem (in intravenous formulation).

[0039] Figure 2 A graph showing the mean (± standard deviation) plasma concentration (μg / ml) of valproic acid when administered alone and in combination with imipenem (in oral formulation).

[0040] Figure 3 A graph showing the mean (± standard deviation) plasma concentration (μg / ml) of valproic acid when administered alone and in combination with imipenem and probenecid (in oral formulation). DETAILED DESCRIPTION

[0041] In some aspects, the present disclosure provides a method of treating or preventing a disease, comprising administering to a subject in need thereof:

[0042] a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0043] a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0044] a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0045] In some aspects, the present disclosure provides a method of treating or preventing a disease in a subject administered valproic acid or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof:

[0046] a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0047] a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0048] In some aspects, the present disclosure provides a method of treating or preventing a disease in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof:

[0049] a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0050] In some aspects, the present disclosure provides a method of reducing or alleviating side effects in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof:

[0051] a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0052] In some aspects, the present disclosure provides a combination for treating or preventing a disease, wherein the combination comprises:

[0053] a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0054] a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0055] a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0056] In some aspects, the present disclosure provides a combination for treating or preventing a disease in a subject administered valproic acid or a pharmaceutically acceptable salt thereof, wherein the combination comprises:

[0057] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0058] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0059] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for treating or preventing a disease in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0060] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for reducing or alleviating side effects in a subject administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0061] Effect of the method

[0062] In some embodiments, administration reduces or alleviates side effects.

[0063] In some embodiments, administration reduces or alleviates side effects of administering valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof without administering probenecid or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the side effects are mania, seizures, increased likelihood of seizures, decreased valproic acid concentration in the subject, neuromotor impairment, or the likelihood of neuromotor impairment.

[0065] In some embodiments, the side effect is mania.

[0066] In some embodiments, the side effect is mania associated with bipolar disorder and / or migraine.

[0067] In some embodiments, the side effect is seizures.

[0068] In some embodiments, the side effect is an increased likelihood of seizures.

[0069] In some embodiments, the side effect is a decrease in valproic acid concentration in the subject.

[0070] In some embodiments, the side effect is neuromotor impairment.

[0071] In some embodiments, the side effect is the likelihood of neuromotor impairment.

[0072] In some embodiments, the side effect is seizures associated with administration of a β-lactam compound.

[0073] In some embodiments, the side effect is seizures associated with co - administration of a β - lactam compound and valproic acid.

[0074] In some embodiments, the side effect is an increased likelihood of seizures associated with administration of a β - lactam compound.

[0075] In some embodiments, the side effect is an increased likelihood of seizures associated with co - administration of a β - lactam compound and valproic acid.

[0076] In some embodiments, the side effect is a decrease in valproic acid concentration in a subject associated with co - administration of a β - lactam compound. In some embodiments, the side effect is neuro - motor impairment associated with administration of a β - lactam compound.

[0077] In some embodiments, the side effect is neuro - motor impairment associated with co - administration of a β - lactam compound and valproic acid.

[0078] In some embodiments, the side effect is the likelihood of neuro - motor impairment associated with administration of a β - lactam compound.

[0079] In some embodiments, the side effect is the likelihood of neuro - motor impairment associated with co - administration of a β - lactam compound and valproic acid.

[0080] In some embodiments, compared to comparable subjects administered in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in a lower likelihood of seizures in the subject.

[0081] In some embodiments, compared to comparable subjects administered in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in an increase in valproic acid concentration in the subject.

[0082] In some embodiments, compared to comparable subjects administered in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in a lower likelihood of neuro - motor impairment in the subject.

[0083] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to comparable subjects administered a β - lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in a higher area under the curve (AUC) of the plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in subjects in need thereof.

[0084] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in subjects in need thereof having a greater area under the curve (AUC) of about 0.1% or greater, about 0.25% or greater, about 0.5% or greater, about 0.75% or greater, about 1% or greater, about 2% or greater, about 3% or greater, about 4% or greater, about 5% or greater, about 6% or greater, about 7% or greater, about 8% or greater, about 9% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 80% or greater, about 100% or greater, about 150% or greater, about 200% or greater, about 300% or greater, about 400% or greater, or about 500% or greater.

[0085] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in subjects in need thereof having a higher maximum plasma concentration (C max )

[0086] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, administration results in a maximum plasma concentration (C max ) of valproic acid or a pharmaceutically acceptable salt thereof that is about 0.1% or greater, about 0.25% or greater, about 0.5% or greater, about 0.75% or greater, about 1% or greater, about 2% or greater, about 3% or greater, about 4% or greater, about 5% or greater, about 6% or greater, about 7% or greater, about 8% or greater, about 9% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 80% or greater, about 100% or greater, about 150% or greater, about 200% or greater, about 300% or greater, about 400% or greater, or about 500% or greater in subjects in need thereof.

[0087] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to comparable subjects administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, administration results in valproic acid or a pharmaceutically acceptable salt thereof having a substantially identical area under the curve (AUC) in subjects in need thereof.

[0088] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, administration results in valproic acid or a pharmaceutically acceptable salt thereof having an area under the curve (AUC) in the range of about 50% - about 150%, about 60% - about 140%, about 70% - about 130%, about 80% - about 120%, about 90% - about 110%, or about 95% - about 105% of the area under the curve (AUC) resulting in comparable subjects administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof in subjects in need thereof.

[0089] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof that has an area under the curve (AUC) that is about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 102%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140%, or about 150% of the area under the curve (AUC) that would be caused by administration of valproic acid or a pharmaceutically acceptable salt thereof in a comparable subject without a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof without a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof that has a substantially the same maximum plasma concentration (C max ).

[0091] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof that has a maximum plasma concentration (C max ) that is in the range of about 50% - about 150%, about 60% - about 140%, about 70% - about 130%, about 80% - about 120%, about 90% - about 110%, or about 95% - about 105% of the maximum plasma concentration (C max ) caused by administration of valproic acid or a pharmaceutically acceptable salt thereof in a comparable subject without a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof that is about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 102%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140%, or about 150% of the maximum plasma concentration (C max ) caused in comparable subjects administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof. max )

[0093] Subjects and Diseases Treated

[0094] In some embodiments, the subject in need thereof is an animal. In some embodiments, the subject in need thereof is a human.

[0095] In some embodiments, the subject in need thereof is a human 18 years of age or older.

[0096] In some embodiments, the subject in need thereof is a human less than 18 years of age.

[0097] In some embodiments, the disease is associated with a decrease in the level of gamma-aminobutyric acid (GABA) in the subject (e.g., in the central nervous system of the subject). In some embodiments, the administration results in an increase in the level of gamma-aminobutyric acid (GABA) in the subject (e.g., in the central nervous system of the subject).

[0098] In some embodiments, the disease is associated with an increase or decrease in the population of one or more microorganisms (e.g., bacteria) in the subject.

[0099] In some embodiments, the disease is associated with an increase in the population of one or more microorganisms (e.g., bacteria) in the subject. In some embodiments, the administration results in a decrease in the population of one or more microorganisms (e.g., bacteria) in the subject.

[0100] In some embodiments, the disease is associated with a decrease in the population of one or more microorganisms (e.g., bacteria) in the subject. In some embodiments, the administration results in an increase in the population of one or more microorganisms (e.g., bacteria) in the subject.

[0101] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides coprocola, Prevotella copri, Porphyromonas asaccharolytica, and Prevotella bivia; or any organism of the following genera: Succinivibrio ( Succinivibrio ), Alistipes ( Alistipes ), Prevotella ( Prevotella ), Paraprevotella ( Paraprevotella ), Parabacteroides ( Parabacteroides ), and Odoribacter ( Odoribacter ).

[0102] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from: Staphylococcus epidermidis, Streptococcus pneumonia, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pyogenes.

[0103] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus influenza, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens.

[0104] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from: Bacteroides vulgatus, Clostridium perfringens, and Fusobacterium spp.

[0105] In some embodiments, the disease is associated with an infection. In some embodiments, the infection is a Gram-negative infection. In some embodiments, the infection is a Gram-positive infection.

[0106] In some embodiments, when administered in the absence of probenecid or a pharmaceutically acceptable salt thereof, the infection is resistant to one or more antibiotics.

[0107] In some embodiments, when administered in the absence of probenecid or a pharmaceutically acceptable salt thereof, the infection is resistant to one or more β-lactam compounds.

[0108] In some embodiments, the disease is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection, and infectious diarrhea.

[0109] In some embodiments, the disease is associated with (e.g., caused by) an alteration in the microbiome of the subject.

[0110] In some embodiments, a disease is associated with (e.g., caused by) an alteration in the microbiome in a human subject.

[0111] In some embodiments, the disease is mania.

[0112] In some embodiments, the disease is mania associated with bipolar disorder and / or migraine.

[0113] In some embodiments, the disease is a neurodegenerative disease.

