1h-pyrazolo[3,4-d]pyrimidin-4-amines as Anti-infectious agents

Abstract

Provided are compounds, compositions, and methods of using those compounds and compositions. The compounds and compositions may be suitable to treat individuals having a Cryptosporidium infection or a method for prophylaxis. The compounds a 1H-pyrazolo[3.4-d]pyrimidin-4-amine scaffold, having the following structure:

Description

1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINES AS ANTI-INFECTIOUS AGENTS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 504,716, filed May 26, 2023, and U.S. Provisional Patent Application No.63 / 562,667, filed on March 7, 2024, the disclosures of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant no. AI141184 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE DISCLOSURE

[0003] The apicomplexan parasites 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. Unfortunately, the development of novel therapeutics for cryptosporidiosis has proven to be extremely difficult as a result of the financial obstacles that plague drug discovery for diseases that disproportionately affect the developing world, as well as technical limitations associated with the laboratory study of Cryptosporidium parasites.

[0004] While cryptosporidiosis is a significant cause of self-limited diarrhea in immunocompetent individuals who may be exposed to parasites through contaminated municipal and recreational water supplies or through occupational exposures, the burden of cryptosporidiosis is even more substantial in immunocompromised and pediatric populations. Immunodeficient individuals, including patients maintained on immunosuppressive regimens following organ transplantation and AIDS patients, in particular, risk developing chronic, fulminant, and sometimes fatal disease (especially when CD-4+T-cell counts drop below 50 cells / mm3). 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. BRIEF SUMMARY OF THE PRESENT DISCLOSURE

[0005] 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.

[0006] 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. R2is 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, or a substituted or unsubstituted -CH2- aryl group. R5is 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). R3is H or a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group) and R4is a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted -CH2-aryl group (e.g., a benzyl group), or a substituted or unsubstituted -CH2-heteroaryl group.

[0007] In various examples, R3and R4are connected such that a ring is formed. In various embodiments, R1is not a substituted or unsubstituted aryl group or a substituted or unsubstituted -CH2-aryl group. In various embodiments, R5is not H, a cyano group, a substituted or unsubstituted alkyl group, a carboxylic acid / carboxylate, a substituted or unsubstituted amine, a substituted or unsubstituted imidamide, or a halogen.

[0008] In various embodiments, a compound does not have the following structure: H . ng one ormore compound(s) of the present disclosure. The compositions may further comprise one or more pharmaceutically acceptable carrier(s).

[0010] In an aspect, 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.

[0011] In an embodiment, 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.

[0012] The compounds may be used to treat a cryptosporidium infection caused by any species of Cryptosporidium. Examples of 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.

[0013] In one aspect, the disclosure provides a kit for treating a Cryptosporidium infection in an individual is provided and includes a compound of the present disclosure, pharmaceutically acceptable esters, salts, and prodrugs thereof, and instructions for use. In certain embodiments, the disclosure provides: a kit for treating a Cryptosporidium infection, in an individual, the kit comprising a compound of the present disclosure. The kit may also include instructions for administration of the compound or composition. The instructions may include details on one or more of the following: dosage, frequency, number ofadministrations to be carried out (such as number of tablets to be consumed), whether the composition needs to be taken with food, water etc., storage of the composition, and the like.

[0014] In an aspect, a compound as described herein exhibits activity against Cryptosporidium. In certain embodiments, the Cryptosporidium infection is from the Cryptosporidium parvum, Cryptosporidium hominis, Cryptosporidium andersoni, or a combination thereof. In various embodiments, the compounds of the disclosure are those which display in vitro EC50 values less than or equal to 10 µM, less than or equal to 9 µM, less than or equal to 8 µM, less than or equal to 7 µM, less than or equal to 6 µM, less than or equal to 5 µM, less than or equal to 4 µM, less than or equal to 3 µM, or less than or equal to 2 µM against Cryptosporidium parvum. BRIEF DESCRIPTION OF THE FIGURES

[0015] For a fuller understanding of the nature and objects of the disclosure, reference should be made to the following detailed description taken in conjunction with the accompanying figures.

[0016] Figure 1 shows EC50 curves from an Cp HCT-8 assay showing the percent inhibition by SLU-0002815, SLU-1110726 and SLU-10906-002.

[0017] Figure 2 shows PDEi efficacy in established murine C. parvum infection. (A) The indicated compounds were tested for efficacy in NSG mice. C. parvum infection on day 0, followed by incubation without treatment for 7 days, and then treatment by oral gavage (50 mpk BID) on days 8, 9, 10, 11, 12, 13, 14. Paromomycin was dosed at 1000mpk BID. Fecal parasite shedding was determined by qPCR on the indicated days. Data are the mean and SEM (n = 4 mice per experimental group) of parasite fecal shedding per mg of feces. Data points below the limit of qPCR detection are shown on the x-axis. P values are vs vehicle control by one-way ANOVA with Dunnett’s multiple comparisons test. Compound SLU- 2665 = SLU-0002665. (B) The indicated compounds were tested for efficacy in NSG mice. C. parvum infection on day 0, followed by incubation without treatment for 14 days, and then treatment by oral gavage with SLU-1072650 mpk BID or paromomycin 1000 mpk BID on days 15,16,17, and 18. Paromomycin was dosed at 1000mpk BID. Fecal parasite shedding was determined by qPCR on the indicated days. Data are the mean and SEM (n = 4 mice per experimental group; one mouse died in the SLU-10726 group related to blood draw) of parasite fecal shedding per mg of feces. P values are vs vehicle control by one-way ANOVA with Dunnett’s multiple comparisons test. SLU-10726 = SLU-0010726.

[0018] FIgur 3 shows the improved in vivo efficacy of potent benoxaborole PDE inhibitor SLU-11695. (A) Schematic describing study protocol with compounds dosed at 50 mg / kg twice daily on days 8, 9, 10, and 11 post infection. Parasite shedding in feces was measured by qPCR on days 7, 12, and 19 post infection. (B) Graph showing results for vehicle control (DMSO), SLU-2815, and SLU-11695 Data are mean and SEM for fecal parasite shedding on the dinicated days post infection (n = 4 mice per group). Data points below the limit of detection are plotted on the x-axis. *indicates p<0.02 versus day- matchedvehicle control by non-parametric Kruskal-Wallis test for multiple comparisons. DETAILED DESCRIPTION OF THE DISCLOSURE

[0019] Although claimed subject matter will be described in terms of certain examples, other examples, including examples that do not provide all of the benefits and features set forth herein, are also within the scope of this disclosure. Various structural, logical, process step, and electronic changes may be made without departing from the scope of the disclosure.

[0020] As used herein, unless otherwise indicated, “about”, “substantially”, or “the like”, when used in connection with a measurable variable (such as, for example, a parameter, an amount, a temporal duration, or the like) or a list of alternatives, is meant to encompass variations of and from the specified value including, but not limited to, those within experimental error (which can be determined by, e.g., a given data set, an art accepted standard, etc. and / or with, e.g., a given confidence interval (e.g.90%, 95%, or more confidence interval from the mean), such as, for example, variations of + / -10% or less, + / -5% or less, + / -1% or less, and + / -0.1% or less of and from the specified value), insofar such variations in a variable and / or variations in the alternatives are appropriate to perform in the instant disclosure. As used herein, the term “about” may mean that the amount or value in question is the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, compositions, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error, or the like, or other factors known to those of skill in the art such that equivalent results or effects are obtained. In general, an amount, size, composition, parameter, or other quantity or characteristic, or alternative is “about” or “the like,” whether or not expressly stated to be such. It is understood that where “about,” is used before aquantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0021] Ranges of values are disclosed herein. The ranges set out a lower limit value and an upper limit value. Unless otherwise stated, the ranges include the lower limit value, the upper limit value, and all values between the lower limit value and the upper limit value, including, but not limited to, all values to the magnitude of the smallest value (either the lower limit value or the upper limit value) of a range. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “0.1% to 5%” should be interpreted to include not only the explicitly recited values of 0.1% to 5%, but also, unless otherwise stated, include individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5% to 1.1%; 0.5% to 2.4%; 0.5% to 3.2%, and 0.5% to 4.4%, and other possible sub-ranges) within the indicated range. It is also understood (as presented above) that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about, it will be understood that the particular value forms a further disclosure. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0022] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0023] As used herein, unless otherwise stated or indicated, “s” refers to second(s), “min” refers to minute(s), and “h” refers to hour(s).

[0024] The phrase “therapeutically effective amount” is used herein to mean an amount sufficient to reduce by at least about 15 percent, preferably by at least 50 percent, more preferably by at least 90 percent, and most preferably prevents oxidative stress in the individual. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in the individual.

[0025] As used herein, unless otherwise stated, the term “group” refers to a chemical entity that is monovalent (i.e., has one terminus that can be covalently bonded to otherchemical species), divalent, or polyvalent (i.e., has two or more termini that can be covalently bonded to other chemical species). The term “group” also includes radicals (e.g., monovalent and multivalent, such as, for example, divalent radicals, trivalent radicals, and the like). Illustrative examples of groups include: and . d, the term “alkyl” or “alkyl group”refers to branched or unbranched, linear saturated hydrocarbon groups and / or cyclic hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl groups, ethyl groups, propyl groups, butyl groups, isopropyl groups, tert-butyl groups, cyclopropyl groups, cyclopentyl groups, cyclohexyl groups, and the like. Alkyl groups are saturated groups, unless it is a cyclic group. For example, an alkyl group is a C1to C40alkyl group, including all integer numbers of carbons and ranges of numbers of carbons therebetween (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, and C40). The alkyl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), halogenated aliphatic groups (e.g., trifluoromethyl group), aryl groups, halogenated aryl groups, alkoxide groups, amine groups, nitro groups, carboxylate groups, carboxylic acids, ether groups, alcohol groups, alkyne groups (e.g., acetylenyl groups and the like), and the like, and combinations thereof.

[0027] As used herein, the term “cycloalkyl” or “cycloalkyl group” refers to a cyclic hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl groups. Cycloalkyl groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three substituents. Each substituent is independently chosen from alkyl, -NH2, oxo (=O), phenyl, haloalkyl (e.g., -CF3), halo (e.g., -F, -Cl, -Br, -I), alkoxy, and –OH groups. Additionally, alkyl substituents may be substituted with various other functional groups. Additional non-limiting examples include aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), halogenated aliphatic groups (e.g., trifluoromethyl group), aryl groups, halogenated aryl groups, alkoxide groups, nitro groups, carboxylate groups, carboxylic acids, ether groups, alkyne groups (e.g., acetylenyl groups and the like), and the like, and combinations thereof.

[0028] As used herein, unless otherwise indicated, the term “aryl” or “aryl group” refers to C5to C30aromatic 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, C10, C11, C12,C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, and C30). An aryl group may also be referred to as an aromatic group. The aryl groups may comprise polyaryl groups such as, for example, fused rings, biaryl groups, or a combination thereof. The aryl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), aryl groups, alkoxides, carboxylates, carboxylic acids, ether groups, and the like, and combinations thereof. Examples of aryl groups include, but are not limited to, phenyl groups, biaryl groups (e.g., biphenyl groups and the like), fused ring groups (e.g., naphthyl groups and the like), hydroxybenzyl groups, tolyl groups, xylyl groups, and the like.

[0029] As used herein, the term “heteroaryl” or “hereteroaryl” refers to a monocyclic or bicyclic ring system comprising one or two aromatic rings and containing at least one nitrogen or oxygen atom in an aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one or two, substituents. Non-limiting examples of substituents include halogens (-F, -Cl, -Br, and -I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, and the like), halogenated aliphatic groups (e.g., trifluoromethyl group), aryl groups, halogenated aryl groups, alkoxide groups, amine groups, nitro groups, carboxylate groups, carboxylic acids, ether groups, alcohol groups, alkyne groups (e.g., acetylenyl groups and the like), and the like, and combinations thereof. Examples of heteroaryl groups include, benzofuranyl, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl groups, and substituents analogs of any of the foregoing heteroaryl groups.

[0030] As used herein, unless otherwise indicated, the term “alkoxy” or “alkoxy group” refers to where Rais a linear, branched or cyclic C1-C6alkyl group, including all integer numbof carbons and ranges of numbers of carbons therebetween. For example, suitable alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, sec-butoxy, tert-butoxy, and hexoxy groups. Additionally, alkyl substituents can be substituted with various other functional groups, e.g. functional groups disclosed herein.

[0031] As used herein, unless otherwise indicated, the term “amino” or “amino group” refers to where each Rbis selected independently from the group consisting of hydrogen atom, substituted or unsubstituted C1-C10alkyl, including all integer numbers of carbons and ranges of numbers of carbons therebetween, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted carbonyl, substituted sulfonyl, haloalkyl, and substituted or unsubstituted benzyl groups.

[0032] As used herein, unless otherwise indicated, the term “benzyl” or “benzyl group” refers to where Rcis a substituent on the phenyl ring and n is from 0 to 5. The substituents can be the same or different. For example, the substituents on the benzyl group include substituted or unsubstituted alkyl, -NH2, phenyl, haloalkyl (e.g., -CF3), halo (e.g., -F, -Cl, -Br, -I), alkoxy (e.g., -OMe), and –OH groups.

[0033] As used herein, unless otherwise indicated, halogen means fluorine, chlorine, bromine, and iodine, and halo means fluoro, chloro, bromo, and iodo.

[0034] As used herein, unless otherwise indicated, the term “phenoxy” or “phenoxy group” (-OPh) refers to where each Y is independently selected from the group consisting of F, Cl, Br, and I and m can be 0, 1 or 2.

[0035] As used herein, unless otherwise indicated, the term “phenyl” or “phenyl group” means where each Rdis an independent substituent on the phenyl group and n is from 0 to 5. The substituents at different occurrences can be the same or different. For example, the substituents on the phenyl group include substituted or unsubstituted C1-C6alkyl, including all integer numbers of carbons and ranges of numbers of carbons therebetween, substituted or unsubstituted amino, haloalkyl (e.g., -CF3), halo (e.g., -F, -Cl, - Br, -I), substituted or unsubstituted alkoxy (e.g., -OMe), and sulfonyl group. In certain instances, two adjacent R groups can be connected through to form a dioxolyl group.

[0036] All boron-containing groups and compounds herein may also encompass the related hydrate salts formed therefrom.

[0037] The present disclosure provides compounds and methods for treating a Cryptosporidium infection or a method for prophylaxis and / or treatment comprisingadministering to an individual a therapeutically effective amount of a compound having a 1H-pyrazolo[3,4-d]pyrimidin-4-amine scaffold.

[0038] A compound of the present disclosure can have the following structure: , H, a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group), asubstituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl, or a substituted or unsubstituted -CH2-aryl group. R2is 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, or a substituted or unsubstituted -CH2- aryl group. R5is 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). R3is H or a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group) and R4is a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted -CH2-aryl group (e.g., a benzyl group), or a substituted or unsubstituted -CH2-heteroaryl group.

[0039] In various examples, R3and R4are connected such that a ring is formed. In various embodiments, R1is not a substituted or unsubstituted aryl group or a substituted or unsubstituted -CH2-aryl group. In various embodiments, R5is not H, a cyano group, a substituted or unsubstituted alkyl group, a carboxylic acid / carboxylate, a substituted or unsubstituted amine, a substituted or unsubstituted imidamide, or a halogen.

[0040] In various embodiments, a compound does not have the following structure: H . Examplesof R5groups include, but are not limited to, H, a cyano, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, 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). Examples of such substituents include, but are not limited to, ,R8N , , oreR6group chosen from H, halogens (e.g., F, Cl), substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted CO-alkyl group, substituted and unsubstituted CONH-alkyl group, substituted and unsubstituted CON-dialkyl group, substituted and unsubstituted aryl groups, an aldehyde, and substituted and unsubstituted -CH2-aryl group, and n is 0 to 4. R8is chosen from H, substituted and unsubstituted alkyl groups, substituted and unsubstituted C(=O)-alkyl groups, substituted and unsubstituted -C(=O)-O-alkyl groups, substituted and unsubstituted -C(=O)NH-alkyl groups, substituted and unsubstituted -C(=O)N-dialkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted -CH2-aryl groups and there may be one or more R8groups. Each R9may independently be H, substituted or unsubstituted aliphatic groups (e.g., alkyl groups, such as, for example, methyl and ethyl), substituted or unsubstituted aryl groups, or the like. Each R9may be the same or different. Specific examples of R5groups include, but are not limited to, ,,OH B B O O , , , , , , , , , ,O,

[0000] compoun may ave var ous groups. n varous em o ments, may be 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. For example, R1is a substituted or unsubstituted alkyl group, such as, for example, methyl, ethyl, isopropyl, propyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and trifluoromethyl. In various examples, R1is methyl.

[0043] A compound may have various R2groups. In various embodiments, R2may be H, a halogen, a cyano, a substituted or unsubstituted aliphatic group (e.g., including substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, and substituted and unsubstituted alkynyl groups), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl, or a substituted or unsubstituted -CH2-aryl group. In various examples, R2is chosen from methyl, ethyl, isopropyl, propyl, cyclopropyl, butyl, phenyl, benzyl, cyano, bromo, and trifluoromethyl. In various examples, R2is a substituted or unsubstituted alkyl group. In various examples, R2is ethyl.

[0044] A compound may have various R3and R4groups. Each R3and R4group may be the same or different. In various examples R3is H or a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group) and R4is a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group) , a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted -CH2-aryl group (e.g., a benzyl group), or a substituted or unsubstituted -CH2-heteroaryl group; or R3and R4are connected such that a ring is formed. In various examples, R3is H and R4is a substituted benzyl group (e.g., substituted with a halogen (e.g., F or C) and one or more alkoxy groups (e.g., methoxy). In various non-limiting examples, when R3and R4form a ring, the ring may be one of the following: ,wherein R8is optional and is chosen from H, substituted and unsubstituted alkyl groups, substituted and unsubstituted C(=O)-alkyl groups, substituted and unsubstituted -C(=O)-O- alkyl groups, substituted and unsubstituted -C(=O)NH-alkyl groups, substituted and unsubstituted -C(=O)N-dialkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted -CH2-aryl groups and there may be one or more R8groups. Various examples of R3and R4groups include, but are not limited to,-H, -CH3, ,. 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). In various examples, a compouthe present disclosure has the following, ethyl, -Cl, -F, -OMe, -NMe2, -CF3, and alkoxy, and there may be one or more R7groups. Further examples include, but are not limited to, .HN HN N R7R7orHN N R7N N . de, but are not limited to:.,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 R9may be the same or different.

[0046] In various examples, a compound of the present disclosure has the following structure: ,, stituted alkyl, substitutedand unsubstituted CO-alkyl, substituted and unsubstituted CONH-alkyl, substituted and unsubstituted CON-dialkyl, substituted and unsubstituted aryl, and substituted and unsubstituted -CH2-aryl and there may be one or more R8groups. Further examples include, but are not limited to, .O F OH OH OH ,following structure:,,, ,, ,O H , O H ,Cl F Cl F Cl OH F O H ,F O F F O , O ,OH HN HN N O NN N N N N N N N N N N N N NF HN HN HN N Cl N N O N N NHN Cl HN HN N F ,,F H , , , ,, , , H ,, H , , ,F H , , , ,, , , , , ,HNFHNF, ngcompounds.

[0048] The present disclosure includes all possible stereoisomers and geometric isomers of a compound of the present disclosure. The present disclosure includes both racemic compounds and optically active isomers. When a compound of the present disclosure is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883- 888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of a compound of the present disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.

[0049] 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. Silverman, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, San Diego, chapter 8, (1992); K.M. Hillgren et al., Med. Res. Rev., 15, 83 (1995)).

[0050] Compounds of the present disclosure can contain one or more functional groups. The functional groups, if desired or necessary, can be modified to provide a prodrug.Suitable prodrugs include, for example, acid derivatives, such as amides and esters. It also is appreciated by those skilled in the art that N-oxides can be used as a prodrug.

[0051] Compounds of the disclosure may exist as salts. Pharmaceutically acceptable salts of the compounds of the disclosure generally are preferred in the methods of the disclosure. As used herein, 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. Nonlimiting examples of salts of compounds of the disclosure include, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2- hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulphonate, and p-toluenesulfonate salts. In addition, 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. In light of the foregoing, 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.

[0052] The compounds may exhibit wide variability in pharmacokinetic and physicochemical properties while still retaining desirable biological activity as described herein. For example, solubility, e.g., log P, is variable while still retaining desirable biological activity as described herein.

[0053] In an aspect, the present disclosure provides compositions comprising one or more compound(s) of the present disclosure. The compositions may further comprise one or more pharmaceutically acceptable carrier(s).

[0054] 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. Injections may be prepared by dissolving, suspending, or emulsifying one or more of the active ingredient(s) in a diluent. Non-limiting examples of diluents include distilled water (e.g., for injection), physiological saline, vegetable oil, alcohol, and the like, and combinations thereof. Injections may contain, for example, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, and the like, and combinations thereof. Injections may be sterilized in the final formulation step or prepared by sterile procedure. A pharmaceutical composition of the disclosure may also be formulated into a sterile solid preparation, for example, by freeze-drying, and may be used after sterilized or dissolved in sterile injectable water or other sterile diluent(s) immediately before use. Additional examples of pharmaceutically acceptable carriers include, but are not limited to, sugars, such as, for example, lactose, glucose, and sucrose; starches, such as, for example, corn starch and potato starch; cellulose, such as, for example, sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as, for example, cocoa butter and suppository waxes; oils, such as, for example, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as, for example, propylene glycol; polyols, such as, for example, glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as, for example, ethyl oleate and ethyl laurate; agar; buffering agents, such as, for example, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; other non-toxic compatible substances employed in pharmaceutical formulations, and the like, and combinations thereof. Non-limiting examples of pharmaceutically acceptable carriers are found in: Remington: The Science and Practice of Pharmacy (2012) 22nd Edition, Philadelphia, PA. Lippincott Williams & Wilkins.

[0055] Compositions of the disclosure can comprise more than one pharmaceutical agent. For example, 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 desiredprophylaxis or therapy in an individual. Further, compositions of the disclosure can be prepared using mixed preparations of any of the compounds disclosed herein.

[0056] 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.

[0057] Various antioxidants may be used. Examples of 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.

[0058] 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. A compound of the present disclosure may also be administered as a bolus, electuary or paste.

[0059] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), 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) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical 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.

[0060] 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.

[0061] 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. They 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. Examples of 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.

[0062] Liquid dosage forms for oral administration of a compound of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, 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.

[0063] In addition to inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0064] 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.

[0065] The composition may be for administration to an individual in need of treatment.

[0066] In various examples, a composition comprises a pH sensitive polymer.

[0067] In an embodiment 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.

[0068] In an embodiment, 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. In another embodiment, the anionic polymer can be a natural anionic polymer such as hyaluronic acid, alginic acid, carboxymethyl cellulose, carboxymethyl dextran, poly(aspartic acid), or heparin. Several commercial pH sensitive polymers are available. For example, Eudragit L, Eudragit S from Röhm Pharma GmBH (based on methacrylic acid and methyl methacrylate) or CMEC from Freund Sangyo Co., Ltd; CAP from Wako Pure Chemicals Ltd.; or HP-50 and ASM from Shin-Etsu Chemical Co., Ltd. (derived from cellulose) can be used.

[0069] Without intending to be bound by any particular theory, it is considered that compounds with minimal solubility to access the parasites within intestinal epithelial cells with poor metabolic stability may be desired. For example, compounds are desired to be largely retained at the site of infection within the gut rather than rapid absorption and systemic exposure in the plasma in order to maximize efficacy against the parasite while minimizing systemic off-target effects. In essence, compounds for treatment of cryptosporidiosis may break some of Lipinski’s rules for selection of drug leads. Thus, physiochemical properties and formulations of each scaffold that are optimized for treatment of cryptosporidiosis will be distinct from physiochemical properties and formulations appropriate for treatment of a systemic infection such as malaria. Drug exposure (both theability to penetrate the cell and parasitophorous vacuole, and retention at the site of infection rather than oral absorption) will be equivalent. In an example, the compounds are not significantly distributed systemically but are preferentially retained in the gastrointestinal tract. In an example, the compounds of the method are taken up by the cells of the lumen of the gastrointestinal tract. In another example, 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.

[0070] In an embodiment, 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. For example, pH sensitive polymers can be used as described herein.

[0071] In an aspect, 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.

[0072] In an embodiment, 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.

[0073] The compounds may be used to treat a cryptosporidium infection caused by any species of Cryptosporidium. Examples of 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.

[0074] 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. In some instances, 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. In areas where Cryptosporidium infection are highly endemic, treatment for cryptosporidiosis may be provided (alone or in combination with treatment for other enteric infections) for suspected infection without microbiologic confirmation.

[0075] 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.

[0076] Compositions comprising a compound of the disclosure and a pharmaceutical agent can be prepared at a patient’s bedside, or by a pharmaceutical manufacture. In the latter case, 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. In particular, 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.

[0077] 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. The 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.

[0078] It is envisioned, therefore, that a compound of the present disclosure is useful in the treatment of a cryptosporidium infection. Thus, 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.

[0079] 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. Thus, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure together with a pharmaceutically acceptable diluent or carrier therefor. Also provided is a process of preparing a pharmaceutical composition comprising admixing a compound of the present disclosure with a pharmaceutically acceptable diluent or carrier therefor.

[0080] In one embodiment, 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.

[0081] In certain embodiments, these pharmaceutical compositions are suitable for oral administration to an individual. In other embodiments, as described in detail below, 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.

[0082] 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.

[0083] 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.

[0084] When a compound of the present disclosure is administered as pharmaceuticals to humans and animals, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.

[0085] In certain embodiments, 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. McGraw-Hill N.Y., NY; and the Physicians Desk Reference 50th Edition 1997, Oradell New Jersey, Medical Economics Co., the complete contents of which are expressly incorporated herein by reference. 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).

[0086] 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). In other methods, 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.

[0087] 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. For the prophylactic use, 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. In one embodiment, 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. For immmuosuppressed hosts such as those with AIDS, long-term suppressive treatment may be warranted.

[0088] 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 acondition(s) capable of increasing susceptibility to a Cryptosporidium infection. In an embodiment, 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. In another embodiment, 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. In an embodiment, an individual can take a therapeutically effective amount of a compound of the present disclosure shortly after exposure to Cryptosporidium infection.

[0089] In another aspect, the disclosure provides a packaged composition including a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable carrier or diluent. The composition may be formulated for treating an individual suffering from or susceptible to a Cryptosporidium infection and packaged with instructions to treat an individual suffering from or susceptible to a Cryptosporidium infection.

[0090] In one aspect, the disclosure provides a kit for treating a Cryptosporidium infection in an individual is provided and includes a compound of the present disclosure, pharmaceutically acceptable esters, salts, and prodrugs thereof, and instructions for use. In certain embodiments, the disclosure provides: a kit for treating a Cryptosporidium infection, in an individual, the kit comprising a compound of the present disclosure. The kit may also include instructions for administration of the compound or composition. The instructions may include details on one or more of the following: dosage, frequency, number of administrations to be carried out (such as number of tablets to be consumed), whether the composition needs to be taken with food, water etc., storage of the composition, and the like.

[0091] For veterinary use, a compound of the present disclosure, or a pharmaceutically acceptable salt or prodrug, is administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal. Animals treatable by the present compounds and methods include, but are not limited to, bovines or ungulates.

[0092] When administered in combination with other therapeutics, a present compound may be administered at relatively lower dosages. In addition, the use of targetingagents may allow the necessary dosage to be relatively low. Certain compounds may be administered at relatively high dosages due to factors including, but not limited to, low toxicity and high clearance.

[0093] For human use, a compound of the present disclosure can be administered alone, but generally is administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carrier comprising excipients and auxiliaries that facilitate processing of a compound of the present disclosure into pharmaceutical preparations.

[0094] In an aspect, a compound as described herein exhibits activity against Cryptosporidium. In certain embodiments, the Cryptosporidium infection is from the Cryptosporidium parvum, Cryptosporidium hominis, Cryptosporidium andersoni, or a combination thereof. In various embodiments, the compounds of the disclosure are those which display in vitro EC50 values less than or equal to 10 µM, less than or equal to 9 µM, less than or equal to 8 µM, less than or equal to 7 µM, less than or equal to 6 µM, less than or equal to 5 µM, less than or equal to 4 µM, less than or equal to 3 µM, or less than or equal to 2 µM against Cryptosporidium parvum.

[0095] As appreciated by persons skilled in the art, additional active or ancillary agents can be used in the methods described herein. Reference herein to treatment also extends to prophylaxis, as well as to treatment of established diseases or symptoms.

[0096] A method of the present disclosure be applied to cell populations ex vivo. For example, 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.

[0097] 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. Thus, in an embodiment, the method consists essentially of a combination of the steps of the method disclosed herein. In another embodiment, the method consists of such steps.

[0098] 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), asubstituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl, or a substituted or unsubstituted -CH2-aryl group; R2is 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 - CH2-aryl group; R5is 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); and R3is H or a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group) and R4is a substituted or unsubstituted alkyl group (e.g., a halogenated alkyl group), a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted -CH2-aryl group (e.g., a benzyl group) , or a substituted or unsubstituted -CH2-heteroaryl group; or R3and R4are connected such that a ring is formed, with the proviso the compound does not have the following structure: H .Example 2. A compound according Example 1, wherein R5is chosen from: , , ,ne or more R6group chosen from H, halogens (e.g., F, Cl), substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, an aldehyde, and the like, wherein R8isH, a substituted or substituted alkyl group, a substituted or unsubstituted CO-alkyl, a substituted or unsubstituted CONH-alkyl, a substituted or unsubstituted CON-dialkyl, a substituted or unsubstituted aryl group, or a substituted or unsubstituted -CH2-aryl and there may be one or more R8groups, wherein each R9(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, and n is 0 to 4. Example 3. A compound according to Example 1 or Example 2, wherein R5is chosen from ,, , ,OH B O , , each R9(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 4. A compound according to Example 3, wherein R5is chosen from ,, h R9(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 R1is a substituted or unsubstituted alkyl group. Example 6. A compound according to any one of Examples 1–5, wherein R1is 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 R1is methyl. Example 8. A compound according to any one of the preceding Examples, wherein R2is a substituted or unsubstituted alkyl group. Example 9. A compound according to any one of Examples 1–8, wherein R2is 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 R2is ethyl or propyl. Example 11. A compound according to any one of the preceding Examples, wherein R4is ,,p . p g y p g p , n R3is H then R4is ,.p . p g y p g p , e compound has the following structure: ,,is chosen from methyl, -Cl, -F, alkoxy group, -CF3, -NMe2, and the like and there may be one or more R7groups.Example 14. A compound according to any one of the preceding Examples, wherein the compound has the following structure: Cl R2 HNR2 HNN O N ,und has the following structure: HN HN N R7R7N N orp . p g y p g p s, wherein the compound has the following structure: Cl HN HN orExample 17. A compound according to any one of the preceding Examples, wherein R5is chosen fromO F OH OH ,compound has the following structure: , , ,Cl , , ,,,,N F F F O H , O H ,Cl Cl O , O , O ,Cl Cl Cl O H ,F F HN HN HN N N O N H , ,Cl Cl HN HN HN N O ,,F H , , , ,, H , , ,F , , ,, , ,F F H ,following structure: , ,,pound has the following structure: .Example 21. A compound according to any one of Examples 1–12, wherein the compound has the following structure:, substituted andunsubstituted 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 -CH2-aryl groups, and the like and there may be one or more R8groups. 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:O N ,compound according to any one of the preceding Examples. 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 kit 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.

