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WO2024249380A2 - 1h-pyrazolo [3,4-d] pyrimidin-4-amines en tant qu'agents anti-infectieux - Google Patents

1h-pyrazolo [3,4-d] pyrimidin-4-amines en tant qu'agents anti-infectieux Download PDF

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Publication number
WO2024249380A2
WO2024249380A2 PCT/US2024/031193 US2024031193W WO2024249380A2 WO 2024249380 A2 WO2024249380 A2 WO 2024249380A2 US 2024031193 W US2024031193 W US 2024031193W WO 2024249380 A2 WO2024249380 A2 WO 2024249380A2
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substituted
mmol
unsubstituted
methyl
ethyl
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WO2024249380A3 (fr
Inventor
Christopher HUSTON
Makafui GASONOO
Maryam ZANGI
Soumitra GUIN
Anusha GOKANAPALLE
Ankita Sarkar
Marvin J. Meyers
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University of Vermont
St Louis University
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University of Vermont
St Louis University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Cryptosporidium parvum and Cryptosporidium hominis are major etiologic agents of cryptosporidiosis in humans. Infection is typically self- limited in immunocompetent adults, but it can lead to chronic and fulminant disease in immunocompromised patients, as well as malnutrition and stunting in children. Nitazoxanide is the current standard of care for cryptosporidiosis, but the drug only exhibits partial efficacy in children and is no more effective than placebo in AIDS patients.
  • Diarrhea is also a leading cause of death in children under 5 years of age, and the recent Global Enteric Multicenter Study (GEMS) identified Cryptosporidium as a major cause of life-threatening diarrhea during the first two years of life. Moreover, cryptosporidiosis has been associated with malnutrition and persistent deficits in development in this population.
  • GEMS Global Enteric Multicenter Study
  • the present disclosure provides compounds and methods for treating a Cryptosporidium infection or a method for prophylaxis and/or treatment comprising administering to an individual a therapeutically effective amount of a compound having a 1H-pyrazolo[3,4-d]pyrimidin-4-amine scaffold.
  • a compound of the present disclosure can have the following structure: , H, a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl, or a substituted or unsubstituted -CH2-aryl group.
  • a substituted or unsubstituted alkyl group e.g., a halogenated alkyl group
  • a substituted or unsubstituted cycloalkyl group e.g., a substituted or unsubstituted aryl
  • a substituted or unsubstituted -CH2-aryl group e.g., a substituted or unsubstituted -CH2-aryl group.
  • R 5 is H, a cyano, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group (including benzoxaboroles), a substituted or unsubstituted heteroaryl group, a heteroaryl substituted amine, an aryl substituted amine, a substituted or unsubstituted cycloaliphatic group, a carboxylic acid, a substituted or unsubstituted amine, a substituted or unsubstituted imidamide, or a halogen (e.g., Cl, F).
  • a cyano e.g., Cl, F
  • aryl refers to C 5 to C 30 aromatic or partially aromatic carbocyclic groups, including all integer numbers of carbons and ranges of numbers of carbons therebetween (e.g., C5, C6, C7, C8, C9, C 10 , C 11 , C 12, C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , and C30).
  • An aryl group may also be referred to as an aromatic group.
  • R 3 and R 4 groups include, but are not limited to,-H, -CH 3 , , . e: (forming a pyrrolidyl group (forming a pyrrolidyl group), (forming a piperidinyl group (forming a piperidinyl group), (forming a piperazinyl group), an (forming a morpholino group).
  • a compou the present disclosure has the following , ethyl, -Cl, -F, -OMe, -NMe2, -CF3 , and alkoxy, and there may be one or more R 7 groups. Further examples include, but are not limited to, .
  • HN HN N R 7 R 7 or HN N R 7 N N may independently be H, substituted or unsubstituted aliphatic groups (e.g., alkyl groups, such as, for example, methyl or ethyl), substituted or unsubstituted aryl groups, or the like.
  • Each R 9 may be the same or different.
  • Prodrugs of a compound of the present disclosure also can be used as the compound in a method of the present disclosure. It is well established that a prodrug approach, wherein a compound is derivatized into a form suitable for formulation and/or administration, then released as a drug in vivo, has been successfully employed to transiently (e.g., bioreversibly) alter the physicochemical properties of the compound (see, H. Bundgaard, Ed., "Design of Prodrugs," Elsevier, Amsterdam, (1985); R.B.
  • the term "pharmaceutically acceptable salts” refers to salts or zwitterionic forms of a compound of the present disclosure. Salts of compounds of the present disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
  • the pharmaceutically acceptable salts of a compound of the present disclosure are acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • available amino groups present in the compounds of the disclosure can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference to compounds of the present disclosure appearing herein is intended to include a compound of the present disclosure as well as pharmaceutically acceptable salts, hydrates, or prodrugs thereof.
  • compositions comprising one or more compound(s) of the present disclosure.
  • the compositions may further comprise one or more pharmaceutically acceptable carrier(s).
  • the compositions may include one or more pharmaceutically acceptable carrier(s).
  • Non-limiting examples of compositions include solutions, suspensions, emulsions, solid injectable compositions that are dissolved or suspended in a solvent before use, and the like.