[0114] In some embodiments, the disease is amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, schizophrenia, or Huntington's disease.

[0115] In some embodiments, the disease is Alzheimer's disease. Notably, it has been found that probenecid increases the concentration of β-lactam compounds in cerebrospinal fluid (Ralph G. Dacey and Merle A. Sande, Antimicrobial Agents and Chemotherapy 6:437 - 441 (1974)). More recently, a bacterial pathogen, Porphyromonas gingivalis, has been found in the brain Porphyromonas gingivalis ), which is associated with pathological lesions associated with Alzheimer's disease (Dominy etal., Sci. Adv. 5:eaau3333 (2019), and imipenem has activity against this bacterium (Lois M. Ednie and Peter C. Appelbaum, Antimicrobial Agents and Chemotherapy 53: 2163 - 2170(2009)). Without wishing to be bound by theory, it is to be understood that when administered together with probenecid, a β-lactam compound (e.g., compound III-2b) may result in more effective treatment of a brain infection by this organism relative to treatment with imipenem alone.

[0116] In some embodiments, the disease is cancer.

[0117] In some embodiments, the cancer is a solid cancer, such as ovarian cancer, breast cancer, head and neck cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, or lymphoma, or any combination thereof.

[0118] In some embodiments, the cancer is a sarcoma or a carcinoma, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, epithelioma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma.

[0119] In some embodiments, the cancer is leukemia, such as acute lymphocytic leukemia and acute myeloid leukemia (myeloblast, promyelocyte, myelomonocyte, monocyte, and erythroleukemia); or chronic leukemia (chronic myeloid (granulocytic) leukemia and chronic lymphocytic leukemia).

[0120] In some embodiments, the cancer is polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenström's macroglobulinemia, or heavy chain disease.

[0121] In some embodiments, the disease is inflammatory bowel disease.

[0122] In some embodiments, the inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, irritable bowel syndrome, microscopic colitis, diversion colitis, or Behçet's disease.

[0123] In some embodiments, the disease is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, acute bacterial prostatitis, community-acquired bacterial pneumonia, gonococcal urethritis, pelvic inflammatory disease, chronic bacterial prostatitis, Mycobacterium tuberculosis infection, nontuberculous mycobacterial infection, bone and joint infection, acute and chronic sinusitis, diabetic foot infection, or infectious diarrhea (e.g., diarrhea caused by Salmonella, Shigella, or Vibrio cholerae).

[0124] β-lactam compound, probenecid, and valproic acid

[0125] In some embodiments, the β-lactam compound is a monobactam or a prodrug thereof.

[0126] In some embodiments, the β-lactam compound is aztreonam, tigemonam, carumonam, nocardicin A, a prodrug thereof, an analogue thereof, or a derivative thereof.

[0127] In some embodiments, the β-lactam compound is a penem, a carbapenem, an oxapenam, or a prodrug thereof.

[0128] In some embodiments, the β-lactam compound is benzylpenicillin, benzathine benzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin, propicillin, pheneticillin, azidocillin, clometocillin, penamecillin, cloxacillin (e.g., dicloxacillin or flucloxacillin), oxacillin, nafcillin, methicillin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, ticarcillin, carbenicillin, carindacillin, temocillin, piperacillin, azlocillin, mezlocillin, mecillinam (e.g., pivmecillinam), sulbenicillin, a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogue thereof, or a derivative thereof.

[0129] In some embodiments, the β-lactam compound is a penem, a carbapenem, or a prodrug thereof.

[0130] In some embodiments, the β-lactam compound is a thiopenem, an oxapenem, an aminopenem, an alkylpenem, an arylpenem, or a prodrug thereof.

[0131] In some embodiments, the β-lactam compound is ertapenem, an anti-pseudomonal carbapenem (e.g., doripenem, imipenem, meropenem), biapenem, panipenem, sulopenem, tebipenem, faropenem, a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogue thereof, or a derivative thereof.

[0132] In some embodiments, the β-lactam compound is a cephem, a carbacephem, an oxacephem, or a prodrug thereof.

[0133] In some embodiments, the β-lactam compound is cefazolin, cefalexin, cefadroxil, cefapirin, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaloglycin, cefacetrile, cefalonium, cefaloridine, cefalotin, cefatrizine, cefaclor, cefotetan, cephamycin (e.g., cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam, cefmetazole), carbacephem (e.g., loracarbef), cefixime, ceftriaxone, antipseudomonal (e.g., ceftazidime, cefoperazone), cefdinir, cefcapene, cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefetamet, cefodizime, cefpimizole, cefsulodin, cefteram, ceftiolene, oxacephem(such as flomoxef, latamoxef), cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil, ceftolozane, ceftobiprole, ceftiofur, cefquinome, cefovecin, their pharmaceutically acceptable salts, their prodrugs, their analogs or their derivatives.

[0134] In some embodiments, the β-lactam compound is a thienamycin or its prodrug.

[0135] In some embodiments, the β-lactam compound has the formula (I):

[0136]

[0137] (I)

[0138] its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives, wherein R 1 is H or an optionally substituted alkyl.

[0139] In some embodiments, the β-lactam compound has the formula (Ia):

[0140]

[0141] (Ia)

[0142] its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives.

[0143] In some embodiments, the β-lactam compound has the formula (Ib):

[0144]

[0145] (Ib)

[0146] its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives.

[0147] In some embodiments, R 1 is H.

[0148] In some embodiments, the β-lactam compound has the formula (II):

[0149]

[0150] (II)

[0151] Its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives.

[0152] In some embodiments, the β-lactam compound has the formula (IIa):

[0153]

[0154] (IIa)

[0155] Its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives.

[0156] In some embodiments, the β-lactam compound has the formula (IIb):

[0157]

[0158] (IIb)

[0159] Its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives.

[0160] In some embodiments, R 1 is an optionally substituted alkyl.

[0161] In some embodiments, the β-lactam compound has any one of the formulas (III), (IIIa) and (IIIb):

[0162]

[0163] Its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives, wherein R 2 is H or an optionally substituted alkyl.

[0164] In some embodiments, the β-lactam compounds are selected from the following:

[0165] (Compound III-1)

[0166] (Compound III-1a)

[0167] (Compound III-1b)

[0168] Its pharmaceutically acceptable salts, its prodrugs, its analogs and its derivatives.

[0169] In some embodiments, the β-lactam compounds are selected from the following:

[0170] (Compound III-2)

[0171] (Compound III-2a)

[0172] (Compound III-2b)

[0173] Its pharmaceutically acceptable salts, its prodrugs, its analogs and its derivatives.

[0174] In some embodiments, the β-lactam compound is selected from the following:

[0175] (Compound III-2b; also known as Sulopenem Etzadroxil),

[0176] Its pharmaceutically acceptable salts, its prodrugs, its analogs and its derivatives.

[0177] In some embodiments, the β-lactam compound is:

[0178] (Compound III-2b; also known as Sulopenem).

[0179] In some embodiments, the β-lactam compound has any one of formulas (IV), (IVa) and (IVb):

[0180]

[0181] (IV)

[0182]

[0183] (IVa)

[0184]

[0185] (IVb)

[0186] Its pharmaceutically acceptable salts, its prodrugs, its analogs or its derivatives, wherein R 3 is H or optionally substituted alkyl.

[0187] In some embodiments, R 3 is C2-C8 alkyl.

[0188] In some embodiments, R 3 is CH2CH3, CH2CH2CH3 or CH2CH(CH3)2.

[0189] In some embodiments, the pharmaceutical salts of the β-lactam compound are sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts or aluminum salts.

[0190] It should be understood that valproic acid has the following structure:

[0191]

[0192] In some embodiments, the pharmaceutically acceptable salts of valproic acid are sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts or aluminum salts.

[0193] It should be understood that probenecid (sold, for example, under the brand Probalan) has the following structure:

[0194]

[0195] In some embodiments, the pharmaceutically acceptable salts of probenecid are sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts or aluminum salts.

[0196] Administration of valproic acid, β-lactam compounds and probenecid

[0197] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered once or more times daily at a daily dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 20 g, about 30 g, about 40 g or about 50 g.

[0198] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, three times daily or more.

[0199] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered continuously.

[0200] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered for more than about 1 day.

[0201] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, or about 30 days.

[0202] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

[0203] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered without any drug holidays.

[0204] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered enterally.

[0205] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered orally or rectally.

[0206] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered orally.

[0207] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered parenterally.

[0208] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered by injection (e.g., intravenous infusion).

[0209] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered intravenously.

[0210] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof is administered once or more times daily in a daily dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 20 g, about 30 g, about 40 g, or about 50 g.

[0211] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three or more times daily.

[0212] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered continuously.

[0213] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered for more than about 1 day.

[0214] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, or about 30 days.

[0215] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

[0216] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered without any drug holidays.