[0099] The following example is presented to illustrate the present disclosure. It is not intended to be limiting in any matter.EXAMPLE

[0100] This example provides a description of synthesis of compounds of the present disclosure.

[0101] Chemistry. As illustrated in the Scheme 1 below, synthesis of the pyrazolopyrimidine core began by the reaction of malononitrile with ethyl orthopropionate in acetic anhydride at refluxing temperatures to give the fully substituted alkene product I. Compound I was sufficiently pure (>95 % purity by LCMS) that it was used in the next step without further purification. Compound I then was condensed with methyl hydrazine in ethanol to afford the aminocyanopyrazole II (Burch, H. A. Journal of Medicinal Chemistry (1968), 11(1), 79-83). The exact regioisomer of product II from the aforementioned reaction was confirmed by 2D NMR (Nuclear Overhauser Effect). Functional group interconversion of the nitrile group on II to amide functionality in III was achieved by acid-mediated hydrolysis at room temperature overnight. As observed with compound I, aminopyrazole amide III was sufficiently pure (>95 % purity by LCMS) that it was used in the subsequent step without the need of further purification. Reaction of product III with urea at elevated temperatures gave the desired 1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione core IV within 2 hours of refluxing. At refluxing temperatures, a mixture of phosphorus (V) chloride, PCl5 and phosphoryl chloride, POCl3 was required to ensure full conversion of the dione in IV to the dichlorinated product V. The use of only POCl3resulted mostly in the mono chlorinated product and trace of the desired dichlorinated product V. Next, 4- fluorobenzylamine reacted regioselectively at the 4-Cl position of precursor V in the presence of diisopropylethylamine (DIPEA) at room temperature in a nucleophilic aromatic substitution (SNAr) fashion to afford synthetic intermediate VI (SLU-0002812). At room temperature, SNAr reactivity is much faster at the 4-Cl position than the 6-Cl position making this SNAr highly selective towards the 4-position of 4,6-chloropyrazolopyrimidine.

[0102] Scheme 1. Synthesis of 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine, VI. Reagents and conditions: (a) Acetic anhydride, reflux, overnight, 76%; (b) ethanol, 100oC, 3 h, 84%; (c) conc. H2SO4, 25oC, overnight, 56%; (d) urea, 200oC, 2 h, 74%; (e) PCl5, POCl3, 110oC, overnight, 38%; (f) DIPEA, acetonitrile, 25oC, 65%.

[0103] Palladium-catalyzed Suzuki couplings using a range of commercially available or synthesized boronic acid or ester derivatives and VI furnished the 6-substituted pyrazolopyrimidine-based analogs VII as shown in Scheme 2 below. OH HN B HN Ar OH N N FaN or NFce e . y ess o -sus ue--e y- - - uooe y -- e y- 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives via Suzuki-coupling. Reagents and conditions: (a) Pd(dppf)Cl2, K2CO3, DMF:H2O (4:1), 110oC, overnight.

[0105] To expand the scope of substrates explored in this research, a range of amines were coupled with VI under Buchwald-Hartwig amination conditions to achieve products VIII (Examples SLU-0010032, SLU-0010260, SLU-0010266, SLU-0010267, SLU-0010035, SLU-0010268, SLU-0010255 and SLU-0010467) as illustrated in Scheme 3 below.HN HN N FaN NFN

[0106] S enzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives via Buchwald-Hartwig type coupling. Reagents and conditions: (a) amine, Pd(dppf)Cl2, NaOtBu, Dioxane, 100oC, overnight.

[0107] Trifluoroacetic acid mediated deprotection of the Boc- and 2,4- dimethoxybenzyl- group in SLU-0010035 and SLU-0010032 furnished the respective amine products SLU-0010042 and SLU-0010041, Scheme 4 below. HN HN N FaNFFNH

[0108] Sch032. Reagents and conditions: (a) Trifluoroacetice acid, dichloromethane, 25oC, 6 h.

[0109] Base-mediated hydrolysis of the nitrile functionality in SLU-0002813 gave a mixture of the acid SLU-0002815 and amide SLU-0010039 products that were successfully separated via reserved-phase flash chromatography (Scheme 5). HN HN HN NH2

[0110] Scheme 5. Potassium hydroxide mediated hydrolysis of nitriles. Reagents and conditions: (a) KOH, Ethanol:H2O, 80 ºC, overnight.

[0111] Ester hydrolysis of IX generated the respective acid products X using either potassium hydroxide in ethanol or 1 M lithium hydroxide monohydrate solution in THF / methanol, Scheme 6. HN HN N FaN N NF

[0112] S(a) KOH, Ethanol, 100 ºC, overnight or 1 M LiOH ^H2O, THF / methanol.

[0113] Installation of a nitrile group at the 6-position to generate SLU-0010096 was achieved through coupling of intermediate VI with zinc cyanide under palladium catalysis, Scheme 7. 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, 110oC, 16 hrs, 80%; (b) KOH, Ethanol:H2O (1:1), 100 ºC, overnight, 81%; (c) NH2OH ^HCl, Ethanol:H2O (1:1), 100oC, overnight, 76%.

[0115] 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. Selective borylation of 5-bromo-2-chlorobenzaldehyde generated adduct XI that was coupled with VI under palladium catalysis to afford XII. Borylation of chlorobenzaldehyde XII gave XIII which was then reacted with sodium borohydride, NaBH4 and 1 M HCl to produce the desired target SLU-0010906 in low yield (unoptimized). HN BrCHOaO b N F O B CHO N CHO l

[0116] -1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzo[c][1,2]oxaborol-1(3H)-ol, SLU-0010906. Reagents and conditions: (a) B2pin2, Pd(dppf)Cl2^DCM, KOAc, DMSO, 100oC, 1 h, 81%; (b) VI, Pd(dppf)Cl2, K2CO3, DMF:H2O (4:1), 100oC, 1 h, 67%; (c) B2pin2, Pd(dppf)Cl2 ^DCM, KOAc, DMSO, 100oC, 1-2 hrs, 49%; (d) (i) NaBH4, methanol, 25oC, 2 h; (ii) 1 M HCl, 25oC, 18 h, 6%.

[0117] An improved synthesis of benzoxaborole SLU-0010906 was developed (Scheme 8B). Condensation of methyl 2-bromo-5-formylbenzoate with aminopyrazole III under oxidative conditions gave pyrazolopyrimidinone 8B.1. 8B.1 was then converted to the 4-chloro with POCl3and then treated with 4-fluorobenzylamine under basic conditions to yield 8B.2. Under Pd catalysis, bromo 8B.2 was converted to the boronate ester and then treated with sodium borohydride to reduce the ester and induce cyclication to give the target benzoxaborole SLU-0010906 in good yield. Boronate ester intermediate 8B.3 was also hydrolyzed directly with NaOH and, upon acidification, gave SLU-0011527. Subsituted benzoxaboroles 8B.5 and 8B.6 were prepared via either direct treatment of ester 8B.2 with Grignard reagent and subsequent borylation with B2pin2 to give 8B.6 or first conversion of 8B.2 to aldehyde 8B.4 before borylation to give 8B.5 (including SLU-0011695 where R’=H and R=Me).Reaction conditions: a) I2, CH3CN, reflux, 16 h; b) POCl3, 110 °C, 3 h; c) 4- flurobenzylamine, K2CO3, NMP, 80 °C; d) Pd(dppf)Cl2, KOAc, B2pin2, 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) MnO2, DCM, 3 h; j) RMgCl, THF, 0 °C, 2-3 h.

[0119] 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)Cl2, KOAc, B2pin2, 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) MnO2, DCM, 3 h; j) RMgCl, THF, 0 °C, 2-3 h.

[0121] Compounds SLU-0011012, SLU-0011013 and SLU-0011026 were prepared from the respective boronic esters XIV, XV and XVI followed by ester hydrolysis of the crude reaction mixture (Scheme 9). Ester XVII was reduced followed by hydrolysis to give SLU-0011025.O O B HN HN CO2Et N F b N F O2H andSLU-0011026. Reagents and conditions: (a) Pd(dppf)Cl2, K2CO3, DMF:H2O (4:1), 100oC, 6- 18 h; (b) 1M LiOH ^H2O solution, 25oC, 7-8 h or KOH, Ethanol, 100oC, 2-3 h; (c) Pd / C, H2, ethanol.

[0123] Scheme 10 illustrates the multi-step synthesis of target analogs 11i-f. To initiate the process, 5-amino-3-ethyl-1-methyl-1H-pyrazole-4-carboxamide 6 and ethyl 4- cyanobenzoate 7 were heated in sodium ethoxide and ethanol to yield pyrazolopyrimidinone intermediate 8. Intermediate 8 was derivatized by activation with BOP and DIEA followed by treatment with benzylamines 9a-i at room temperature overnight to give derivatized intermediates 10 a-i. Finally, nitriles 10a-i were hydrolized in aq. KOH at elevated temperatures, acidified with HCl, and purified by reverse phase HPLC to give final target analogs, 11a-i.intermediate 8.

[0125] Scheme 11 illustrates another route to synthesize target compounds. 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. Next, POCl3 is used to generate chloro intermediate 17. Subsequently, 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.intermediate 17.

[0127] Scheme 12 illustrates the synthesis of phosphonic acid and esters. Iodo intermediate 12.1 was prepared according to the same procedures used to synthesize 8B.2. Pd-catalyzed insertion of the phosphonate was accomplished with diethyl phosphonate to give SLU-0011571. Acidic hydrolysis gave phosphonic acid SLU-0011626.ctionconditions: a) I2, CH3CN, reflux, 16 h; b) POCl3, 110 C, 3 h; c) 4-flurobenzylamine, K2CO3, NMP, 80 °C; d) Pd(PPh3)4, diethylphosphonate, Et3N, toluene, 110 °C; e) Conc. HCl, 50 °C , 16 h.

[0129] As shown in Scheme 13, pyrazolopyrimidines can be prepared by the reaction of 2,4,6‐trichloropyrimidine‐5‐carbaldehyde 21 with various substituted alkylhydrazines in methanol at -78oC to give 4,6‐dichloro‐1‐substituted-1H‐pyrazolo[3,4‐d]pyrimidines 23a-j. Next, nucleophilic aromatic substitution of intermediates 23a-j with 4-fluorobenzylamine in the presence of diisopropylethylamine (DIPEA) at room temperature formed intermediates 24a-j. Finally, Suzuki coupling of 4-carboxyphenylboronic acid with 24a-j gave target compounds 25a-j. Cl Cl CHOHClab N H2N N NH N

[0130] Sceme . repara on o -su s u e pyrazoopyr mdine compounds 25a- j. Reagents and conditions: (a) NEt3, methanol, -78oC to room temp., 1 h; (b) 4- fluorobenzylamine, DIPEA, acetonitrile, room temp, 7 h; (c) 4-carboxyphenylboronic acid, Pd(PPh3)4, K2CO3, DMF: H2O (3:2), 100oC, microwave, 1 h.

[0131] Schemes 14-16 illustrate the synthesis of R1and R2variation to the target compounds. The overall procedures are similar to those described for Scheme 1 with modest experimental variations. To introduce R1variations, 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 inprevious schemes to give the target analogs 32a-h and 39a-g. Scheme 16 illustrates keeping R1constant as methyl while varying R2. The R2group 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 NH2NCCNaHN bcNdnt

[0132] ounds 32a-j. Reagents and conditions: (a) R1NHNH2, ethanol, 100oC, 1 h; (b) conc. H2SO4, 25oC, overnight; (c) urea, 200oC, 1 h; (d) PCl5, POCl3, 110oC, overnight; (e) 4-fluorobenzylamine, DIPEA, acetonitrile, 25oC; (f) 4-carboxyphenylboronic acid, Pd (PPh3)4, K2CO3, DMF:H2O (3:2), 100oC, microwave, 1 h. O O CNNH2NC CN HN N N R1[01. ds 39a- g. Reagents and conditions: (a) Acetic anhydride, reflux, overnight; (b) ethanol, 100oC, 1 h; (c) conc. H2SO4, 25oC, overnight, 56%; (d) urea, 200oC, 2 h, 74%; (e) PCl5, POCl3, 120oC,overnight; (f) 4-fluorobenzylamine, DIPEA, acetonitrile, 25oC; (g) 4-carboxyphenylboronic acid, Pd (PPh3)4, K2CO3, DMF:H2O (3:2), 100oC, microwave, 1 h. O 2OR2ORCNR2NH2R2a NC CN b c HN NC CN O O NNHN NH d N N 6a-c. Reagents and conditions: (a) Acetic anhydride, reflux, overnight; (b) methylhydrazine, ethanol, 100oC, 1 h; (c) conc. H2SO4, 0 - 25oC, overnight; (d) urea, 200oC, 1 h; (e) PCl5, POCl3, 110oC, overnight; (f) DIPEA, acetonitrile, 25oC, overnight; (g) 4- carboxyphenylboronic acid, Pd (PPh3)4, K2CO3, DMF:H2O (3:2), 100oC, microwave, 1 h

[0135] 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. [01

[0137] Scheme 18 illustrates the synthesis of benzoxaboroles 57 and 59-61 with variable R1, R3, R3, R4and R9groups. The chemistry proceeds are described for previous schemes herein. Furthermore, 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.[ d59-61.

[0139] 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.

[0141] 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 CF3alcohol 65. Subsequent Miraura borylation and treatment with HCl in methanol would generate target compounds 67.

[0142] Scheme 20. Synthesis of Trifluoromethyl-Benzoxaborole Pyrazolopyrimidines 67.

[0143] Scheme 21 illustrates a possible route to yield amine-substituted benzoxaboroles 69 from aldehyde 62 and the corresponding amine 68. -substituted benzoxaboroles 69.

[0145] 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.

[0147] 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.

[0149] 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.. .

[0151] 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.

[0153] 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. Suzuki coupling would give vinyl phenol 83 which could then be treated with boron tribromide and trimethylsilane at low temperature to give target compounds 84 after aqueous quench.

[0155] 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.

[0157] 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 oxidationcould 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. The process is very similar to that described for Schemes 26 and 27 but uses 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane in preparation of intermediate 92.-1- ols 95.

[0161] General Procedure. Unless otherwise stated, all reagents and solvents purchased were used as received without further purifications. Reactions that were heated under microwave irradiation were conducted using a Biotage Inititiator+ Robot8 microwave. 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 μm (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.1H and13C NMR spectra of intermediates and final compound were recorded and acquired in CDCl3or DMSO-d6as solvents using Bruker 400 MHz spectrometer at ambient temperature (400 MHz for1H, and 100 MHz for13C). Chemical shifts for1H NMR (400 MHz) spectra are reported in parts per million (ppm) from either CDCl3 (7.26 ppm) or DMSO-d6 (2.50 ppm) with multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd =doublet of a doublet, td = triplet of a doublet, and m = multiplet) and coupling constants (J) in Hz. Chemical shifts for13C NMR (100 MHz) spectra are reported in parts per million (ppm) from either CDCl3(77.2 ppm) or DMSO-d6 (39.52 ppm). High resolution mass spectrum (HRMS) was obtained with an ABSciex 5600+ instrument. The verified purity of final compound was ≥95% as determined by HPLC UV absorbance unless noted otherwise.

[0162] 2-(1-Ethoxypropylidile (I). Malononitrile (10.0 g, 151 mmol) was dissolved in acetic anhydride (35 mL) before the slow addition of triethyl orthopropionate (30.5 mL, 151 mmol) at room temperature. The resulting solution was heated to 110oC and stirred overnight. After this time, the reaction was cooled to room temperature and poured into a separatory funnel containing ethyl acetate and saturated sodium bicarbonate solution. The organics were washed with brine and dried over magnesium sulfate before filtration. The filtrate was concentrated on a rotary evaporator and the resulting product was sufficiently pure (> 95% purity on LCMS) with a yield of 76% and was used in the next step without further purification (off-brown solid, 17.2 g).1H NMR (400 MHz, CDCl3) δ 4.33 - 4.54 (m, 2H), 2.67 (dq, J = 2.93, 7.62 Hz, 2H), 1.38 - 1.53 (m, 3H), 1.19 - 1.33 (m, 3H). LC- MS m / z (M + H)+= 151.

[0163] 5-Amino-3-ethyl-1-mey py azole-4-carbonitrile (II).2-(1- Ethoxypropylidene)malononitrile (9.64 g, 64.3 mmol) was dissolved in ethanol (50 mL) before the slow addition of methylhydrazine (3.4 mL, 64.3 mmol) at room temperature. Theresulting solution was stirred for 3 hrs. After this time, the ethanol was removed on a rotary evaporator and the resulting crude product purified via flash chromatography reaction (0→ 100% EtOAc / Hexanes) to give the desired product as a yellow solid (8.12 g, 84% yield).1H NMR (400 MHz, CDCl3) δ 3.56 (s, 3H), 2.57 (q, J = 7.58 Hz, 2H), 1.23 (t, J = 7.58 Hz, 3H). LC-MS m / z (M + H)+= 151.

[0164] 5-amino-3-ethyl-1-m ole-4-carboxamide (III). Concentratedsulfuric acid (H2SO4, 35 mL) was poured into a round-bottom flask and cooled in an ice water bath to 0oC.5-Amino-3-ethyl-1-methyl-1H-pyrazole-4-carbonitrile (Burch, H. A. Journal of Medicinal Chemistry (1968), 11(1), 79-83; 8.12 g, 54.1 mmol) was slowly added to the cooled concentrated H2SO4 at 0oC. The ice bath was removed, and the resulting solution allowed to warm to room temperature with stirring overnight. After this time, the reaction was poured on an ice and neutralized with concentrated sodium hydroxide solution to pH 8. The aqueous was transferred into a separatory funnel and extracted 3x with ethyl acetate. The organics were combined, washed with brine, and dried over magnesium sulfate before filtration. The filtrate was concentrated on a rotary evaporator and the resulting light brown solid product (5.1 g) was > 98% purity on LCMS with a yield of 56% and was used in the subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) δ 6.50 (br. s., 2H), 6.13 (s, 2H), 3.46 (s, 3H), 2.65 (q, J = 7.46 Hz, 2H), 1.13 (t, J = 7.46 Hz, 3H). LC- MS m / z (M + H)+= 169.

[0165] 3-ethyl-1-methyl-1H]pyrimidine-4,6(5H,7H)-dione (IV). Urea (6.35 g, 106 mmol) and 5-amino-3-ethyl-1-methyl-1H-pyrazole-4-carboxamide (2.60 g, 15.5 mmol) were weighed into a round bottom flask. The flask was heated to 200oC for 2 h. The reaction was cooled to room temperature and 2M NaOH solution was added to the flask. The resulting solution was acidified with conc. HCl to pH 5 and the solids formed were filtered off. The solids were dried overnight and purified via column chromatography (0 to 20% MeOH / EtOAc) to afford the desired product in 74% yield (2.23 g).1H NMR (400MHz, DMSO-d6): δ ppm 1.19 (t, J = 7.6 Hz, 3H), 2.69 (q, J = 7.6 Hz, 2H), 3.68 (s, 3H), 10.07 (s, 1H), 11.84 (s, 1H). LC-MS m / z (M + H)+= 195.

[0166] 4,6-dichloro-3-ethyl- yrazolo[3,4-d]pyrimidine (V). To around bottom flask containing 3-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)- dione (500 mg, 2.57 mmol) was added phosphorus (V) chloride (1 g, 5.14 mmol) and phosphoryl chloride (10 mL). The mixture was refluxed for 9 h and then allowed to cool room temperature. After POCl3 was removed by rotary evaporation, the solid was washed with water, and the yellow solid residue was purified by flash chromatography on silica gel (EtOAc / Hexane) to provide pure white solid intermediate compound (185 mg, 31%). LC-MS m / z 231 (MH)+.1H NMR (400 MHz, DMSO-d6): δ ppm 1.34 (t, J = 7.2 Hz, 3H), 3.06 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H).

[0167] 6-chloro-3-ethyl-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (VI; SLU-0002812).4,6-dichloro-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidine (1.0 g, 4.33 mmol) was dissolved in 10 mL acetonitrile before adding DIPEA (1.10 mL, 6.50 mmol) and 4-fluorobenzyl amine (0.80 mL, 6.50 mmol). The resulting solution was stirred at room temperature for 6 hrs and concentrated. The crude product was purified via silica gel chromatography (20% MeOH / EtOAc) to afford the desired product in 65% yield (897 mg).1H NMR (400 MHz, DMSO-d6) δ 8.09 (t, J = 5.87 Hz, 1H), 7.40 (dd, J = 5.62, 8.56 Hz, 2H), 7.15 (t, J = 8.80 Hz, 2H), 4.69 (d, J = 5.99 Hz, 2H), 3.78 (s, 3H), 2.98 (q, J = 7.46 Hz, 2H), 1.23 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 320. HN Cl

[0168] 6-chloro-3-ethyl-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (SLU-0010811). To a solution of 4,6-dichloro-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidine (300 mg, 1.00 mmol) and 4-chlorobenzylamine (1.00 mmol) wastreated with base DIPEA (0.20 mL, 1.50 mmol) in acetonitrile. The mixture was stirred at room temperature for 7 h. After the reaction was completed confirmed using TLC, the mixture was extracted with ethyl acetate (3X100 mL) and water (200 mL). The combined organic layer was evaporated under vacuum. This crude product was recrystallized with heptane to obtain a yellow solid (283 mg, 65%). LC-MS m / z 337 (MH)+.1H NMR (400 MHz, DMSO-d6): δ (ppm) 1.25 (t, J = 7.6 Hz, 3H), 3.00 (q J =7.6 Hz, 2H), 3.69 (s, 3H), 4.65 (d, J = 6.0 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H).

[0169] General Method A.6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (SLU-0002812; 1 eq.), the respective boronic acid or ester (1.2 eq.), Pd(dppf)Cl2(0.14 eq.) and K2CO3(2 eq.) were weighed into a 20 mL microwave vial and capped. The vial was vacuumed and backfilled with Argon gas. This process was repeated three times and the vial kept under positive argon pressure. Anhydrous DMF and degassed distilled water were added to the vial in a 4:1 ratio. The microwave vial was placed in a heating block and the block heated to 100oC 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. To ensure sufficiently pure compounds to submit for bioassay, a second reversed phase chromatography eluting with water and acetonitrile with no modifiers was performed.

[0170] p-(3-ethyl-4-{[(pmino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzonitrile (SLU-0002813). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (430.5 mg, 1.88 mmol), Pd(dppf)Cl2(160.2 mg, 0.219 mmol), K2CO3(541.5 mg, 3.92 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 62% yield (374 mg).1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.31 Hz, 2H), 7.92 (d, J = 8.44 Hz, 3H), 7.48 (dd, J = 5.69, 8.38 Hz, 2H), 7.14 (t, J =8.86 Hz, 2H), 4.85 (d, J = 5.75 Hz, 2H), 3.91 (s, 3H), 3.04 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 387.

[0171] ethyl m-(3-ethy hyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoate (SLU-0010258). Using General Method A; 6-chloro-3-ethyl- N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.94 mmol), (4-(ethoxycarbonyl)phenyl)boronic acid (327.8 mg, 1.69 mmol), Pd(dppf)Cl2(95.1 mg, 0.13 mmol), K2CO3 (298.5 mg, 2.16 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 56% yield (226 mg).1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.44 Hz, 2H), 8.05 (d, J = 8.44 Hz, 2H), 7.89 (s, 1H), 7.51 (dd, J = 5.69, 8.50 Hz, 2H), 7.15 (t, J = 8.93 Hz, 2H), 4.85 (d, J = 5.50 Hz, 2H), 4.35 (q, J = 7.09 Hz, 2H), 3.92 (s, 3H), 3.05 (q, J = 7.46 Hz, 2H), 1.35 (t, J = 7.09 Hz, 3H), 1.29 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 434.

[0172] [(p-fluorophenyhyl-6-[6-(trifluoromethyl)-3- pyridyl]-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010083). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (161.5 mg, 0.846 mmol), Pd(dppf)Cl2 (48.1 mg, 0.066 mmol), K2CO3 (149.4 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 70% yield (141 mg).1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.79 (d, J = 7.82 Hz, 1H), 7.87 - 7.99 (m, 2H), 7.48 (dd, J = 5.75, 8.31 Hz, 2H), 7.13 (t, J = 8.86 Hz, 2H), 4.82 (d, J = 5.75 Hz, 2H), 3.87 (s, 3H), 3.01 (q, J = 7.38 Hz, 2H), 1.27 (t, J = 7.46 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.43 (3F), -116.28 to -116.35 (1F). LC-MS m / z (M + H)+= 431.

[0173] [(p-fluorophenyl)methyl][3-ethyl-6-(p-methoxyphenyl)-1-methyl-1H- 1,2,5,7-tetraazainden-4-yl]amine (SLU-0010084). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), (4-methoxyphenyl)boronic acid (128.6 mg, 0.846 mmol), Pd(dppf)Cl2(48.1 mg, 0.066 mmol), K2CO3 (149.4 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 85% yield (156 mg).1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.80 Hz, 2H), 7.72 (t, J = 5.93 Hz, 1H), 7.49 (dd, J = 5.69, 8.38 Hz, 2H), 7.14 (t, J = 8.80 Hz, 2H), 7.00 (d, J = 8.93 Hz, 2H), 4.85 (d, J = 5.75 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.02 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 392.

[0174] [(p-fluorophenyl) methoxyphenyl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0010085). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), (2-methoxyphenyl)boronic acid (128.6 mg, 0.846 mmol), Pd(dppf)Cl2 (48.1 mg, 0.066 mmol), K2CO3(149.1 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 78% yield (144 mg).1H NMR (400 MHz, DMSO-d6) δ 7.68 (t, J = 6.11 Hz, 1H), 7.40 - 7.50 (m, 3H), 7.33 - 7.40 (m, 1H), 7.10 - 7.17 (m, 2H), 7.07 (d, J = 8.07 Hz, 1H), 6.99 (dt, J = 0.79, 7.43 Hz, 1H), 4.76 (d, J = 5.99 Hz, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 3.04 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 392.

[0175] [(p-fluorophehoxyphenyl)-1-methyl-1H- 1,2,5,7-tetraazainden-4-yl]amine (SLU-0010086). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), (3-methoxyphenyl)boronic acid (128.6 mg, 0.846 mmol), Pd(dppf)Cl2 (48.1 mg, 0.066 mmol), K2CO3(149.1 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 79% yield (145 mg).1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 7.70 Hz, 1H),7.92 (d, J = 2.45 Hz, 1H), 7.79 (t, J = 5.93 Hz, 1H), 7.49 (dd, J = 5.62, 8.56 Hz, 2H), 7.36 (t, J = 7.95 Hz, 1H), 7.13 (t, J = 8.86 Hz, 2H), 7.01 (dd, J = 2.38, 8.01 Hz, 1H), 4.84 (d, J = 5.87 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 2.91 - 3.13 (m, 2H), 1.29 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 392.

[0176] [(p-fluorophenyl thyl-6-(5-pyrimidinyl)-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0010087). Using General Method A; 6-chloro-3-ethyl-N- (4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), pyrimidin-5-ylboronic acid (104.6 mg, 0.846 mmol), Pd(dppf)Cl2 (48.1 mg, 0.066 mmol), K2CO3(149.1 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 67% yield (114 mg).1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 2H), 9.18 (s, 1H), 7.88 (t, J = 5.87 Hz, 1H), 7.42 (dd, J = 5.81, 8.25 Hz, 2H), 7.08 (t, J = 8.80 Hz, 2H), 4.76 (d, J = 5.87 Hz, 2H), 3.82 (s, 3H), 2.96 (q, J = 7.34 Hz, 2H), 1.22 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 364.

[0177] [(p-fluorophenyl)methyl-4-isoxazolyl)-3-ethyl-1-methyl- 1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0010088). Using General Method A; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (171.7 mg, 0.846 mmol), Pd(dppf)Cl2 (48.1 mg, 0.066 mmol), K2CO3(149.1 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 43% yield (76 mg).1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.28 (dd, J = 5.62, 8.68 Hz, 2H), 6.99 - 7.13 (m, 2H), 4.73 (d, J = 5.99 Hz, 2H), 3.77 (s, 3H), 2.96 (q, J = 7.46 Hz, 2H), 2.56 (s, 3H), 2.36 (s, 3H), 1.21 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 381.

[0178] [(p-fluorophenyl thyl-6-(4-pyridyl)-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0010089). Using General Method A; 6-chloro-3-ethyl-N- (4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), pyridin-4-ylboronic acid (104 mg, 0.846 mmol), Pd(dppf)Cl2 (48.1 mg, 0.066 mmol), K2CO3 (149.1 mg, 1.08 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 88% yield (149 mg).1H NMR (400 MHz, DMSO-d6) δ 8.59 - 8.76 (m, 2H), 8.15 - 8.28 (m, 2H), 7.90 (t, J = 6.05 Hz, 1H), 7.49 (dd, J = 5.62, 8.56 Hz, 2H), 7.03 - 7.22 (m, 2H), 4.84 (d, J = 5.87 Hz, 2H), 3.89 (s, 3H), 3.03 (q, J = 7.46 Hz, 2H), 1.27 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 363.

[0179] [(p-fluorophenyl)methoxy-3-pyridyl)-1-methyl-1H- 1,2,5,7-tetraazainden-4-yl]amine (SLU-0010097). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), (6-methoxypyridin-3-yl)boronic acid (130 mg, 0.846 mmol), Pd(dppf)Cl2( 48.1 mg, 0.066 mmol), K2CO3 (149.4 mg, 1.081 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 88% (162 mg).1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.20 Hz, 1H), 8.48 (dd, J = 2.32, 8.68 Hz, 1H), 7.74 (t, J = 5.93 Hz, 1H), 7.41 (dd, J = 5.75, 8.44 Hz, 2H), 7.07 (t, J = 8.86 Hz, 2H), 6.81 (d, J = 8.68 Hz, 1H), 4.77 (d, J = 5.87 Hz, 2H), 3.81 (s, 3H), 2.95 (q, J = 7.34 Hz, 2H), 1.21 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+=393.

[0180] m-(3-ethyl-4-{[(p-u p y y amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzenesulfonamide (SLU-0010257). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (106.4 mg, 0.376 mmol), Pd(dppf)Cl2 (32 mg, 0.044 mmol), K2CO3 (108.1 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 43% yield (60 mg).1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.50 (d, J = 7.95 Hz, 1H), 7.81 - 7.90 (m, 2H), 7.61 (t, J = 7.83 Hz, 1H), 7.46 (dd, J = 5.75, 8.44 Hz, 2H), 7.41 (s, 2H), 7.06 (t, J = 8.86 Hz, 2H), 4.78 (d, J = 5.87 Hz, 2H), 3.85 (s, 3H), 2.97 (q, J = 7.46 Hz, 2H), 1.21 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 441.