  • compositions of the disclosure can comprise more than one pharmaceutical agent.
  • a first composition comprising a compound of the disclosure and a first pharmaceutical agent can be separately prepared from a composition which comprises the same compound of the disclosure and a second pharmaceutical agent, and such preparations can be mixed to provide a two-pronged (or more) approach to achieving the desired prophylaxis or therapy in an individual.
  • compositions of the disclosure can be prepared using mixed preparations of any of the compounds disclosed herein.
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • Various antioxidants may be used.
  • antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lec
  • compositions of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present disclosure may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) ab
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of a compound of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to a compound of the disclosure, the composition may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • the composition may be for administration to an individual in need of treatment.
  • a composition comprises a pH sensitive polymer.
  • the composition comprises a compound of the present disclosure encapsulated in a pH sensitive polymer suitable for release of a compound of the disclosure in the small intestines, distal small intestine, or colon.
  • the pH sensitive polymer suitable for such a release can be a synthetic anionic polymer based on a monomer such as acrylic acid, methacrylic acid, propionic acid, 2-acrylmido-2-methylpropylsulfonic acid, 2-methacryloxyethylsulfonic acid, 3-methacryloxy-2-hydroxypropylsulfonic acid, ethylenesulfonic acid, styrenesulfonic acid, sulfoxyethyl methacrylate, or a combination thereof.
  • a monomer such as acrylic acid, methacrylic acid, propionic acid, 2-acrylmido-2-methylpropylsulfonic acid, 2-methacryloxyethylsulfonic acid, 3-methacryloxy-2-hydroxypropylsulfonic acid, ethylenesulfonic acid, styrenesulfonic acid, sulfoxyethyl methacrylate, or a combination thereof.
  • the anionic polymer can be a natural anionic polymer such as hyaluronic acid, alginic acid, carboxymethyl cellulose, carboxymethyl dextran, poly(aspartic acid), or heparin.
  • hyaluronic acid alginic acid
  • carboxymethyl cellulose carboxymethyl dextran
  • poly(aspartic acid) poly(aspartic acid)
  • CMEC CMEC from Freund Sangyo Co., Ltd
  • CAP from Wako Pure Chemicals Ltd.
  • HP-50 and ASM from Shin-Etsu Chemical Co., Ltd. (derived from cellulose) can be used.
  • Drug exposure both the ability to penetrate the cell and parasitophorous vacuole, and retention at the site of infection rather than oral absorption
  • the compounds are not significantly distributed systemically but are preferentially retained in the gastrointestinal tract.
  • the compounds of the method are taken up by the cells of the lumen of the gastrointestinal tract.
  • systemic exposure may be necessary in certain cases. For example, in severely immunocompromised people such as those with AIDS, infection can involve the biliary tree and, rarely, even the lungs. In these circumstances, a drug or formulation that favors systemic absorption, and/or enterohepatic recirculation may be desirable.
  • a formulation comprising a compound of the disclosure is formulated in a manner such that an extended release in the small intestines, distal small intestine, or colon is achieved.
  • pH sensitive polymers can be used as described herein.
  • the present disclosure provides a method for treating an individual diagnosed with or suspected of having a cryptosporidium infection.
  • Compounds of the present disclosure can be used in the methods.
  • a method for treating an individual diagnosed with or suspected of having a cryptosporidium infection comprises administering to the individual a therapeutically effective amount of a compound or composition of the present disclosure.
  • the compounds may be used to treat a cryptosporidium infection caused by any species of Cryptosporidium.
  • Cryptosporidium species include, Cryptosporidium parvum, Cryptosporidium andersoni, Cryptosporidium hominis, Cryptosporidium ryanae, Cryptosporidium bovis, Cryptosporidium meleagridis, Cryptosporidium baileyi, Cryptosporidium galli, Cryptosporidium felis, Cryptosporidium canis, and the like.
  • a subject infected with any one or more of the preceding species may be treated by a method of the present disclosure.
  • Cryptosporidium infection is defined as detection of Cryptosporidium in the feces, by any standard means such as microscopic parasite exam, antigen detection, and polymerase chain reaction.
  • Such individuals may be suffering from diarrhea, but may be asymptomatic where there are indications to treat for prevention of long- term sequelae (such as malnutrition and growth stunting) and for prevention of spreading infection to others.
  • treatment for cryptosporidiosis may be provided (alone or in combination with treatment for other enteric infections) for suspected infection without microbiologic confirmation.
  • the individual to be treated by the method of the disclosure may be human or non-human (e.g., mammal).
  • Non-human animals include ungulates such as bovines. Additional on-limiting examples of non-human mammals include pigs, mice, rats, rabbits, cats, dogs, or other agricultural mammals, pet, or service animals, and the like.
  • compositions comprising a compound of the disclosure and a pharmaceutical agent can be prepared at a patient’s bedside, or by a pharmaceutical manufacture.
  • the compositions can be provided in any suitable container, such as a sealed sterile vial or ampoule, and may be further packaged to include instruction documents for use by a pharmacist, physician, or other health care provider.