[0217] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by enteral administration.

[0218] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by oral administration or rectal administration.

[0219] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by oral administration.

[0220] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by parenteral administration.

[0221] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by injection (e.g., intravenous infusion).

[0222] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by intravenous administration.

[0223] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered once or more than once daily at a daily dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 20 g, about 30 g, about 40 g or about 50 g.

[0224] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, three times daily or more than three times daily.

[0225] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered continuously.

[0226] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered for more than about 1 day.

[0227] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days or about 30 days.

[0228] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

[0229] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered without any drug holidays.

[0230] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by enteral administration.

[0231] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by oral administration or rectal administration.

[0232] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by oral administration.

[0233] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by parenteral administration.

[0234] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by injection (e.g., intravenous infusion).

[0235] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by intravenous administration.

[0236] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.

[0237] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternately.

[0238] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternately.

[0239] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternately.

[0240] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0241] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0242] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0243] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0244] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0245] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0246] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously, and then probenecid or a pharmaceutically acceptable salt thereof is administered.

[0247] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously after probenecid or a pharmaceutically acceptable salt thereof is administered.

[0248] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, and then a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0249] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously after a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0250] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, and then valproic acid or a pharmaceutically acceptable salt thereof is administered.

[0251] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously after valproic acid or a pharmaceutically acceptable salt thereof is administered.

[0252] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0253] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a probenecid compound or a pharmaceutically acceptable salt thereof, and a β-lactam or a pharmaceutically acceptable salt thereof are administered sequentially.

[0254] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof, valproic acid or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0255] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof, probenecid or a pharmaceutically acceptable salt thereof, and valproic acid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0256] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof, a β-lactam or a pharmaceutically acceptable salt thereof, and valproic acid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0257] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof, valproic acid or a pharmaceutically acceptable salt thereof, and a β-lactam or a pharmaceutically acceptable salt thereof are administered sequentially.

[0258] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered in temporal proximity.

[0259] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered in temporal proximity.

[0260] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in temporal proximity.

[0261] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in temporal proximity.

[0262] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof is administered before probenecid or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered before a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

[0265] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered by the same route.

[0266] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

[0267] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

[0268] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered by different routes.

[0269] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered by different routes.

[0270] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by different routes.

[0271] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by different routes.

[0272] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered enterally.

[0273] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered enterally.

[0274] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered enterally.

[0275] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered enterally.

[0276] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered enterally.

[0277] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered enterally.

[0278] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof is administered enterally.

[0279] In some embodiments, enteral administration is oral administration.

[0280] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

[0281] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered orally.

[0282] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

[0283] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered orally.

[0284] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered orally.

[0285] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered orally.

[0286] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof is administered orally.

[0287] In some embodiments, an oral co-formulation comprising valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0288] In some embodiments, an oral co-formulation comprising valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0289] In some embodiments, an oral co-formulation comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0290] In some embodiments, an oral co-formulation comprising a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0291] In some embodiments, the oral co-formulation is administered to a subject once or more than once daily.

[0292] In some embodiments, the oral co-formulation is administered to a subject once daily.

[0293] In some embodiments, a tablet comprising valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0294] In some embodiments, a tablet comprising valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0295] In some embodiments, a tablet comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0296] In some embodiments, a tablet comprising a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0297] In some embodiments, the tablet is a bilayer tablet comprising:

[0298] a second layer comprising a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0299] A first layer comprising probenecid or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the first layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the second layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of a β-lactam compound (such as Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the first layer comprises about 500 ± 450 mg, about 500 ± 400 mg, about 500 ± 350 mg, about 500 ± 300 mg, about 500 ± 250 mg, about 500 ± 200 mg, about 500 ± 150 mg, about 500 ± 100 mg, about 500 ± 90 mg, about 500 ± 80 mg, about 500 ± 70 mg, about 500 ± 60 mg, about 500 ± 50 mg, about 500 ± 45 mg, about 500 ± 40 mg, about 500 ± 35 mg, about 500 ± 30 mg, about 500 ± 25 mg, about 500 ± 20 mg, about 500 ± 15 mg, about 500 ± 10 mg, or about 500 ± 5 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the second layer comprises from about 500 ± 400 mg, about 500 ± 350 mg, about 500 ± 300 mg, about 500 ± 250 mg, about 500 ± 200 mg, about 500 ± 150 mg, about 500 ± 100 mg, about 500 ± 90 mg, about 500 ± 80 mg, about 500 ± 70 mg, about 500 ± 60 mg, about 500 ± 50 mg, about 500 ± 45 mg, about 500 ± 40 mg, about 500 ± 35 mg, about 500 ± 30 mg, about 500 ± 25 mg, about 500 ± 20 mg, about 500 ± 15 mg, about 500 ± 10 mg or about 500 ± 5 mg of a β-lactam compound (such as Compound III-2, Compound III-2a or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the first layer comprises about 500 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the second layer comprises about 500 mg of a β-lactam compound (such as Compound III-2, Compound III-2a or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the bilayer tablet further comprises one or more pharmaceutical excipients.

[0307] In some embodiments, the one or more pharmaceutical excipients are selected from cellulose, sodium carboxymethylcellulose cross-linked, magnesium stearate, lactose monohydrate, and hydroxypropylcellulose.

[0308] In some embodiments, the bilayer tablet is administered to a subject once or more than once daily.

[0309] In some embodiments, the bilayer tablet is administered to a subject once daily.

[0310] In some embodiments, a tablet comprising valproic acid or a pharmaceutically acceptable salt thereof is administered.

[0311] In some embodiments, a tablet comprising a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0312] In some embodiments, a tablet comprising probenecid or a pharmaceutically acceptable salt thereof is administered.

[0313] In some embodiments, the tablet is administered to a subject once or more than once daily.

[0314] In some embodiments, the tablet is administered to a subject once daily.

[0315] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered in separate oral formulations.

[0316] In some embodiments, both tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered in separate oral formulations.

[0317] In some embodiments, both tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in separate oral formulations.

[0318] In some embodiments, both tablets comprising a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in separate oral formulations.

[0319] In some embodiments, the separate oral formulations are administered to a subject once or more than once daily.

[0320] In some embodiments, the separate oral formulations are administered to a subject once daily.

[0321] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered in separate tablets.

[0322] In some embodiments, both tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered in separate tablets.

[0323] In some embodiments, both tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in separate tablets.

[0324] In some embodiments, both a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in separate tablets.

[0325] In some embodiments, the tablets are administered to a subject once or more than once daily.

[0326] In some embodiments, the tablets are administered to a subject once daily.

[0327] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered by parenteral administration.

[0328] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered by parenteral administration.

[0329] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by parenteral administration.

[0330] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by parenteral administration.

[0331] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered by parenteral administration.

[0332] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof is administered by parenteral administration.

[0333] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered by parenteral administration.

[0334] In some embodiments, parenteral administration is intravenous administration.

[0335] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered intravenously.

[0336] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered intravenously.

[0337] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered intravenously.

[0338] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered intravenously.

[0339] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered intravenously.

[0340] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof is administered intravenously.

[0341] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered as a co-formulation.

[0342] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered as a co-formulation.

[0343] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered as a co-formulation.

[0344] In some embodiments, a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered as a co-formulation.

[0345] In some embodiments, the co-formulation is administered to a subject once or more times per day.

[0346] In some embodiments, the co-formulation is administered to a subject once per day.

[0347] In some embodiments, the co-formulation is an oral co-formulation (e.g., a tablet).

[0348] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered in separate formulations.

[0349] Exemplary embodiments of the method

[0350] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 500 mg per day, about 1 g per day, about 2 g per day, about 3 g per day, about 4 g per day, or about 5 g per day.

[0351] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day (e.g., about 500 mg per day).

[0352] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 500 mg per day, about 1 g per day, about 2 g per day, about 3 g per day, about 4 g per day or about 5 g per day.

[0353] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day (e.g., about 500 mg per day).

[0354] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 500 mg per day, about 1 g per day, about 2 g per day, about 3 g per day, about 4 g per day or about 5 g per day.

[0355] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day (e.g., about 500 mg per day).

[0356] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day (e.g., about 500 mg per day);

[0357] A β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day (e.g., about 500 mg per day); and

[0358] Probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day (e.g., about 500 mg per day).

[0359] Combinations, pharmaceutical compositions, and pharmaceutical kits

[0360] In some aspects, the present disclosure provides a combination comprising:

[0361] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0362] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0363] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0364] In some aspects, the present disclosure provides a pharmaceutical composition comprising:

[0365] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0366] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0367] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0368] In some aspects, the present disclosure provides a pharmaceutical kit comprising:

[0369] A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof;

[0370] A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0371] A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0372] Definitions

[0373] As used herein, the terms "about" and "approximately" are used as equivalents. Any number used in this application, with or without about / approximately, is meant to cover any normal fluctuations recognized by one of ordinary skill in the relevant art. In certain embodiments, the term "about" or "approximately" refers to a numerical range within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the reference value, unless otherwise stated or otherwise obvious from the context (unless such a number exceeds 100% of the possible value).