[0181] ethyl m-(3-ethyl-4 ethyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoate (SLU-0010258). Using General Method A; 6-chloro-3-ethyl- N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), (3-(ethoxycarbonyl)phenyl)boronic acid (364.7 mg, 1.88 mmol), Pd(dppf)Cl2 (160.2 mg, 0.219 mmol), K2CO3(541.5 mg, 3.92 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 59% yield (403 mg).1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.60 (d, J = 7.82 Hz, 1H), 8.02 (d, J = 7.70 Hz, 1H), 7.88 (t, J = 5.99 Hz, 1H), 7.59 (t, J = 7.76 Hz, 1H), 7.52 (dd, J = 5.62, 8.44 Hz, 2H), 7.14 (t, J = 8.86 Hz, 2H), 4.83 (d, J = 5.87 Hz, 2H), 4.36 (q, J = 7.09 Hz, 2H), 3.90 (s, 3H), 3.03 (q, J = 7.46 Hz, 2H), 1.35 (t, J = 7.09 Hz, 3H), 1.29 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 434.

[0182] 5-(3-ethyl-4-{[(p-mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-2-pyridinecarbonitrile (SLU-0010261). Using General Method A; 6- chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (432.5 mg, 1.88 mmol), Pd(dppf)Cl2(161 mg, 0.22 mmol), K2CO3(543.2 mg, 3.93 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 54% yield (328 mg).1H NMR (400 MHz, DMSO-d6) δ9.47 (d, J = 1.47 Hz, 1H), 8.72 (dd, J = 2.02, 8.13 Hz, 1H), 8.04 (d, J = 8.07 Hz, 1H), 7.93 (t, J = 5.93 Hz, 1H), 7.42 (dd, J = 5.75, 8.44 Hz, 2H), 7.08 (t, J = 8.86 Hz, 2H), 4.77 (d, J = 5.87 Hz, 2H), 3.84 (s, 3H), 2.97 (q, J = 7.46 Hz, 2H), 1.21 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 388.

[0183] [(p-fluorophenyl -(trifluoromethyl)phenyl]-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010569). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (211.1 mg, 0.941 mmol), Pd(dppf)Cl2 (80.5 mg, 0.11 mmol), K2CO3 (270.9 mg, 1.96 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 55% yield (201 mg).1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.52 (d, J = 8.31 Hz, 1H), 7.90 (t, J = 5.69 Hz, 1H), 7.74 (d, J = 8.31 Hz, 1H), 7.41 (dd, J = 5.87, 7.95 Hz, 2H), 7.06 (t, J = 8.80 Hz, 2H), 4.73 (d, J = 5.62 Hz, 2H), 3.83 (s, 3H), 2.97 (q, J = 7.46 Hz, 2H), 1.22 (t, J = 7.40 Hz, 3H). LC-MS m / z (M + H)+= 464.

[0184] [(p-fluorophenyl-1-methyl-1H- 1,2,5,7-tetraazainden-4-yl]amine (SLU-0010565). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), (3,4-dichlorophenyl)boronic acid (179.6 mg, 0.941 mmol), Pd(dppf)Cl2(80.5 mg, 0.11 mmol), K2CO3 (270 mg, 1.96 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 70% yield (235 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 - 9.32 (m, 2H), 7.96 - 8.20 (m, 3H), 7.71 (br. s., 2H), 6.12 (br. s., 1H), 5.58 (br. s., 2H), 4.66 (br. s., 3H), 3.58 (d, J = 6.24 Hz, 2H), 2.04 (br. s., 3H); δ LC-MS m / z (M + H)+= 430.

[0185] [(p-fluorophenyl)methyl]{6-[3-chloro-4-(trifluoromethyl)phenyl]-3-ethyl- 1-methyl-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010566). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), (3-chloro-4-(trifluoromethyl)phenyl)boronic acid (211.1 mg, 0.941 mmol), Pd(dppf)Cl2 (80.5 mg, 0.11 mmol), K2CO3 (270.9 mg, 1.96 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 73% yield (266 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 - 8.47 (m, 2H), 7.84 - 7.98 (m, 2H), 7.47 (br. s., 2H), 7.13 (br. s., 2H), 4.79 (br. s., 2H), 3.86 (br. s., 3H), 3.01 (d, J = 6.24 Hz, 2H), 1.27 (br. s., 3H); δ LC-MS m / z (M + H)+= 464.

[0186] methyl 4-(3-eth thyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-2-fluorobenzoate (SLU-0010571). Using General Method A; 6- chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 3.13 mmol), (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (1.05 g, 3.76 mmol), Pd(dppf)Cl2 (320.5 mg, 0.44 mmol), K2CO3 (1.08 g, 7.83 mmol), 24 mL DMF and 6 mL H2O, the product was isolated in 43% yield (158 mg).1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.19 Hz, 1H), 8.10 (d, J = 12.47 Hz, 1H), 7.85 - 7.99 (m, 2H), 7.48 (dd, J = 5.87, 7.95 Hz, 2H), 7.14 (t, J = 8.80 Hz, 2H), 4.83 (d, J = 5.50 Hz, 2H), 3.89 (s, 6H), 3.03 (q, J = 7.34 Hz, 2H), 2.95 - 3.09 (m, 2H), 1.28 (t, J = 7.40 Hz, 3H). LC-MS m / z (M + H)+= 438.

[0187] [(p-fluorophenylxyphenyl)-3-ethyl-1-methyl-1H- 1,2,5,7-tetraazainden-4-yl]amine (SLU-0010470). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.940 mmol), (3,4-dimethoxyphenyl)boronic acid (205.6 mg, 1.13 mmol), Pd(dppf)Cl2 (95.1 mg, 0.13 mmol), K2CO3(324.8 mg, 2.35 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 72% yield (285 mg).1H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J = 1.96, 8.44 Hz, 1H), 7.86 (d, J = 1.96 Hz, 1H), 7.68 (t, J = 5.99 Hz, 1H), 7.43 (dd, J = 5.62, 8.56 Hz, 2H), 7.00 - 7.13 (m, 2H), 6.94 (d, J = 8.56 Hz, 1H), 4.76 (d, J = 5.87 Hz, 2H), 3.82 (s, 3H),3.74 (d, J = 2.57 Hz, 6H), 2.96 (q, J = 7.42 Hz, 2H), 1.22 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 422.

[0188] ethyl 5-(3-ethyl- yl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-2-fluorobenzoate (SLU-0010568). Using General Method A; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), (3-(ethoxycarbonyl)-4-fluorophenyl)boronic acid (199.5 mg, 0.941 mmol), Pd(dppf)Cl2(80.5 mg, 0.11 mmol), K2CO3(270.9 mg, 1.96 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 85% yield (301 mg).1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 5.75 Hz, 1H), 8.52 (d, J = 3.06 Hz, 1H), 7.83 (br. s., 1H), 7.40 - 7.49 (m, 2H), 7.35 (t, J = 9.60 Hz, 1H), 7.07 (t, J = 8.68 Hz, 2H), 4.75 (d, J = 5.38 Hz, 2H), 4.31 (q, J = 6.93 Hz, 2H), 3.83 (s, 3H), 3.28 (s, 6H), 2.96 (q, J = 7.38 Hz, 2H), 1.28 (t, J = 7.03 Hz, 3H), 1.22 (t, J = 7.34 Hz, 3H). LC-MS m / z (M + H)+= 452.

[0189] [(p-fluorophenyuoro-3-(trifluoromethyl)phenyl]- 1-methyl-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010567). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (195.7 mg, 0.941 mmol), Pd(dppf)Cl2(80.5 mg, 0.11 mmol), K2CO3(270.9 mg, 1.96 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 89% yield (311 mg).1H NMR (400 MHz, DMSO-d6) δ 8.62 (br. s., 1H), 8.56 (d, J = 6.72 Hz, 1H), 7.91 (t, J = 5.20 Hz, 1H), 7.54 (t, J = 9.60 Hz, 1H), 7.41 - 7.50 (m, 2H), 7.12 (t, J = 8.62 Hz, 2H), 4.78 (d, J = 5.26 Hz, 2H), 3.87 (s, 3H), 3.02 (q, J = 7.21 Hz, 2H), 1.28 (t, J = 7.34 Hz, 3H). LCMS: m / z (M + H)+= 448.

[0190] General Method B.6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (1 eq. ), the respective amine substrate (1.2 eq.), Pd(dppf)Cl2 (0.10 eq.) and NaOtBu (2 eq.) were weighed into a 20 mL microwave vial and capped. The vial was vacuumed and backfilled with Argon gas. This process was repeated 3Xand the vial kept under positive Argon pressure before adding anhydrous dioxane. The microwave vial was placed in a heating block and the block heated to 100oC 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. To ensure sufficiently pure compounds to submit for bioassay, a second reversed phase chromatography eluting with water and acetonitrile with no modifiers was performed.

[0191] tert-butyl 4-(3-el)methyl]amino}-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)-1-piperazinecarboxylate (SLU-0010032).1-Boc-piperazine (247.9 mg, 1.33 mmol) and sodium hydride in mineral oil (35 mg, 1.45 mmol) were weighed into a flask before adding 5 mL DMF. The resulting solution was stirred for 5 mins before adding 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (387.4 mg, 1.21 mmo) in 5 mL DMF. The reaction was heated to 130oC with stirring for 5 days. After this time, the reaction was cooled to room temperature, quenched with 1 M HCl solution, and extracted 3X with ethyl acetate. The organics were combined, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the crude product purified via reversed-phase chromatography. The product was isolated in 76 % yield (429 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 7.47 (s, 1H), 7.39 (dd, J = 5.62, 8.56 Hz, 2H), 7.08 - 7.15 (m, 2H), 4.62 (d, J = 5.75 Hz, 2H), 3.67 (d, J = 4.77 Hz, 4H), 3.64 (s, 3H), 3.24 - 3.33 (m, 4H), 2.88 (q, J = 7.46 Hz, 2H), 1.41 (s, 9H), 1.21 (t, J = 7.46 Hz, 3H); δ LC- MS m / z (M + H)+= 470.

[0192] p-(3-ethyl-4-{[(p- amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-ylamino)benzonitrile (SLU-0010266). Using General Method B; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), 4-aminobenzonitrile (222.1 mg, 1.88 mmol), Pd(dppf)Cl2 (114.9 mg, 0.157 mmol), NaOtBu (226.8 mg, 2.36 mmol), and 15 mL dioxane, the product was isolated in 70% yield (439 mg).1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.85 (d, J = 8.68 Hz, 2H), 7.59 (t, J = 5.99 Hz, 1H), 7.54 (d, J = 8.68 Hz, 2H), 7.37 (dd, J = 5.81, 8.25 Hz, 2H), 7.10 (t, J = 8.80 Hz, 2H), 4.70 (d, J = 5.75 Hz, 2H), 3.70 (s, 3H), 2.90 (q, J = 7.42 Hz, 2H), 1.19 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 402.

[0193] m-(3-ethyl-4-{[(p-]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-ylamino)benzonitrile (SLU-0010267). Using General Method B; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), 3-aminobenzonitrile (222.1 mg, 1.88 mmol), Pd(dppf)Cl2 (114.9 mg, 0.157 mmol), NaOtBu (226.8 mg, 2.36 mmol), and 15 mL dioxane, the product was isolated in 62% yield (392 mg).1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.27 (s, 1H), 7.99 (d, J = 8.19 Hz, 1H), 7.62 (t, J = 5.87 Hz, 1H), 7.34 - 7.47 (m, 3H), 7.29 (d, J = 7.58 Hz, 1H), 7.14 (t, J = 8.80 Hz, 2H), 4.77 (d, J = 5.87 Hz, 2H), 3.76 (s, 3H), 2.95 (q, J = 7.42 Hz, 2H), 1.25 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 402.

[0194] methyl 6-(3-ethyl methyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-ylamino)nicotinate (SLU-0010268). Using General Method B; 6- chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), methyl 6-aminonicotinate (286 mg, 1.88 mmol), Pd(dppf)Cl2(114.9 mg, 0.157 mmol), NaOtBu (226.8 mg, 2.36 mmol), and 15 mL dioxane, the product was isolated in 41% yield (281 mg).1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.75 (d, J = 1.71 Hz, 1H), 8.32 (d, J = 8.93 Hz, 1H), 8.01 (dd, J = 1.96, 8.93 Hz, 1H), 7.64 (t, J = 5.93 Hz, 1H), 7.42 (dd, J = 5.93, 8.13 Hz, 2H), 7.07 (t, J = 8.80 Hz, 2H), 4.66 (d, J = 5.75 Hz, 2H), 3.77 (s, 3H), 3.72 (s, 3H), 2.89 (q, J = 7.46 Hz, 2H), 1.18 (t, J = 7.40 Hz, 3H). LC-MS m / z (M + H)+= 436.

[0195] 1-(3-ethyl-4-{[(pmino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-4-piperidinecarbonitrile (SLU-0010260). Using General Method B; 6- chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.57 mmol), piperidine-4-carbonitrile (207.1 mg, 1.88 mmol), Pd(dppf)Cl2 (114.9 mg, 0.157 mmol), NaOtBu (226.8 mg, 2.36 mmol), and 15 mL dioxane, the product was isolated in 54% yield (334 mg).1H NMR (400 MHz, DMSO-d6) δ 7.37 (t, J = 5.93 Hz, 1H), 7.32 (dd, J = 5.75, 8.44 Hz, 2H), 7.05 (t, J = 8.86 Hz, 2H), 4.54 (d, J = 5.75 Hz, 2H), 3.89 - 4.00 (m, 2H), 3.57 (s, 3H), 3.34 - 3.45 (m, 2H), 2.98 (td, J = 4.29, 8.41 Hz, 1H), 2.81 (q, J = 7.46 Hz, 2H), 1.71 (ddd, J = 3.00, 6.17, 9.66 Hz, 2H), 1.40 - 1.56 (m, 2H), 1.14 (t, J = 7.40 Hz, 3H). LC- MS m / z (M + H)+= 394.

[0196] General Method C.6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (1 eq. ), the respective imidazole derivate (1.5 to 2.0 eq.), CuBr (0.20 eq.) and Cs2CO3 (2 eq.) were weighed into a 20 mL microwave vial and capped. The vial was vacuumed and backfilled with Argon gas. This process was repeated three timesand the vial kept under positive Argon pressure before adding anhydrous DMF or DMSO. The microwave vial was placed in a Biotage microwave reactor and irradiated to 100 to 120oC 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. To ensure sufficiently pure compounds to submit for bioassay, a second reversed phase chromatography eluting with water and acetonitrile with no modifiers was performed.

[0197] methyl 1-(3-ethylmethyl]amino}-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)-5-imidazolecarboxylate (SLU-0010098). Using General Method C; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4- amine (500 mg, 1.57 mmol), methyl 1H-imidazole-5-carboxylate (356.9 mg, 0.705 mmol), CuBr (45 mg, 0.314 mmol), Cs2CO3 (1.2 g, 3.68 mmol), and 15 mL DMSO, the product was isolated in 57% yield (365 mg).1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.51 (s, 1H), 7.29 (dd, J = 5.32, 8.50 Hz, 2H), 7.00 (t, J = 8.50 Hz, 2H), 4.80 (d, J = 5.14 Hz, 2H), 3.88 (s, 6H), 2.85 (q, J = 7.54 Hz, 2H), 1.31 (t, J = 7.52 Hz, 3H). LC-MS m / z (M + H)+= 410.

[0198] [(p-fluorophenyl)midazolyl)-1-methyl-1H-1,2,5,7- tetraazainden-4-yl]amine (SLU-0010100). Using General Method C; 6-chloro-3-ethyl-N- (4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), 1H- imidazole (48 mg, 0.705 mmol), CuBr (13.5 mg, 0.094 mmol), Cs2CO3 (306.3 mg, 0.940 mmol), and 10 mL DMF, the product was isolated in 43% yield (71 mg).1H NMR (400 MHz, CDCl3) δ 8.74 (br. s., 1H), 7.91 (br. s., 1H), 7.28 (d, J = 5.62 Hz, 2H), 6.98 (t, J = 8.38Hz, 2H), 5.73 (br. s., 1H), 4.78 (d, J = 5.01 Hz, 2H), 3.84 (br. s., 3H), 2.85 (q, J = 7.42 Hz, 2H), 1.30 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 352.

[0199] General Method D. The respective carboxylate derivative was weighed into a round bottom flask before adding ethanol and KOH. The flask was placed in a heating block and heated to 100oC for 2h with a condenser on top. After this time, the reaction was cooled to room temperature, acidified with 1 M HCl solution to pH 6 and concentrated. The resulting crude product was purified via reversed phase chromatography eluting with H2O:CH3CN.

[0200] p-(3-ethyl-4-{[( mino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (SLU-0002815). Using General Method D; ethyl 4-(3- ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (100 mg, 0.231 mmol), KOH ( 23.3 mg, 0.347 mmol) and 10 mL ethanol, the product was isolated in 73% yield (68 mg).1H NMR (400 MHz, DMSO-d6) δ 13.03 (br. s., 1H), 8.48 (d, J = 8.31 Hz, 2H), 8.03 (d, J = 8.31 Hz, 2H), 7.92 (t, J = 5.87 Hz, 1H), 7.51 (dd, J = 5.81, 8.25 Hz, 2H), 7.15 (t, J = 8.80 Hz, 2H), 4.86 (d, J = 5.50 Hz, 2H), 3.91 (s, 3H), 3.05 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 406. HRMS (ESI) m / z: [M + H]+Calcd for C22H20FN5O2406.1679; found 406.1670. HN F H

[0201] m-(3-ethyl-4-{[(p-]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (SLU-0010269). Using General Method D; 3-(3-ethyl-4- ((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (250 mg, 0.577 mmol), KOH (129.5 mg, 2.31 mmol), and 10 mL ethanol, the product was isolated in 84% yield (196 mg).1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.52 (d, J = 7.82 Hz, 1H), 7.96 (d, J = 7.58 Hz, 1H), 7.86 (t, J = 5.56 Hz, 1H), 7.53 (t, J = 7.70 Hz, 1H), 7.46 (dd, J = 5.93, 7.76 Hz, 2H), 7.07 (t, J = 8.80 Hz, 2H), 4.77 (d, J = 5.26 Hz, 2H), 3.84 (s, 3H), 2.98 (q, J = 7.34 Hz, 2H), 1.22 (t, J = 7.40 Hz, 3H). LC-MS m / z (M + H)+= 406.HN N F N 2H

[0202] 5-(3-ethyl-4-{[( mino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-2-pyridinecarboxylic acid (SLU-0010496). Using General Method D; 65-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)picolinonitrile (100 mg, 0.258 mmol), KOH (101.3 mg, 1.81 mmol), 6 mL ethanol and 5 mL deionized water, the product was isolated in 57% yield (60 mg).1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 1.47 Hz, 1H), 8.72 (dd, J = 2.08, 8.19 Hz, 1H), 8.07 (d, J = 8.19 Hz, 1H), 7.91 (t, J = 5.99 Hz, 1H), 7.43 (dd, J = 5.62, 8.56 Hz, 2H), 7.08 (t, J = 8.86 Hz, 2H), 4.79 (d, J = 5.75 Hz, 2H), 3.85 (s, 3H), 2.98 (q, J = 7.50 Hz, 2H), 1.22 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 407.

[0203] 5-(3-ethyl-4-{[(pino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-2-fluorobenzoic acid (SLU-0010615). Using General Method D; ethyl 5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2- fluorobenzoate (302.7 mg, 0.671 mmol), KOH (226.1 mg, 4.03 mmol), 20 mL ethanol, the product was isolated in 34% yield (107 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (br. s., 1H), 8.43 - 8.69 (m, 1H), 7.87 (br. s., 1H), 7.32 - 7.70 (m, 4H), 7.12 (br. s., 1H), 4.80 (br. s., 2H), 3.88 (br. s., 3H), 3.02 (br. s., 2H), 1.27 (br. s., 3H); LC-MS m / z (M + H)+= 424.

[0204] 4-(3-ethyl-4-{[(pmino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-2-fluorobenzoic acid (SLU-0010614). Using General Method D; methyl 4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2- fluorobenzoate (90 mg, 0.206 mmol), KOH (70 mg, 1.24 mmol), 15 mL ethanol, the product was isolated in 33% yield (28.5 mg).1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.07 Hz,1H), 8.11 (d, J = 12.23 Hz, 1H), 7.87 - 8.00 (m, 2H), 7.42 - 7.55 (m, 2H), 7.14 (t, J = 8.74 Hz, 2H), 4.84 (d, J = 5.38 Hz, 2H), 3.91 (s, 3H), 3.04 (q, J = 1.00 Hz, 2H), 1.28 (t, J = 7.40 Hz, 3H). LC-MS m / z (M + H)+= 424.

[0205] 6-{[(2,4-dimeth -3-ethyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazaindene (SLU-0010035).6- Chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.25 mmol) was dissolved in 10 mL dioxane before adding DIPEA (0.3 mL, 1.88 mmol) and (2,4-dimethoxyphenyl)methanamine (0.3 mL, 1.88 mmol). The resulting solution was heated to 100oC with stirring for 48 h. After this time, the reaction mixture was cooled to room temperature, concentrated on a rotovap and purified via reversed-phase chromatography. Product was isolated in 56% yield (314 mg).1H NMR (400 MHz, CDCl3) δ ppm 9.06 (br. s., 1H), 8.05 (br. s., 2H), 7.62 - 7.86 (m, 3H), 7.08 (br. s., 1H), 5.42 (d, J = 5.75 Hz, 2H), 5.19 (br. s., 2H), 4.52 (s, 3H), 4.47 (s, 6H), 3.63 (q, J = 7.38 Hz, 2H), 3.24 (br. s., 2H), 1.94 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 451.

[0206] 6-amino-3-ethyl-ethyl]amino}-1-methyl-1H-1,2,5,7- tetraazaindene (SLU-0010042).6-{[(2,4-dimethoxyphenyl)methyl]amino}-3-ethyl-4-{[(p- fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazaindene (158.2 mg, 0.352 mmol) was dissolved in 15 mL DCM before adding trifluoroacetic acid (1 mL, 13.07 mmol) at room temperature. The reaction mixture was stirred overnight. After this time, the reaction mixture was concentrated, and purified via reversed-phased chromatography. The product was isolated in 89% yield (94 mg).1H NMR (400 MHz, DMSO-d6) δ 8.15 (br. s., 1H), 7.36 (dd, J = 5.56, 8.62 Hz, 2H), 6.96 - 7.20 (m, 2H), 4.66 (d, J = 5.99 Hz, 2H), 3.68 (s, 3H), 2.82 (q, J = 7.46 Hz, 2H), 1.13 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 301.

[0207] [p-(3-ethyl-4-{[( mino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)phenyl]methanol (SLU-0010034). A round bottom flask containing 1 mL THF was cooled to 0oC before adding 0.1 mL of 1 M LiAlH4in THF solution. Ethyl 4- (3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (358 mg, 0.083 mmol) dissolved in 4 mL THF was added to the cooled flask and the reaction mixture warmed to room temperature. After 15 mins, the reaction mixture was quenched with conc. HCl and extracted 3X with DCM. The organics was washed with brine, dried over MgSO4and filtered. The filtrate was concentrated and purified via reversed-phase chromatography. The product was isolated in 74% yield ( 24mg).1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.19 Hz, 2H), 7.78 (t, J = 5.81 Hz, 1H), 7.49 (dd, J = 5.81, 8.38 Hz, 2H), 7.40 (d, J = 8.19 Hz, 2H), 7.14 (t, J = 8.93 Hz, 2H), 4.85 (d, J = 5.75 Hz, 2H), 4.56 (s, 2H), 3.90 (s, 3H), 3.03 (q, J = 7.34 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 392.

[0208] p-(3-ethyl-4-{[(ino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzamide (SLU-0010039).4-(3-ethyl-4-((4-fluorobenzyl)amino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzonitrile (100 mg, 0.259 mmol) was added to a round bottom flask and cooled to ) oC before adding 5 mL H2SO4. The cooling bath was removed, and the flask warmed to room temperature before stirring overnight. After this time, the reaction mixture was poured into ice, basified (pH 9) and extracted 3x with ethyl acetate. The organics were combined, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated on a rotary evaporator and the crude product purified via silica gel chromatography eluting with EtOAc:MeOH. The product was isolated in 47% yield (49.4 mg).1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.44 Hz, 2H), 8.04 (br. s., 1H), 7.95 (d, J = 8.44 Hz, 2H), 7.85 (t, J = 6.05 Hz, 1H), 7.50 (dd, J = 5.69, 8.50 Hz, 2H), 7.42 (br. s., 1H),7.15 (t, J = 8.86 Hz, 2H), 4.86 (d, J = 5.75 Hz, 2H), 3.92 (s, 3H), 3.04 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 405.

[0209] tert-butyl 4-(4-( )amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoyl)piperazine-1-carboxylate.4-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoic acid (300 mg, 0.740 mmol) and 1-Boc-piperazine (138 mg.0.740 mmol) were weighed into a round bottom flask. Anhydrous dichloromethane (DCM, 10 mL) was added and stirred for 10 mins before the addition of HATU (281 mg, 0.740 mmol) and DIPEA (0.30 mL, 1.48 mmol). The resulting solution was stirred at room temperature overnight. After this time, the reaction mixture was transferred into a separatory funnel containing DCM and saturated sodium bicarbonate solution. The organics were separated and washed sequentially with 1N HCl solution, water, and brine before drying over magnesium sulfate. The filtrate was concentrated and purified via reversed-phase chromatography eluting with water:acetonitrile. The product was isolated in 76% yield (324 mg).1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.19 Hz, 2H), 7.51 (d, J = 8.31 Hz, 2H), 7.41 (dd, J = 5.38, 8.56 Hz, 2H), 7.07 (t, J = 8.62 Hz, 2H), 4.99 (d, J = 5.50 Hz, 2H), 4.05 (s, 3H), 3.78 (br. s., 2H), 3.29 - 3.64 (m, 6H), 2.88 - 3.01 (m, 2H), 1.49 (s, 9H), 1.39 (t, J = 7.58 Hz, 3H). LC-MS m / z (M + H)+= 574.

[0210] [p-(3-ethyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)phenyl](1-piperazinyl)methanone (SLU-0010040). Tert-butyl 4-(4-(3- ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzoyl)piperazine-1-carboxylate (200 mg, 0.349 mmol) was weighed into a round bottom flask before the addition of anhydrous dichloromethane (DCM, 10 mL). Trifluoroacetic acid (0.50 mL,6.53 mmol) was slowly added, and the resulting solution stirred at room temperature for 1-2 h. After this time, the solvents were removed on a rotovap and the crude product purified via reversed-phase chromatography. Product was isolated in 76% yield (126 mg).1H NMR (400 MHz, DMSO-d6) δ 9.07 (br. s., 1H), 8.45 (d, J = 8.31 Hz, 2H), 7.87 (t, J = 5.99 Hz, 2H), 7.56 (d, J = 8.31 Hz, 2H), 7.49 (dd, J = 5.62, 8.56 Hz, 2H), 7.06 - 7.21 (m, 2H), 4.87 (d, J = 5.87 Hz, 2H), 3.91 (s, 3H), 3.73 (br. s., 4H), 3.19 (br. s., 4H), 3.04 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 474.

[0211] 3-ethyl-4-{[(p1-methyl-1H-1,2,5,7- tetraazaindene-6-carbonitrile (SLU-0010096).6-chloro-3-ethyl-N-(4-fluorobenzyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 3.13 mmol), zinc cyanide (235 mg, 2.0 mmol), and Pd(PPh3)4(231 mg, 0.2 mmol) were weighed into a 20 mL microwave vial and capped. 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 110oC 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 desired product is isolated in 80% yield (496 mg).1H NMR (400 MHz, DMSO-d6) δ 8.16 (t, J = 6.05 Hz, 1H), 7.25 - 7.41 (m, 2H), 6.99 - 7.16 (m, 2H), 4.66 (d, J = 5.99 Hz, 2H), 3.80 (s, 3H), 2.96 (q, J = 7.46 Hz, 2H), 1.18 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 311.HN N H F N H

[0212] 3-ethyl-4-{[(p-flu no}-6-(hydroxyamino)carboximidoyl-1-methyl-1H-1,2,5,7-tetraazaindene (SLU-0010256). Hydroxylamine hydrochloride (134.5 mg, 1.94 mmol) was weighed into a flask containing 10 mL of distilled water followed by the addition of sodium bicarbonate (189.7 mg, 2.26 mmol) and 20 mL of ethanol. The resulting solution was stirred at room temperature for 10-15 mins before adding 3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- carbonitrile (500 mg, 1.61 mmol). The reaction mixture was heated to 80oC with stirring overnight. After this time, the reaction was cooled to room temperature and poured into a separatory funnel containing saturated ammonium chloride solution and ethyl acetate. The organics were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated, and the crude product purified via silica gel chromatography. The product was isolated in 76% yield (420 mg).1H NMR (400 MHz, DMSO-d6) δ 9.93 (br. s., 1H), 7.70 (t, J = 5.93 Hz, 1H), 7.39 (dd, J = 5.75, 8.31 Hz, 2H), 7.05 (t, J = 8.86 Hz, 2H), 5.63 (br. s., 2H), 4.71 (d, J = 5.87 Hz, 2H), 3.77 (s, 3H), 2.93 (q, J = 7.46 Hz, 2H), 1.17 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 344.

[0213] m-(3-ethyl-4-{[(p-fll]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzenesulfonamide (SLU-0010257). Using General Method A; 6- chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (106 mg, 0.376 mmol), Pd(dppf)Cl2 (32 mg, 0.14 mmol), K2CO3 (108 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 43% yield (60 mg).1H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1H), 8.36 (d, J = 7.95 Hz, 1H), 7.68 - 7.74 (m, 2H), 7.46 (t, J = 7.83 Hz, 1H), 7.32 (dd, J = 5.75, 8.44 Hz,2H), 6.92 (t, J = 8.86 Hz, 2H), 4.64 (d, J = 5.87 Hz, 2H), 3.70 (s, 3H), 2.83 (q, J = 7.46 Hz, 2H), 2.27 - 2.31 (m, 2H), 1.07 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 441.

[0214] [(p-fluoropheny yl-6-[p-(1H-tetraazol-5-yl)phenyl]-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010033). Aluminum (III) chloride (5.2 mg, 0.039 mmol) was weighed into a microwave vail before adding 5 mL of 1-methyl-2- pyrrolidinone, NMP. The 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). The reaction mixture was irradiated in a Biotage microwave at 200oC for 20 mins. After this time, the reaction was cooled to room temperature and poured into a separatory funnel containing ethyl acetate and water. The aqueous was extracted 2X with ethyl acetate and the organics were combined, washed with brine, dried over MgSO4and filtered. The filtrate was concentrated and purified via reversed- phased chromatography. The product was isolated in 28% yield (31.3 mg).1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.19 Hz, 2H), 8.14 (d, J = 7.95 Hz, 2H), 7.88 (br. s., 1H), 7.53 (br. s., 2H), 7.01 - 7.26 (m, 2H), 4.88 (br. s., 2H), 3.92 (s, 3H), 2.91 - 3.16 (m, 2H), 1.16 - 1.23 (m, 3H). LC-MS m / z (M + H)+= 430. [0215thyl-6-(1,4-thiazinan-4-yl)-1H- 1,2,5,7-tetraazainden-4-yl]amine (SLU-0010467). Using General Method B; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), thiomorpholine (97.1 mg, 0.941 mmol), Pd(dppf)Cl2(57.4 mg, 0.078 mmol), NaOtBu (113.4 mg, 1.18 mmol), and 12 mL dioxane, the product was isolated in 42% yield (128 mg).1H NMR (400 MHz, DMSO-d6) δ 7.51 (t, J = 5.75 Hz, 1H), 7.38 (dd, J = 5.69, 8.50 Hz, 2H), 7.12 (t, J = 8.86 Hz, 2H), 4.60 (d, J = 5.75 Hz, 2H), 3.95 - 4.04 (m, 4H), 3.64 (s, 3H), 2.89 (q, J = 7.46 Hz, 2H), 2.41 - 2.49 (m, 4H), 1.22 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 387.