  • the compositions can be provided as a liquid, or as a lyophilized or powder form that can be reconstituted, if necessary, when ready for use.
  • the compositions can be provided in combination with any suitable delivery form or vehicle, examples of which include, for example, liquids, caplets, capsules, tablets, inhalants, or aerosol, etc.
  • the delivery devices may comprise components that facilitate release of the pharmaceutical agents over certain time periods and/or intervals and can include compositions that enhance delivery of the pharmaceuticals, such as nanoparticle, microsphere or liposome formulations, a variety of which are known in the art and are commercially available.
  • the dose of the composition comprising a compound of the present disclosure and a pharmaceutical agent generally depends upon the needs of the individual to whom the composition of the disclosure is to be administered. These factors include, for example, the weight, age, sex, medical history, and nature and stage of the disease for which a therapeutic or prophylactic effect is desired.
  • compositions can be used in conjunction with any other conventional treatment modality designed to improve the disorder for which a desired therapeutic or prophylactic effect is intended, non-limiting examples of which include surgical interventions and radiation therapies.
  • the compositions can be administered once, or over a series of administrations at various intervals determined using ordinary skill in the art and given the benefit of the present disclosure.
  • a compound of the present disclosure is useful in the treatment of a cryptosporidium infection.
  • the present disclosure concerns the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of such conditions and diseases.
  • the compounds of the present disclosure can be therapeutically administered as the neat chemical, but it is preferred to administer a compound of the present disclosure as a pharmaceutical composition or formulation.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure together with a pharmaceutically acceptable diluent or carrier therefor.
  • a process of preparing a pharmaceutical composition comprising admixing a compound of the present disclosure with a pharmaceutically acceptable diluent or carrier therefor.
  • the pharmaceutically acceptable formulation is such that it provides sustained delivery of a compound of the present disclosure to an individual for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically acceptable formulation is administered to the individual.
  • these pharmaceutical compositions are suitable for oral administration to an individual.
  • the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, and pastes.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, and pastes.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the individual being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a compound of the present disclosure which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, more preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • a compound of the present disclosure When administered as pharmaceuticals to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
  • the methods of the disclosure include administering to an individual a therapeutically effective amount of a compound of the present disclosure in combination with another pharmaceutically active ingredient.
  • Pharmaceutically active ingredients that may be used can be found in Harrison’s Principles of Internal Medicine, Thirteenth Edition, Eds. T.R. Harrison et al.
  • a compound of the present disclosure and the pharmaceutically active ingredient may be administered to the individual in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • Methods delineated herein include those wherein the individual is identified as in need of a particular stated treatment. Identifying an individual in need of such treatment can be in the judgment of an individual or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • the individual is prescreened or identified as in need of such treatment by assessment for a relevant marker or indicator of suitability for such treatment.
  • the compounds and compositions disclosed in the present disclosure can also be used for prophylaxis in an individual who is at risk of being exposed to cryptosporidium.
  • a prophylactic use may be useful, for example, in an individual who is about to undertake a journey to a region where an outbreak of cryptosporidium has been reported or is known to occur.
  • one or more doses of a composition comprising the compounds of the present disclosure may be administered. Dosing for prophylactic treatment may vary compared to dosing of known cryptosporidium infections. In one embodiment treatment may be given 1-3 times a day for 1 to 10 days or longer.
  • treatment is given for up to three times (such as 1 to 3 times) daily for up to 10 days (such as 1-10 days) in immunocompetent hosts.
  • immmuosuppressed hosts such as those with AIDS
  • long-term suppressive treatment may be warranted.
  • the identification of those patients who are in need of prophylactic treatment for a Cryptosporidium infection can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination and medical/family history.
  • the individual may have a Cryptosporidium infection, may be at risk of developing a Cryptosporidium infection, or may need prophylactic treatment prior to anticipated or unanticipated exposure to a condition(s) capable of increasing susceptibility to a Cryptosporidium infection.
  • those in need of prophylactic treatment for a Cryptosporidium infection can take a therapeutically effective amount of a compound of the present disclosure from 1 to 30 days prior to an anticipated or unanticipated exposure to a condition(s) capable of increasing susceptibility to a Cryptosporidium infection.
  • those in need of prophylactic treatment for a Cryptosporidium infection can take a therapeutically effective amount of a compound of the present disclosure from 1 to 24 hours prior to an anticipated or unanticipated exposure to a condition(s) capable of increasing susceptibility to a Cryptosporidium infection.
  • an individual can take a therapeutically effective amount of a compound of the present disclosure shortly after exposure to Cryptosporidium infection.
  • a method of the present disclosure be applied to cell populations ex vivo.
  • the present compounds can be used ex vivo to determine the optimal schedule and/or dosing of administration of the present compound for a given indication, cell type, patient, and other parameter. Information gleaned from such use can be used for experimental purposes or in the clinic to set protocol for in vivo treatment. Other ex vivo uses for which the disclosure is suited are apparent to those skilled in the art.
  • the steps of the method described in the various embodiments and examples disclosed herein are sufficient to treat an individual diagnosed with or suspected of having a cryptosporidium infection or a method for prophylaxis in an individual diagnosed with or suspected of having a cryptosporidium infection.