[0374] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" are intended to include C1, C2, C3, C4, C5 or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl groups include moieties having 1-6 carbon atoms, such as (but not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl or n-hexyl. In certain embodiments, the straight-chain or branched-chain alkyl has 6 or fewer carbon atoms (e.g., for straight-chain C1-C6, for branched-chain C3-C6), and in another embodiment, the straight-chain or branched-chain alkyl has 4 or fewer carbon atoms.

[0375] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon mono- or polycyclic (e.g., fused, bridged or spirocyclic) system having 3-30 carbon atoms (e.g., C3-C 12 , C3-C 10 or C3-C8). Examples of cycloalkyl groups include (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl and adamantyl.

[0376] Unless otherwise specified, as used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic 3- to 8-membered ring, 7- to 12-membered bicyclic (fused, bridged or spiro) or 11- to 14-membered tricyclic system (fused, bridged or spiro) having one or more heteroatoms (such as O, N, S, P or Se), for example 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyl include (but are not limited to) piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuryl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-azaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridine]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, etc. In the case of polycyclic non-aromatic rings, only one of the rings needs to be non-aromatic (such as 1,2,3,4-tetrahydronaphthyl or 2,3-dihydroindole).

[0377] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl in which one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone are substituted with a specified substituent. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkanesulfinyl, sulfonato, sulfamoyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic group, alkylaryl or an aromatic or heteroaromatic moiety.

[0378] As used herein, the term "alkenyl" includes an unsaturated aliphatic group having a length and possible substitution similar to the above alkyl but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched-chain alkenyl. In certain embodiments, the straight-chain or branched-chain alkenyl has 6 or fewer carbon atoms in its backbone (e.g., for straight-chain C2-C6, for branched-chain C3-C6). The term "C2-C6" includes alkenyls containing 2-6 carbon atoms. The term "C3-C6" includes alkenyls containing 3-5 carbon atoms.

[0379] As used herein, the term "alkynyl" includes an unsaturated aliphatic group having a length and possible substitution similar to the above alkyl but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl. In certain embodiments, the straight-chain or branched-chain alkynyl has 6 or fewer carbon atoms in its backbone (e.g., for straight-chain C2-C6, for branched-chain C3-C6). The term "C2-C6" includes alkynyls containing 2-6 carbon atoms. The term "C3-C6" includes alkynyls containing 3-6 carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a divalent unsaturated aliphatic hydrocarbon group of C2, C3, C4, C5 or C6 chain (linear or branched). For example, C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.

[0380] Other optional substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include both unsubstituted moieties and moieties having one or more specified substituents. For example, substituted heterocycloalkyl includes those heterocycloalkyls substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0381] As used herein, the term "aryl" includes groups having aromaticity, including "conjugated" or polycyclic systems having one or more aromatic rings and containing no heteroatoms in the ring structure. Examples include phenyl, naphthyl, etc.

[0382] As used herein, the term "heteroaryl" is intended to include stable 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocycles, which are composed of carbon atoms and one or more heteroatoms, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur, or for example 1, 2, 3, 4, 5 or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N O and S(O) p , where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc.

[0383] In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl, such as tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indazole.

[0384] A cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more ring positions (e.g., a ring-forming carbon or heteroatom such as N) by such substituents as described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkanesulfinyl, sulfonato, sulfamoyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic group, alkylaryl or an aromatic or heteroaromatic moiety. An aryl and heteroaryl may also be fused or bridged to an alicyclic or heterocyclic ring that is not aromatic, thereby forming a polycyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0385] As used herein, the term "heterocycle" or "heterocyclic group" includes any ring structure (saturated, unsaturated or aromatic) containing at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O and S). Heterocycles include heterocycloalkyl and heteroaryl. Examples of heterocycles include (but are not limited to) morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine and tetrahydrofuran.

[0386] Examples of heterocyclic groups include (but are not limited to) acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a H -carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2 H ,6 H -1,5,2-dithiazinyl, dihydrofuro[2,3 b tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indazinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][1,3]dioxol-5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol-5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4 H -quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thieno[2,3-d]thiazole, thieno[2,3-d]isoxazole, thieno[2,3-d]imidazole, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0387] As used herein, the term "substituted" means that any one or more of the hydrogen atoms on the specified atom is replaced by a group selected from the specified groups, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. When the substituent is an oxo group or a keto group (i.e., =O), then two hydrogen atoms on the atom are replaced. The keto substituent is not present on the aromatic moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" mean a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[0388] When a bond to a substituent shows crossing a bond connecting two atoms in a ring, such a substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom through which such a substituent is bonded to the remainder of the compound of a given formula, such a substituent may be bonded through any atom in such a formula. Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds.

[0389] When any variable (e.g., R) occurs more than once in any component of a compound or in a formula, its definition at each occurrence is independent of its definition at each other occurrence. Thus, for example, if a group is shown to be substituted by 0 - 2 R moieties, the group may optionally be substituted by up to two R moieties, and R at each occurrence is independently selected from the definition of R. Additionally, combinations of substituents and / or variables are permitted only if such combinations result in stable compounds.

[0390] As used herein, the term "hydroxy" or "hydroxyl" includes groups having -OH or -O - -.

[0391] As used herein, the terms "halo" or "halogen" refer to fluorine, chlorine, bromine, and iodine. The term "perhalogenated" generally refers to moieties in which all hydrogen atoms have been replaced by halogen atoms. The terms "haloalkyl" or "haloalkoxy" refer to an alkyl or alkoxy group substituted by one or more halogen atoms.

[0392] As used herein, the term "carbonyl" includes compounds and moieties containing carbon double-bonded to an oxygen atom. Examples of moieties containing a carbonyl include (but are not limited to) aldehydes, ketones, carboxylic acids, amides, esters, acid anhydrides, etc.

[0393] As used herein, the term "carboxy" refers to -COOH or its C1 - C6 alkyl esters.

[0394] As used herein, the term "acyl" includes moieties containing an acyl group (R-C(O)-) or a carbonyl group. As used herein, the term "substituted acyl" includes acyl groups in which one or more hydrogen atoms are replaced by, for example, alkyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkanesulfinyl, sulfonato, sulfamoyl, sulfonylamino, nitro, trifluoromethyl, cyano, azido, heterocyclic group, alkylaryl or an aromatic or heteroaromatic moiety.

[0395] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include (but are not limited to) methoxy, ethoxy, isopropoxy, propoxy, butoxy and pentyloxy. Examples of substituted alkoxy include halogenated alkoxy. The alkoxy may be substituted by groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkanesulfinyl, sulfonato, sulfamoyl, sulfonylamino, nitro, trifluoromethyl, cyano, azido, heterocyclic group, alkylaryl or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy include (but are not limited to) fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0396] As used herein, the term "ether" or "alkoxy" includes a compound or moiety containing an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl", which refers to an alkyl, alkenyl or alkynyl group covalently bonded to an oxygen atom that is covalently bonded to an alkyl group.

[0397] As used herein, the term "ester" includes a compound or moiety containing a carbon or heteroatom bonded to an oxygen atom that is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and the like.

[0398] As used herein, the term "thioalkyl" includes a compound or moiety containing an alkyl group attached to a sulfur atom. The thioalkyl group can be substituted by groups such as alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkanesulfinyl, sulfonato, sulfamoyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic group, alkylaryl or an aromatic or heteroaromatic moiety.

[0399] As used herein, the term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties containing a carbon double-bonded to a sulfur atom.

[0400] As used herein, the term "thioether" includes a moiety containing a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include (but are not limited to) alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" includes a moiety having an alkyl, alkenyl or alkynyl group bonded to a sulfur atom that is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" refers to a moiety in which an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom that is covalently bonded to an alkenyl group; and "alkthioalkynyls" refers to a moiety in which an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom that is covalently bonded to an alkynyl group.

[0401] As used herein, the term "amine" or "amino" refers to -NH2. "Alkylamino" includes the group of compounds in which the nitrogen of -NH2 is bonded to at least one alkyl group. Examples of alkylamino include benzylamino, methylamino, ethylamino, phenethylamino, and the like.

[0402] As used herein, the term "dialkylamino" includes the group in which the nitrogen of -NH2 is bonded to two alkyl groups. Examples of dialkylamino include (but are not limited to) dimethylamino and diethylamino.

[0403] As used herein, the terms "arylamino" and "diarylamino" include the groups in which nitrogen is bonded to at least one or two aryl groups, respectively.

[0404] As used herein, the terms "aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy groups substituted with an amino group.