[0216] 6-[m-(benzylamin thyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazaindene (SLU-0010806). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (25 mg, 0.078 mmol), N-benzyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzenesulfonamide (43.7 mg, 0.117 mmol), Pd(dppf)Cl2 (8 mg, 0.011 mmol), K2CO3(27 mg, 0.195 mmol), 4 mL DMF and 1 mL H2O, the product was isolated in 30% yield (12.2 mg).1H NMR (400 MHz, DMSO-d6) δ 8.73 - 8.80 (m, 1H), 8.52 (d, J = 7.82 Hz, 1H), 8.21 (br. s., 1H), 7.87 (t, J = 5.93 Hz, 1H), 7.82 (d, J = 8.07 Hz, 1H), 7.60 (t, J = 7.76 Hz, 1H), 7.45 (dd, J = 5.69, 8.50 Hz, 2H), 7.09 - 7.22 (m, 5H), 7.04 (t, J = 8.86 Hz, 2H), 4.77 (d, J = 5.75 Hz, 2H), 3.95 (d, J = 2.45 Hz, 2H), 3.85 (s, 3H), 2.98 (q, J = 7.46 Hz, 2H), 1.22 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 517.

[0217] 2-{[m-(3-ethyl-l]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)phenylsulfonyl](2-hydroxyethyl)amino}ethanol (SLU-0010802). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (100 mg, 0.313 mmol), N,N-bis(2-hydroxyethyl)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzenesulfonamide (139.5 mg, 0.376 mmol), Pd(dppf)Cl2(32.0 mg, 0.044 mmol), K2CO3 (102 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 52% yield (87 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (br. s., 1H), 8.62 (d, J = 7.34 Hz, 1H), 7.91 (d, J = 7.09 Hz, 2H), 7.70 (t, J = 7.64 Hz, 1H), 7.52 (br. s., 2H),7.14 (t, J = 8.50 Hz, 2H), 4.83 (br. s., 4H), 3.90 (br. s., 3H), 3.56 (br. s., 4H), 3.23 (d, J = 5.14 Hz, 4H), 3.04 (d, J = 7.34 Hz, 2H), 1.28 (t, J = 7.21 Hz, 3H); LC-MS m / z (M + H)+= 543.

[0218] [(p-fluorophenyl) thyl-6-phenyl-1H-1,2,5,7-tetraazainden-4-yl)amine (SLU-0010801). Using General Method A; 6-chloro-3-ethyl-N- (4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.157 mmol), phenylboronic acid (28.8 mg, 0.236 mmol), Pd(dppf)Cl2 (16 mg, 0.022 mmol), K2CO3 (54.3 mg, 0.393 mmol), 4 mL DMF and 1 mL H2O, the product was isolated in 39% yield (22.2 mg).1H NMR (400 MHz, DMSO-d6) δ 8.39 (dt, J = 2.14, 3.76 Hz, 2H), 7.80 (t, J = 5.99 Hz, 1H), 7.38 - 7.58 (m, 5H), 7.05 - 7.23 (m, 2H), 4.86 (d, J = 5.87 Hz, 2H), 3.90 (s, 3H), 3.03 (q, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 362.

[0219] [(p-fluorophenyboryl)phenyl]-3-ethyl-1-methyl- 1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010726). Using General Method A; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250 mg, 0.784 mmol), 1,4-phenylenediboronic acid (156 mg, 0.941 mmol), Pd(dppf)Cl2 (80.5 mg, 0.11 mmol), K2CO3(270.9 mg, 1.96 mmol), 12 mL DMF and 3 mL H2O, the product was isolated in 28% yield (88 mg) which as repurified to give 15 mg.1H NMR (300 MHz, CDCl3): δ (ppm) 8.33 (d, J = 8.4 Hz, 2H), 8.10 (s, 2H), 7.86 (d, J = 7.7 Hz, 2H), 7.79 (t, J = 5.6 Hz, 1H), 7.47-7.49 (m, 2H), 7.14 (t, J = 9.1 Hz, 2H), 4.85 (d, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.01-3.04 (m, 2H), 1.28 (t, J = 8.4 Hz, 3H).13C NMR (700 MHz, DMSO-d6) δ ppm 161.74, 160.37, 160.28, 156.28, 154.99, 145.15, 139.60, 136.48, 133.98, 129.16, 129.11, 126.87, 114.98, 114.86, 97.15, 42.99, 33.06, 21.47, 13.53. HRMS [ESI] m / z: [M + H]+Calcd for C21H21BFN5O2406.1850; found 408.1840.

[0220] Alternative preparation. To microwave vial were added DMF / H2O (10 mL), 6‐chloro‐3‐ethyl‐N‐[(4‐fluorophenyl) methyl] ‐1‐methyl‐1H‐pyrazolo[3,4‐d] pyrimidin‐4‐amine (319 mg, 1.00 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol). This reaction mixture was stirred under N2for 10 min and then added K2CO3(414 mg, 3.00 mmol) and 1,4- benzenediboronic acid (249 mg, 1.5 mmol). The container was sealed and microwave for 1 hour at 110oC. After that, the resulting mixture was vacuum filtered with a Buchner funnel and extracted with ethyl acetate (3X100). The organic layer was dried over Na2SO4 and concentrated. The crude substance was purified using reverse-phase HPLC (5-95%, CH3CN / H2O) to yield the desired [(p-fluorophenyl)methyl]{6-[p-(dihydroxyboryl)phenyl]-3- ethyl-1-methyl-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0010726) (60 mg, 15%) and side products p-(3-ethyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden- 6-yl)phenol (SLU-0011168) (67 mg, 18%) and [(p-fluorophenyl)methyl](3-ethyl-1-methyl-6- phenyl-1H-1,2,5,7-tetraazainden-4-yl)amine (SLU-0010801) (36 mg, 10%). HPLC purity was greater than 95%.

[0221] 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%). LC-MS m / z 377 (MH)+. HPLC purity 96%.1H NMR (400 MHz, DMSO-d6): δ ppm 9.79 (s, 1H), 8.24 (d, J = 8.4 Hz, 2H), 7.73 (m, 1H), 7.49 (t, J = 6.4 Hz, 2H), 7.15 (t, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 5.6 Hz, 2H), 3.86 (s, 1H), 3.03 (m, 2H), 1.31 (t, J = 7.6 Hz, 3H). HN F O O

[0222] [(p-fluorophenyl), zodioxol-5-yl)-3-ethyl-1-methyl- 1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0010687). Using General Method A; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (93.2 mg, 0.376 mmol), Pd(dppf)Cl2(32.2 mg, 0.044 mmol), K2CO3(108.2 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 41% yield (52 mg).1H NMR (400 MHz, DMSO-d6) δppm 7.95 - 8.06 (m, 1H), 7.72 - 7.85 (m, 2H), 7.46 (br. s., 2H), 7.13 (t, J = 7.95 Hz, 2H), 6.98 (d, J = 8.07 Hz, 1H), 6.08 (br. s., 2H), 4.82 (d, J = 4.03 Hz, 2H), 3.87 (br. s., 3H), 3.01 (d, J = 7.21 Hz, 2H), 1.26 (t, J = 6.79 Hz, 3H); LC-MS m / z (M + H)+= 406.

[0223] 3-ethyl-4-{[(p 1-methyl-6-(5-phthalideyl)-1H-1,2,5,7-tetraazaindene (SLU-0010686). Using General Method A; 6-chloro-3-ethyl-N- (4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (97.8 mg, 0.376 mmol), Pd(dppf)Cl2 (32.2 mg, 0.044 mmol), K2CO3 (108.2 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 8% yield (9.8 mg).1H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.59 (m, 2H), 7.73 - 7.93 (m, 2H), 7.43 (dd, J = 5.69, 8.50 Hz, 2H), 7.08 (t, J = 8.86 Hz, 2H), 5.43 (s, 2H), 4.81 (d, J = 5.87 Hz, 2H), 3.85 (s, 3H), 2.96 (q, J = 1.00 Hz, 2H), 1.21 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 418.

[0224] mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-1-isoindolinone (SLU-0010685). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (97 mg, 0.376 mmol), Pd(dppf)Cl2(32.2 mg, 0.044 mmol), K2CO3(108.2 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 62% yield (81 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (br. s., 1H), 8.52 (br. s., 1H), 7.71 - 7.90 (m, 2H), 7.50 (br. s., 4H), 7.14 (br. s., 1H), 4.87 (br. s., 2H), 4.45 (br. s., 2H), 3.90 (br. s., 3H), 3.02 (br. s., 2H), 1.27 (br. s., 3H). LC-MS m / z (M + H)+= 417.

[0225] 5-(3-ethyl-4-((4 ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-benzo[d]imidazol-2(3H)-one. Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (97.8 mg, 0.376 mmol), Pd(dppf)Cl2 (32.2 mg, 0.044 mmol), K2CO3 (108.2 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 28% yield (36.7 mg).1H NMR (400 MHz, DMSO-d6) δ 10.65 - 10.83 (m, 2H), 7.97 - 8.22 (m, 2H), 7.65 - 7.77 (m, 1H), 7.49 (dd, J = 5.69, 8.50 Hz, 1H), 7.37 (dd, J = 5.62, 8.56 Hz, 1H), 7.08 - 7.19 (m, 1H), 6.97 (d, J = 8.31 Hz, 1H), 4.70 - 4.86 (m, 2H), 3.87 (s, 3H), 3.82 (s, 1H), 3.00 (q, J = 7.46 Hz, 2H), 1.25 (q, J = 7.58 Hz, 3H); LC-MS m / z (M + H)+= 418.

[0226] 3-ethyl-4-{[(p-fluino}-1-methyl-1H-1,2,5,7- tetraazaindene-6-carboxylic acid (SLU-0010667). Using General Method D; 3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (250 mg, 0.806 mmol), KOH (1.36 g, 24.18 mmol), 20 mL ethanol and 20 mL deionized water, the product was isolated in 81% yield (216 mg).1H NMR (400 MHz, DMSO-d6) δ 12.99 (br. s., 1H), 7.91 (t, J = 5.87 Hz, 1H), 7.46 (dd, J = 5.75, 8.31 Hz, 2H), 7.13 (t, J = 8.80 Hz, 2H), 4.79 (d, J = 5.87 Hz, 2H), 3.87 (s, 3H), 3.02 (q, J = 7.38 Hz, 2H), 1.25 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 330.

[0227] [(p-fluorophenyl)methyl](3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-4- yl)amine (SLU-0010619). 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (250 mg, 0.784 mmol), B2pin2 (299 mg, 1.176 mmol), KOAc (231 mg, 2.35 mmol), and Pd(dppf)Cl2(86.3 mg, 0.118 mmol), were combined in a microwave vial which was vacuumed and backfilled with argon (3x) before addition of DMSO (10 mL) under positive pressure. The resulting solution was heated at 100 ^C in a microwave reactor until the reaction was complete. The reaction was cooled and filtered through a short pad of celite, eluting with ethyl acetate. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered, and purified over florisil (Hexane / EtOAc) to give the title compound in 46% yield (102 mg).1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.35 (dd, J = 5.38, 8.56 Hz, 2H), 6.94–7.12 (m, 2H), 4.86 (d, J = 5.62 Hz, 2H), 3.97 (s, 3H), 2.91 (q, J = 7.50 Hz, 2H), 1.36 (t, J = 7.52 Hz, 3H). LC-MS m / z (M + H)+= 286.

[0228] 3-(3-ethyl-4-{[(p-mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)propionic acid (SLU-0011013). Using General Method A; 6-chloro-3- ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.470 mmol), ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (130 mg, 0.564 mmol), Pd(dppf)Cl2(48 mg, 0.066 mmol), K2CO3(162.4 mg, 1.175 mmol), 8 mL DMF and 2 mL H2O. After completion, the reaction mixture was cooled to room temperature and transferred into a 100 mL round bottom flask.10 mL 1M LiOH ^H2O solution was added and stirred at room temperature for 2 hrs. LCMS analysis show presence of trace product and another 30 mL 1M LiOH ^H2O solution was added and further stirred for 4 hrs. LCMS analysis show unreacted starting ester product. LiOH ^H2O (446 mg, 10.63 mmol) was subsequently added and the reaction mixture stirred for 1-2 hrs. LCMS show hydrolyzed product and trace of unreacted ester product. The reaction was stopped and anhydrous Na2SO4 was added before filtering. The filtrate was concentrated on a rotary evaporator and purified via reversed-phased chromatography. The product was isolated in 4% yield over two steps (7.5 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (t, J = 5.99 Hz, 1H), 7.42 (dd, J =5.75, 8.31 Hz, 2H), 7.11 (t, J = 8.86 Hz, 2H), 4.70 (d, J = 5.87 Hz, 2H), 3.77 (s, 3H), 2.95 (q, J = 7.46 Hz, 2H), 2.89 (t, J = 7.09 Hz, 2H), 2.61 - 2.68 (m, 2H), 1.22 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 386. F OH

[0229] [p-(3-ethyl-4-{ ino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)phenyl]acetic acid (SLU-0011012). Using General Method A; 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (109 mg, 0.376 mmol), Pd(dppf)Cl2(32.2 mg, 0.044 mmol), K2CO3(108.2 mg, 0.783 mmol), 8 mL DMF and 2 mL H2O, the crude product was used in General Method D without further purification. Using General Method D; crude ethyl 2-(4-(3-ethyl-4-((4-fluorobenzyl)amino)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)acetate (129.1 mg, 0.289 mmol), KOH (182.5 mg, 3.25 mmol), and 15 mL ethanol, the product was isolated in 71% yield over two steps (86 mg).1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.07 Hz, 2H), 7.78 (t, J = 5.75 Hz, 1H), 7.46 - 7.52 (m, 2H), 7.34 (d, J = 8.07 Hz, 2H), 7.13 (t, J = 8.74 Hz, 2H), 4.84 (d, J = 5.62 Hz, 2H), 3.89 (s, 3H), 3.63 (br. s., 2H), 3.02 (q, J = 7.42 Hz, 2H), 1.27 (t, J = 7.40 Hz, 3H); LC-MS m / z (M + H)+= 420.

[0230] 4-(3-ethyl-4-{[(p- u p y y mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-3-cyclohexene-1-carboxylic acid (SLU-0011026). A dry pressure vialwith a stirring bar was charged with 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (SLU-0002812; 50.0 mg, 0.156 mmol), ethyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (52.6 mg, 0.188 mmol), Pd(dppf)Cl2(5.72 mg, 0.00782 mmol), Cs2CO3(153 mg, 0.429 mmol). The solid mixture was purged with nitrogen or Argon after which, dioxane / H2O (4:1) was added to the mixture. The reaction mixture was heated at 100°C for 16 h. The reaction mixture was allowed to cool to room temperature, filtered and purified by reverse-phase HPLC (5 ^95% CH3CN / H2O) to obtain 4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)cyclohex-3-enecarboxylate. (35 mg, 51%), LC-MS: m / z 438 (MH)+, HPLC purity 98%.

[0231] 4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin- 6-yl)cyclohex-3-enecarboxylate (16 mg, 0.0365 mmol) was dissolved in 5 mL of MeOH and 2M LiOH(aq)(6 mL) was added to the mixture. The mixture was stirred in for 16 h and quenched with 1M HCl, after which the mixture was extracted using ethyl acetate and water three times, dried over Na2SO4and concentrated under vacuum. The crude compound was purified by reverse-phase HPLC (5 ^95% CH3CN / H2O) to obtain the desired product as a white solid. (10 mg, 66%), LC-MS: m / z 410 (MH)+, HPLC purity 98%.1H NMR (400 MHz, DMSO-d6) d 11.97 - 12.49 (m, 1H), 7.58 (s, 1H), 7.41 (dd, J = 5.75, 8.68 Hz, 2H), 7.13 (t, J = 8.93 Hz, 3H), 4.73 (d, J = 5.87 Hz, 2H), 3.80 (s, 3H), 2.97 (q, J = 7.34 Hz, 2H), 2.63 - 2.84 (m, 1H), 2.39 (d, J = 14.67 Hz, 2H), 1.98 - 2.12 (m, 2H), 1.52 - 1.70 (m, 2H), 1.24 (t, J = 7.46 Hz, 3H). HRMS (ESI) m / z: [M + H]+Calcd for C22H24FN5O2410.4650; found 410.1987.

[0232] 4-(3-ethyl-4-{[(pino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)cyclohexanecarboxylic acid (SLU-0011025). 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 andpurified by flash chromatography using normal phase with EtOAc and hexane to obtain the title compound (9 mg, 64%). LC-MS: m / z 412 (MH)+, HPLC purity 98%.1H NMR (400 MHz, DMSO-d6) d 11.37 - 12.93 (m, 1H), 7.60 (d, J = 6.11 Hz, 1H), 7.33 - 7.49 (m, 2H), 7.05 - 7.18 (m, 2H), 3.69 - 3.87 (m, 2H), 2.88 - 3.06 (m, 3H), 2.65 (br. s., 1H), 2.54 (s, 3H), 1.90 (d, J = 10.76 Hz, 4H), 1.46 - 1.71 (m, 4H), 1.16 - 1.30 (m, 3H). HRMS (ESI) m / z: [M + H]+Calcd for C22H26FN5O2412.4810; found 412.2143.

[0233] [(p-fluorophenyl)thyl-6-(1-piperazinyl)-1H-1,2,5,7- tetraazainden-4-yl]amine (SLU-0010041). Tert-butyl 4-(3-ethyl-4-((4-fluorobenzyl)amino)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperazine-1-carboxylate (180.1 mg, 0.385 mmol) was weighed into a flask before adding 10 mL DCM. Trifluoroacetic acid (0.6 mL, 7.84 mmol) was added, and the reaction mixture stirred at room temperature overnight. After this time, the reaction mixture was concentrated and purified via reversed-phased chromatography. The product was isolated in 78% yield (111 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (br. s., 2H), 7.57 (br. s., 1H), 7.39 (dd, J = 5.87, 8.19 Hz, 2H), 7.11 (t, J = 8.86 Hz, 2H), 4.62 (d, J = 5.62 Hz, 2H), 3.87 (br. s., 4H), 3.65 (s, 3H), 2.89 (q, J = 7.38 Hz, 2H), 2.54 (s, 1H), 1.21 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 370.

[0234] 6-[m-(dimethyy y o]-3-ethyl-4-{[(p- fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazaindene (SLU-0010255). Using General Method B; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.313 mmol), 3-amino-N,N-dimethylbenzenesulfonamide (75.3 mg, 0.376 mmol), Pd(dppf)Cl2(22.9 mg, 0.031 mmol), NaOtBu (45.2 mg, 0.470 mmol), and 10 mL dioxane, the product was isolated in 63% yield (95 mg).1H NMR (400 MHz, CDCl3-d) δ 8.46 (s, 1H), 7.79 (d, J = 8.19 Hz, 1H), 7.38 (t, J = 6.05 Hz, 2H), 7.26 - 7.33 (m, 3H), 7.06 (d, J = 7.82 Hz, 1H), 6.98 (t, J = 8.86 Hz, 2H), 4.65 (d, J = 5.87 Hz, 2H), 3.61 (s, 3H), 2.79 (q, J = 7.46 Hz, 2H), 2.42 - 2.46 (m, 6H), 1.08 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 484.

[0235] 1-(3-ethyl-4-{[(ino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-4-piperidinecarboxylic acid (SLU-0010468). Using General Method D; 1-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)piperidine-4-carbonitrile (100 mg, 0.254 mmol), KOH (99.8 mg, 1.78 mmol), 6 mL ethanol and 5 mL deionized water, the desired carboxylic acid product was isolated in 47% yield (48.7 mg) along with 1-(3-ethyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)-4-piperidinecarboxamide (SLU-0010469; 39.6 mg). SLU- 0010468:1H NMR (400 MHz, CDCl3-d) δ 7.51 - 7.64 (m, 3H), 7.27 (t, J = 8.74 Hz, 2H), 4.77 (d, J = 5.75 Hz, 2H), 4.66 (d, J = 13.08 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 1H), 3.01 - 3.14 (m, 3H), 2.58 - 2.78 (m, 2H), 1.93 (d, J = 10.76 Hz, 1H), 1.52 (q, J = 10.88 Hz, 2H), 1.37 (t, J = 7.40 Hz, 3H); LC-MS m / z (M + H)+= 413.

[0236] 1-(3-ethyl-4-{[(p-mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-4-piperidinecarboxamide (SLU-0010469). Isolated from the synthesis of SLU-0010468 as a minor product (39.6 mg).1H NMR (400 MHz, CDCl3) δ ppm 7.51 -7.58 (m, 3H), 7.23 - 7.30 (m, 2H), 4.77 (d, J = 5.87 Hz, 2H), 4.67 (d, J = 13.20 Hz, 2H), 3.79 (s, 3H), 3.00- 3.13 (m, 4H), 2.67 (td, J = 1.74, 3.61 Hz, 2H), 2.61 (br. s., 1H), 1.93 (d, J = 10.88 Hz, 2H), 1.45 - 1.58 (m, 2H), 1.37 (t, J = 7.46 Hz, 3H). LC-MS m / z (M + H)+= 412.

[0237] 6-(3-ethyl-4-{[ ino}-1-methyl-1H-1,2,5,7-tetraazainden-6-ylamino)nicotinic acid (SLU-0010497). Using General Method D; methyl 6-((3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)amino)nicotinate (150 mg, 0.254 mmol), KOH (116.1 mg, 2.07 mmol), and 15 mL ethanol, the product was isolated in 88% yield (128 mg).1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.74 (s, 1H), 8.35 (d, J = 8.93 Hz, 1H), 8.06 (dd, J = 2.32, 8.93 Hz, 1H), 7.69 (t, J = 6.11 Hz, 1H), 7.49 (dd, J = 5.69, 8.74 Hz, 2H), 7.10 - 7.18 (m, 2H), 4.73 (d, J = 5.99 Hz, 2H), 3.78 (s, 3H), 2.95 (q, J = 7.46 Hz, 2H), 1.25 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 422.

[0238] p-(3-ethyl-4-{[(p-flul]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-ylamino)benzamide (SLU-0010498). Using General Method D; p-(3- ethyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6- ylamino)benzonitrile (SLU-0010266; 150 mg, 0.374 mmol), KOH (483 mg, 8.60 mmol), water (15 mL) and 18 mL ethanol, the product was isolated as an off-white powder (69 mg).1H NMR (400 MHz, CDCl3) δ ppm 8.90 (s, 1H), 7.29 - 7.35 (m, 2H), 7.25 (s, 1H), 7.09 (t, J = 6.05 Hz, 1H), 6.97 (dd, J = 5.75, 8.56 Hz, 2H), 6.61 - 6.73 (m, 3H), 4.30 (d, J = 5.87 Hz, 2H), 3.28 (s, 3H), 2.47 (q, J = 7.46 Hz, 2H), 2.01 - 2.05 (m, 1H), 0.77 (t, J = 7.46 Hz, 3H);

[0239] [(p-fluorophenyl) hydroxy-1,3-dihydro-2,1- benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0010906). Using General Method A; 6-chloro-3-ethyl-N-(4-fluorobenzyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (1.0 g, 3.13 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzaldehyde (1.0 g, 3.76 mmol), Pd(dppf)Cl2 (321.9 mg, 0.44 mmol), K2CO3 (1.08 g, 37.83 mmol), 32 mL DMF and 8 mL H2O, the crude product, 2-chloro-5-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzaldehyde was used in the next step without further purification. Using General Method A; 2-chloro-5-(3-ethyl-4- ((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzaldehyde (640.4 mg, 1.51 mmol), bis(pinacolato)diboron (576.4 mg, 2.27 mmol), Pd(dppf)Cl2^DCM (185.4 mg, 0.227 mmol), KOAc (444.6 mg, 4.53 mmol), 10 mL DMSO, the crude product (5-(3- ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde) was used in the next step without further purification. The crude product, 5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (380.1 mg, 0.738 mmol) weighed into a round bottom flask before adding 20 mL methanol. After complete dissolution, sodium borohydride (34 mg, 0.899 mmol) was added and the reaction mixture stirred at room temperature for 2 hrs followed by the adding 8 mL 1M HCl and further stirred overnight. After this time, the solvents were removed and the crude product purified via reversed-phase chromatography. The product, 5-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzo[c][1,2]oxaborol- 1(3H)-ol was isolated in 6% over three steps (off-white solid; 17.5 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (br. s., 1H), 8.35 - 8.40 (m, 2H), 7.76 - 7.84 (m, 2H), 7.49 (dd, J = 5.69, 8.50 Hz, 2H), 7.14 (t, J = 8.86 Hz, 2H), 5.07 (s, 2H), 4.86 (d, J = 5.75 Hz, 2H), 3.88 - 3.92 (m, 3H), 3.03 (q, J = 7.46 Hz, 2H), 1.27 (t, J = 7.46 Hz, 3H); LC-MS m / z (M + H)+= 418.

[0240] Improved synthesis of [(p-fluorophenyl)methyl][3-ethyl-6-(1-hydroxy-1,3- dihydro-2,1-benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU- 0010906; Scheme 8B).

[0241] Step 1. Synthesis of methyl 2-bromo-5-(3-ethyl-4-hydroxy-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.1): To a stirred solution of 5-amino-3-ethyl-1- methyl-1H-pyrazole-4-carboxamide (1 equiv.) and methyl 2-bromo-5-formylbenzoate (1.2 equiv.) in acetonitrile was added iodine (1.5 equiv.) and refluxed under inert atmosphere for 16 h. After completion, the volatiles were removed under reduced pressure and the crude was dissolved in EtOAc and then washed with saturated solution of Na2S2O3. The organic layer was concentrated under reduced pressure to afford the crude 8B.1.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.22 (dd, J = 8.5, 1.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 3.91 (d, J = 12.8 Hz, 6H), 2.85 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

[0242] Step 2. Synthesis of 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2). The crude 8B.1 was taken in a round bottom flask then POCl3(10 equiv.) was added slowly under inert atmosphere. The resulting mixture was then heated to reflux for 3 h. Volatiles were removed under reduced pressure and the crude was dried under vacuum. The crude was then taken in a reaction vial, 4-fluorobenzylamine (1.2 equiv.), K2CO3 (1.5 equiv.) and NMP were added. The reaction mixture was then heated to 80 °C for 16 h. After completion, volatiles were removed under reduced pressure to afford the crude. The crude was purified by normal phase chromatography (0-50% EtOAc / Hexane) to afford methyl 2-bromo-5-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate 8B.2 as off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 7.86 (dd, J = 23.3, 13.2 Hz, 2H), 7.62 – 7.39 (m, 2H), 7.14 (t, J = 8.5 Hz, 2H), 4.80 (d, J = 4.8 Hz, 2H), 3.91 (d, J = 18.8 Hz, 6H), 3.04 (q, J = 7.3 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H) ppm.

[0243] Step 3. Synthesis of [(p-fluorophenyl)methyl][3-ethyl-6-(1-hydroxy-1,3- dihydro-2,1-benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU- 0010906). To a stirred solution of 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (0.4 mmol) in 1,4-dioxane was added KOAc (0.8 mmol), B2pin2(0.8 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2(0.04 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude. The crude was then dissolved in MeOH and cooled to 0 °C under inert atmosphere. NaBH4(8 mmol) was then added in a portion wise manner over 30 min and the rection mixture was allowed to warm to room temperature. After 4 h, the rection mixture was quenched with the addition of 1 M HCl. Then volatiles were removed under reduced pressure and the crude was purified by reverse phasechromatography (5-100 % acetonitrile / Water). Pure fractions were then lyophilized to afford the pure product as white solid (119 mg, 71.3%),1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.37 (d, J = 5.8 Hz, 2H), 7.80 (dd, J = 10.3, 4.9 Hz, 2H), 7.49 (dd, J = 8.6, 5.7 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 5.07 (s, 2H), 4.86 (d, J = 5.8 Hz, 2H), 3.90 (s, 3H), 3.03 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H) ppm; LC-MS m / z (M + H)+= 418

[0244] 6-(3-ethyl-4-{[(p mino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-1-methyl-1H-indazol-3-ol (SLU-0010964). 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 120oC for 15 mins. LCMS analysis show trace of desired product formation. Another 1.5 mL methylhydrazine was added and reaction temperature decreased to 90oC and stirred for 30 mins. LCMS analysis show presence of unreacted starting material and an additional 4 mL methylhydrazine added and stirred for 1.5 hrs. After this time, the reaction mixture was cooled to room temperature, concentrated on a rotary evaporator and purified via reversed- phased chromatography. The product was isolated in 44% (43 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (br. s., 1H), 8.30 (br. s., 1H), 8.06 (d, J = 7.70 Hz, 1H), 7.83 (br. s., 1H), 7.65 (d, J = 7.58 Hz, 1H), 7.54 (br. s., 2H), 7.15 (br. s., 2H), 4.87 (br. s., 2H), 3.92 (br. s., 3H), 3.84 (br. s., 3H), 3.05 (d, J = 5.99 Hz, 2H), 1.29 (br. s., 3H); LC-MS m / z (M + H)+= 432.

[0245] 6-(3-ethyl-4-{[(p mino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-1H-indazol-3-ol (SLU-0010963). 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 hydrazine monohydrate (1.0 mL, 21.0 mmol). The reaction mixture was heated to 100oC for 1 hour. LCMS analysis show trace of desired product formation. Another 1 mL hydrazine monohydrate was added and reaction temperature increased to 120oC and stirred for 1 hour. LCMS analysis show presence of unreacted starting material and an additional 4 mL hydrazine monohydrate added and stirred overnight. After this time, the reaction mixture was cooled to room temperature, concentrated on a rotary evaporator and purified via reversed- phased chromatography. The product was isolated in 35% (22.3 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 - 11.74 (m, 1H), 10.34 - 10.77 (m, 1H), 8.34 (s, 1H), 8.07 (d, J = 8.44 Hz, 1H), 7.80 (t, J = 5.87 Hz, 1H), 7.66 (d, J = 8.44 Hz, 2H), 7.51 (dd, J = 5.69, 8.50 Hz, 2H), 7.16 (t, J = 8.93 Hz, 2H), 4.87 (d, J = 5.75 Hz, 2H), 3.91 (s, 3H), 3.03 (q, J = 7.42 Hz, 2H), 1.28 (t, J = 7.46 Hz, 4H); LC-MS m / z (M + H)+= 418.

[0246] Ethyl 4-(methylsulfonyl)benzoate. 4-(Methylsulfonyl)benzoic acid (2.00 g, 9.99 mmol) was dissolved in ethanol (30 mL), treated with conc. sulfuric acid (0.2 mL) and refluxed overnight. The solvents were removed under vacuum and the resultant residue was dissolved with diethyl ether and washed with satd sodium bicarbonate and brine before drying over magnesium sulfate, filtering and concentrating to give the title compound in >90% purity as determined by LC-MS (1.92 g, 84%). LC-MS m / z (M + H)+= 229.