  • the method consists essentially of a combination of the steps of the method disclosed herein. In another embodiment, the method consists of such steps.
  • the following Examples are not intended to be limiting in any manner. Example 1.
  • a compound having the following structure H, a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl, or a substituted or unsubstituted -CH2-aryl group;
  • R 2 is H, a halogen, a cyano, a substituted or unsubstituted aliphatic group (e.g., a halogenated alkyl group), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted - CH 2 -aryl group;
  • R 5 is H, a cyano, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group (including benzoxaboro
  • Example 3 A compound according to Example 1 or Example 2, wherein R 5 is chosen from , , , , OH B O , , each R 9 (which may be the same or different) may independently be H, substituted or unsubstituted aliphatic groups (e.g., alkyl groups, such as, for example, methyl, ethyl), substituted or unsubstituted aryl groups, or the like.
  • R 5 is chosen from , , , , OH B O , , each R 9 (which may be the same or different) may independently be H, substituted or unsubstituted aliphatic groups (e.g., alkyl groups, such as, for example, methyl, ethyl), substituted or unsubstituted aryl groups, or the like.
  • R 5 is chosen from , , , , OH B O ,
  • each R 9 may independently be H, substituted or unsubstituted aliphatic groups (e
  • a compound according to Example 3, wherein R 5 is chosen from , , h R 9 may independently be H, substituted or unsubstituted aliphatic groups (e.g., alkyl groups, such as, for example, methyl, ethyl), substituted or unsubstituted aryl groups, or the like.
  • R 5 is chosen from , , h R 9 (which may be the same or different) may independently be H, substituted or unsubstituted aliphatic groups (e.g., alkyl groups, such as, for example, methyl, ethyl), substituted or unsubstituted aryl groups, or the like.
  • Example 5 A compound according to any one of the preceding Examples, wherein R 1 is a substituted or unsubstituted alkyl group.
  • Example 7 A compound according to any one of Examples 1–5, wherein R 1 is chosen from H, methyl, ethyl, isopropyl, propyl, cyclopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, trifluoromethyl, and the like.
  • Example 7 A compound according to any one of the preceding Examples, wherein R 1 is methyl.
  • Example 8 A compound according to any one of the preceding Examples, wherein R 2 is a substituted or unsubstituted alkyl group.
  • Example 9 A compound according to any one of Examples 1–5, wherein R 1 is chosen from H, methyl, ethyl, isopropyl, propyl, cyclopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, trifluoromethyl, and
  • Example 10 A compound according to any one of Examples 1–8, wherein R 2 is chosen from ethyl, isopropyl, propyl, cyclopropyl, phenyl, benzyl, cyano, bromo, trifluoromethyl, and the like.
  • Example 10 A compound according to any one of the preceding Examples, wherein R 2 is ethyl or propyl.
  • Example 11 A compound according to any one of the preceding Examples, wherein R 4 is ,
  • R 3 is H then R 4 is ,
  • e compound has the following structure: , is chosen from methyl, -Cl, -F, alkoxy group, -CF 3 , -NMe 2 , and the like and there may be one or more R 7 groups.
  • Example 14 A compound according to any one of the preceding Examples, wherein the compound has the following structure: Cl R 2 HN R 2 HN N O N , und has the following structure: HN HN N R 7 R 7 N N or p . p g y p g p s, wherein the compound has the following structure: Cl HN HN or Example 17.
  • R 5 is chosen from O F OH OH
  • compound has the following structure: , , , Cl , , , , , , ,
  • Example 21 A compound according to any one of Examples 1–12, wherein the compound has the following structure: , substituted and unsubstituted alkyl groups, substituted and unsubstituted CO-alkyl groups, substituted and unsubstituted CONH-alkyl groups, substituted and unsubstituted CON-dialkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted -CH 2 -aryl groups, and the like and there may be one or more R 8 groups.
  • Example 22 A compound according to Example 21, wherein the compound has the following structure: . is chosen from . p . p g p , p following structure:
  • Example 26 A composition according to Example 25, wherein the composition is for oral administration and the one or more compounds are encapsulated in a pH sensitive polymer suitable for release of the compound in the small intestines, distal small intestine, or colon.
  • Example 27 A method for treating an individual diagnosed with or suspected of having a Cryptosporidium infection or prophylaxis in an individual who is at risk of having a Cryptosporidium infection comprising administering a compound according to any one of Examples 1–24 or a composition according to any one of Examples 25 or 26.
  • Example 28 A method for treating an individual diagnosed with or suspected of having a Cryptosporidium infection or prophylaxis in an individual who is at risk of having a Cryptosporidium infection comprising administering a compound according to any one of Examples 1–24 or a composition according to any one of Examples 25 or 26.
  • kits comprising one or more compounds according to any one of Examples 1– 24 or a composition according to any one of Examples 25 or 26 or materials to prepare the composition according to any one of Examples 25 or 26 and instructions on administration details to an individual who has been diagnosed with or who is at risk of getting Cryptosporidium infection wherein the details comprise one or more of the following: dosage, frequency, and length of time for administration of the compound or the composition.