[0405] As used herein, the terms "alkylarylamino", "alkylaminoaryl", or "arylaminoalkyl" refer to an amino group bonded to at least one alkyl group and at least one aryl group.

[0406] As used herein, the term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bonded to a nitrogen atom that is also bonded to an alkyl group.

[0407] As used herein, the term "acylamino" includes the group in which nitrogen is bonded to an acyl group. Examples of acylamino include (but are not limited to) alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido.

[0408] As used herein, the terms "amide" or "aminocarboxy" include a compound or moiety containing a nitrogen atom that is bonded to the carbon of a carbonyl or thiocarbonyl group.

[0409] As used herein, the term "alkaminocarboxy" includes an alkyl, alkenyl, or alkynyl group bonded to an amino group that is bonded to the carbon of a carbonyl or thiocarbonyl group.

[0410] As used herein, the term "arylaminocarboxy" includes an aryl or heteroaryl moiety bonded to an amino group that is bonded to the carbon of a carbonyl or thiocarbonyl group.

[0411] As used herein, the terms "alkylaminocarboxy", "alkenylaminocarboxy", "alkynylaminocarboxy", and "arylaminocarboxy" include the moieties in which the alkyl, alkenyl, alkynyl, and aryl moieties are respectively bonded to a nitrogen atom that is in turn bonded to the carbon of a carbonyl group.

[0412] The amide can be substituted by substituents such as straight-chain alkyl, branched-chain alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. The substituents on the amide group can be further substituted.

[0413] By treating with an oxidizing agent (such as 3-chloroperoxybenzoic acid ( m CPBA) and / or hydrogen peroxide), the nitrogen-containing compounds of the present disclosure can be converted into N-oxides to provide other compounds of the present disclosure. Accordingly, all the nitrogen-containing compounds shown and claimed are considered to include both the shown compounds and their N-oxide derivatives (which may be designated as N O or N + -O-) when the valence and structure permit. In addition, in other cases, the nitrogen in the compounds of the present disclosure can be converted into N-hydroxy or N-alkoxy compounds. For example, the N-hydroxy compounds can be prepared by oxidizing the parent amine with an oxidizing agent such as m -CPBA. All the nitrogen-containing compounds shown and claimed are also considered to cover both the shown compounds and their N-hydroxy (i.e., N-OH) and N-alkoxy derivatives when the valence and structure permit.

[0414] In this specification, for convenience, the structural formula of a compound represents a certain isomer in some cases, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc. It should be understood that not all isomers may have the same activity level. Additionally, there may be crystal polymorphs for the compounds represented by the formula. It is noted that any crystal form, mixture of crystal forms or their anhydrides or hydrates are included within the scope of the present disclosure.

[0415] As used herein, the term "isomerism" means compounds having the same molecular formula but different orders of atomic bonding or different spatial arrangements of their atoms. Isomers with different spatial arrangements of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are non-superimposable mirror images of each other are called enantiomers, or sometimes called optical isomers. A mixture containing equal amounts of the single enantiomeric forms with opposite chirality is called a "racemic mixture".

[0416] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0417] As used herein, the term "chiral isomer" means a compound having at least one chiral center. A compound having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers, called a "mixture of diastereomers". When there is one chiral center, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. According to the sequence rules of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116), the substituents attached to the chiral center under consideration are ranked.

[0418] As used herein, the term "geometric isomer" means a diastereomer that exists due to restricted rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate whether the groups are on the same side or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0419] It should be understood that the compounds of the present disclosure can be depicted as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral isomer or geometric isomer forms, all isomer forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomer form, but it should be understood that not all isomers may have the same activity level.

[0420] It should be understood that the structures and other compounds discussed in the present disclosure include all atropisomers thereof. It should also be understood that not all atropisomers may have the same activity level.

[0421] As used herein, the term "atropisomer" is a type of stereoisomer in which the atomic spatial arrangements of the two isomers are different. Atropisomers exist due to restricted rotation caused by the hindrance of large groups rotating around a central bond. Such atropisomers usually exist as a mixture, however, due to recent advances in chromatographic techniques, in selected cases, a mixture of two atropisomers can be separated.

[0422] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of an adjacent conjugated double bond. Tautomers exist as a mixture of tautomer groups in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Among the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, both an electron and a hydrogen atom move simultaneously. Ring-chain tautomerism occurs due to the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, as shown in glucose for example.

[0423] It should be understood that the compounds of the present disclosure can be depicted as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a higher activity level than other isomers.

[0424] As used herein, the terms "crystal polymorph", "polymorph", or "crystal form" mean crystal structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may result in one crystal form being dominant. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0425] It should be understood that the compounds of any formula described herein include the compound itself as well as its salts and its solvates (if applicable). For example, salts can be formed between an anion and a positively charged group (such as an amino group) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (such as trifluoroacetate).

[0426] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations and negatively charged groups (such as carboxylate) on the substituted benzene compounds. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations, such as tetramethylammonium ion. Substituted benzene compounds also include those salts containing a quaternary nitrogen atom.

[0427] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0428] As used herein, the term "solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, where the water maintains its molecular state as H2O.

[0429] As used herein, the term "analogue" refers to a compound that is structurally similar to another but has a slightly different composition (such as one atom being replaced by an atom of a different element or in the presence of a specific functional group, or one functional group being replaced by another functional group). Thus, an analogue is a compound that is similar or comparable in function and appearance, but whose structure or origin is not similar or comparable to the reference compound.

[0430] As used herein, the term "derivative" refers to a compound having a common core structure and substituted by various groups as described herein.

[0431] As used herein, the term "bioisostere" refers to a compound produced by the exchange of one atom or a group of atoms with another atom or group of atoms that is generally similar. The purpose of bioisosteric replacement is to create a new compound with biological properties similar to the parent compound. Bioisosteric replacement can be based on physicochemistry or topology. Examples of carboxylic acid bioisosteres include (but are not limited to) acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0432] It should be understood that the present disclosure is intended to include all isotopes of atoms that occur in the present compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0433] As used herein, the expressions "one or more of A, B, or C", "one or more of A, B, and C", "one or more selected from A, B, and C", "selected from the group consisting of A, B, and C", "selected from A, B, and C", etc. are used interchangeably and all refer to being selected from A, B, and / or C, i.e., one or more of A, one or more of B, one or more of C, or any combination thereof, unless otherwise specified.

[0434] As used herein, the term "substantially the same" refers to a value that falls within any normal range of a reference value (e.g., the value in a comparable subject), as would be recognized by a person of ordinary skill in the relevant art. In some embodiments, the term "substantially the same" refers to a value that falls within the range of about 40% - about 160%, about 50% - about 150%, about 60% - about 140%, about 70% - about 130%, about 80% - about 120%, about 90% - 110%, or about 95% - about 105% of the reference value (e.g., the value in a comparable subject). In some embodiments, the term "substantially the same" refers to a value that is about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 102%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140%, or about 150% of the reference value (e.g., the value in a comparable subject).

[0435] It should be understood that the present disclosure provides methods for synthesizing compounds of any formula described herein. The present disclosure also provides detailed methods for synthesizing the various disclosed compounds of the present disclosure according to the following schemes and those shown in the examples.

[0436] It should be understood that throughout the description, when a composition is described as having, including, or containing a particular component, it is contemplated that the composition also consists essentially of or consists of the said component. Similarly, when a method or process is described as having, including, or containing a particular process step, the process also consists essentially of or consists of the said process step. Further, it should be understood that as long as the present invention remains operable, the order of steps or the order for performing certain actions is not important. In addition, two or more steps or actions can be carried out simultaneously.

[0437] It should be understood that the synthetic methods of the present disclosure allow a wide variety of functional groups, and thus various substituted starting materials can be used. The methods generally provide the desired final compounds at or near the end of the overall process, although in some cases it may be desirable to further convert the compounds into their pharmaceutically acceptable salts.

[0438] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art based on the teachings herein, using commercially available starting materials, compounds known in the literature, or intermediates prepared easily. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 5th Edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis , 3rd Edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, Editor, Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995), which are incorporated herein by reference, are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

[0439] Those of ordinary skill in the art should note that during the reaction sequences and synthetic schemes described herein, the order of certain steps can be varied, such as the introduction and removal of protecting groups. Those of ordinary skill in the art will recognize that certain groups may need to be protected using protecting groups from the reaction conditions. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis , 3rd Edition, John Wiley & Sons: New York, 1999.

[0440] It should be understood that, unless otherwise specified, any description of a method of treatment includes the use of a compound to provide such treatment or prophylaxis as described herein, and the use of a compound to prepare a medicament for treating or preventing such a disorder. Treatment includes treating a human or non-human animal, including rodents and other disease models.

[0441] As used herein, the term "subject" may be interchangeable with the term "subject in need thereof", both of which refer to a subject suffering from a disease or at increased risk of developing the disease. "Subject" includes mammals. The mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human.