[0247] 3-Ethyl-1-methyl-6-(4-(methylsulfonyl)phenyl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one.5-amino-3-ethyl-1-methyl-1H-pyrazole-4-carboxamide 6 (738 mg, 4.39 mmol) and ethyl 4-(methylsulfonyl)benzoate (1000 mg, 4.39 mmol) were weighed into a round bottom flask. Ethanol (50 mL) was added followed by 9 mL of 1M NaOEt in EtOH (8.78 mmol). The resulting solution was stirred at 100°C for 6 h. The reaction mixture was cooled to room temperature followed by slow addition of 6 N HCl. Solid formed were collected by filtration and dried overnight to afford the title compound (800 mg, 55%). LC-MS m / z (M + H)+= 333.

[0248] [(p-fluorophenyl esylphenyl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0002816). Crude 3-ethyl-1-methyl-6-(4- (methylsulfonyl)phenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (300 mg, 0.90 mmol) and BOP (518 mg, 1.17 mmol) were weighed into a round bottom flask. DMF (10 mL) was added and the reaction stirred for 10 minutes. After adding DIEA (0.24 mL, 1.35 mmol), 4-fluorobenzylamine (0.2 mL, 1.35 mmol) was added and the resulting solution stirred 5 h. The mixture was washed with water and brine and dried over magnesium sulfate and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford the title compound (28.2 mg, 7%).1H NMR (400 MHz, CDCl3-d) δ ppm 8.69 (d, J = 8.56 Hz, 2H), 8.02 (d, J = 8.56 Hz, 2H), 7.41 (dd, J = 5.32, 8.62 Hz, 2H), 7.07 (t, J = 8.68 Hz, 2H), 5.50 (t, J = 5.38 Hz, 1H), 4.98 (d, J = 5.62 Hz, 2H), 4.05 (s, 3H), 3.10 (s, 3H), 2.95 (q, J = 7.58 Hz, 2H), 1.40 (t, J = 7.58 Hz, 3H); LC-MS m / z (M + H)+= 440.

[0249] 4-(3-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzonitrile (8).5-amino-3-ethyl-1-methyl-1H-pyrazole-4-carboxamide 6 (5004.61 mg, 29.78 mmol) and ethyl 4-cyanobenzoate 7 (5238.84 mg, 29.93 mmol) were weighed into a 250 mL round bottom flask. Ethanol was added followed by 60 mL of NaOEt (1 M in EtOH). The resulting solution was stirred at 100°C for 6 h. The reaction mixture was cooled to room temperature followed by slow addition of 6 N HCl. Solid formed were collected by filtration and dried overnight to afford 8 (7.01 g, 84%). ESI-MS m / z [C15H13N5O+H]+279.11.

[0250] 4-(4-((4-chlorobenzyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10a). Crude 8 (516.38 mg, 1.85 mmol) and BOP (1038.18 mg, 2.40 mmol) were weighed into a 250 mL round bottom flask. Acetonitrile (30 mL) was added and the reaction stirred for 10 minutes. After adding DIEA (0.5 mL, 2.77 mmol), 4- chlorobenzylamine 9a (393.08 mg, 2.77 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10a (124.20 mg, 17%). ESI-MS m / z [C22H19ClN6+H]+403.14.

[0251] 4-(3-ethyl-4-((4-methoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10b). Crude 8 (310.56 mg, 1.11 mmol) and BOP (738.90 mg, 1.66 mmol) were weighed into a 250 mL round bottom flask. DMF (25 mL) was added and the reaction stirred for 10 minutes. After adding DBU (168.98 mg, 1.11 mmol), 4- methoxybenzylamine 9b (227.71 mg, 1.67 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10b (198.20 mg, 44%). ESI-MS m / z [C23H22N6O +H]+399.19.

[0252] 4-(3-ethyl-4-((3-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10c). Crude 8 (860.1 mg, 3.08 mmol) and BOP (2065.30 mg, 4.62 mmol) were weighed into a 250 mL round bottom flask. DMF (35 mL) was added and the reaction stirred for 10 minutes. After adding DBU (938.40 mg, 6.16 mmol), 3- flurobenzylamine 9c (578.56 mg, 4.63 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10c (402.10 mg, 34%). ESI-MS m / z [C22H19FN6 +H]+387.17.

[0253] 4-(3-ethyl-4-((2-methoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10d). Crude 8 (908.90 mg, 3.254 mmol) and BOP (2.176 g, 4.88 mmol) were weighed into a 250 mL round bottom flask. DMF (35 mL) was added and the reaction stirred for 10 minutes. After adding DBU (986.51 mg, 6.48 mmol), 2- methoxybenzylamine 9d (669.43 mg, 4.88 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10d (394.20 mg, 30%). ESI-MS m / z [C23H22N6O +H]+399.19.

[0254] 4-(4-((2-chlorobenzyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10e). Crude 8 (498.10 mg, 1.78 mmol) and BOP (1.25 g,2.67 mmol) were weighed into a 250 mL round bottom flask. DMF (25 mL) was added and the reaction stirred for 10 minutes. After adding DBU (270.98 mg, 1.78 mmol), 2- chlorobenzylamine 9e (379.19 mg, 2.67 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by normal phase chromatography using hexane / ethylacetate as eluent to afford product 10e (215.21 mg, 30%). ESI-MS m / z [C22H19ClN6+H]+403.14.

[0255] 4-(4-((2,4-difluorobenzyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10f). Crude 8 (990.44 mg, 3.54 mmol) and BOP (2331.60 mg, 5.27 mmol) were weighed into a 250 mL round bottom flask. DMF (35 mL) was added and the reaction stirred for 10 minutes. After adding DBU (1077.80 mg, 7.08 mmol), 2,4 difluorobenzylamine 9f (760.07 mg, 5.31 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10f (317.12 mg, 22%). ESI-MS m / z [C22H18F2N6+H]+405.16.

[0256] 4-(4-((2,6-difluorobenzyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10g). Crude 8 (529.60 mg, 1.89 mmol) and BOP (1.29 g, 2.85 mmol) were weighed into a 250 mL round bottom flask. DMF (25 mL) was added and the reaction stirred for 10 minutes. After adding DBU (288.95 mg, 1.89 mmol), 2,6 difluorobenzylamine 9g (407.56 mg, 2.84 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10g (183.72 mg, 24%). ESI-MS m / z [C22H18F2N6+H]+405.16.

[0257] 4-(4-((cyclohexylmethyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10h). Crude 8 (1054.30 mg, 3.77 mmol) and BOP (2.50 g, 5.65 mmol) were weighed into a 250 mL round bottom flask. DMF (35 mL) was added and the reaction stirred for 10 minutes. After adding DBU (1.14 g, 7.54 mmol), cyclohexylmethanamine 9h (640.71 mg, 5.65 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10h (478.20 mg, 34%). ESI-MS m / z [C22H26N6 +H]+375.22.

[0258] (R)-4-(3-ethyl-1-methyl-4-((1-phenylethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (10i). Crude 8 (1058.60 mg, 3.79 mmol) and BOP (2.51 g, 5.69 mmol) were weighed into a 250 mL round bottom flask. DMF (35 mL) was added and the reaction stirred for 10 minutes. After adding DBU (1153.97 mg, 7.58 mmol), (S)-1-phenylethan-1-amine 9i (689.51 mg, 5.69 mmol) was added and the resulting solution stirred overnight. Mixture concentrated and the crude residue was purified by reverse phase chromatography using water / acetonitrile no TFA as eluent to afford product 10i (456.27 mg, 31%). ESI-MS m / z [C23H22N6+H]+383.19.

[0259] p-(4-{[(p-chlorop -3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid. (11a, SLU-0010270). Compound 10a (124.20 mg, 0.31 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11a (5.12 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J = 8.19 Hz, 2H), 7.96 - 8.01 (m, 2H), 7.86 (t, J = 5.93 Hz, 1H), 7.44 (d, J = 8.31 Hz, 2H), 7.32 - 7.36 (m, 2H), 4.81 (d, J = 5.62 Hz, 2H), 3.87 (s, 3H), 3.00 (q, J = 7.42 Hz, 2H), 1.24 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H20ClN5O2422.1384 ; found 422.1382.

[0260] p-(3-ethyl-4-{[(o-mhyl]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (11d, SLU-0010271). Compound 10d (394.20 mg, 30%) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11d (21.12 mg, 5%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 8.44 Hz, 2H), 8.00 (d, J = 8.44 Hz, 2H), 7.67 (s, 1H), 7.27 (d, J = 7.70 Hz, 1H), 7.20 (s, 1H), 7.04 (d, J = 7.95 Hz, 1H), 6.86 (s, 1H), 4.87 (d, J = 5.75 Hz, 2H), 3.92 (s, 3H), 3.91 (s,3H), 3.05 (d, J = 7.46 Hz, 2H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O3418.1879; found 418.1875.

[0261] p-(3-ethyl-4-{[(m- amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid.(11c, SLU-0010272). Compound 10c (402.10 mg, 1.04 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11c (16.71 mg, 3%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (d, J = 8.19 Hz, 2H), 7.95 (d, J = 8.19 Hz, 2H), 7.84 (t, J = 5.69 Hz, 1H), 7.27 - 7.34 (m, 1H), 7.18 - 7.26 (m, 2H), 6.97 (t, J = 8.44 Hz, 1H), 4.82 (d, J = 5.75 Hz, 2H), 3.85 (s, 3H), 2.98 (q, J = 7.42 Hz, 2H), 1.22 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H20FN5O2 406.1679; found 406.1668.

[0262] p-(4-{[(2,4-difluorno}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (11f, SLU-0010462). Compound 10f (317.12 mg, 0.78 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11f (3.1 mg, 0.9%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, J = 8.44 Hz, 2H), 7.84 (d, J = 8.44 Hz, 2H), 7.70 - 7.75 (m, 1H), 7.46 - 7.54 (m, 1H), 7.21 - 7.28 (m, 1H), 6.98 - 7.04 (m, 1H), 4.87 (d, J = 5.50 Hz, 2H), 3.89 (s, 3H), 3.03 (d, J = 7.46 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H19F2N5O2 424.1585; found 424.1577.

[0263] p-{4-[(S)-1-phenyl 1-methyl-1H-1,2,5,7-tetraazainden- 6-yl}benzoic acid. (11i, SLU-001063). Compoun 0i (456.27 mg, 1.19 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11i (25.03 mg, 5%) and amide side product SLU-0010464 p-{4-[(S)-1- phenylethylamino]-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl}benzamide (4.92 mg, 1%). 11i, SLU-0010463:1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, J = 8.07 Hz, 2H), 7.87 (d, J = 8.19 Hz, 2H), 7.51 (d, J = 7.58 Hz, 2H), 7.28 (t, J = 7.52 Hz, 2H), 7.10 -7.17 (m, 1H), 5.67 - 5.73 (m, 1H), 3.84 (s, 3H), 3.07 (q, J = 7.42 Hz, 2H), 2.46 (br. s., 1H), 1.60 (d, J = 6.97 Hz, 3H), 1.25 (t, J = 7.40 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O2 402.1930; found 402.1921.

[0264] p-{4-[(S)-1-pheny1-methyl-1H-1,2,5,7-tetraazainden- 6-yl}benzamide (SLU-0010464). Isolated as a byproduct from the preparation of p-{4-[(S)- 1-phenylethylamino]-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl}benzoic acid (11i, SLU-0010463).1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J = 8.44 Hz, 2H), 7.93 (d, J = 8.44 Hz, 2H), 7.55 (d, J = 7.34 Hz, 2H), 7.41 (br. s., 1H), 7.32 (t, J = 7.64 Hz, 2H), 7.18 - 7.23 (m, 2H), 5.70 - 5.76 (m, 1H), 3.90 (s, 3H), 3.08 - 3.18 (m, 2H), 1.65 (d, J = 6.97 Hz, 3H), 1.29 (t, J = 7.46 Hz, 3H); ESI-MS m / z [C23H24N6O +H]+401.20.

[0265] p-(3-ethyl-4-{[(p-methoxyphenyl)methyl]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (11b, SLU-0010465). Compound 10b (198.20 mg, 0.49 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11b (8.00 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 - 8.07 (m, 2H), 7.78 - 7.85 (m, 2H), 7.11 (s, 1H), 6.89 - 6.95 (m, 2H), 6.46 - 6.53 (m, 2H), 4.70 - 4.78 (m, 1H), 4.31 - 4.39 (m, 2H), 3.49 (broad peak, 5H), 3.43 (s, 3H), 1.04 (t, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O3418.1879; found 418.1869.

[0266] p-{4-[(cyclohexyl -1-methyl-1H-1,2,5,7-tetraazainden-6-yl}benzoic acid. (11h, SLU-0010466). Compound 10h (478.20 mg, 1.27 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11h (18.02 mg, 4%).1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.82 Hz, 2H), 7.88 (d, J = 7.82 Hz, 2H), 7.09 (t, J = 5.07 Hz, 1H), 3.84 (s, 3H), 3.49 (br. s., 2H), 2.95 (q, J = 7.21 Hz, 2H), 2.46 (br. s., 2H), 1.75 (d, J = 10.39 Hz, 2H), 1.65 (br. s., 2H), 1.57 (s, 1H), 1.21 (t, J = 7.40 Hz, 3H), 1.13 (d, J = 8.19 Hz, 2H), 0.95 - 1.05 (m, 2H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H27N5O2394.2243; found 394.2225.

[0267] p-(4-{[(2,6-difluoropmino}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (11g, SLU-0010562). Compound 10g (183.72 mg, 0.45 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reactionmixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11g (0.30 mg, 0.2%). HRMS (ESI) m / z: [M + H]+ Calcd for C22H19F2N5O2424.1585; found 424.1584.

[0268] p-(4-{[(o-chloroph -3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid. (11e, SLU-0010563). Compound 10e (215.21 mg, 0.53 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating for 2 hours at 100°C. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford target 11e (7.01 mg, 3%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (d, J = 7.70 Hz, 2H), 7.97 (d, J = 8.07 Hz, 2H), 7.87 (br. s., 1H), 7.50 (d, J = 4.28 Hz, 1H), 7.41 (d, J = 4.16 Hz, 1H), 7.26 (d, J = 4.03 Hz, 2H), 4.96 (d, J = 5.38 Hz, 2H), 3.92 (s, 3H), 3.07 (q, J = 6.81 Hz, 2H), 2.07 (s, 1H), 1.31 (t, J = 7.27 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H20ClN5O2422.1384; found 422.1381.

[0269] methyl 4-(4-{[(p-mino}-3-ethyl-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)-2-fluorobenzoate (SLU-0010826). Using General Method A; 6- chloro-3-ethyl-N-(4-chlorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.49 mmol), (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (354 mg, 1.79 mmol), Pd(dppf)Cl2(154 mg, 0.21 mmol), K2CO3(516 mg, 3.73 mmol), 24 mL DMF and 6 mL H2O, the product was isolated in 53% yield (355 mg).1H NMR (400 MHz, CDCl3) δ ppm 8.24 (d, J = 8.19 Hz, 1H), 8.17 (d, J = 12.35 Hz, 1H), 7.92 (t, J = 7.76 Hz, 1H), 7.16 - 7.33 (m, 3H), 5.42 (br. s., 1H), 4.89 (d, J = 5.50 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.41 (s, 1H), 2.86 (q, J = 7.46 Hz, 2H), 1.31 (t, J = 7.52 Hz, 3H); LC-MS m / z (M+H)+454.

[0270] 3-bromo-N-(2-hydroxyethyl)benzenesulfonamide. 3- bromobenzenesulfonamide (2.1 g, 8.89 mmol) was dissolved in DMSO (20 mL) and treated with 2-bromoethanol (0.5 mL, 6.84 mmol) and cesium carbonate (3.3 g, 10.3 mmol). The reaction mixture was heated at 80 ^C overnight. The reaction was cooled to room temp and treated with satd sodium bicarbonate and extracted with EtOAc. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound in 31% yield (767 mg; LC-MS m / z (M+H)+281) along with dialkylated product 3-bromo-N,N- bis(2-hydroxyethyl)benzenesulfonamide (577 mg; LC-MS m / z (M+H)+325).

[0271] N-(2-hydroxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzenesulfonamide. 3-bromo-N-(2-hydroxyethyl)benzenesulfonamide (250 mg, 0.893 mmol), B2pin2(340 mg, 1.34 mmol), KOAc (293 mg, 2.68 mmol), and Pd(dppf)Cl2(98.0 mg, 0.134 mmol), were combined in a microwave vial which was vacuumed and backfilled with argon (3x) before addition of DMSO (10 mL) under positive pressure. The resulting solution was heated at 100 ^C in a microwave reactor until the reaction was complete. The reaction was cooled and filtered through a short pad of celite, eluting with ethyl acetate. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered, and purified over florisil (Hexane / EtOAc) to give the title compound in 31% yield (92 mg). LC-MS m / z (M+H)+328.

[0272] 2-[m-(4-{[(p-chloroino}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)phenylsulfonylamino]ethanol (SLU-0010890). Using General Method A; 6-chloro-3-ethyl-N-(4-chlorobenzyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (78 mg, 0.229 mmol), N-(2-hydroxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzenesulfonamide (90 mg, 0.275 mmol), Pd(dppf)Cl2 (23.4 mg, 0.032 mmol), K2CO3 (79.2 mg, 0.573 mmol), 8 mL DMF and 2 mL H2O, the product was isolated in 22% yield (24.9 mg).1H NMR (400 MHz, CDCl3) δ ppm 8.59 - 8.73 (m, 2H), 8.44 - 8.51 (m, 1H), 7.82 - 7.89 (m, 1H), 7.78 (d, J = 7.70 Hz, 1H), 7.59 (t, J = 7.70 Hz, 1H), 7.36 - 7.42 (m, 2H), 7.22- 7.29 (m, 2H), 4.71 (d, J = 5.62 Hz, 2H), 3.80 (s, 3H), 3.43 (t, J = 6.30 Hz, 2H), 3.28 (t, J = 6.36 Hz, 1H), 3.05 - 3.13 (m, 1H), 2.90 - 2.98 (m, 1H), 2.72 (q, J = 6.32 Hz, 1H), 2.39 (d, J = 1.59 Hz, 1H), 1.18 (t, J = 7.40 Hz, 3H); LC-MS m / z (M+H)+501.

[0273] 4-(4-{[(p-chlo ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-2-fluorobenzoic acid (SLU-0010891). Methyl 4-(4-{[(p- chlorophenyl)methyl]amino}-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)-2- fluorobenzoate (170 mg, 0.375 mmol) was dissolved in 10 mL MeOH and 10 mL THF and treated with 5 mL 1M LiOH. After stirring at room temp for 5 h, 1M HCl was added and the reaction was concentrated to give crude product which was purified by reverse phase HPLC (acetonitrile / water) to give the title compound in 75% yield (123 mg).1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 - 8.25 (m, 1H), 8.07 (d, J = 12.23 Hz, 1H), 7.88 - 7.95 (m, 2H), 7.44 - 7.49 (m, 2H), 7.35 - 7.40 (m, 2H), 4.84 (d, J = 5.75 Hz, 2H), 3.91 (s, 3H), 3.04 (q, J = 7.38 Hz, 2H), 1.25 - 1.31 (m, 3H); LC-MS m / z (M+H)+440.

[0274] 4-(4-chloro-3-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzonitrile (12). Crude 8 (4.01 g, 14.33 mmol) was weighed into a 250 mL round bottom flask and submerged in a sand bath then POCl3 (20 mL) was slowly added to the compound with constant stirring. The mixture was then heated overnight. Reaction mixture was cooled to room temperature followed by pouring on ice and basified with NaOH 6M to pH around 7- 8. The mixture was vacuum filtered and washed with water. Then concentrated under reduced pressure to afford 12 (2.45 g, 57%). Crude was relatively pure and used in the next step without further purification. ESI-MS m / z [C15H12ClN5+H]+298.08.

[0275] 4-(3-ethyl-1-methyl-4-((2-methylbenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (13j). Crude 12 (74.35 mg, 0.25 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (1 mL). Then o- tolylmethanamine 9j (50.80 mg, 0.41 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 13j (25.31 mg, 26%). Crude was directly used in the next step without further purification. ESI-MS m / z [C13H13NO2+H]+382.19.

[0276] 4-(3-ethyl-1-methyl-4-((3-methylbenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzonitrile (13k). Crude 12 (76.55 mg, 0.20 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (1 mL). Then m- tolylmethanamine 9k (50.60 mg, 0.42 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 13k (46.36 mg, 47%). Crude was directly used in the next step without further purification. ESI-MS m / z [C13H13NO2+H]+382.19.

[0277] p-(3-ethyl-1 ]amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid. (14a, SLU-0011164). Compound 13j (25.31, 0.06 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (1.5 mL). The resulting solution subjected to heating at 109°C overnight. Reaction mixture was cooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford the target compound (4.10 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 - 8.44 (m, 1H), 8.34 - 8.38 (m, 1H), 7.97 - 8.02 (m, 1H), 7.90 - 7.94 (m, 1H), 7.68 - 7.73 (m, 1H), 7.29 - 7.33 (m, 1H), 7.18 - 7.22 (m, 1H), 7.09 - 7.15 (m, 2H), 4.85 - 4.90 (m, 2H), 3.92 (s, 3H), 3.06 (d, J = 7.34 Hz, 2H), 2.43 (s, 3H), 1.28 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O2402.1930; found 402.1916.

[0278] p-(3-ethyl-1-methyl-thyl]amino}-1H-1,2,5,7-tetraazainden- 6-yl)benzoic acid. (14b, SLU-0011206). Compound 13k (46.36 mg, 0.12 mmol) was dissolved in EtOH into a 25 mL round bottom flask before adding 1 M KOH (aq) solution (2 mL). The resulting solution subjected to heating at 100°C overnight. Reaction mixture wascooled to room temperature. Then acidified with 1 N HCl. The product was concentrated and purified by reverse phase chromatography using water / acetonitrile no TFA as eluent afford the target compound (14.10 mg, 17%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (d, J = 8.31 Hz, 2H), 8.01 (d, J = 8.44 Hz, 2H), 7.83 (t, J = 5.99 Hz, 1H), 7.29 (s, 1H), 7.17 - 7.26 (m, 2H), 7.02 (d, J = 7.46 Hz, 1H), 4.84 (d, J = 5.87 Hz, 2H), 3.91 (s, 3H), 3.04 (q, J = 7.46 Hz, 2H), 2.27 (s, 3H), 1.28 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O2402.1930; found 402.1915.

[0279] methyl 4-(3-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (16).5-amino-3-ethyl-1-methyl-1H-pyrazole-4-carboxamide 6 (3.00 g, 17.85 mmol), 4-Formylbenzoic acid 15 (2.93 g, 17.85 mmol) and K2CO3(2.46 g,17.58 mmol) were weighed into a 250 mL round bottom flask. DMF was added and the mixture first stirred for 15 minutes and then iodine (6.79 g, 26.78 mmol) was added into the resulting solution and the mixture subjected to heating at 90°C overnight. Reaction mixture was cooled to room temperature followed by quenching with 1 M HCl (30 mL). The mixture was extracted with water and EtOAc. The organic layer washed with sodium thiosulfate and then concentrated under reduced pressure and purified by combiflash chromatography (silica gel, hexane / EtOAc) to afford 16 (4.56 g, 82%). ESI-MS m / z [C16H16N4O3+H]+313.12.

[0280] methyl 4-(4-chloro-3-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzoate (17). Crude 16 (4.56 g, 14.42 mmol) was weighed into a 250 mL round bottom flask and submerged in a sand bath then POCl3 (25 mL) was slowly added to the compound with constant stirring. The mixture was then heated overnight at 110°C. Reaction mixture was cooled to room temperature followed by pouring on ice and basified with NaOH 6M to pH around 7-8. Collected the precipitated solid and rested in lyophilizer to afford 17 (3.27 g, 68%). Crude was relatively pure and used in the next step without further purification. ESI- MS m / z [C16H15ClN4O2+H]+331.09.

[0281] Alternative synthesis of 4-chloro-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (17). In an oven dried 25mL round bottom flask methyl 4-(3- ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (1.20 g, 3.84 mmol, 1 Eq) was weighed. POCl3(5.37 mL, 15 Eq, 57.6 mmol) was slowly added into it followed by PCl5 (1.60 g, 2 Eq, 7.68 mmol). The crude mixture was then stirred for 18 hours at 120 °C, increasing the temperature slowly until reaching the desired temperature. After 18 hours the crude mixture was allowed to come to room temperature and then the mixture was evaporated on a rotavator until dried completely. Next the reaction was quenched with ice and neutralized (pH = ~7) by using NaOH. The crude mixture was then worked up with ethylacetate, aq. NaOH, water and brine. The organic layer was dried in the rotavapor to yield the title compound as a yellow solid (1.20 g, 3.84 mmol, 75% yield). The crude product was used directly in the next steps without further purification.1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.5 Hz, 2H), 4.15 (s, 3H), 3.99 (s, 3H), 3.17 (q, J = 7.5 Hz, 2H), 1.45 (t, J = 7.5 Hz, 3H). LC-MS m / z (M+H)+= 331.

[0282] methyl 4-(3-ethyl-4-((2-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18l). Crude 17 (105.01 mg, 0.31 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.5 mL). Then 2- flurobenzylamine 9l (72.40 mg, 0.47 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18l. Crude was directly used in the next step without further purification. ESI-MS m / z [C23H22FN5O2 +H]+420.18.

[0283] methyl 4-(3-ethyl-4-((3-methoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18m). Crude 17 (102.20 mg, 0.31 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.5 mL). Then 3- methoxybenzylamine 9m (71.90 mg, 0.47 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18m. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H25N5O3+H]+432.20.

[0284] methyl 4-(3-ethyl-1-methyl-4-((3-(trifluoromethyl)benzyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18n). Crude 17 (123.50 mg, 0.37 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.4 mL). Then 3-(trifluoromethyl)phenyl)methanamine 9n (112.33 mg, 0.56 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18n. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H22F3N5O2+H]+470.17.

[0285] methyl 4-(3-ethyl-1-methyl-4-((2-(trifluoromethyl)benzyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18o). Crude 17 (168.20 mg, 0.51 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.7 mL). Then (2-(trifluoromethyl)phenyl)methanamine 9o (203.00 mg, 1.16 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated toremove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18o. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H22F3N5O2+H]+470.17.

[0286] methyl 4-(4-((3-chlorobenzyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18p). Crude 17 (103.70 mg, 0.31 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.4 mL). Then (3- chlorophenyl)methanamine 9p (70.10 mg, 0.47 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18p. Crude was directly used in the next step without further purification. ESI-MS m / z [C23H22ClN5O2+H]+436.15.

[0287] methyl 4-(4-((4-chloro-3-(trifluoromethyl)benzyl)amino)-3-ethyl-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18q). Crude 17 (266.80 mg, 0.81 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.7 mL). Then (4-chloro-3-(trifluoromethyl)phenyl)methanamine 9q (258.50 mg, 1.21 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18q. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H21ClF3N5O2+H]+504.13.

[0288] methyl 4-(4-((3-chloro-4-methoxybenzyl)amino)-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18r). Crude 17 (53.71 mg, 0.16 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.3 mL). Then (3-chloro-4-methoxyphenyl)methanamine 9r (65.12 mg, 0.32 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18r. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H24ClN5O3+H]+466.16.

[0289] methyl 4-(4-((4-chloro-3-fluorobenzyl)amino)-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18s). Crude 17 (125.22 mg, 0.38 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.5 mL). Then (4-chloro-3-fluorophenyl)methanamine 9s (106.80 mg, 0.57 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl andbrine. Organics were dried over MgSO4 to afford 18s. Crude was directly used in the next step without further purification. ESI-MS m / z [C23H21ClFN5O2+H]+454.14.

[0290] methyl 4-(4-((3,4-dichlorobenzyl)amino)-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18t). Crude 17 (258.90 mg, 0.78 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.8 mL). Then (3,4-dichlorophenyl)methanamine 9t (209.21 mg, 1.18 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18t. Crude was directly used in the next step without further purification. ESI-MS m / z [C23H21Cl2N5O2+H]+470.11.

[0291] methyl 4-(3-ethyl-1-methyl-4-((4-(trifluoromethyl)benzyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18u). Crude 17 (262.70 mg, 0.80 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.8 mL). Then (4-(trifluoromethyl)phenyl)methanamine 9u (219.43 mg, 1.19 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18u. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H22F3N5O2+H]+470.17.

[0292] methyl 4-(3-ethyl-1-methyl-4-((3-phenylpropyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18v). Crude 17 (62.29 mg, 0.19 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.3 mL). Then 3-phenylpropan-1- amine 9v (57.10 mg, 0.28 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18v. Crude was directly used in the next step without further purification. ESI-MS m / z [C25H27N5O2+H]+430.22.

[0293] methyl 4-(3-ethyl-1-methyl-4-(propylamino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18w). Crude 17 (129.45 mg, 0.39 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.4 mL). Then propan-1-amine 9w (41.40 mg, 0.59 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18w. Crude was directly used in the next step without further purification. ESI-MS m / z [C19H23N5O2+H]+354.19.

[0294] methyl 4-(3-ethyl-1-methyl-4-((4,4,4-trifluorobutyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18x). Crude 17 (61.71 mg, 0.18 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.1 mL). Then 4,4,4-trifluorobutan-1-amine 9x (38.00 mg, 0.28 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18x. Crude was directly used in the next step without further purification. ESI-MS m / z [C20H22F3N5O2+H]+422.17.

[0295] methyl 4-(3-ethyl-4-(isopentylamino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18y). Crude 17 (60.18 mg, 0.18 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.3 mL). Then 3-methylbutan-1- amine 9y (41.91 mg, 0.28 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18y. Crude was directly used in the next step without further purification. ESI-MS m / z [C21H27N5O2+H]+382.22.

[0296] methyl 4-(3-ethyl-1-methyl-4-((pyridin-2-ylmethyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18z). Crude 17 (59.00 mg, 0.18 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.1 mL). Then pyridin-2-ylmethanamine 9z (32.12 mg, 0.27 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18z. Crude was directly used in the next step without further purification. ESI-MS m / z [C22H22N6O2+H]+403.18.

[0297] methyl 4-(4-((4-(dimethylamino)benzyl)amino)-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18aa). Crude 17 (36.00 mg, 0.11 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.1 mL). Then 4-(aminomethyl)-N,N-dimethylaniline 9aa (26.10 mg, 0.17 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18aa. Crude was directly used in the next step without further purification. ESI-MS m / z [C25H28N6O2+H]+445.23.

[0298] methyl 4-(4-(benzyl(methyl)amino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18ab). Crude 17 (74.80 mg, 0.22 mmol) was weighed into a 25mL round bottom flask and dissolved in MeCN and DIEA (0.1 mL). Then N-methyl-1- phenylmethanamine 9ab (42.11 mg, 0.34 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18ab. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H25N5O2+H]+416.20.

[0299] methyl 4-(3-ethyl-1-methyl-4-(3-phenylpyrrolidin-1-yl)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18ac). Crude 17 (53.55 mg, 0.16 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.3 mL). Then 3- phenylpyrrolidine 9ac (50.10 mg, 0.32 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18ac. Crude was directly used in the next step without further purification. ESI-MS m / z [C26H27N5O2+H]+442.22.

[0300] methyl 4-(4-((2,6-dichlorophenethyl)amino)-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18ad). Crude 17 (49.66 mg, 0.15 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.3 mL). Then 2-(2,4-dichlorophenyl)ethan-1-amine 9ad (61.67 mg, 0.32 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18ad. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H23Cl2N5O2+H]+484.12.

[0301] methyl (S)-4-(3-ethyl-4-((1-(4-fluorophenyl)ethyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18ae). Crude 17 (153.80 mg, 0.46 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.7 mL). Then (S)-1-(4-fluorophenyl)ethan-1-amine 9ae (146.13 mg, 1.05 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18ae. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H24FN5O2+H]+434.19.