  • SLU-0010667 was achieved under potassium hydroxide mediated hydrolysis while SLU-0010256 was generated from the reaction of SLU-0010096 with hydroxylamine hydrochloride HN HN HN a b N F N F N F [0114] . thyl-1H- pyrazolo[3,4-d]pyrimidine-6-carbonitrile, SLU-0010096 under palladium catalysis.
  • Reagents and conditions (a) Zn(CN)2, Pd(PPh3)4, DMF, 110 o C, 16 hrs, 80%; (b) KOH, Ethanol:H2O (1:1), 100 oC, overnight, 81%; (c) NH 2 OH ⁇ HCl, Ethanol:H 2 O (1:1), 100 o C, overnight, 76%.
  • Benzoxaborole SLU-0010906 was initially prepared via a 4-step reaction sequence starting with commercially available 5-bromo-2-chlorobenzaldehyde as depicted in Scheme 8A below.
  • Reagents and conditions (a) B 2 pin 2 , Pd(dppf)Cl 2 ⁇ DCM, KOAc, DMSO, 100 o C, 1 h, 81%; (b) VI, Pd(dppf)Cl2, K2CO3, DMF:H2O (4:1), 100 o C, 1 h, 67%; (c) B2pin2, Pd(dppf)Cl2 ⁇ DCM, KOAc, DMSO, 100 o C, 1-2 hrs, 49%; (d) (i) NaBH4, methanol, 25 o C, 2 h; (ii) 1 M HCl, 25 o C, 18 h, 6%.
  • Reaction conditions a) I2, CH3CN, reflux, 16 h; b) POCl3, 110 °C, 3 h; c) 4- flurobenzylamine, K 2 CO 3 , NMP, 80 °C; d) Pd(dppf)Cl 2 , KOAc, B 2 pin 2 , 1,4-dioxane, 80 °C; e) NaBH4, MeOH, 0 °C-rt, 4 h; f) 1 M NaOH, MeOH, 2 h; g) 1 M HCl; h) DIBAL-H, DCM, 0 °C, 1 h; i) MnO 2 , DCM, 3 h; j) RMgCl, THF, 0 °C, 2-3 h.
  • Scheme 8C illustrates the synthesis of isomeric benzoxaborole analogs such as SLU-0011570 and SLU-0011769 using methods analogous to those described for Scheme 8B.
  • conditions a) I2, CH3CN, reflux, 16 h; b) POCl3, 110 °C, 3 h; c) 4-flurobenzylamine, K2CO3, NMP, 80 °C; d) Pd(dppf)Cl 2 , KOAc, B 2 pin 2 , 1,4-dioxane, 80 °C; e) NaBH 4 , MeOH, 0 °C-rt, 4 h; f) 1 M NaOH, MeOH, 2 h; g) 1 M HCl; h) DIBAL-H, DCM, 0 °C, 1 h; i) MnO2, DCM, 3 h; j) RMgCl, THF, 0 °C, 2-3 h.
  • This modified route involved an initial step wherein 5-amino-3-ethyl-1-methyl-1H-pyrazole-4- carboxamide 6 and 4-formylbenzoic acid 15, along with K2CO3, are dissolved in DMF and treated with iodine and heated at a temperature of 90 °C for an extended period overnight, resulting in the formation of intermediate 16.
  • POCl3 is used to generate chloro intermediate 17.
  • intermediate 17 and DIEA were dissolved in acetonitrile, followed by the addition of amine derivatives 9l-ah. The resulting mixture was stirred at room temperature overnight to give analog methyl ester precursors 18l-ah. Hydrolysis followed by reverse phase HPLC purification yielded the desired target analogs 19l-ah.
  • ction conditions a) I 2 , CH 3 CN, reflux, 16 h; b) POCl 3 , 110 C, 3 h; c) 4-flurobenzylamine, K 2 CO 3 , NMP, 80 °C; d) Pd(PPh3)4, diethylphosphonate, Et3N, toluene, 110 °C; e) Conc. HCl, 50 °C , 16 h.
  • pyrazolopyrimidines can be prepared by the reaction of 2,4,6 ⁇ trichloropyrimidine ⁇ 5 ⁇ carbaldehyde 21 with various substituted alkylhydrazines in methanol at -78 o C to give 4,6 ⁇ dichloro ⁇ 1 ⁇ substituted-1H ⁇ pyrazolo[3,4 ⁇ d]pyrimidines 23a-j.
  • nucleophilic aromatic substitution of intermediates 23a-j with 4-fluorobenzylamine in the presence of diisopropylethylamine (DIPEA) at room temperature formed intermediates 24a-j.
  • DIPEA diisopropylethylamine
  • Suzuki coupling of 4-carboxyphenylboronic acid with 24a-j gave target compounds 25a-j.
  • Schemes 14-16 illustrate the synthesis of R 1 and R 2 variation to the target compounds. The overall procedures are similar to those described for Scheme 1 with modest experimental variations. To introduce R 1 variations, the corresponding alkyl or aryl hydrazine is condensed with I or 33 as illustrated in Schemes 14 and 15. The resultant aminocyanopyrazoles 27a-h and 34a-g are carried forward over 5 steps as described in previous schemes to give the target analogs 32a-h and 39a-g. Scheme 16 illustrates keeping R 1 constant as methyl while varying R 2 .