[0442] As used herein, the term "comparable subject" refers to a subject having comparable parameters or being in comparable conditions to the subject being compared (e.g., the subject being treated). For example, a "comparable subject" may have the same disease as the subject being compared, or be at increased risk of developing the same disease as the subject being compared. For another example, a "comparable subject" may exhibit one or more plasma pharmacokinetic parameters (e.g., C maxor AUC). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of a β-lactam compound, probenecid, and / or valproic acid) can undergo a condition as a "comparable subject" before treatment (e.g., administering a β-lactam compound and probenecid without valproic acid). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of a β-lactam compound, probenecid, and / or valproic acid) can undergo a condition as a "comparable subject" before treatment (e.g., administering a β-lactam compound and valproic acid without probenecid). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of a β-lactam compound, probenecid, and / or valproic acid) can undergo a condition as a "comparable subject" before treatment (e.g., administering valproic acid and probenecid without a β-lactam compound). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of a β-lactam compound and / or valproic acid) can undergo a condition as a "comparable subject" before treatment (e.g., administering a β-lactam compound without valproic acid). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of a β-lactam compound and / or probenecid) can undergo a condition as a "comparable subject" before treatment (e.g., administering a β-lactam compound without probenecid). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of probenecid and / or a β-lactam compound) can undergo a condition as a "comparable subject" before treatment (e.g., administering probenecid without a β-lactam compound). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of probenecid and / or valproic acid) can undergo a condition as a "comparable subject" before treatment (e.g., administering probenecid without valproic acid). In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of valproic acid and / or a β-lactam compound) can undergo a condition as a "comparable subject" before treatment (e.g., administering valproic acid without a β-lactam compound).In some embodiments, a "comparable subject" can be a subject being compared at different times. For example, a subject being treated (e.g., by administering a combination of valproic acid and / or probenecid) can be subject to a condition as a "comparable subject" before treatment (e.g., administering valproic acid without probenecid).

[0443] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, disorder or condition, and includes administering a compound of the present disclosure or a pharmaceutically acceptable salt, polymorph or solvate thereof to alleviate symptoms or complications of the disease, disorder or condition, or to eliminate the disease, disorder or condition. The term "treatment" can also include treatment of in vitro cell or animal models.

[0444] As used herein, the term "temporally proximate" means that the administration of one therapeutic agent (e.g., a β-lactam, probenecid or valproic acid compound disclosed herein) occurs within a period of time before or after the administration of another therapeutic agent (e.g., a β-lactam, probenecid or valproic acid) such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, "temporally proximate" means that the administration of one therapeutic agent occurs within a period of time before or after the administration of another therapeutic agent such that there is a synergistic effect between the one therapeutic agent and the other therapeutic agent. "Temporally proximate" can vary according to various factors, including (but not limited to) the age, sex, weight, genetic background, medical condition, medical history and treatment history of the subject to whom the therapeutic agent is to be administered; the disease or disorder to be treated or improved; the therapeutic outcome to be achieved; the dose, dosing frequency and dosing duration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some embodiments, "temporally proximate" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can occur temporally proximate to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0445] It should be understood that the compounds of the present disclosure or pharmaceutically acceptable salts, polymorphs or solvates thereof can or may also be used for preventing related diseases, disorders or conditions, or for identifying suitable candidates for such purposes.

[0446] As used herein, the terms "preventing", "prevent", or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such disease, disorder or condition.

[0447] It should be understood that for a detailed description of known or equivalent techniques discussed herein, those skilled in the art may refer to general reference texts. These texts include Ausubel et al. , Current Protocols in Molecular Biology , John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al. . , Current Protocols in Immunology , John Wiley & Sons, N.Y.; Enna et al. . , Current Protocols in Pharmacology , John Wiley & Sons, N.Y.; Fingl et al. . , The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, PA, 18th Edition (1990), Mandell et al., Principles and Practice of Infectious Diseases , Saunders Publishing (8th Edition, 2014). Of course, these texts may also be referred to in the preparation or use of aspects of the present disclosure.

[0448] It should be understood that the present disclosure also provides pharmaceutical compositions comprising a combination of any of the compounds described herein with at least one pharmaceutically acceptable excipient or carrier.

[0449] As used herein, the term "pharmaceutical composition" refers to a preparation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk form or unit dosage form. The unit dosage form can be any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps on aerosol inhalers, or vials. The amount of the active ingredient (e.g., a preparation of the disclosed compound or its salt, hydrate, solvate, or isomer) in the unit dosage composition is an effective amount and varies depending on the particular treatment involved. Those skilled in the art will understand that conventional variations in the dosage are sometimes required depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhaled, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the disclosed compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0450] As used herein, the term "pharmaceutically acceptable" means those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0451] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and otherwise not undesirable for use in the preparation of pharmaceutical compositions and includes excipients acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one of such excipients.

[0452] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The pH may be adjusted with an acid or a base, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in ampoules made of glass or plastic, disposable syringes, or multi-dose vials.

[0453] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapeutic treatment. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or administered orally or through the skin with a patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. Preferably, the patient's disease condition and health are closely monitored during and for a reasonable time after treatment.

[0454] As used herein, the term "therapeutically effective amount" refers to an amount of an agent that treats, ameliorates, or prevents an identified disease or disorder, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the disorder; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0455] It should be understood that for any compound, the therapeutically effective amount can initially be estimated, for example, in cell culture assays of neoplastic cells, or in animal models, typically rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine the useful dose and route for human administration. Therapeutic / preventive efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose effective in treating 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, and can be expressed as the ratio, LD 50 / ED 50Pharmaceutical compositions showing a large therapeutic index are preferred. The dosage can vary within this range, depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0456] The dosage and administration are adjusted to provide an adequate level of the active agent or to maintain the desired effect. Factors to be considered include the severity of the disease state, the general health of the subject, the age, weight, and sex of the subject, diet, the time and frequency of administration, drug combination, response sensitivity, and tolerance / reactivity to the therapy. Depending on the half-life and clearance rate of the particular formulation, long-acting pharmaceutical compositions may be administered every 3 - 4 days, weekly, or bi-weekly.

[0457] Pharmaceutical compositions containing the active compounds of the present disclosure can be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, dragee preparation, grinding, emulsifying, encapsulating, entrapping, or lyophilizing processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers that include excipients and / or auxiliaries that facilitate processing of the active compounds into a pharmaceutically usable preparation. Of course, the appropriate formulation depends on the chosen route of administration.

[0458] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy injectability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, polyols (such as mannitol and sorbitol), and sodium chloride. Prolonged absorption of the injectable composition can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0459] A sterile injectable solution can be prepared by incorporating the required amount of the active compound into a suitable solvent with one or a combination of the ingredients listed above, and then, if desired, filtering the solution to sterilize it. Generally, a dispersion is prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying to produce a powder of the active ingredient plus any other desired ingredients from its previously sterile filtered solution.

[0460] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a liquid carrier to be used as a mouthwash, wherein the compound in the liquid carrier is orally administered, swished around, and then either spat out or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of a similar nature: binding agents such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0461] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (e.g., a gas such as carbon dioxide) or a nebulizer.

[0462] Systemic administration can also be effected by transmucosal or transdermal means. For transmucosal or transdermal administration, permeating agents suitable for the barrier to be permeated are used in the formulation. Such permeating agents are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be effected by using a nasal spray or a suppository. For transdermal administration, the active compound is formulated as an ointment, paste, gel, or cream as is generally known in the art.

[0463] The active compound can be prepared with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. The methods for preparing such formulations should be obvious to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0464] It is particularly advantageous to formulate the oral or parenteral composition in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unit doses for the subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification of the unit dosage form of the present disclosure is determined by and directly depends on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0465] In therapeutic applications, the dosage of the pharmaceutical composition used according to the present disclosure varies according to the following: the agent, the recipient patient's drug, age, weight, and clinical condition, and the experience and judgment of the clinician or practitioner administering the therapy and other factors affecting the selected dosage. Generally, the dosage should be sufficient to cause a reduction in the symptoms of the disease and preferably regression, and also preferably lead to the complete regression of the disease. The dosage can be in the range of about 0.01 mg / kg per day to about 5000 mg / kg per day. In a preferred aspect, the dosage can be in the range of about 1 mg / kg per day to about 1000 mg / kg per day. In one aspect, the dosage will be in the range of about 0.1 mg / day to about 50 g / day, about 0.1 mg / day to about 25 g / day, about 0.1 mg / day to about 10 g / day, about 0.1 mg to about 3 g / day, or about 0.1 mg to about 1 g / day in single, divided, or continuous doses (the dosage of which can be adjusted according to the patient's weight (kg), body surface area (m 2 ) and age (years)). An effective amount of the agent is a drug that provides an objectively recognizable improvement as indicated by a clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term "dosage effective manner" refers to the amount of the active compound that produces the desired biological effect in a subject or cell.