[0302] methyl (R)-4-(3-ethyl-4-((1-(4-fluorophenyl)ethyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (18af). Crude 17 (150.12 mg, 0.45 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.6 mL). Then (R)-1-(4-fluorophenyl)ethan-1-amine 9af (145.22 mg, 1.04 mmol) was added and theresulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18af. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H24FN5O2+H]+434.19.

[0303] methyl 4-(4-(benzylamino)-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18ag). Crude 17 (121.58 mg, 0.37 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.5 mL). Then phenylmethanamine 9ag (75.43 mg, 0.55 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4 to afford 18ag. Crude was directly used in the next step without further purification. ESI-MS m / z [C23H23N5O2+H]+402.19.

[0304] methyl 4-(3-ethyl-1-methyl-4-(phenethylamino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (18ah). Crude 17 (140.89 mg, 0.43 mmol) was weighed into a 25 mL round bottom flask and dissolved in MeCN and DIEA (0.7 mL). Then 2-phenylethan-1- amine 9ah (48.58 mg, 0.63 mmol) was added and the resulting solution stirred at room temperature overnight. Crude product was concentrated to remove MeCN and the resulting solid dissolved in EtOAc washed with saturated NH4Cl and brine. Organics were dried over MgSO4to afford 18ah. Crude was directly used in the next step without further purification. ESI-MS m / z [C24H25N5O2+H]+416.20.

[0305] p-(4-{[(3-chloro-4-hyl]amino}-3-ethyl-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)benzoic acid. (19r, SLU-0002643).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18r followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19r (6.00 mg, 8%).1H NMR (700 MHz, DMSO-d6) δ ppm 8.46 - 8.48 (m, 2H), 8.01 - 8.03 (m, 2H), 7.83 (t, J = 5.99 Hz, 1H), 7.55 (d, J = 2.14 Hz, 1H), 7.41 (dd, J = 2.14, 8.40 Hz, 1H), 7.09 (d, J = 8.58 Hz, 1H), 4.78 (d, J = 6.08 Hz, 2H), 3.90 (s, 3H),3.79 (s, 3H), 3.03 (q, J = 7.44 Hz, 2H), 1.26 - 1.29 (m, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H22ClN5O3452.1489; found 452.1485.

[0306] p-(4-benzylamino-3- ,5,7-tetraazainden-6-yl)benzoic acid. (19ag, SLU-0002665).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18ag followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19ag (23.82 mg, 17%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, J = 8.31 Hz, 2H), 8.01 (d, J = 8.31 Hz, 2H), 7.86 (t, J = 5.93 Hz, 1H), 7.45 (d, J = 7.46 Hz, 2H), 7.32 (t, J = 7.58 Hz, 2H), 7.18 - 7.23 (m, 1H), 4.88 (d, J = 5.87 Hz, 2H), 3.91 (s, 3H), 3.04 (q, J = 7.34 Hz, 2H), 1.28 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H21N5O2388.1773; found 388.1755.thyl}amino)-3-ethyl-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl]benzoic acid. (19aa, SLU-0011160).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18aa followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19aa (9.70 mg, 21%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J = 8.44 Hz, 2H), 8.04 (d, J = 8.44 Hz, 2H), 7.70 - 7.74 (m, 1H), 7.30 (d, J = 8.68 Hz, 2H), 6.67 (d, J =8.68 Hz, 2H), 4.77 (d, J = 5.99 Hz, 2H), 3.90 (s, 3H), 3.02 (d, J = 7.58 Hz, 2H), 2.82 (s, 6H), 1.26 (t, J = 7.52 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C24H26N6O2431.2195; found 431.2191.

[0308] p-(3-ethyl-1-methy thyl]amino}-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid.(19z, SLU-0011161).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18z followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19z (11.90 mg, 18%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (d, J = 3.91 Hz, 1H), 8.38 (d, J = 8.07 Hz, 2H), 7.97 (d, J = 8.07 Hz, 2H), 7.92 (br. s., 1H), 7.70 - 7.75 (m, 1H), 7.40 (d, J = 7.70 Hz, 1H), 7.22 - 7.27 (m, 1H), 4.96 (d, J = 5.26 Hz, 2H), 3.92 (s, 3H), 3.07 (q, J = 7.17 Hz, 2H), 1.31 (t, J = 7.34 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C21H20N6O2389.1726; found 389.1711.

[0309] p-[3-ethyl-1-methyl-obutylamino)-1H-1,2,5,7- tetraazainden-6-yl]benzoic acid (19x, SLU-0011162). 1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18x followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluentto afford product 19x (51.00 mg, 70%). HRMS (ESI) m / z: [M + H]+Calcd for C19H20F3N5O2408.1647; found 408.1641.

[0310] p-{4-[(benzyl)-N-me yl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl}benzoic acid. (19ab, SLU-0011163).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18ab followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19ab (9.70 mg, 12%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (d, J = 8.31 Hz, 2H), 8.02 (d, J = 8.31 Hz, 2H), 7.33 - 7.37 (m, 4H), 7.28 (d, J = 5.62 Hz, 1H), 5.10 (s, 2H), 3.96 (s, 3H), 2.96 (q, J = 7.42 Hz, 2H), 1.24 (t, J = 7.40 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O2402.1930; found 402.1919.

[0311] p-[3-ethyl-1-methyl-omethyl)phenyl]methyl}amino)-1H- 1,2,5,7-tetraazainden-6-yl]benzoic acid. (19u, SLU-0011165).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18u followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19u (4.51 mg, 1%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (d, J = 8.19 Hz, 2H), 7.98 (d, J = 8.31 Hz, 2H), 7.92 - 8.01 (m, 3H), 7.64 - 7.73 (m, 4H), 4.95 (d, J = 5.50 Hz, 2H), 3.91 (s, 3H), 3.05 (q, J = 7.42 Hz, 2H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H20F3N5O2456.1647; found 456.1641.

[0312] p-[4-({[4-chloro-3-(t henyl]methyl}amino)-3-ethyl-1- methyl-1H-1,2,5,7-tetraazainden-6-yl]benzoic acid. (19q, SLU-0011166).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18q followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19q (34.50 mg, 8%).1H NMR (400 MHz, DMSO- d6) δ ppm 8.42 (d, J = 8.31 Hz, 2H), 8.04 (s, 1H), 7.95 - 8.02 (m, 3H), 7.77 (d, J = 8.44 Hz, 1H), 7.65 - 7.69 (m, 1H), 4.89 (d, J = 5.75 Hz, 2H), 3.91 (s, 3H), 3.05 (q, J = 7.50 Hz, 2H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H19ClF3N5O2490.1258; found 490.1255.

[0313] p-(4-{[(3,4-dichloropmino}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (19t, SLU-0011167).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18t followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19t (8.30 mg, 2%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 8.31 Hz, 2H), 8.01 (d, J = 8.31 Hz, 2H), 7.91 (s, 1H), 7.75 (d, J = 1.59 Hz, 1H), 7.58 (d, J = 8.31 Hz, 1H), 7.46 (d, J = 1.47 Hz, 1H), 4.84 (d, J = 5.87 Hz, 2H), 3.91 (s, 3H), 3.05 (d, J = 7.46 Hz, 2H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H19Cl2N5O2 456.0994; found 456.0991.

[0314] p-[3-ethyl-1-methyl-4- pyrrolidinyl)-1H-1,2,5,7-tetraazainden- 6-yl]benzoic acid. (19ac, SLU-0011207).1:0.8 m xture of THF and MeOH (total 4.5 mL) was added to crude 18ac followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19ac (4.27 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (d, J = 8.31 Hz, 2H), 8.03 (d, J = 8.19 Hz, 2H), 7.34 - 7.44 (m, 4H), 7.28 (d, J = 6.97 Hz, 1H), 4.32 (d, J = 2.32 Hz, 1H), 4.00 - 4.09 (m, 1H), 3.95 (s, 3H), 3.80 - 3.91 (m, 1H), 3.55 (d, J = 7.46 Hz, 1H), 3.17 (s, 1H), 3.04 (q, J = 7.30 Hz, 2H), 2.38 - 2.45 (m, 1H), 2.14 - 2.22 (m, 1H), 1.29 (t, J = 7.27 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C25H25N5O2428.2086; found 428.2085.

[0315] p-{4-[2-(2,6-dichloroino]-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl}benzoic acid. (19ad, SLU-0011208).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18ad followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19ad (3.22 mg, 5%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, J = 8.19 Hz, 2H), 8.04 (d, J = 8.31 Hz, 2H), 7.53 (d, J = 1.59 Hz, 1H), 7.30 - 7.38 (m, 3H), 3.90 (s, 3H), 3.16 (d, J = 9.05 Hz, 2H), 2.95 (d, J = 7.46 Hz, 2H), 1.21 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H21Cl2N5O2470.1150; found 470.1153.

[0316] p-(3-ethyl-4-{[(o-fl ]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (19l, SLU-0011212).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18l followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19l (8.10 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 8.31 Hz, 2H), 7.99 (d, J = 8.31 Hz, 2H), 7.84 (t, J = 5.50 Hz, 1H), 7.45 (t, J = 7.46 Hz, 1H), 7.18 - 7.29 (m, 2H), 7.10 - 7.15 (m, 1H), 4.92 (d, J = 5.87 Hz, 2H), 3.91 (s, 3H), 3.05 (q, J = 7.46 Hz, 2H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H20FN5O2 406.1679; found 406.1668.

[0317] p-(4-{[(m-chloroph}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (19p, SLU-0011213).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18p followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19p (8.23 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 8.31 Hz, 2H), 8.00 (d, J = 8.31 Hz, 2H), 7.90 (br. s., 1H), 7.54 (br. s., 1H), 7.41 - 7.45 (m, 1H), 7.35 (t, J = 7.76 Hz, 1H), 7.28 (d, J = 6.72 Hz, 1H), 4.85 (d, J = 5.50 Hz, 2H), 3.91 (s, 3H), 3.05 (q, J = 7.38 Hz, 2H), 1.29 (t, J = 7.40 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H20ClN5O2422.1384; found 422.138.

[0318] p-[3-ethyl-1-methyl- pylamino)-1H-1,2,5,7-tetraazainden-6- yl]benzoic acid. (19v, SLU-0011214).1:0.8 m xture of THF and MeOH (total 4.5 mL) was added to crude 18v followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19v (21.63 mg, 29%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 8.44 Hz, 2H), 8.03 (d, J = 8.44 Hz, 2H), 7.23 - 7.32 (m, 5H), 7.17 - 7.22 (m, 1H), 3.90 (s, 3H), 3.65 - 3.72 (m, 2H), 2.99 (q, J = 7.46 Hz, 2H), 2.72 (t, J = 7.40 Hz, 2H), 2.01 (quin, J = 7.34 Hz, 2H), 1.25 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C24H25N5O2416.2086; found 416.2077.

[0319] p-[3-ethyl-4-(isopen yl-1H-1,2,5,7-tetraazainden-6-yl]benzoic acid. (19y, SLU-0011215).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18y followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19y (27.81 mg, 41%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J = 8.44 Hz, 2H), 8.04 (d, J = 8.31 Hz, 2H), 7.19 (t, J = 5.62 Hz, 1H), 3.90 (s, 3H), 3.65 - 3.72 (m, 2H), 2.98 (q, J = 7.46 Hz, 2H), 1.69 (td, J = 6.51, 13.14 Hz, 1H), 1.60 (q, J = 6.81 Hz, 2H), 1.25 (t, J = 7.46 Hz, 3H), 0.97 (d, J = 6.48 Hz, 6H); HRMS (ESI) m / z: [M + H]+ Calcd for C20H25N5O2368.2086 ; found 368.2074.

[0320] p-(4-{[(4-chloro-3-fl hyl]amino}-3-ethyl-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)benzoicacid. (19s, SLU-0011217).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18s followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19s (10.03 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 8.44 Hz, 2H), 8.01 (d, J = 8.44 Hz, 2H), 7.90 (s, 1H), 7.53 (t, J = 8.07 Hz, 1H), 7.48 (dd, J = 1.53, 10.58 Hz, 1H), 7.33 (d, J = 8.31 Hz, 1H), 4.86 (d, J = 5.87 Hz, 2H), 3.91 (s, 3H), 3.05 (d, J = 7.46 Hz, 2H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C22H19ClFN5O2440.1289; found 440.1284.

[0321] p-[3-ethyl-1-methylmethyl)phenyl]methyl}amino)-1H- 1,2,5,7-tetraazainden-6-yl]benzoic acid. (19n, SLU-0011218).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18n followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19n (16.71 mg, 10%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J = 8.44 Hz, 2H), 7.96 - 8.02 (m, 3H), 7.89 (s, 1H), 7.77 (d, J = 6.85 Hz, 1H), 7.53 - 7.60 (m, 2H), 4.92 (d, J = 5.62 Hz, 2H), 3.91 (s, 3H), 3.05 (q, J = 7.38 Hz, 2H), 1.26 - 1.33 (m, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H20F3N5O2456.1647; found 456.1642.

[0322] p-(3-ethyl-4-{[(m-m thyl]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid. (19m, S U-00 73).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18m followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19m (5.20 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 - 8.62 (m, 2H), 7.99 - 8.12 (m, 2H), 7.85 (t, J = 5.93 Hz, 1H), 7.23 (t, J = 7.82 Hz, 1H), 7.00 - 7.08 (m, 1H), 6.78 (dd, J = 2.08, 8.19 Hz, 1H), 4.85 (d, J = 5.87 Hz, 1H), 3.91 (s, 2H), 3.70 (s, 3H), 3.17 (s, 3H), 3.04 (q, J = 7.46 Hz, 2H), 1.23 - 1.33 (m, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H23N5O3418.1879; found 418.1870.

[0323] p-[3-ethyl-1-methyH-1,2,5,7-tetraazainden-6- yl]benzoic acid. (19w, SLU-0011274).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18w followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19w (9.81 mg, 7%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (d, J = 8.31 Hz, 2H), 8.04 (d, J = 8.31 Hz, 2H), 7.21 (t, J = 5.62 Hz, 1H), 3.90 (s, 3H), 3.64 (q, J = 6.56 Hz, 2H), 3.00 (q, J = 7.34 Hz, 2H), 1.67 - 1.78 (m, 2H), 1.25 (t, J = 7.46 Hz, 3H), 0.97 (t, J = 7.40 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C18H21N5O2340.1773; found 340.1769.

[0324] p-[3-ethyl-1-methyl ethyl)phenyl]methyl}amino)-1H- 1,2,5,7-tetraazainden-6-yl]benzoicacid. (19o, SLU-0011296).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18o followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19o (49.21 mg, 21%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (d, J = 8.44 Hz, 2H), 7.93 (d, J = 8.44 Hz, 3H), 7.78 (d, J = 7.82 Hz, 1H), 7.53 - 7.60 (m, 2H), 7.41 - 7.46 (m, 1H), 5.07 (d, J = 5.50 Hz, 2H), 3.93 (s, 3H), 3.10 (q, J = 7.46 Hz, 2H), 1.33 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H20F3N5O2456.1647; found 456.1643.

[0325] p-{4-[(S)-1-(p-fluoroino]-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl}benzoic acid. (19ae, SLU-0011297).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18ae followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19ae (11.62 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 8.44 Hz, 2H), 8.02 (d, J = 8.44 Hz, 2H), 7.59 (dd, J = 5.56, 8.50 Hz, 2H), 7.23 (d, J = 7.58 Hz, 1H), 7.15 (t, J = 8.93 Hz, 2H), 5.72 (t, J = 7.21 Hz, 1H), 3.90 (s, 3H), 3.11 (q, J = 7.42 Hz, 2H), 1.64 (d, J = 6.97 Hz, 3H), 1.29 (t, J = 7.40 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H22FN5O2420.1836; found 420.1829.

[0326] p-{4-[(R)-1-(p-fluoro ino]-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl}benzoic acid. (19af, SLU-0011298).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18af followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19af (20.41 mg, 11%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J = 8.44 Hz, 2H), 7.59 (dd, J = 5.62, 8.68 Hz, 2H), 7.23 (d, J = 7.58 Hz, 1H), 7.15 (t, J = 8.93 Hz, 2H), 5.72 (t, J = 7.21 Hz, 1H), 3.90 (s, 3H), 3.11 (q, J = 7.50 Hz, 2H), 1.64 (d, J = 6.97 Hz, 3H), 1.29 (t, J = 7.46 Hz, 3H); HRMS (ESI) m / z: [M + H]+ Calcd for C23H22FN5O2 420.1836; found 420.1826.

[0327] p-[3-ethyl-1-methyo)-1H-1,2,5,7-tetraazainden-6- yl]benzoic acid. (19ah, SLU-0011474).1:0.8 mixture of THF and MeOH (total 4.5 mL) was added to crude 18ah followed by 1 M LiOH (2 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was acidified with HCl to pH around 4-5. Crude product was evaporated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography using water / acetonitrile with no TFA as eluent to afford product 19ah (6.77 mg, 4%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (d, J = 7.95 Hz, 2H), 8.06 (d, J = 7.82 Hz, 2H), 7.26 - 7.36 (m, 5H), 7.21 (br. s., 1H), 3.84 - 3.94 (m, 5H), 3.03 (t, J = 6.79 Hz, 2H), 2.95 (q, J = 7.09 Hz, 2H), 1.20 (t, J = 7.21 Hz, 3H).

[0328] [(p-chlorophenyl)m droxyboryl)phenyl]-3-ethyl-1- methyl-1H-1,2,5,7-tetraazainden-4-yl}amine (SLU-0011357). To microwave vial were added DMF / H2O (10 mL), 6‐chloro‐3‐ethyl‐N‐[(4-chlorophenyl) methyl]‐1‐methyl‐1H‐ pyrazolo[3,4‐d] pyrimidin‐4‐amine (1.00 mmol), Pd(dppf)Cl2 (0.10 mmol). This reaction mixture was stirred under N2for 10 min and then added K2CO3(3.00 mmol) and 1,4- benzenediboronic acid (1.5 mmol). The container was sealed and microwave for 1 hour at 110oC. After that, the resulting mixture was vacuum filtered with a Buchner funnel and extracted with ethyl acetate (3X100). The organic layer was dried over Na2SO4 and concentrated. The crude substance was purified using reverse-phase HPLC (5-95%, CH3CN / H2O) to yield the the title compound as white solid (63 mg, 15%). LC-MS m / z 422 (MH)+. HPLC purity 99%.1H NMR (300 MHz, DMSO-d6) : δ ppm 8.32 (d, J = 7.8 Hz, 2H), 8.11 (s, 2H), 7.69-7.86 (m, 3H), 7.49 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.00-3.07 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H).13C NMR (700 MHz, DMSO-d6) δ ppm 160.28, 156.27, 154.98, 145.17, 139.55, 139.41, 133.97, 131.08, 129.04, 128.16, 126.87, 97.16, 43.11, 33.07, 21.48, 13.53. HRMS [ESI] m / z: [M + H]+Calcd for C21H21BClN5O2422.1555; found 408.1544.

[0329] p-(4-{[(p-chlorophe}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)phenol (SLU-0011355). Isolated as a side product from the synthesis of SLU-0011357. White solid (70 mg, 18%). LC-MS m / z 394 (MH)+. HPLC purity 99%.1H NMR (300 MHz, DMSO-d6): δ ppm 9.71 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 ( d, J = 8.4 Hz, 2H), 6.75 (d, J = 11.4 Hz, 2H), 4.76 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 2.88-2.95 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H).

[0330] [(p-chlorophenyl)me -methyl-6-phenyl-1H-1,2,5,7- tetraazainden-4-yl)amine (SLU-0011359). Iso ated as a side product from the synthesis of SLU-0011357. White solid LC-MS m / z 377 (MH)+. HPLC purity 97%.1H NMR (300 MHz, DMSO-d6):δ ppm 8.28-8.31 (m, 2H), 7.76 (t, J = 6.0 Hz, 1H), 7.28-7.41 (m, 7H), 4.79 (d, J = 5.7 Hz, 2H), 3.83 (s, 3H), 2.92-3.00 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H).

[0331] p-(4-{[(3,4-dichlorop mino}-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)phenol (SLU-0011169). To microwave vial were added DMF / H2O (10 mL), 6‐chloro‐3‐ethyl‐N‐[(3,4-dichlorophenyl) methyl] ‐1‐methyl‐1H‐pyrazolo[3,4‐d] pyrimidin‐4‐amine (1.00 mmol), Pd(dppf)Cl2 (0.10 mmol). This reaction mixture was stirred under N2for 10 min and then added K2CO3(3.00 mmol) and 1,4-benzenediboronic acid (1.5 mmol). The container was sealed and microwave for 1 hour at 110oC. After that, the resulting mixture was vacuum filtered with a Buchner funnel and extracted with ethyl acetate (3X100). The organic layer was dried over Na2SO4 and concentrated with a Rota evaporator. The crude substance was purified using reverse-phase HPLC (5-95%, CH3CN / H2O) to yield the the title compound as a side product, white solid (37 mg, 10%). LC-MS m / z 428 (MH)+. HPLC purity 99%.1H NMR (400 MHz, DMSO-d6): δ ppm 9.89 (s, 1H), 8.33 (d, J = 8.4 Hz, 2H), 7.82 (m, 1H), 7.59 (t, J = 6.4 Hz), 7.25 (t, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 4.93 (d, J = 4.8 Hz), 3.95 (s, 1H), 3.12 (m, 2H), 1.38 (t, J = 7.6 Hz, 3H).

[0332] p-(3-ethyl-1-methyl-4-morpholino-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (SLU-0011000). Crude 17 (34.9 mg, 0.1057 mmol) was reacted with morpholine (0.015 mL, 0.1710 mmol) and DIEA (3 drops) at room temperature in acetonitrile (4 mL). Solvent was evaporated off and the crude ester was redissolved in a 2:2:1 mixture of THF, MeOH, and 1 M aqueous LiOH (5 mL total). Ester hydrolysis proceeded under these conditions at room temperature. The LiOH was then neutralized with 1 M HCl, and solvent was evaporated, yielding a crude yellow solid. Purification was done via reverse-phase chromatography using a gradient of water and acetonitrile to give the title compound as an off-white solid (5 mg, 10% yield).1H NMR (400 MHz, DMSO-d6) d ppm 1.29 (t, J=7.40 Hz, 3 H) 2.95 (q, J=7.46 Hz, 2 H) 3.79 (s, 8 H) 3.97 (s, 3 H) 8.06 (m, J=8.31 Hz, 2 H) 8.54 (m, J=8.31 Hz, 2 H).

[0333] p-[4-({[p-(benzyo)-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl]benzoic acid (SLU-0011374). To a solution of methyl 4-(4-chloro-3- ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (0.12 mmol) and 4- hydroxybenzylamine (0.18 mmol) in CH3CN (1.5 mL) was added DIPEA (0.18 mmol) and stirred for 16 hours at room temperature. The volatiles were then 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 methyl 4-(3-ethyl-4-((4- hydroxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate as white solid (32 mg, 64 %).

[0334] 4-(3-ethyl-4-((4-hydroxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (0.08 mmol), PPh3 (0.11 mmol), and benzyl alcohol (0.11 mmol) were dissolved in dry THF (2 mL) and cooled to 0 °C and stirred for 2-5 min under inert atmosphere. Then DIAD (0.11 mmol) was added to it and the reaction was warmed to room temperature and stirred for 16 hours. The volatiles were removed under reduced pressure to afford the crude as gummy solid. 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 solutionand 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 (2.33 mg, 5.9 % over two steps).1H NMR (300 MHz, DMSO) δ 13.05 (s, 1H), 8.50 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.80 (s, 1H), 7.45 – 7.23 (m, 7H), 6.96 (d, J = 8.4 Hz, 2H), 5.05 (s, 2H), 4.82 (d, J = 5.4 Hz, 2H), 3.91 (s, 3H), 3.03 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H). LC-MS m / z (M + H)+= 494.

[0335] p-(3-ethyl-4-{[(mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (SLU-0011375). To a solution of methyl 4-(4-chloro-3-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (0.3 mmol) and 4- hydroxybenzylamine (0.45 mmol) in CH3CN (1.5 mL) was added DIPEA (0.45 mmol) and stirred for 16 hours at room temperature. 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 (11.91 mg, 9.8 % over 2 steps).1H NMR (300 MHz, DMSO) δ 9.16 (s, 1H), 8.44 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.68 (t, J = 6.0 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 4.70 (d, J = 5.8 Hz, 2H), 3.84 (s, 3H), 2.95 (q, J = 7.4 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H). LC-MS m / z (M + H)+= 404.

[0336] p-[3-ethyl-4-({[p-( exy oxy)p eny ]met yl}amino)-1-methyl-1H-1,2,5,7- tetraazainden-6-yl]benzoic acid (SLU-0011436). To a solution of methyl 4-(4-chloro-3- ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (17, 0.12 mmol) and 4-hydroxybenzylamine (0.18 mmol) in CH3CN (1.5 mL) was added DIPEA (0.18 mmol) and stirred for 16 hours at room temperature. The volatiles were then 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 4-(3-ethyl-4-((4- hydroxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate as white solid (32 mg, 64%).

[0337] 4-(3-ethyl-4-((4-hydroxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (0.08 mmol), PPh3(0.11 mmol), and 1-hexanol (0.11 mmol) were dissolved in dry THF (2 mL) and cooled to 0 °C and stirred for 2-5 min under inert atmosphere. Then DIAD (0.11 mmol) was added to it and the reaction was warmed to room temperature and stirred for 16 hours. The volatiles were removed under reduced pressure to afford the crude as gummy solid. 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).1H NMR (400 MHz, DMSO) δ 13.01 (s, 1H), 8.50 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.79 (t, J = 6.0 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.80 (d, J = 5.9 Hz, 2H), 3.94 – 3.85 (m, 5H), 3.03 (q, J = 7.5 Hz, 2H), 1.69 – 1.60 (m, 2H), 1.36 (dd, J = 14.0, 6.4 Hz, 2H), 1.27 (dd, J = 9.7, 5.1 Hz, 7H), 0.85 (t, J = 6.9 Hz, 3H). LC-MS m / z (M + H)+= 489.

[0338] p-(3-ethyl-4-{[(m-hhyl]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (SLU-0011451). To a solution of methyl 4-(4-chloro-3- ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (17, 0.3 mmol) and 3- hydroxybenzylamine (0.45 mmol) in CH3CN (1.5 mL) was added DIPEA (0.45 mmol) and stirred for 16 hours at room temperature. 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).1H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 8.47 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.81 (t, J = 5.6 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.83 (s, 1H), 6.59 (d, J = 7.9 Hz, 1H), 4.81 (d, J = 5.9 Hz, 2H), 3.93 (d, J = 13.5 Hz, 3H), 3.04 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H). LC-MS m / z (M + H)+= 404.