  • the R 2 group is introduced in the first step from commercially available alkyl or aryl orthoformates, which, upon condensation with malononitrile and subsequently with methylhydrazine, gives aminocyanopyrazoles 43a-c. 43a-c were then transformed over 5 steps as described in previous schemes to give target compounds 46a-c.
  • O O CN NH 2 N C CN a HN b c N d nt [0132] ounds 32a- j. Reagents and conditions: (a) R 1 NHNH2, ethanol, 100 o C, 1 h; (b) conc.
  • Reagents and conditions (a) Acetic anhydride, reflux, overnight; (b) ethanol, 100 o C, 1 h; (c) conc. H2SO4, 25 o C, overnight, 56%; (d) urea, 200 o C, 2 h, 74%; (e) PCl5, POCl3, 120 o C, overnight; (f) 4-fluorobenzylamine, DIPEA, acetonitrile, 25 o C; (g) 4-carboxyphenylboronic acid, Pd (PPh 3 ) 4 , K 2 CO 3 , DMF:H 2 O (3:2), 100 o C, microwave, 1 h.
  • Scheme 17 illustrates the synthesis of pyrazolopyrimidines in a manner that permits selective substitution in any position off the pyrazolopyrimidine ring system using the methods described herein over 6 steps to the pentultimate chloropyridimine 52 and concludes with a Suzuki coupling to give target aryl substituted pyrazolopyrimidines 53.
  • Scheme 18 illustrates the synthesis of benzoxaboroles 57 and 59-61 with variable R 1 , R 3 , R 3 , R 4 and R 9 groups.
  • the chemistry proceeds are described for previous schemes herein.
  • the individual enantiomers of benzoxaborole 59 will be resolved via chiral HPLC or chiral SFC methods using commercial chiral stationary phase columns to give the individual S- and R-enantiomers, 60 and 61, respectively.
  • Scheme 19 illustrates a possible route by which benzodiazaborine 63 and benzoxazaborine 64 may be synthesized.
  • Intermediate 58 may be subjected to Miyaura borylation to give boronic acid 62 which would expect to give 63 and 64 upon treatment with hydrazine or hydroxylamine, respectively.
  • benzoxazaborine 64 is synthesized.
  • Scheme 20 illustrates a possible route by which trifluoromethyl benzoxaborole 67 may be synthesized from aldehyde 58. Treatment with TMS-CF3 and CsF is expected to give CF 3 alcohol 65. Subsequent Miraura borylation and treatment with HCl in methanol would generate target compounds 67.
  • Scheme 20 Synthesis of Trifluoromethyl-Benzoxaborole Pyrazolopyrimidines 67.
  • Scheme 21 illustrates a possible route to yield amine-substituted benzoxaboroles 69 from aldehyde 62 and the corresponding amine 68. -substituted benzoxaboroles 69.
  • Scheme 22 illustrates a possible synthesis of aminomethyl substituted benzoxaboroles 72 from aldehyde 58. Treatment with potassium cyanide would be expected to give cyanohydrin 70. Subsequent Miyuara borylation, acidification and reduction with DIBAL-H would generate target compounds 72.
  • Scheme 23 illustrates a possible synthesis of carboxylic acid substituted benxoxaborole 73 by hydrolysis of nitrile 71 followed by borane reduction to give hydroxymethyl benzoxaborole 74. benzoxaboroles 73 and 74, respectively.
  • Scheme 24 illustrates a possible synthesis of acetic acid substituted benzoxaborole 77. The approach starts with a Reformatsky reaction with aldehyde 58 to give beta-hydroxyester 75. Miyuara borylation and acidification would give ester target 76 which could be hydrolyzed under basic conditions to give acetic acid derivatives 77. . .
  • Scheme 25 illustrates a possible synthesis of azabenzoxaboroles 80.
  • Oxidative condensation of aminopyrazole 49 with a pyridinyl aldehyde would give 78.
  • Subsequent tranformations as described for Scheme 8B would then give target compounds 80.
  • Scheme 26 illustrates a possible synthesis of 3,4-dihydro-2H- benzo[e][1,2]oxaborinin-2-ols 84.
  • Phenol 81 could be obtained via oxidative condensation of 49 with 3-bromo-4-hydroxybenzaldehyde. Chlorination with POCl3 followed by displacement with the desired alkylamine would provide elaborated bromophenol 82.
  • Scheme 27 illustrates a possible synthesis of 3,4-dihydro-1H- benzo[c][1,2]oxaborinin-1-ols 87.
  • Vinyl phenol 83 can be converted to aryl triflate 85 with triflic anhydride.
  • Hydroboration oxidation would then give alcohol 86.
  • Miyuara borylation and acidification would then give the target compounds 87.