[0466] It should be understood that the pharmaceutical composition may be included in a container, package, or dispenser together with instructions for administration.

[0467] It should be understood that for the compounds of the present disclosure that are capable of further forming salts, all such forms are also considered to be within the scope of the claimed disclosure.

[0468] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, wherein the parent compound is modified by preparing its acid or base salt. In some embodiments, the pharmaceutically acceptable salts of the compounds (such as the β-lactam compounds or probenecid described herein) are also prodrugs of the compounds. Examples of pharmaceutically acceptable salts include (but are not limited to) mineral or organic acid salts of basic residues such as amines, and base or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include (but are not limited to) those derived from inorganic and organic acids selected from the following: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinol, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (napsylic), nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0469] Other examples of pharmaceutically acceptable salts include caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present disclosure also includes salts formed when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth ions, or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0470] It should be understood that all references to pharmaceutically acceptable salts include solvate addition forms (solvates) or crystal forms (polymorphs) of the same salt as defined herein.

[0471] As used herein, the term "prodrug" refers to any agent that is converted, in whole or in part, to the targeted compound (e.g., a β-lactam compound or probenecid as described herein) when administered to a mammal. In some embodiments, a prodrug of a compound (e.g., a β-lactam compound or probenecid as described herein) is also a pharmaceutically acceptable salt of the compound.

[0472] It should be understood that the compounds of the present disclosure can also be prepared as esters, e.g., pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, e.g., a methyl ester, an ethyl ester, or other esters. In addition, an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate ester, a propionate ester, or other esters.

[0473] The compounds or their pharmaceutically acceptable salts are administered orally, nasally, transdermally, pulmonary, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compounds are administered orally. Those skilled in the art will appreciate the advantages of certain routes of administration.

[0474] The dosing regimen for using the compounds is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the kidney and liver function of the patient; and the particular compound or its salt employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, combat, or arrest the progression of the condition.

[0475] Techniques for formulating and administering the compounds of the present disclosure are found in Remington: the Science and Practice of Pharmacy , 19th Edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds and their pharmaceutically acceptable salts described herein are combined with a pharmaceutically acceptable carrier or diluent for a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

[0476] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the various examples. The examples provided illustrate different components and methods useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, those skilled in the art can identify and employ other components and methods useful in practicing the present disclosure.

[0477] In the synthetic schemes described herein, for simplicity, compounds may be depicted as having a specific configuration. Such a specific configuration should not be construed as limiting the disclosure to one or the other isomers, tautomers, regioisomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0478] Once compounds designed, selected, and / or optimized by the above methods are produced, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including (but not limited to) those described below, to determine whether they have predicted activity, binding activity, and / or binding specificity.

[0479] In addition, high-throughput screening can be used to accelerate the analysis using such assays. As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening , Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including (but not limited to) those described below.

[0480] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to admit that any one is relevant prior art, nor does it constitute any admission as to its content or date. The invention has now been described by written description, and those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and the foregoing description and the following examples are for illustrative purposes and not to limit the appended claims. Examples

[0481] Example 1. Effects of Sulopenem and Sulopenem Esters on Valproic Acid Administration

[0482] For Group 1, relative to valproic acid administered alone, multiple-dose intravenous sulopenem (1,000 mg infused over 3 hours) extrapolated from time 0 to the area under the plasma concentration-time curve (AUC 0-tau ) and the maximum observed plasma concentration (C maxSS)Decreased by approximately 33% and 28%, respectively. Compared to valproic acid administered alone, co - administration of valproic acid and tialampicillin (500 mg) without probenecid decreased the valproic acid AUC 0-tau and C maxSS by approximately 25% and 19%, respectively (Tables 1 - 3 and Figure 1-2 ). In contrast, for AUC 0-tau and C maxSS , the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of valproic acid and the bilayer tablets to valproic acid alone were within the 80 - 125% criteria used to demonstrate bioequivalence.

[0483] Table 1

[0484]

[0485] Table 2

[0486]

[0487] Table 3

[0488]

[0489] Example 2. Effect of Probenecid on the Bioavailability of Valproic Acid Administered with Tialampicillin

[0490] For Groups 2 and 3, all patients received valproic acid daily. Starting on Day 5, Group 3 received tialampicillin tablets (“Etzadroxil tablets”) alone and Group 2 received bilayer tablets of tialampicillin and probenecid (500 mg tialampicillin + 500 mg probenecid film - coated bilayer tablets; “bilayer tablets”). The effects on the bioavailability of valproic acid are shown in Figure 3 and Tables 4 - 6. After oral administration of a single dose of tialampicillin (bilayer or etzadroxil tablets), the median time to reach the maximum observed plasma concentration (t max ) was 2.000 hours. The tialampicillin / probenecid bilayer tablets had no effect on the steady - state pharmacokinetic characteristics of valproic acid in healthy adult male subjects, while the effect of multiple - dose intravenous tialampicillin or tialampicillin tablets was weak. These findings confirm that the effect of probenecid on the bioavailability of valproic acid can occur as early as 3 days.

[0491] Overall, valproic acid and tialampicillin were well - tolerated and safe in all formulations. The most common treatment - emergent adverse events (TEAEs) related to the drugs were mild diarrhea and abnormal urine odor. There were no deaths or serious adverse events (SAEs). No clinically significant changes in vital signs, 12 - lead electrocardiograms, physical examinations, or clinical laboratory parameters were reported during the study.

[0492] Table 4. Overview of the pharmacokinetic parameters of valproic acid.

[0493]

[0494] Table 5. Overview of the pharmacokinetic parameters of valproic acid (ng / mL) in the second group on the 5th day - pharmacokinetic parameter group.

[0495]

[0496]

[0497] Table 6. Overview of the pharmacokinetic parameters of plasma valproic acid (μg / mL) in the third group - pharmacokinetic parameter group

[0498]

[0499]

[0500] Example 3. Effect of probenecid on the bioavailability of meropenem in subjects administered valproic acid and etimicin

[0501] For the second and third groups, all patients were administered valproic acid daily. Starting on the 5th day, the third group was administered etimicin tablets ("Etzadroxil tablets") alone and the second group was administered a bilayer tablet of etimicin and probenecid (500 mg etimicin + 500 mg probenecid film-coated bilayer tablet; "bilayer tablet"). The effects of the administration on the bioavailability of meropenem are shown in Tables 7 - 10. The comparison between Tables 7 and 9 shows that the pharmacokinetic parameters of meropenem were improved by administering the bilayer tablet after 5 days. The comparison between Tables 8 and 10 shows that the pharmacokinetic parameters of meropenem were improved by administering the bilayer tablet after 7 days.

[0502] Table 7. Overview of the pharmacokinetic parameters of meropenem (ng / mL) in the second group on the 5th day - pharmacokinetic parameter group.

[0503]

[0504]

[0505] Table 8. Overview of the pharmacokinetic parameters of meropenem (ng / mL) in the second group on the 7th day - pharmacokinetic parameter group.

[0506]

[0507]

[0508] Table 9. Overview of the pharmacokinetic parameters of meropenem (ng / mL) for the treatment of Group 3 on Day 5 - Pharmacokinetic parameter group.

[0509]

[0510] Table 10. Overview of the pharmacokinetic parameters of meropenem (ng / mL) for the treatment of Group 3 on Day 7 - Pharmacokinetic parameter group.

[0511]

[0512]

[0513] Equivalents

[0514] It should be understood that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. Accordingly, the foregoing embodiments are to be considered in all respects as illustrative rather than restrictive of the invention described herein. Therefore, the scope of the present invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A combination product for treating or preventing a disease, which is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection or infectious diarrhea, wherein the combination product comprises: A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof; Wherein the β-lactam compound is: Or a pharmaceutically acceptable salt thereof; and Wherein the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

2. A combination product for treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof, which is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection or infectious diarrhea, wherein the combination product comprises: A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof; Wherein the β-lactam compound is: Or a pharmaceutically acceptable salt thereof; and The valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

3. The combination product of claim 2, wherein the administration reduces or alleviates side effects.

4. The combination product of claim 2, wherein the administration reduces or alleviates side effects of administering valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof in the absence of administering probenecid or a pharmaceutically acceptable salt thereof.

5. The combination product of claim 3 or 4, wherein the side effects are mania, seizure, increased likelihood of seizure, decreased valproic acid concentration in the subject, neuro-motor impairment or the likelihood of neuro-motor impairment.

6. The combination product of claim 5, wherein the side effect is decreased valproic acid concentration in the subject associated with co-administering a β-lactam compound.

7. The combination product of claim 2, wherein the administration results in an increase in valproic acid concentration in the subject as compared to comparable subjects administered in the absence of probenecid or a pharmaceutically acceptable salt thereof.

8. The combination product of claim 2, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, the administration results in a higher area under the curve (AUC) of the plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in subjects in need thereof.