[0339] p-(4-anilino-3-eth 7-tetraazainden-6-yl)benzoic acid(SLU-0011488). Crude methyl 4-(4-chloro-3-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin- 6-yl)benzoate (17, 402.11 mg, 1.21 mmol) was weighed into a in 25 mL round bottom flask and dissolved in dioxane. Then aniline (170.65 mg, 1.82 mmol) was added to the solution followed by addition of Pd2(dba)3 (17.10 mg, 0.01 mmol), RuPhos (14.71 mg, 0.02 mmol) and NaOtBu (576.10 mg, 6.09 mmol) under inert atmosphere. The resulting solution stirred at 100°C overnight. The resultant mixture was concentrated and subjected to purification (twice) via flash column chromatography using a reverse-phase column, employing a water / acetonitrile solution without formic acid (FA) as the eluent. This process led to the isolation of the purified target compound (2.5 mg, 0.5%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.46 (d, J = 8.19 Hz, 2H), 8.04 (d, J = 8.19 Hz, 2H), 7.80 (d, J = 7.82 Hz, 2H), 7.45 (t, J = 7.64 Hz, 2H), 7.16 - 7.22 (m, 1H), 3.97 (s, 3H), 3.18 (q, J = 7.21 Hz, 2H), 1.31 (t, J = 7.40 Hz, 3H). MeCl1. K2CO3, NMP, 80 ºCR R’ Me N N R R’ OH

[0340] , ]pyrimidin- 6-yl)benzoic acids (20). General Method E. Methyl 4-(4-chloro-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (17, 1.0 equiv.) was weighed into a 25 mL round bottom flask followed by the amine (HNRR’, 1.25 equiv.) and potassium carbonate (2.0equiv.). Then n-methyl-2-pyrrolidone (NMP, 1.50 mL) was added to it and stirred overnight at 80 °C for 18 hours. After 18 hours the reaction mixture was cooled to room temperature and then 1N lithium hydroxide solution (5 equiv.) was added directly to the reaction mixture and stirred overnight at room temperature for 18 hours. After the completion (checked by LCMS), the pH of the reaction mixture was brought to ~3 using 1N HCl. The reaction mixture was extracted with ethyl acetate (2 X 20 mL) and washed with water (2 X 30 mL) and brine (20 mL). The organic layer was collected and dried with anhyd. sodium sulfate and filtered. The filtrate was concentrated in vacuo. Subsequently, it was diluted with 2.0 mL of DMSO and then purified by flash reversed-phase chromatography using a RediSep Prep C18 ,100 Å, 5 ^m (length: 250 mm, ID: 30 mm) column with gradient elution from 90% H2O (with 0.1% formic acid) in MeCN to 100% MeCN (with 0.1% formic acid) to provide the desired product 20 in >95% purity. Me HN H

[0341] p-[3-ethyl-4-(1-in 2,5,7-tetraazainden-6- yl]benzoic acid (SLU-0011537).General Method E was followed using 17 (0.1 mmol, 1.0 equiv.), 2,3-dihydro-1H-inden-1-amine hydrochloride (0.125 mmol, 1.25 equiv.), K2CO3 (0.3 mmol, 3.00 equiv.), NMP (1.50 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.003 g (7%) of the title compound as a colorless solid.1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 6.14 (q, J = 7.8 Hz, 1H), 5.33 (d, J = 7.9 Hz, 1H), 3.99 (s, 3H), 3.08 – 2.93 (m, 2H), 2.87 – 2.79 (m, 3H), 1.99 – 1.90 (m, 1H), 1.30 (t, J = 7.5 Hz, 3H). Me HN N H

[0342] p-(3-ethyl-4-{[yl]amino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (SLU-0011539). General Method E was followed using 17 (0.3 mmol, 1.0 equiv.), (6-methoxypyridin-3-yl)methanamine (0.375 mmol, 1.25 equiv.), K2CO3(0.6 mmol, 2.0 equiv.), NMP (2.00 mL). Extraction of the compound performed withEtOAc followed by reversed-phase chromatographic purification provided 0.010 g (7%) of the title compound as a yellowish solid.1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.2 Hz, 2H), 8.30 (s, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.88 – 7.76 (m, 2H), 6.77 (d, J = 8.5 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.02 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H). LC-MS m / z (M+H)+= 419. Me HN N N Cl H

[0343] p-(4-{[(6-chlor 3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (SLU-0011540). General Method E was followed using 17 (0.2 mmol, 1.0 equiv.), (6-chloropyridin-3-yl)methanamine (0.25 mmol, 1.25 equiv.), K2CO3(0.4 mmol, 2.0 equiv.), NMP (1.50 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.003 g (3.4%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 8.71 (s, 1H), 8.47 – 8.42 (m, 2H), 8.02 (d, J = 7.8 Hz, 2H), 7.92 – 7.85 (m, 2H), 7.34 (t, J = 5.8 Hz, 1H), 4.90 (d, J = 5.1 Hz, 2H), 3.92 (s, 3H), 3.05 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H). LC-MS m / z (M+H)+= 423. Me N H

[0344] p-[3-ethyl-1-minyl)-1H-1,2,5,7-tetraazainden- 6-yl]benzoic acid (SLU-0011542). General Method E was followed using 17 (0.2 mmol, 1.0 equiv.), 2-phenylpyrrolidine (0.25 mmol, 1.25 equiv.), K2CO3 (0.4 mmol, 2.0 equiv.), NMP (1.50 mL). Extraction of the compound performed with EtOAc followed by reversed- phase chromatographic purification provided 0.005 g (5.7%) of the title compound as a yellow semi solid.1H NMR (400 MHz, DMSO-d6) δ 12.97 (brs, 1H), 8.18 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.24 (t, J = 7.5 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 5.49 (t, J = 7.1 Hz, 1H), 4.14 (dd, J = 16.1, 7.8 Hz, 1H), 3.95 (brs, 1H), 3.84 (s, 3H), 3.11 – 2.94 (m, 2H), 2.40 – 2.34 (m, 1H), 2.11 – 2.01 (m, 1H), 1.95 – 1.87 (m, 1H), 1.84 – 1.75 (m, 1H), 1.27 (t, J = 7.3 Hz, 3H). LC-MS m / z (M+H)+= 389.Me N H

[0345] p-(3-ethyl-1-methyl-4 azainden-6-yl)benzoic acid(SLU-0011549). General Method E was followed using 17 (0.2 mmol, 1.0 equiv.), piperidine (0.25 mmol, 1.25 equiv.), K2CO3(0.4 mmol, 2.0 equiv.), NMP (1.50 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.005 g (7.1%) of the title compound as a reddish solid.1H NMR (400 MHz, DMSO-d6) δ 12.68 (brs, 1H), 8.46 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.67 (brs, 4H), 2.87 (q, J = 7.4 Hz, 2H), 1.63 (brs, 6H), 1.22 (t, J = 7.4 Hz, 3H). LC-MS m / z (M+H)+= 366. Me HN H

[0346] p-[4-(cyclopen1H-1,2,5,7-tetraazainden-6- yl]benzoic acid (SLU-0011550). General Method E was followed using 17 (0.3 mmol, 1.0 equiv.), cyclopentanamine (0.375 mmol, 1.25 equiv.), K2CO3 (0.6 mmol, 2.0 equiv.), NMP (2.00 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.015 g (13.5%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 13.12 (brs, 1H), 8.54 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 7.0 Hz, 1H), 4.80 – 4.72 (m, 1H), 3.91 (s, 3H), 3.04 (q, J = 7.4 Hz, 2H), 2.12 – 2.09 (m, 2H), 1.77 – 1.62 (m, 6H), 1.26 (t, J = 7.5 Hz, 3H). LC-MS m / z (M+H)+= 366. H

[0347] p-[4-(cyclohexylamino)-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6- yl]benzoic acid (SLU-0011551). General Method E was followed using 17 (0.3 mmol, 1.0 equiv.), cyclohexanamine (0.375 mmol, 1.25 equiv.), K2CO3 (0.6 mmol, 2.0 equiv.), NMP (2.00 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.016 g (14.0%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 13.07 (brs, 1H), 8.52 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 6.5 Hz, 1H), 4.38 – 4.34 (m, 1H), 3.90 (s, 3H), 3.03 (q, J = 7.3 Hz, 2H), 2.06 – 1.98 (m, 2H), 1.85 – 1.78 (m, 2H), 1.69 – 1.62 (m, 1H), 1.58 – 1.39 (m, 4H), 1.26 (t, J = 7.4 Hz, 3H), 1.20 – 1.10 (m, 1H). LC-MS m / z (M+H)+= 380. Me HN N N H

[0348] p-(3-ethyl-1-m amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (SLU-0011552). General Method E was followed using 17 (0.3 mmol, 1.0 equiv.), pyridin-3-ylmethanamine (0.375 mmol, 1.25 equiv.), K2CO3 (0.6 mmol, 2.0 equiv.), NMP (2.00 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.004 g (3.4%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 13.03 (brs, 1H), 8.71 (s, 1H), 8.47 – 8.42 (m, 2H), 8.02 (d, J = 7.8 Hz, 2H), 7.92 (t, J = 5.1 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 5.8 Hz, 1H), 4.90 (d, J = 5.1 Hz, 2H), 3.92 (s, 3H), 3.05 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H). LC-MS m / z (M+H)+= 389. Boc N H

[0349] p-[4-(4-tert-bu-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl]benzoic acid (SLU-0011557). General Method E was followed using 17 (0.3 mmol, 1.0 equiv.), tert-butyl piperazine-1-carboxylate (0.375 mmol, 1.25 equiv.), K2CO3 (0.6 mmol, 2.0 equiv.), NMP (2.00 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.019 g (13.0%)of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 3.89 (s, 3H), 3.70 (br, 4H), 3.49 (br, 4H), 2.90 (q, J = 7.4 Hz, 2H), 1.38 (s, 9H), 1.23 (t, J = 7.4 Hz, 3H). LC-MS m / z (M+H)+= 467. Me HN N N H

[0350] p-(3-ethyl-1-m amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (SLU-0011558). General Method E was followed using 17 (0.2 mmol, 1.0 equiv.), pyridin-4-ylmethanamine (0.25 mmol, 1.25 equiv.), K2CO3 (0.4 mmol, 2.0 equiv.), NMP (1.50 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.003 g (3.7%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 5.3 Hz, 2H), 8.37 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 7.94 (t, J = 5.9 Hz, 1H), 7.43 (d, J = 5.6 Hz, 2H), 4.88 (d, J = 5.8 Hz, 2H), 3.92 (s, 3H), 3.07 (d, J = 7.5 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H). LC-MS m / z (M+H)+= 389. H

[0351] p-[3-ethyl-1-myl)-1H-1,2,5,7-tetraazainden-6- yl]benzoic acid (SLU-0011559). General Method E was followed using 17 (0.2 mmol, 1.0 equiv.), 2-phenylpiperidine (0.25 mmol, 1.25 equiv.), K2CO3 (0.4 mmol, 2.0 equiv.), NMP (1.50 mL). Extraction of the compound performed with EtOAc followed by reversed-phase chromatographic purification provided 0.003 g (3.3%) of the title compound as a colorless solid.1H NMR (400 MHz, DMSO-d6) δ 13.10 (brs, 1H), 8.42 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.2 Hz, 2H), 7.48 – 7.30 (m, 4H), 7.21 (t, J = 6.9 Hz, 1H), 5.72 (brs, 1H), 4.15 – 4.05 (m, 1H), 3.98 (s, 3H), 3.37 – 3.30 (m, 1H), 2.98 – 2.90 (m, 2H), 2.36 – 2.33 (m, 1H), 2.04 – 1.99 (m, 1H), 1.75 – 1.66 (m, 4H), 1.31 (t, J = 7.3 Hz, 3H). LC-MS m / z (M+H)+= 442.

[0352] p-[3-ethyl-4-({[ l}amino)-1-methyl-1H-1,2,5,7-tetraazainden-6-yl]benzoic acid (SLU-0011568). To a solution of methyl 4-(4-chloro-3- ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (17, 0.5 mmol) and 3- hydroxybenzylamine (0.75 mmol) in CH3CN (2.5 mL) was added DIPEA (0.75 mmol) and stirred for 16 hours at room temperature. The volatiles were then 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 methyl 4-(3-ethyl-4-((3- hydroxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate as white solid (135 mg, 0.32 mmol, 64%). Methyl 4-(3-ethyl-4-((3-hydroxybenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (135 mg, 0.32 mmol), 1-bromohexane (64.06 mg, 0.39 mmol) and cesium carbonate (158 mg, 0.49 mmol) were dissolved in dry DMF (3 mL) and was stirred at 25oC for 18 h. After the completion of the reaction, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to give a yellow oil. 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 (32.38 mg, 20.2 % over two steps).1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.51 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.86 (t, J = 6.0 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.76 (dd, J = 8.1, 2.0 Hz, 1H), 4.84 (d, J = 5.9 Hz, 2H), 3.95 – 3.82 (m, 5H), 3.05 (q, J = 7.4 Hz, 2H), 1.62 (dd, J = 14.4, 6.8 Hz, 2H), 1.27 (td, J = 16.2, 6.2 Hz, 9H), 0.83 (t, J = 6.8 Hz, 3H). LC-MS m / z (M)+= 487.60.

[0353] p-{3-ethyl-1-metisoxazolyl)methyl]phenyl}methyl)amino]-1H-1,2,5,7-tetraazainden-6-yl}benzoic acid (SLU-0011569). To a solution of methyl 4-(4-chloro-3-ethyl-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (17, 0.18 mmol) and (4-((5-phenylisoxazol-3- yl)methyl)phenyl)methanamine (0.27 mmol) in CH3CN (1 mL) was added DIPEA (0.27 mmol) and stirred for 16 hours at room temperature. 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 (38.62 mg, 40 % over two steps).1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.48 (t, J = 8.6 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.89 – 7.82 (m, 1H), 7.76 (dd, J = 7.4, 2.2 Hz, 2H), 7.48 (ddd, J = 16.0, 13.4, 8.1 Hz, 5H), 7.28 (t, J = 7.1 Hz, 2H), 6.80 (s, 1H), 4.89 (dd, J = 19.0, 5.8 Hz, 2H), 4.00 (d, J = 8.2 Hz, 2H), 3.91 (s, 3H), 3.08 – 3.00 (m, 2H), 1.31 – 1.25 (m, 3H). LC-MS m / z (M+H)+= 545.60.

[0354] p-(4-{[(p-{2-[3-(- yl]ethoxy}phenyl)methyl]amino}-3-ethyl-1-methyl-1H-1,2,5,7-tetraazainden-6- yl)benzoic acid (SLU-0011628). To a solution of methyl 4-(4-chloro-3-ethyl-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (17, 0.14 mmol) and 4-hydroxybenzylamine (0.21 mmol) in CH3CN (1.5 mL) was added DIPEA (0.21 mmol) and stirred for 16 hours at room temperature. The volatiles were then removed under reduced pressure to afford the crude. The crude was purified by reverse phase chromatography (5-100 % CH3CN / H2O). The purefractions were lyophilized to get methyl 4-(3-ethyl-4-((4-hydroxybenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate as white solid (40 mg, 0.09 mmol, 64%). 4-(3- Ethyl-4-((4-hydroxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (40 mg, 0.09 mmol), 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (28.5 mg, 0.12 mmol) and cesium carbonate (46.8 mg, 0.14 mmol) were dissolved in dry DMF (3 mL) and was stirred at 25oC for 18 h. After the completion of the reaction, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to give a yellow oil. 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. The pure fractions were lyophilized to get the product as white solid (5.02 mg, 0.009 mmol, 10 % over two steps).1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.79 (t, J = 5.8 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.81 (d, J = 5.9 Hz, 2H), 3.91 (s, 3H), 3.76 (t, J = 6.1 Hz, 2H), 3.02 (q, J = 7.4 Hz, 2H), 2.79 (t, J = 2.6 Hz, 1H), 2.00 (td, J = 7.4, 2.6 Hz, 2H), 1.82 (t, J = 6.1 Hz, 2H), 1.62 (t, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H). LC-MS m / z (M+H)+= 524.20.

[0355] p-(4-{[(p-aminopheo}-3-ethyl-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (SLU-0011726). To a solution of methyl 4-(4-chloro-3- ethyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (17, 200 mg, 0.6 mmol) and 4- (aminomethyl)aniline (88.63 mg, 0.73 mmol) in NMP (2.5 mL) was added potassium carbonate (125.3 mg, 0.91 mmol) and stirred for 16 hours at room temperature. The volatiles were then 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 an off-white solid (119.6 mg, 47.5 %).1H NMR (400 MHz, DMSO-d6) δ8.56 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.3 Hz, 2H), 7.68 (t, J = 5.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.50 (d, J = 8.2 Hz, 2H), 4.91 (s, 2H), 4.72 (d, J = 5.7 Hz, 2H), 3.90 (d, J = 5.7 Hz, 6H), 3.02 (q, J = 7.4 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H). LC-MS m / z (M + H)+= 417. 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 % CH3CN / H2O). The pure fractions were lyophilized to get the product as white solid (18.04 mg, 0.04 mmol, 31.62 %).1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.66 (t, J = 5.9 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 6.51 (d, J = 8.3 Hz, 2H), 4.72 (d, J = 5.8 Hz, 2H), 3.91 (s, 3H), 3.32 (s, 2H), 3.02 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H). LC-MS m / z (M + H)+= 403.

[0356] 5-(3-ethyl-4-{[(ino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)-1-hydroxy-2,1-benzoxaborol-3(1H)-one (SLU-0011527). To a stirred solution of 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)benzoate (8B.2; 0.2 mmol) in 1,4-dioxane was added KOAc (0.4 mmol), B2pin2 (0.4 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2 (0.02 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude. The crude was then dissolved in MeOH and cooled to 0 °C, then 1 M NaOH (0.4 mmol) solution was added. After completion, 1 M HCl was added, and the volatiles were removed under reduced pressure and the crude was purified by reverse phase chromatography (5-100 % Acetonitrile / Water). Pure fractions were then lyophilized to afford the pure product as white solid (59.2 mg, 68.5%),1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.52 (s, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 8.3 Hz, 2H), 4.87 (s, 2H), 3.90 (s, 3H), 3.02 (d, J = 6.5 Hz, 2H), 1.27 (t, J = 6.3 Hz, 3H) ppm; LC-MS m / z (M + H)+= 432.

[0357] [(p-fluorophenyl) ydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011570). To a stirred solution of methyl 2-bromo-4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8C.2; 0.1 mmol) in 1,4-dioxane was added KOAc (0.2 mmol), B2pin2 (0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2 (0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude. The crude was then dissolved in MeOH and cooled to 0 °C under inert atmosphere. NaBH4 (4 mmol) was then added in a portion wise manner over 30 min and the rection mixture was allowed to warm to room temperature. After 4 h, the rection mixture was quenched with the addition of 1 M HCl. Then volatiles were removed under reduced pressure and the crude was purified by reverse phase chromatography (5-100 % acetonitrile / Water). Pure fractions were then lyophilized to afford the pure product as off white solid (23.4 mg, 55.9%),1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.76 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 5.9 Hz, 1H), 7.51 – 7.33 (m, 3H), 7.06 (t, J = 8.8 Hz, 2H), 4.98 (s, 2H), 4.82 (d, J = 5.7 Hz, 2H), 3.84 (s, 3H), 2.96 (q, J = 7.4 Hz, 2H), 1.20 (t, J = 7.4 Hz, 3H) ppm; LC-MS m / z (M + H)+= 418.

[0358] General Method F: To a stirred solution of methyl 2-bromo-5-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2; 1 equiv.) in dry DCM at 0 °C was added DIBAL-H (2.2 equiv.) and the resulting mixture was stirred for 1 h. After completion, the reaction was quenched by the addition of 1 M HCl and extracted with DCM. The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude. The crude was then dissolved in DCM and activated MnO2(10 equiv.) was added to it. After 3 h, the resulting mixture was passed through a short celite pad and washed with DCM. Then volatiles were removed under reduced pressure to afford the crude 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzaldehyde 8B.4. It was taken to next step without purification. LC-MS m / z (M + H)+= 468.

[0359] General Method G: To a stirred solution of 2-bromo-5-(3-ethyl-4-((4- fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzaldehyde (8B.4; 1 equiv.) in dry THF, was added Grignard reagent (1.2 equiv.) at 0 °C and the reaction mixture was allowed to come to room temperature. After 2-3 h, the reaction was quenched with the addition of aq. NH4Cl and extracted with EtOAc. The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude. The crude was taken to next step without purification.

[0360] [(p-fluoropheny droxy-3-methyl-1,3-dihydro-2,1-benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011695). Using General Method F, methyl 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2; 0.1 mmol) was converted into 2-bromo-5- (3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzaldehyde 8B.4 which was then reacted with MeMgCl (0.12 mmol) following the General Method G to afford 1-(2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ethan-1-ol which was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2(0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2 (0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (19.2 mg, 44.4 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.28 (s, 1H), 7.84 (t, J = 5.8 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.50 (dd, J = 8.4, 5.7 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 5.30 (q, J = 6.6 Hz, 1H), 4.93 – 4.74 (m, 2H), 3.91 (s, 3H), 3.04 (q, J = 7.4 Hz, 2H), 1.44 (d, J = 6.6 Hz, 3H), 1.28 (t, J = 7.5 Hz, 3H) ppm; LC-MS m / z (M + H)+= 432.

[0361] [(p-fluorophenyl)m 1-hydroxy-1,3-dihydro-2,1- benzoxaborol-5-yl)-1-methyl-1H-, , , ]amine (SLU-0011745). Using General Method F, methyl 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2; 0.1 mmol) was converted into 2-bromo-5- (3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzaldehyde 8B.4 which was then reacted with EtMgCl (0.12 mmol) following the General Method G to afford 1-(2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)propan-1-ol was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2 (0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2 (0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (20.07 mg, 45 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.27 (s, 1H), 7.83 (t, J = 5.9 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.49 (dd, J = 8.6, 5.6 Hz, 2H), 7.18 – 7.06 (m, 2H), 5.17 (dd, J = 7.2, 3.8 Hz, 1H), 4.83 (qd, J = 15.1, 5.9 Hz, 2H), 3.90 (d, J = 5.0 Hz, 3H), 3.04 (q, J = 7.4 Hz, 2H), 2.00 (ddd, J = 14.0, 7.3, 3.9 Hz, 1H), 1.57 (dt, J = 14.2, 7.3 Hz, 1H), 1.28 (t, J = 7.5 Hz, 3H), 0.88 (q, J = 7.2 Hz, 3H) ppm; LC-MS m / z (M + H)+= 446.

[0362] [(p-fluorophenydroxy-3-isopropyl-1,3-dihydro- 2,1-benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011746). Using General Method F, methyl 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2; 0.1 mmol) was converted into 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzaldehyde 8B.4 which was then reacted with i-PrMgCl (0.12 mmol) following the General Method G to afford 1-(2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-2-methylpropan-1-ol was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2 (0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2(0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (7.64 mg, 16.6 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.21 (s, 1H), 7.77 (t, J = 5.8 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 8.5, 5.7 Hz, 2H), 7.05 (t, J = 8.9 Hz, 2H), 5.06 (d, J = 2.9 Hz, 1H), 4.77 (ddd, J = 31.7, 15.3, 6.0 Hz, 2H),3.84 (s, 3H), 2.97 (q, J = 7.4 Hz, 2H), 2.14 – 2.04 (m, 1H), 1.22 (t, J = 7.5 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.49 (d, J = 6.8 Hz, 3H) ppm; LC-MS m / z (M + H)+= 460.

[0363] [(p-fluorophenydroxy-3-phenyl-1,3-dihydro-2,1- benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011756). Using General Method F, methyl 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2; 0.1 mmol) was converted into 2-bromo-5- (3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzaldehyde 8B.4 which was then reacted with PhMgCl (0.12 mmol) following the General Method G to afford (2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)(phenyl)methanol was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2 (0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2(0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (40.8 mg, 82.7 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.40 (d, J = 7.7 Hz,1H), 8.13 (s, 1H), 7.83 (dd, J = 14.4, 6.9 Hz, 2H), 7.48 – 7.35 (m, 4H), 7.33 (d, J = 7.4 Hz, 3H), 7.03 (t, J = 8.8 Hz, 2H), 6.28 (s, 1H), 4.75 (ddd, J = 60.5, 15.0, 6.0 Hz, 2H), 3.86 (s, 3H), 3.01 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H) ppm; LC-MS m / z (M + H)+= 494.

[0364] [(p-fluoropheny droxy-3,3-dimethyl-1,3-dihydro-2,1-benzoxaborol-5-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011724). To a stirred solution of methyl 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8B.2; 0.1 mmol) in dry THF, was added MeMgCl (0.25 mmol) at 0 °C and the reaction mixture was allowed to come to room temperature. After 2-3 h, the reaction was quenched with the addition of aq. NH4Cl and extracted with EtOAc. The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude. The crude was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2(0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2(0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (29.4 mg, 66.1 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.33 (d, J = 7.7 Hz, 1H), 8.19 (s, 1H), 7.86 (t, J = 5.8 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 8.4, 5.6 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 4.82 (d, J = 5.7 Hz, 2H), 3.90 (d, J = 6.6 Hz, 3H), 3.05 (q, J = 7.4 Hz, 2H), 1.49 (s, 6H), 1.29 (dd, J = 9.8, 5.1 Hz, 3H) ppm; LC-MS m / z (M + H)+= 446.

[0365] methyl 2-bromnzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8C.2). The title compound was prepared from III (0.51 mmol) and methyl 2-bromo-4-formylbenzoate (0.61 mmol) in three steps by a method analogous to that described for 8B.2. The crude was purified by normal phasechromatography (40-100 % EtOAc / Hexane) and the product was isolated as off-white solid (190 mg, 79.7 %).1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.04 – 7.78 (m, 2H), 7.49 (dd, J = 8.5, 5.7 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 4.82 (d, J = 5.7 Hz, 2H), 3.90 (d, J = 8.0 Hz, 6H), 3.05 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H) ppm; LC-MS m / z (M + H)+= 498.

[0366] 2-bromo-4-(3-et mino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzaldehyde (8C.4). The title compound was prepared according to General Method F from ester 8C.2 (0.2 mmol). The product was isolated as off-white gummy solid (82 mg, 87 % over 2 steps).1H NMR(400 MHz, DMSO) δ 9.63 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.04 – 7.78 (m, 2H), 7.48 (dd, J = 8.5, 5.7 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 4.83 (d, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.06 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H) ppm; LC-MS m / z (M + H)+= 468.

[0367] [(p-fluorophenyldroxy-3-methyl-1,3-dihydro-2,1- benzoxaborol-6-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011769). Using General Method F, methyl 2-bromo-5-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8C.2; 0.1 mmol) was converted into 2-bromo-4- (3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)benzaldehyde 8C.4 which was then reacted with MeMgCl (0.12 mmol) following the General Method G to afford 1-(2-bromo-4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ethan-1-ol which was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2(0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2 (0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (23.7 mg, 54.9 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.79 (s, 1H), 8.50 (dd, J= 8.0, 1.1 Hz, 1H), 7.78 (t, J = 6.0 Hz, 1H), 7.54 – 7.44 (m, 3H), 7.14 (t, J = 8.9 Hz, 2H), 5.27 (q, J = 6.5 Hz, 1H), 4.89 (d, J = 5.9 Hz, 2H), 3.92 (s, 3H), 3.03 (q, J = 7.4 Hz, 2H), 1.44 (d, J = 6.6 Hz, 3H), 1.28 (t, J = 7.5 Hz, 3H) ppm; LC-MS m / z (M + H)+= 432.

[0368] [(p-fluorophenyl ydroxy-3,3-dimethyl-1,3-dihydro-2,1-benzoxaborol-6-yl)-1-methyl-1H-1,2,5,7-tetraazainden-4-yl]amine (SLU-0011712). To a stirred solution of methyl 2-bromo-4-(3-ethyl-4-((4-fluorobenzyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)benzoate (8C.2; 0.1 mmol) in dry THF, was added MeMgCl (0.25 mmol) at 0 °C and the reaction mixture was allowed to come to room temperature. After 2-3 h, the reaction was quenched with the addition of aq. NH4Cl and extracted with EtOAc. The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crude. The crude was then dissolved in dioxane and was added KOAc (0.2 mmol), B2pin2(0.2 mmol) and then degassed for 10 min. Then Pd(dppf)Cl2(0.01 mmol) was added and the rection mixture was heated to 80 °C for 6 h. After completion, the reaction mixture was passed through a short celite pad and washed with EtOAc. Volatiles were removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography to afford the pure product as white solid (28.5 mg, 64 % over 2 steps),1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.72 (s, 1H), 8.49 – 8.40 (m, 1H), 7.77 (t, J = 5.9 Hz, 1H), 7.58 – 7.40 (m, 3H), 7.13 (t, J = 8.8 Hz, 2H), 4.88 (d, J = 5.8 Hz, 2H), 3.90 (s, 3H), 3.02 (q, J = 7.4 Hz, 2H), 1.48 (s, 6H), 1.27 (t, J = 7.4 Hz, 3H) ppm; LC-MS m / z (M + H)+= 446.

[0369] 3-ethyl-N-(4-fluorobenzyl)-6-(4-iodophenyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (12.1). The title compound was prepared from III and 4- iodobenzaldehyde in three steps by a method analogous to that described for 8B.2. The crude was taken to next step without further purification. LC-MS m / z (M + H)+= 488.

[0370] diethyl [p-(3-eth ethyl]amino}-1-methyl-1H- 1,2,5,7-tetraazainden-6-yl)phenyl] phosphonate (SLU-0011571). To a stirred solution of 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), Et3N (0.2 mmol) and Pd(PPh3)4. The resulting mixture was heated to 110 °C for 16 hours. After completion, it was passed through a short celite pad and washed with DCM. Volatiles were then removed under reduced pressure to afford the crude which was then purified by reverse phase chromatography (5-100 % Acetonitrile / Water + 0.1 % formic acid) to afford the pure product as off white solid (39.5 mg, 77.4 %),1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 8.3, 3.9 Hz, 2H), 7.89 (t, J = 6.0 Hz, 1H), 7.82 (dd, J = 12.7, 8.3 Hz, 2H), 7.50 (dd, J = 8.6,5.7 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 4.86 (d, J = 5.9 Hz, 2H), 4.10 – 3.99 (m, 4H), 3.91 (s, 3H), 3.05 (q, J = 7.5 Hz, 2H), 1.31 – 1.22 (m, 9H) ppm; LC-MS m / z (M + H)+= 498.

[0371] [p-(3-ethyl-4-{[(mino}-1-methyl-1H-1,2,5,7- tetraazainden-6-yl)phenyl]phosphonic acid (SLU-0011626). In a reaction vial diethyl [p- (3-ethyl-4-{[(p-fluorophenyl)methyl]amino}-1-methyl-1H-1,2,5,7-tetraazainden-6-yl)phenyl] phosphonate (0.05 mmol) was taken and was added concentrated HCl. The resulting mixture was stirred at 50 °C for 16 h. After completion it was purified by reverse phase chromatography (5-100 % Acetonitrile / Water + 0.1 % formic acid) to afford the pure product as white solid (11.2 mg, 52 %),1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 8.0, 3.1 Hz, 2H), 7.84 (t, J = 5.9 Hz, 1H), 7.76 (dd, J = 12.4, 8.2 Hz, 2H), 7.56 – 7.42 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.84 (d, J = 5.7 Hz, 2H), 3.90 (s, 3H), 3.03 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H) ppm; LC-MS m / z (M + H)+= 442.

[0372] General Method H. Synthesis of 4,6‐Dichloro‐1‐substituted-1H‐ pyrazolo[3,4‐d] pyrimidine Intermediates 23a-j. 2,4,6‐trichloropyrimidine‐5‐carbaldehyde21 (300 mg, 1.42 mmol) was dissolved in methanol (10 mL) and the solution was cooled to - 78oC and triethylamine was (3 mmol) added followed by addition of different substituted hydrazine hydrochloride 22a-j (1 mmol). The solution was stirred at -78oC for 0.5 h and then warmed up to room temperature. The reaction mixture was concentrated to remove methanol and residue was dissolved in ethyl acetate and transferred into separating funnel then washed with H2O. The organic portion was collected and dried over anhydrous sodium sulphate and concentrated to give a thick yellow solid. The crude material was purified by normal phase chromatography using ethyl acetate and hexane as solvent to give intermediates 23a-j as yellow solid.

[0373] General Method I. Synthesis of 6‐Chloro‐N‐[(4‐fluorophenyl)methyl]‐1‐ substituted-1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine Intermediates 24a-j. Dichloropyrimidine intermediate 23a-j (1.0 mmol) was dissolved in 10 mL acetonitrile then added DIPEA (diisopropylethylamine) (2.00 mmol) and stirred for 10 min at room temperature.4-Fluorobenzylamine (1.00 mmol) was added to the reaction mixture and stirred overnight at room temperature. After this time the resulting solution was concentrated. The residue was extracted with ethyl acetate (3X50 mL) and water (100 mL). The combined organic layers were concentrated in vacuum to give residue, which was purified by silica gel column chromatography (0 → 100% EtOAc / Hexanes) to afford intermediates 24a-j as white solids.

[0374] General Method J. Synthesis of R1-substituted Compounds 25a-j. In a 10 mL microwave vial charged with 6‐chloro‐N‐[(4‐fluorophenyl) methyl]‐1‐substituted-1H‐ pyrazolo[3,4‐d] pyrimidin‐4‐amine intermediate 24a-j (1 eq.) and dissolved in a mixture of DMF (3 mL) H2O (2 mL). To this solution, Pd(PPh3)4(0.1 eq.) was added, and the reaction mixture was degassed for about 15 mins with argon. K2CO3 (3 eq.) and 4- carboxyphenylboronic acid (1.2 eq.) were added. The microwave vial was sealed with cap and stirred reaction mixture in microwave for 1 h at 100oC. After this time, the reaction mixture was filtered through Celite pad followed by ethyl acetate washing. The filtrate was transferred into separating funnel, added 50 mL water, and extracted with ethyl acetate (2X50ml). The combined organic was dried over anhydrous Na2SO4and concentrated. The obtained residue was purified by prep-HPLC eluting with water and acetonitrile with 0.1% of formic acid to give target compounds 25a-j with >95% purity.

[0375] 4,6‐dichloro‐1‐methylpyrazolo[3,4‐d]pyrimidine (23a): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), methyl hydrazine(0.7 mL, 1.42 mmol), the intermediate 23a was isolated (266 mg, 86% yield).1H NMR (400 MHz, DMSO-d6). δ 8.07 (s, 1H), 4.04 (s, 3H). LC-MS: m / z (M + H)+= 204.

[0376] 6‐chloro‐N‐[(4‐fluorophenyl)methyl]‐1‐methylpyrazolo[3,4‐d]pyrimidin‐ 4‐amine (24a). Following General Method I: 4,6‐dichloro‐1‐methylpyrazolo[3,4‐ d]pyrimidine (250 mg, 1.2 mmol), DIPEA (0.42 mL, 2.4), 4-fluorobenzylamine (0.14 mL, 1.2 mmol), the intermediate 24a was isolate (217 mg, 60% yield).1H NMR (400 MHz, DMSO- d6). δ 8.79 (s, 1H), 8.37 (d, J = 8.4 Hz, 2H), 8.15 (t, J = 5.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 4.71 (d, J = 5.6 Hz, 1H), 3.92 (s, 3H). LC-MS: m / z (M + H)+= 292.

[0377] p-(4-{[(p-fluoro -methyl-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (25a; SLU-0011473). Using General Method E: 6‐chloro‐N‐[(4‐ fluorophenyl)methyl]‐1‐methyl‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine (50 mg, 0.17 mmol), Pd(PPh3)4 (20 mg, 0.01 mmol), K2CO3 (71 mg, 0.51 mmol), 4-carboxyphenylboronic acid (35 mg, 0.21 mmol), DMF: H2O, the product was isolated (10 mg 15% yield) as a white solid.1H NMR (400 MHz, DMSO-d6). δ 8.82 (s, 1H), 8.48 (d, J = 8.4 Hz, 2H), 8.07 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.43 - 7.41 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 4.81 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H). LC-MS m / z (M + H)+= 378.