  • Scheme 28 illustrates a possible synthesis of 4,5- dihydrobenzo[c][1,2]oxaborepin-1(3H)-ols 91. Suzuki coupling of bromophenol 82 can give olefin 88. The phenol can then be converted to the triflate 89 and hydroboration oxidation could give alcohol 90. Miyuara borylation and acidification would then give target compounds 91. [01 [0159] Scheme 29 illustrates a possible synthesis of 4-methyl-3,4-dihydro-1H- benzo[c][1,2]oxaborinin-1-ols 95.
  • HPLC and LC ⁇ MS analyses were performed on an Agilent 1100 HPLC/MSD electrospray mass spectrometer in positive ion mode with a scan range of 100 ⁇ 1000 Da or an Agilent 1260 HPLC/MSD electrospray mass spectrometer in positive and negative ion modes with a scan range of 100-1000 Da .
  • Preparative normal-phase chromatography was performed on a CombiFlash Rf+ (Teledyne Isco) with SiliaFlash F6040 ⁇ 63 ⁇ m (230 ⁇ 400 mesh) silica gel (SiliCycle Inc.).
  • Preparative reverse phase HPLC was performed on a ACCQPrep HP150 (Teledyne Isco) equipped with 20x250mm or 30x250mm C18 RediSep Prep HPLC columns or a CombiFlash Rf+ (Teledyne Isco) with RediSep Rf Gold pre-packed C18 cartridges and an acetonitrile/water with or without 0.1% formic acid gradient.
  • 1 H and 13 C NMR spectra of intermediates and final compound were recorded and acquired in CDCl 3 or DMSO-d 6 as solvents using Bruker 400 MHz spectrometer at ambient temperature (400 MHz for 1 H, and 100 MHz for 13 C).
  • the microwave vial was placed in a heating block and the block heated to 100 o C overnight with stirring. After this time, the reaction was cooled to room temperature and filtered through a short pad of Celite eluting with ethyl acetate. The organic was transferred into a separatory funnel containing water. The aqueous layer was extracted two times with ethyl acetate. All the organics were combined, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the crude product purified via silica gel chromatography eluting with hexanes and ethyl acetate.
  • the microwave vial was placed in a Biotage microwave reactor and irradiated to 100 to 120 o C for 4 hrs with stirring. After this time, the reaction was cooled to room temperature and filtered through a short pad of celite eluting with ethyl acetate. The organic was transferred into a separatory funnel containing water. The aqueous layer was extracted two times with ethyl acetate. All the organics were combined, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the crude product purified via silica gel chromatography eluting with hexanes and ethyl acetate.
  • the vial was vacuumed and backfilled with Argon gas. This process was repeated three times and the vial kept under positive Argon pressure before adding 15 mL of anhydrous DMF.
  • the microwave vial was placed in a heating block and the block heated to 110 o C overnight with stirring. After this time, the reaction was cooled to room temperature and filtered through a short pad of Celite eluting with ethyl acetate. The organic was transferred into a separatory funnel containing water. The aqueous layer was extracted two times with ethyl acetate. All the organics were combined, washed with brine, dried over magnesium sulfate, and filtered.
  • reaction mixture was stirred for 1 mins before adding sodium azide (50.5 mg, 0.777 mmol) and 4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (100 mg, 0.259 mmol).
  • sodium azide 50.5 mg, 0.777 mmol
  • 4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile 100 mg, 0.259 mmol.
  • the reaction mixture was irradiated in a Biotage microwave at 200 o C for 20 mins. After this time, the reaction was cooled to room temperature and poured into a separatory funnel containing ethyl acetate and water.
  • HPLC purity was greater than 95%.
  • p-(3-ethyl-4- ⁇ [(p-flu ]amino ⁇ -1-methyl-1H-1,2,5,7- tetraazainden-6-yl)phenol (SLU-0011168).
  • White solid (67 mg, 18%).
  • a hydrogenation reaction vessel was charged with 4-(3-ethyl-4- ⁇ [(p-fluorophenyl)methyl]amino ⁇ -1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-3-cyclohexene-1-carboxylic acid (SLU-0011026, 15.0 mg, 0.0342 mmol) and Pd/C(1.5 mg, 10% mol) was dissolved in MeOH (15 mL).
  • the reaction mixture was hydrogenated by a pressure of 60 psi of H2 (g) for 24 h.
  • the reaction mixture was filtered and purified by flash chromatography using normal phase with EtOAc and hexane to obtain the title compound (9 mg, 64%).
  • Methyl 4-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluorobenzoate (100 mg, 0.229 mmol) was weighed into a round bottom flask before addition of 5 mL butanol and methylhydrazine (0.05 mL, 0.458 mmol). The reaction mixture was heated to 120 o C for 15 mins. LCMS analysis show trace of desired product formation. Another 1.5 mL methylhydrazine was added and reaction temperature decreased to 90 o C and stirred for 30 mins.
  • the crude was then dissolved in THF:MeOH (1:1, 2 mL) and a solution of LiOH (1 M, 2 mL)) was added. The reaction was then stirred at room temperature. After 16 hours, the reaction was quenched by the addition of 1 M HCl solution and then the volatiles were removed under reduced pressure to afford the crude.