9. The combination product of claim 8, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, the administration results in an area under the curve (AUC) of the plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof that is 0.1% or greater, 0.25% or greater, 0.5% or greater, 0.75% or greater, 1% or greater, 2% or greater, 3% or greater, 4% or greater, 5% or greater, 6% or greater, 7% or greater, 8% or greater, 9% or greater, 10% or greater, 15% or greater, 20% or greater, 25% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 80% or greater, 100% or greater, 150% or greater, 200% or greater, 300% or greater, 400% or greater, or 500% or greater in subjects in need thereof.

10. The combination product of claim 2, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, the administration results in a higher maximum plasma concentration (C max ) of valproic acid or a pharmaceutically acceptable salt thereof in subjects in need thereof.

11. The combination product of claim 10, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days after administration, compared to comparable subjects administered a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof in the absence of probenecid or a pharmaceutically acceptable salt thereof, the administration results in a maximum plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in subjects in need thereof that is 0.1% or greater, 0.25% or greater, 0.5% or greater, 0.75% or greater, 1% or greater, 2% or greater, 3% or greater, 4% or greater, 5% or greater, 6% or greater, 7% or greater, 8% or greater, 9% or greater, 10% or greater, 15% or greater, 20% or greater, 25% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 80% or greater, 100% or greater, 150% or greater, 200% or greater, 300% or greater, 400% or greater or 500% or greater than (C max ).

12. The combination product of claim 2, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, compared to comparable subjects administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, the administration results in an area under the curve (AUC) of the plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof that is substantially the same in subjects in need thereof.

13. The combination product of claim 12, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having an area under the curve (AUC) within the range of 50%-150%, 60%-140%, 70%-130%, 80%-120%, 90%-110%, or 95%-105% of the area under the curve (AUC) caused by a comparable subject administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof.

14. The combination product of claim 12, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having an area under the curve (AUC) that is 50%, 60%, 70%, 80%, 90%, 95%, 98%, 102%, 105%, 110%, 115%, 120%, 125%, 130%, 140%, or 150% of the area under the curve (AUC) caused by a comparable subject administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof.

15. The combination product of claim 2, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, compared to comparable subjects administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof having substantially the same maximum plasma concentration (C max ) in subjects in need thereof.

16. The combination product of claim 15, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof that is within 50%-150%, 60%-140%, 70%-130%, 80%-120%, 90%-110%, or 95%-105% of the maximum plasma concentration (C max ) caused by a comparable subject administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof max .

17. The combination product of claim 15, wherein within 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days after administration, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof that is 50%, 60%, 70%, 80%, 90%, 95%, 98%, 102%, 105%, 110%, 115%, 120%, 125%, 130%, 140% or 150% of the maximum plasma concentration (C max ) caused by a comparable subject administered valproic acid or a pharmaceutically acceptable salt thereof in the absence of a β-lactam compound, probenecid or a pharmaceutically acceptable salt thereof. max ) 18. The combination product of claim 2, wherein the subject in need thereof is a human.

19. The combination product of claim 1 or 2, wherein the β-lactam compound is selected from: and its pharmaceutically acceptable salts.

20. The combination product of claim 19, wherein the β-lactam compound is selected from: and its pharmaceutically acceptable salts.

21. The combination product of claim 20, wherein the β-lactam compound is:

22. The combination product of claim 1 or 2, wherein the pharmaceutical salt of valproic acid is sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, or aluminum salt.

23. The combination product of claim 2, wherein valproic acid or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three or more times daily.

24. The combination product of claim 2, wherein valproic acid or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

25. The combination product of claim 2, wherein valproic acid or a pharmaceutically acceptable salt thereof is administered without any drug holidays.

26. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three or more times daily.

27. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

28. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof is administered without any drug holiday.

29. The combination product of claim 2, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, three times daily or more.

30. The combination product of claim 2, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

31. The combination product of claim 2, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered without any drug holiday.

32. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof and the probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or alternately.

33. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof and the probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

34. The combination product of claim 2, wherein an oral co-formulation comprising the β-lactam compound or a pharmaceutically acceptable salt thereof and the probenecid or a pharmaceutically acceptable salt thereof is administered.

35. The combination product of claim 2, wherein a tablet comprising the β-lactam compound or a pharmaceutically acceptable salt thereof and the probenecid or a pharmaceutically acceptable salt thereof is administered.

36. The combination product of claim 35, wherein the tablet is a bilayer tablet, comprising: a second layer comprising the β-lactam compound or a pharmaceutically acceptable salt thereof; and a first layer comprising probenecid or a pharmaceutically acceptable salt thereof.

37. The combination product of claim 36, wherein the first layer comprises 20 mg - 5 g, 50 mg - 2 g, 80 mg - 1 g, 100 mg - 900 mg, 200 mg - 800 mg, 300 mg - 700 mg, 400 mg - 600 mg, 450 mg - 550 mg or 480 mg - 520 mg of probenecid or a pharmaceutically acceptable salt thereof.

38. The combination product of claim 36, wherein the second layer comprises 20 mg - 5 g, 50 mg - 2 g, 80 mg - 1 g, 100 mg - 900 mg, 200 mg - 800 mg, 300 mg - 700 mg, 400 mg - 600 mg, 450 mg - 550 mg or 480 mg - 520 mg of the β-lactam compound or a pharmaceutically acceptable salt thereof.

39. The combination product of claim 36, wherein the first layer comprises 500 ± 450 mg, 500 ± 400 mg, 500 ± 350 mg, 500 ± 300 mg, 500 ± 250 mg, 500 ± 200 mg, 500 ± 150 mg, 500 ± 100 mg, 500 ± 90 mg, 500 ± 80 mg, 500 ± 70 mg, 500 ± 60 mg, 500 ± 50 mg, 500 ± 45 mg, 500 ± 40 mg, 500 ± 35 mg, 500 ± 30 mg, 500 ± 25 mg, 500 ± 20 mg, 500 ± 15 mg, 500 ± 10 mg or 500 ± 5 mg of probenecid or a pharmaceutically acceptable salt thereof.

40. The combination product of claim 36, wherein the second layer comprises 500 ± 400 mg, 500 ± 350 mg, 500 ± 300 mg, 500 ± 250 mg, 500 ± 200 mg, 500 ± 150 mg, 500 ± 100 mg, 500 ± 90 mg, 500 ± 80 mg, 500 ± 70 mg, 500 ± 60 mg, 500 ± 50 mg, 500 ± 45 mg, 500 ± 40 mg, 500 ± 35 mg, 500 ± 30 mg, 500 ± 25 mg, 500 ± 20 mg, 500 ± 15 mg, 500 ± 10 mg or 500 ± 5 mg of the β-lactam compound or a pharmaceutically acceptable salt thereof.

41. The combination product of claim 36, wherein the bilayer tablet further comprises one or more pharmaceutical excipients.

42. The combination product of claim 41, wherein the one or more pharmaceutical excipients are selected from cellulose, sodium carboxymethylcellulose cross-linked, magnesium stearate, lactose monohydrate and hydroxypropylcellulose.

43. The combination product of claim 2, wherein the valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 50 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 500 mg per day, 1 g per day, 2 g per day, 3 g per day, 4 g per day or 5 g per day.

44. The combination product of claim 2, wherein the valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day.

45. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 50 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 500 mg per day, 1 g per day, 2 g per day, 3 g per day, 4 g per day or 5 g per day.

46. The combination product of claim 2, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day.

47. The combination product of claim 2, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of 50 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 500 mg per day, 1 g per day, 2 g per day, 3 g per day, 4 g per day or 5 g per day.

48. The combination product of claim 2, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day.

49. The combination product of claim 2, wherein: The valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day; The β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day; and The probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of 500 ± 300 mg per day, 500 ± 250 mg per day, 500 ± 200 mg per day, 500 ± 150 mg per day, 500 ± 100 mg per day, 500 ± 90 mg per day, 500 ± 80 mg per day, 500 ± 70 mg per day, 500 ± 60 mg per day, 500 ± 50 mg per day, 500 ± 40 mg per day, 500 ± 30 mg per day, 500 ± 20 mg per day, 500 ± 10 mg per day, 500 ± 5 mg per day, 500 ± 4 mg per day, 500 ± 3 mg per day, 500 ± 2 mg per day, 500 ± 1 mg per day.

50. Use of a pharmaceutical composition in the preparation of a medicament for treating or preventing a disease, wherein the disease is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection or infectious diarrhea, wherein the pharmaceutical composition comprises: A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof: wherein the β-lactam compound is: or a pharmaceutically acceptable salt thereof, and wherein the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

51. A pharmaceutical kit for treating or preventing a disease, which is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection or infectious diarrhea, and the pharmaceutical kit comprises: A pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; A pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof; wherein the β-lactam compound is: or a pharmaceutically acceptable salt thereof, and wherein the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

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