  • the crude was purified by reverse phase chromatography (5-100 % CH 3 CN/H 2 O). The pure fractions were lyophilized to get the product as white solid (2.33 mg, 5.9 % over two steps).
  • the crude was dissolved in THF:MeOH (1:1, 2 mL) and a solution of LiOH (1 M, 2 mL) was added. The reaction was then stirred at room temperature. After 16 hours, the reaction was quenched by the addition of 1 M HCl solution and then the volatiles were removed under reduced pressure to afford the crude.
  • the crude was purified by reverse phase chromatography (5-100 % CH3CN/H2O). The pure fractions were lyophilized to get the product as white solid (11.91 mg, 9.8 % over 2 steps).
  • the crude was then dissolved in THF:MeOH (1:1, 2 mL) and a solution of LiOH (1 M, 2 mL)) was added. The reaction was then stirred at room temperature. After 16 hours, the reaction was quenched by the addition of 1 M HCl solution and then the volatiles were removed under reduced pressure to afford the crude.
  • the crude was purified by reverse phase chromatography (5-100 % CH3CN/H2O). The pure fractions were lyophilized to get the product as white solid (10.61 mg, 27 % over two steps).
  • the volatiles were then removed under reduced pressure to afford the crude.
  • the crude was dissolved in THF:MeOH (1:1, 2 mL) and a solution of LiOH (1 M, 2 mL) was added. The reaction was then stirred at room temperature. After 16 hours, the reaction was quenched by the addition of 1 M HCl solution and then the volatiles were removed under reduced pressure to afford the crude.
  • the crude was purified by reverse phase chromatography (5-100 % CH3CN/H2O). The pure fractions were lyophilized to get the product as white solid (14.1 mg, 11.7 % over 2 steps).
  • the crude was then dissolved in THF:MeOH (1:1, 2 mL) and a solution of LiOH (1 M, 2 mL)) was added. The reaction was then stirred at room temperature. After 16 hours, the reaction was quenched by the addition of 1 M HCl solution and then the volatiles were removed under reduced pressure to afford the crude.
  • the crude was purified by reverse phase chromatography (5-100 % CH 3 CN/H 2 O). The pure fractions were lyophilized to get the product as white solid (32.38 mg, 20.2 % over two steps).
  • the purified fraction (59.1 mg, 0.14 mmol) was dissolved in THF:MeOH (1:1, 2 mL) and a solution of LiOH (1 M, 2 mL) was added. The reaction was then stirred at room temperature. After 16 hours, the reaction was quenched by the addition of 1 M HCl solution and then the volatiles were removed under reduced pressure to afford the crude.
  • the crude was purified by reverse phase chromatography (5-100 % CH 3 CN/H 2 O). The pure fractions were lyophilized to get the product as white solid (18.04 mg, 0.04 mmol, 31.62 %).
  • diethyl [p-(3-eth ethyl]amino ⁇ -1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)phe nyl] phosphonate SLU-0011571.
  • 3-ethyl-N-(4-fluorobenzyl)-6-(4-iodophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4- amine (12.1; 0.1 mmol) in dry toluene, was added diethylphosphonate (0.12 mmol), Et 3 N (0.2 mmol) and Pd(PPh3)4. The resulting mixture was heated to 110 °C for 16 hours.
  • 2-(1-methoxypropylidene)malononitrile (33) The title compound prepared according to the procedure described for 2-(1-ethoxypropylidene)malononitrile I from malononitrile (10 g, 151 mmol), trimethyl orthoacetate (21 mL, 151 mmol), acetic anhydride (25 mL), the product was isolated with 75% yield.
  • LC-MS m/z (M + H) + 123.
  • N-benzyl[6-(1-h ydro-2,1-benzoxaborol-5-yl)-1- methyl-3-propyl-1,2,5,7-tetraaza-1H-inden-4-yl]amine (SLU-0011897).
  • Cp HCT-8 Cryptosporidium parvum-infected HCT-8 Cell Assay
  • parvum oocysts and compounds were dosed by oral gavage beginning 7 days post-infection according to the regimen specified for each experiment (four mice per experimental group).
  • Compound doses were prepared by sonicating aliquoted DMSO stock solutions followed by storage at -80°C for ⁇ 10 days and, on the day of dosing, dilution in 1% hydroxypropyl methylcellulose (HPMC) to a final concentration of 5% DMSO in 100 ⁇ l of 1% HPMC per dose. Oocyst shedding in feces was monitored at the specified time points qPCR using a previously described protocol. Results for examples SLU-2815, SLU-10726, and SLU-10906 are provided in Figure 2. [0547] Table 1.

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Abstract

L'invention concerne des composés, des compositions et des méthodes d'utilisation de ces composés et compositions. Les composés et les compositions conviennent au traitement des individus infectés par un Cryptosporidium ou à un procédé prophylactique. Les composés d'un échafaudage 1H-pyrazolo [3,4-d] pyrimidin-4-amine, ayant la structure suivante :
PCT/US2024/031193 2023-05-26 2024-05-27 1h-pyrazolo [3,4-d] pyrimidin-4-amines en tant qu'agents anti-infectieux Pending WO2024249380A2 (fr)

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