[0378] 4,6‐dichloro‐1‐ethylpyrazolo[3,4‐d]pyrimidine (23b). Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), ethyl hydrazine hydrochloride (137 mg, 1.42 mmol), NEt3 (0.15 mL, 4.26 mmol), the intermediate 23b was isolated (272 mg, 88% yield).1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS m / z (M + H)+= 218.

[0379] 6‐chloro‐1‐ethyl‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐d]pyrimidin‐4‐ amine (24b). Following General Method I: 4,6‐dichloro‐1‐ethylpyrazolo[3,4‐d]pyrimidine (23b) (260 mg, 1.2 mmol), DIPEA (0.4 mL, 2.4 mmol), 4-fluorobenzylamine (0.13 mL, 1.2 mmol), the intermediate 24b was isolated (217 mg, 59% yield).1H NMR (400 MHz, DMSO- d6) δ 8.59 (s, 1H), 8.33 (d, J = 8.4 Hz, 2H), 8.11 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS: m / z (M + H)+= 306.

[0380] p-(1-ethyl-4-{[( ino}-1H-1,2,5,7-tetraazainden-6- yl)benzoic acid (25b; SLU-0011815). Using General Method E: 6‐chloro‐1‐ethyl‐N‐[(4‐ fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine (50 mg, 0.16 mmol), Pd(PPh3)4(19 mg, 0.01 mmol), K2CO3 (68 mg, 0.50 mmol), 4-carboxyphenylboronic acid (33 mg, 0.20 mmol), DMF: H2O, ,the product was isolated (12 mg 18% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 5.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.55 - 7.41 (m, 2H), 7.18 (t, J = 8.0 Hz, 2H), 4.87 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS m / z (M + H)+= 392.

[0381] 4,6‐dichloro‐1‐isopropylpyrazolo[3,4‐d]pyrimidine (23c): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde 21 (300 mg, 1.42 mmol), isopropyl hydrazine hydrochloride (157 mg, 1.42 mmol), NEt3(0.58 mL, 4.26 mmol), the intermediate 23c was isolated (238 mg, 73% yield).1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 8.28 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 8.4 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H), 5.17 - 5.10 (m, 1H), 4.85 (d, J = 6.0 Hz, 2H), 1.49 (d, J = 6.8 Hz, 6H). LC-MS m / z (M + H)+= 232.

[0382] 6‐chloro‐N‐[(4‐fluorophenyl)methyl]‐1‐isopropylpyrazolo[3,4‐ d]pyrimidin‐4‐amine (24c). Following General Method I: 4,6‐dichloro‐1‐ isopropylpyrazolo[3,4‐d]pyrimidine (23c) (200 mg, 0.9 mmol), DIPEA (0.3 mL, 1.8 mmol), 4-fluorobenzylamine (0.1 mL, 0.9 mmol), the intermediate 24c was isolated (150 mg, 54% yield).1H NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 7.2 Hz, 1H), 8.61 (d, J = 8.4 Hz, 2H), 8.21 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H), 5.19 - 5.17 (m, 1H), 4.56 (d, J = 5.6 Hz, 2H), 1.41 (d, J = 6.8 Hz, 6H). LC-MS m / z (M + H)+= 320.

[0383] p-(4-{[(p-fluoroisopropyl-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (25c; SLU-0011715). Using General Method J; 6‐chloro‐ N‐[(4‐fluorophenyl) methyl] ‐1‐(propan‐2‐yl) ‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine (50 mg,0.15 mmol), Pd(PPh3)4 (18 mg, 0.01 mmol), K2CO3 (65 mg, 0.46 mmol), 4- carboxyphenylboronic acid (31 mg, 0.18 mmol), DMF: H2O, the product was isolated (8.2 mg, 13% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 7.2 Hz, 1H), 8.50 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 8.28 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 8.4 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H), 5.17 - 5.10 (m, 1H), 4.85 (d, J = 6.0 Hz, 2H), 1.49 (d, J = 6.8 Hz, 6H). LC-MS m / z (M + H)+= 406.

[0384] 1‐tert‐butyl‐4,6‐dichloropyrazolo[3,4‐d]pyrimidine (23d): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), tert- butylhydrazine hydrochloride (137 mg, 1.42 mmol), the intermediate 23d was isolated (272 mg, 88% yield).1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.85 (t, 9H). LC-MS m / z (M + H)+= 246.

[0385] 1‐tert‐butyl‐6‐chloro‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐ d]pyrimidin‐4‐amine (24d). Following General Method I: 1‐tert‐butyl‐4,6‐ dichloropyrazolo[3,4‐d]pyrimidine 23d (260 mg, 1.2 mmol), DIPEA (0.3 mL, 1.8 mmol), 4- fluorobenzylamine (0.13 mL, 1.2 mmol), the intermediate 24d was isolated (217 mg, 59% yield).1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.21 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). LC- MS: m / z (M + H)+= 306.

[0386] p-[1-(tert-butyl)hyl]amino}-1H-1,2,5,7- tetraazainden-6-yl]benzoic acid (25d; SLU-0011722).1‐tert‐butyl‐6‐chloro‐N‐[(4‐ fluorophenyl) methyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine (50 mg, 0.15 mmol), Pd(PPh3)4 (18 mg, 0.01 mmol), K2CO3(63 mg, 0.45 mmol), 4-carboxyphenylboronic acid (28 mg, 0.16 mmol), DMF: H2O, the product was isolated (13.53 mg 22% yield) as a white solid.1H NMR (400 MHz, DMSO) δ 8.86 (t, J = 6.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 2H), 8.13 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.50 – 7.47 (m, 2H), 7.19 (t, J = 8.8 Hz, 2H), 4.86 (d, J = 5.2 Hz, 2H), 1.79 (s, 9H). LC-MS m / z (M + H)+= 420.

[0387] 4,6‐dichloro‐1‐cyclopropylpyrazolo[3,4‐d]pyrimidine (23e): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), NEt3(0.6 mL, 4.26 mmol), cyclopropylhydrazine hydrochloride (154 mg, 1.42 mmol), theintermediate 23e was isolated (280 mg, 86% yield).1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 4.20 - 4.16 (m, 1H), 1.54 - 1.49 (m, 2H), 1.02 – 0.97 (m, 2H). LC-MS m / z (M + H)+= 230.

[0388] 6‐chloro‐1‐cyclopropyl‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐ d]pyrimidin‐4‐amine (24e). Following General Method I: 4,6‐dichloro‐1‐ cyclopropylpyrazolo[3,4‐d]pyrimidine (23e) (250 mg, 1.1 mmol), DIPEA (0.4 mL, 2.18 mmol), 4-fluorobenzylamine (0.12 mL, 1.1 mmol), the intermediate 24e was isolated (192 mg, 55% yield).1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 7.2 Hz, 1H), 8.37 (d, d, J = 8.4 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.27 (s, 1H), 3.85 - 3.81 (m, 1H), 1.15 - 1.11 (m, 2H), 1.05 - 1.02 (m, 2H). LC-MS: m / z (M + H)+= 306.

[0389] p-(1-cycloprop thyl]amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (25e; SLU-0011716). Using General Method J; 6‐chloro‐1‐ cyclopropyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine 24e (50 mg, 0.15 mmol), Pd(PPh3)4 (18 mg, 0.01 mmol), K2CO3 (65 mg, 0.47 mmol.), 4- carboxyphenylboronic acid (29 mg, 0.17 mmol), DMF (4 mL) and H2O (2 mL), the product was isolated (5.24 mg 8% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.79 (t, J = 7.2 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.03 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 4.78 (d, J = 5.6 Hz, 2H), 3.90- 3.86 (m, 1H), 1.18 - 1.13 (m, 2H), 1.10 - 1.06 (m, 2H). LC-MS m / z (M + H)+= 404.

[0390] 4,6‐dichloro‐1‐cyclobutyl‐1H‐pyrazolo[3,4‐d]pyrimidine (23f): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), NEt3 (0.58 mL, 4.26 mmol), 1-cyclobutylhydrazine hydrochloride (174 mg, 1.42 mmol), the intermediate 23f was isolated (265 mg, 77% yield).1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 4.43 - 4.41 (m, 1H), 2.51 - 2.49 (m, 2H), 2.04 – 2.02 (m, 2H), 1.66 - 1.68 (m, 2H). LC- MS m / z (M + H)+= 244.

[0391] 6‐chloro‐1‐cyclobutyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐ d]pyrimidin‐4‐amine (24f). Following General Method I: 4,6‐dichloro‐1‐cyclobutyl‐1H‐ pyrazolo[3,4‐d]pyrimidine 23f (250 mg, 1.03 mmol), DIPEA (0.4 mL, 2.06 mmol), 4- fluorobenzylamine (0.12 mL, 1.03 mmol), the intermediate 24f was isolated (221 mg, 65%yield).1H NMR (400 MHz, DMSO-d6) δ 8.57 (t, J =7.2 Hz, 1H), 8.41(d, J = 8.4 Hz, 2H), 8.39 (d, J = 8.4 Hz, 2H), 8.17 (s, 1H), 4.27 – 4.25 (m, 1H), 2.39 - 2.37 (m, 2H), 1.89 – 1.87(m 2H), 1.47 – 1.45(m, 2H). LC-MS: m / z (M + H)+= 332.

[0392] p-(1-cyclobutyl yl]amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (25f; SLU-0011717).6-chloro-1-cyclobutyl-N-(4- fluorobenzyl)-1H-indazol-4-amine 24f (50 mg, 0.15 mmol), Pd(PPh3)4 (18 mg, 0.01 mmol), K2CO3(63 mg, 0.45 mmol), 4-carboxyphenylboronic acid (30 mg, 0.18 mmol), DMF:H2O the product was isolated (6.50 mg 11% yield) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ 8.76 (t, J = 7.2 Hz, 1H), 8.53 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.09 - 7.08 (t, J = 8.8 Hz, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.18 - 4.16 (m, 1H), 2.37 - 2.33 (m, 2H), 1.96 - 1.93 (m, 2H). LC-MS m / z (M + H)+= 418.

[0393] 4,6‐dichloro‐1‐cyclopentyl‐1H‐pyrazolo[3,4‐d]pyrimidine (23g): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), NEt3 (0.58 mL, 4.26 mmol), cyclopentylhydrazine hydrochloride (194 mg, 1.42 mmol), the intermediate 23g was isolated (295 mg, 80% yield).1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 4.72 - 4.67 (m, 1H), 2.29 - 2.25 (m, 2H), 1.95 -1.89 (m, 2H), 1.86 - 1.79 (m, 2H). LC-MS m / z (M + H)+= 258.

[0394] 6‐chloro‐1‐cyclopentyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐ d]pyrimidin‐4‐amin (24g). Following General Method I: 4,6‐dichloro‐1‐cyclopentyl‐1H‐ pyrazolo[3,4‐d]pyrimidine 23g (250 mg, 1.0 mmol), DIPEA (0.3 mL, 2.0 mmol), 4- fluorobenzylamine (0.11 mL, 1.0 mmol), the intermediate 24g was isolated (225 mg, 67% yield).1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.41 (d, J = 8.4 Hz, 2H), 8.24 (t, J = 5.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 4.93 - 4.88 (m ,1H), 2.25-2.21 (m, 2H), 2.04 - 2.01 (m, 2H), 1.97 - 1.92 (m, 2H), 1.89 - 1.86 (m 2H). LC-MS: m / z (M + H)+= 347.

[0395] p-(1-cyclopentyl-4-{[(p-fluorophenyl)methyl]amino}-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (25g; SLU-0011718). Using General Method J; 6‐chloro‐1‐ cyclopentyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine 24g (50 mg, 0.14 mmol), Pd(PPh3)4(17 mg, 0.01 mmol), K2CO3(60 mg, 0.43 mmol), 4- carboxyphenylboronic acid (29 mg, 0.17 mmol), DMF: H2O, the product was isolated (5.24 mg 8% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.89 (t, J = 5.6 Hz, 1H), 8.53 (d, J = 8.4 Hz, 2H), 8.16 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 8.4 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 5.34 - 5.28 (m, 1H), 4.87 (d, J = 5.2 Hz, 2H), 2.15 - 2.09 (m, 2H), 2.04 - 1.99 (m, 2H), 1.93 - 1.90 (m, 2H), 1.89 - 1.71 (m, 2H). LC-MS m / z (M + H)+= 432.

[0396] 4,6‐dichloro‐1‐cyclohexyl‐1H‐pyrazolo[3,4‐d]pyrimidine (23h): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), NEt3 (0.58 mL, 4.26 mmol), cyclohexylhydrazine hydrochloride (214 mg, 1.42 mmol), the intermediate 23h was isolated (295 mg, 77% yield).1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 4.63 - 4.58 (m, 1H), 1.89 - 1.85 (m, 4H), 1.84 – 1.78 (m, 4H), 1.58 - 1.53 (m, 2H). LC-MS m / z (M + H)+= 272.

[0397] 6‐chloro‐1‐cyclohexyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐ d]pyrimidin‐4‐amine (24h): Following General Method I: 4,6‐dichloro‐1‐cyclohexyl‐1H‐ pyrazolo[3,4‐d]pyrimidine 23h (250 mg, 0.9 mmol), DIPEA (0.3 mL, 1.8 mmol), 4- fluorobenzylamine (0.11 mL, 0.9 mmol), the intermediate 24h was isolated (215 mg, 65 % yield).1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.43 (d, J = 8.4 Hz, 2H), 8.24 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 4.92 - 4.86 (m, 1H), 2.32 -2.29 (m, 6H), 2.12 - 2.08 (m, 4H). LC-MS: m / z (M + H)+= 362.

[0398] p-(1-cyclohexyyl]amino}-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (25h; SLU-0011719). Using General Method J; 6‐chloro‐ 1‐cyclohexyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine 24h (50 mg, 0.14 mmol), Pd(PPh3)4(16 mg, 0.01 mmol), K2CO3(57 mg, 0.41 mmol), 4- carboxyphenylboronic acid (26 mg, 0.15 mmol), DMF: H2O, the product was isolated (10.31 mg 17% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.88 (t, J = 5.2 Hz, 1H), 8.52 (d, J = 8.4 Hz, 2H), 8.15 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 8.4 Hz, 2H),7.19 (t, J = 8.8 Hz, 2H), 4.86 (d, J = 5.6 Hz, 2H), 4.75 - 4.70 (m, 1H), 1.98 - 1.71 (m, 6H), 1.52 (d, J = 4.6 Hz, 1H), 1.46 - 1.22 (m, 3H).

[0399] 4,6‐dichloro‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine (23i): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), NEt3(0.58 mL, 4.26 mmol), phenylhydrazine hydrochloride (205 mg, 1.42 mmol), the intermediate 23i was isolated (272 mg, 88% yield).1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.61 (t, J = 8.8 Hz, 2H), 7.44 (t, J = 8.8 Hz, 1H). LC-MS m / z (M + H)+= 266.

[0400] 6‐chloro‐N‐[(4‐fluorophenyl)methyl]‐1‐phenyl‐1H‐pyrazolo[3,4‐ d]pyrimidin‐4‐amine (24i). Following General Method I: 4,6‐dichloro‐1‐phenyl‐1H‐ pyrazolo[3,4‐d]pyrimidine 23i (250 mg, 0.9 mmol), DIPEA (0.3 mL, 1.8 mmol), 4- fluorobenzylamine (0.11 mL, 0.9 mmol), the intermediate 24i was isolated (284 mg, 85% yield).1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (t, J = 5.2 Hz, 1H), 8.46 (d, J = 8.4 Hz, 2H), 8.39 (d, J = 8.4 Hz, 2H), 8.09 (t, J = 8.8 Hz, 2H), 7.89 (t, J = 8.8 Hz, 2H), 7.63 (t, J = 8.8 Hz, 2H), 4.72 (t, J = 5.6 Hz, 2H). LC-MS: m / z (M + H)+= 355.

[0401] p-(4-{[(p-fluorophenyl-1H-1,2,5,7-tetraazainden- 6-yl)benzoic acid (25i; SLU-0011720). Using General Method J; 6-chloro-N-(4- fluorobenzyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 24i (200 mg, 0.56 mmol), Pd(PPh3)4 (65 mg, 0.05 mmol), K2CO3 (234 mg, 1.70 mmol), 4-carboxyphenylboronic acid (103 mg, 0.62 mmol), DMF: H2O, the product was isolated (10.31 mg 17% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.11 (t, J = 5.2 Hz, 1H), 8.56 (d, J = 8.4 Hz, 2H), 8.45 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.62 - 7.39 (m, 4H), 7.22 (t, J = 8.8 Hz, 2H), 7.20 (t, J = 8.8 Hz, 2H), 4.96 (d, J = 5.6 Hz, 2H).

[0402] 1‐benzyl‐4,6‐dichloro‐1H‐pyrazolo[3,4‐d]pyrimidine (23j): Following General Method H: 2,4,6‐trichloropyrimidine‐5‐carbaldehyde (300 mg, 1.42 mmol), NEt3 (0.6 mL, 4.26 mmol), 1-benzylhydrazine hydrochloride (225 mg, 1.42 mmol), the intermediate 23j was isolated (190mg, 49% yield).1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.4 Hz, 2H), 7.75 (t, J = 8.8 Hz, 2H), 7.42 (t, J = 8.8 Hz, 1H), 5.52 (s, 2H). LC-MS m / z(M + H)+= 280. A byproduct 1‐benzyl‐2‐{1‐benzyl‐6‐chloro‐1H‐pyrazolo[3,4‐d]pyrimidin‐ 4‐yl}hydrazine 26 was also formed and isolated.

[0403] 1‐benzyl‐6‐chloro‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐ d]pyrimidin‐4‐amine (24j). Following General Method I: 1‐benzyl‐4,6‐dichloro‐1H‐ pyrazolo[3,4‐d]pyrimidine 23j (180 mg, 0.65 mmol), DIPEA (0.22 mL, 1.29 mmol), 4- fluorobenzylamine (74 µL, 0.64 mmol), the intermediate 24j was isolated (190 mg, 80% yield).1H NMR (400 MHz, DMSO-d6) δ 8.92(d, J = 5.2 Hz, 1H), 8.57 (d, J = 8.4 Hz, 2H), 8.46 (s, 1H), 8.29 (t, (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.65 (t, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS: m / z (M + H)+= 369.

[0404] p-(1-benzyl-4-{[( amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (25j; SLU-0011809). Using General Method J: 1-benzyl-6-chloro-N-(4- fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 24j (100 mg, 0.27 mmol), Pd(PPh3)4(31 mg, 0.02 mmol), K2CO3 (113 mg, 0.81 mmol), 4-carboxyphenylboronic acid (68 mg, 0.40 mmol), DMF:H2O, the product was isolated (15.65 mg ,20% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 5.6 Hz, 1H), 8.56 (d, J = 8.4 Hz, 2H), 8.19 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.32 - 7.28 (m, 5H), 7.20 (t, J = 8.8 Hz, 2H), 5.61 (s, 2H), 4.84 (d, J = 5.2 Hz, 2H).

[0405] p-[1-benzyl-,2,5,7-tetraazainden-6-yl]benzoic acid (SLU-0011812). Using General Method J: 1‐benzyl‐2‐{1‐benzyl‐6‐chloro‐1H‐ pyrazolo[3,4‐d]pyrimidin‐4‐yl}hydrazine 26 (60 mg, 0.16 mmol), Pd(PPh3)4 (19 mg, 0.02 mmol), K2CO3(68 mg, 0.49 mmol), 4-carboxyphenylboronic acid (55 mg, 0.33 mmol),DMF:H2O, the product was isolated (10.52 mg 15% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 8.4 Hz, 2H), 8.30 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.34 - 7.19 (m, 11H), 5.54 (s, 2H), 5.18 (s, 2H), 5.14 (d, J = 6.0 Hz, 2H).

[0406] Method K. Synthesis of R1-Substituted Aminocyanopyrazole Intermediates 27a-h. 2-(1-Ethoxypropylidene)malononitrile I was dissolved in ethanol (10 mL). To this R1-hydrazine was added slowly at room temperature. The reaction mixture was stirred at 100oC for 1 h. The resulting solution was allowed to cool room temperature and ethanol was removed on a rotary evaporator and the residue was purified via flash chromatography (0→ 100% EtOAc / Hexanes) to give the desired intermediates 27a-h.

[0407] Method L. Synthesis of R1-Substituted Aminocarboxamidopyrazole Intermediates 28a-h. Concentrated sulfuric acid (H2SO4, 5 mL) was taken into 25 mL round bottom flask and cooled to 0oC. To this, compound 27a-h was added slowly for 10 mins. After addition of compound, the reaction mixture was stirred for 30 min at 0oC temperature. Then reaction was stirred at room temperature overnight. The resulting solution was poured into 100 mL beaker containing ice, this solution was neutralized with 2M NaOH solution to pH 8. The aqueous was transferred into a separatory funnel and extracted 3x50 mL EtOAc. The organics were combined, washed with brine, and dried over Na2SO4.The filtrate was concentrated using rotary evaporator to give intermediate (28a-h) with > 95% purity by LCMS. This intermediate was used directly in the next step.

[0408] Method M. Synthesis of R1-Substituted Pyrazolopyrimidine‐4,6‐dione Intermediates 29a-h. The compound 28a-h and urea were weighed into 50 mL round bottom flask, the flask was heated to 200oC for 1 h. After this time the flask was cooled to room temperature and solid was dissolved in 2M NaOH solution. The resulting solution was acidified with glacial CH3COOH to pH 5 and the solids formed were filtered off. The solids were dried for 1h using high vacuum. The obtained solid 29a-h was used next step without any further purification.

[0409] Method N. Synthesis of R1-Substituted Dichloropyrazolopyrimidine Intermediates 29a-h. Phosphorus (V) chloride (1 g), and phosphoryl chloride 5 mL was added to the round bottom flask containing crude compound 29a-i. The reaction mixture stirred at 120oC for 9 h. Ater this time POCl3 was removed by rotary evaporation and the solid was washed with ice water to give compound 30a-i. This yellow residue was used for the next step.

[0410] 5‐amino‐1,3‐diethyl‐1H‐pyrazole‐4‐carbonitrile (27a): The title compound prepared using General Method K: 2-(1-ethoxypropylidene)malononitrile I (500 mg, 3.32mmol), ethylhydrazine hydrochloride (322 mg, 3.32 mmol), NEt3 (1.4 mL, 9.9 mmol). the product was isolated with 86% yield. LC-MS m / z (M + H)+= 165.2.

[0411] 5‐amino‐1,3‐diethyl‐1H‐pyrazole‐4‐carboxamide (28a): The title compound prepared from 27a using General Method L. LC-MS m / z (M + H)+= 183.2.

[0412] 1,3‐diethyl‐1H,4H,5H,6H,7H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐dione (29a). The title compound was prepared from 28a using General Method M. LC-MS m / z (M + H)+= 209.1.

[0413] 4,6‐dichloro‐1,3‐diethyl‐1H‐pyrazolo[3,4‐d]pyrimidine (30a):The title compound was prepared from 29a following General Method N. LC-MS m / z (M + H)+= 245.1.

[0414] 6‐chloro‐1,3‐diethyl‐N‐[(4‐fluorophenyl)methyl]‐1H‐pyrazolo[3,4‐ d]pyrimidin‐4‐amine (31a):The title compound was prepared from 30a following General Method I. LC-MS m / z (M + H)+= 334.1.

[0415] p-(1-ethyl-3-etthyl]amino}-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (32a; SLU-0011817). Using General Method J: 6-chloro- 1,3-diethyl-N-[(4-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 31a (50 mg, 0.15 mmol), Pd(PPh3)4 (17 mg, 0.01 mmol), K2CO3 (62 mg, 0.45 mmol), 4-carboxyphenylboronic acid (37 mg, 0.18 mmol), DMF: H2O, the product was isolated (10.02 mg 16% yield) as a white solid.1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.80 (t, J = 5.6 Hz, 1H), 7.68 (t, J = 5.6 Hz, 6H), 7.50 – 7.41 (m, 2H), 7.09 (t, J = 8.8 Hz, 1H), 6.99 (t, J = 8.8 Hz, 1H), 4.79 (d, J = 6.0 Hz, 1H), 4.69 (d, J = 5.1 Hz, 1H), 4.30 - 4.22 (m, 3H), 3.00 - 2.93 (m, 3H), 1.34 - 1.28 (m, 3H), 1.22 - 1.17 (m, 3H). LC-MS m / z (M + H)+= 420.

[0416] 5‐amino‐3‐ethyl‐1‐(propan‐2‐yl)‐1H‐pyrazole‐4‐carbonitrile (27b): The title compound prepared using General Method K: 2-(1-ethoxypropylidene)malononitrile I (500 mg, 3.32 mmol), isopropylhydrazine hydrochloride (368 mg, 3.32 mmol), NEt3(1.4 mL, 9.9 mmol). the product was isolated with 88 % yield. LC-MS m / z (M + H)+= 179.2.

[0417] 5‐amino‐3‐ethyl‐1‐(propan‐2‐yl)‐1H‐pyrazole‐4‐carboxamide (28b): The title compound prepared from 27b using General Method L. LC-MS m / z (M + H)+= 197.0.

[0418] 3‐ethyl‐1‐isopropyl‐5H,7H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐dione (29b). The title compound was prepared from 28b using General Method M. LC-MS m / z (M + H)+= 223.1.

[0419] 4,6‐dichloro‐1,3‐diethyl‐1H‐pyrazolo[3,4‐d]pyrimidine (30b):The title compound was prepared from 29b following General Method N. LC-MS m / z (M + H)+= 260.

[0420] 6‐chloro‐3‐ethyl‐N‐[(4‐fluorophenyl)methyl]‐1‐isopropylpyrazolo[3,4‐ d]pyrimidin‐4‐amine (31b):The title compound was prepared from 30b following General Method I. LC-MS m / z (M + H)+= 348.1.

[0421] p-(3-ethyl-4-{[( ino}-1-isopropyl-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (32b; SLU-0011750). Using General Method J: 6-chloro- 3-ethyl-N-(4-fluorobenzyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 31b (100 mg, 0.29 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), K2CO3 (119 mg, 0.87 mmol), 4- carboxyphenylboronic acid (57 mg, 0.34 mmol), DMF (4 mL) and H2O (2 mL), the product was isolated (29.02 mg 23% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.85 (t, J = 6.0 Hz, 1H), 7.52 -7.48 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.10 - 5.05 (m, 1H), 4.86 (d, J = 6.0 Hz, 2H), 3.07 (m, 2H), 1.48 (d, J = 6.8 Hz, 6H), 1.29 (t, J = 7.6 Hz, 3H). LC-MS m / z (M + H)+= 434.

[0422] 5‐amino‐1‐cyclopropyl‐3‐ethylpyrazole‐4‐carbonitrile (27c): The title compound prepared using General Method K: 2-(1-ethoxypropylidene)malononitrile I (500 mg, 3.32 mmol), ethylhydrazine hydrochloride (362 mg, 3.32 mmol), NEt3 (1.4 mL, 9.9 mmol). the product was isolated with 87% yield. LC-MS m / z (M + H)+= 177.2.

[0423] 5‐amino‐1‐cyclopropyl‐3‐ethylpyrazole‐4‐carboxamide (28c): The title compound prepared from 27c using General Method L. LC-MS m / z (M + H)+= 195.1.

[0424] 1‐cyclopropyl‐3‐ethyl‐5H,7H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐dione (29c). The title compound was prepared from 28c using General Method M. LC-MS m / z (M + H)+= 221.

[0425] 4,6‐dichloro‐1‐cyclopropyl‐3‐ethylpyrazolo[3,4‐d]pyrimidine (30c):The title compound was prepared from 29c following General Method N. LC-MS m / z (M + H)+= 257.1.

[0426] 6‐chloro‐1‐cyclopropyl‐3‐ethyl‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐ d]pyrimidin‐4‐amine (31c): The title compound was prepared from 30c following General Method I. LC-MS m / z (M + H)+= 346.1.

[0427] p-(1-cycloprop nyl)methyl]amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (32c; SLU-0011807). Using General Method J: 6-chloro-1- cyclopropyl-3-ethyl-N-(4-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 31c (100 mg, 0.29 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), K2CO3 (120 mg, 0.87 mmol), 4- carboxyphenylboronic acid (57 mg, 0.34 mmol), DMF (4 mL) and H2O (2 mL), the product was isolated (21.50 mg 17% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.86 (t, J = 6.0 Hz, 1H), 7.51 - 7.51 - 7.47 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.46 (d, J = 5.6 Hz, 2H), 3.88 - 3.82 (m, 1H), 3.04 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H), 1.19 - 1.13 (m, 2H), 1.09 - 1.05 (m, 2H). LC-MS m / z (M + H)+= 432.

[0428] 5‐amino‐1‐cyclobutyl‐3‐ethylpyrazole‐4‐carbonitrile (27d): The title compound prepared using General Method K: 2-(1-ethoxypropylidene)malononitrile I (500 mg, 3.32 mmol), cyclobutylhydrazine hydrochloride (408 mg, 3.32 mmol), NEt3 (1.4 mL, 9.9 mmol). the product was isolated with 81% yield. LC-MS m / z (M + H)+= 191.2.

[0429] 5‐amino‐1‐cyclobutyl‐3‐ethylpyrazole‐4‐carboxamide (28d): The title compound prepared from 27d using General Method L. LC-MS m / z (M + H)+= 209.2.

[0430] 1‐cyclobutyl‐3‐ethyl‐5H,7H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐dione (29d). The title compound was prepared from 28d using General Method M. LC-MS m / z (M + H)+= 235.1.

[0431] 4,6‐dichloro‐1‐cyclobutyl‐3‐ethylpyrazolo[3,4‐d]pyrimidine (30d): The title compound was prepared from 29d following General Method N. LC-MS m / z (M + H)+= 272.1.

[0432] 6‐chloro‐1‐cyclobutyl‐3‐ethyl‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐ d]pyrimidin‐4‐amine (31d): The title compound was prepared from 30d following General Method I. LC-MS m / z (M + H)+= 334.1.

[0433] p-(1-cyclobutyl yl)methyl]amino}-1H-1,2,5,7-tetraazainden-6-yl)benzoic acid (32d; SLU-0011751). Using General Method J: 6-chloro- 1-cyclobutyl-3-ethyl-N-(4-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 31d (200 mg, 0.55 mmol), Pd(PPh3)4(64 mg, 0.05 mmol), K2CO3(230 mg, 1.67 mmol), 4- carboxyphenylboronic acid (111 mg, 0.66 mmol), DMF: H2O, the product was isolated (62.18 mg 25% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 13.01 (s, 1H), 8.47 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz 2H) 7.88 (t, J = 6.0 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H),5.40 - 5.31 (m, 1H), 4.86 (d, J = 5.6 Hz, 2H), 3.09 (q, J= 7.6 Hz, 2H), 2.72 - 2.64 (m, 2H), 2.40- 2.38 (m, 2H), 1.91 - 1.85 (m, 2H), 1.31 (t, J= 7.6 Hz, 3 H). LC-MS m / z (M + H)+= 446.

[0434] 5‐amino‐1‐cyclopentyl‐3‐ethylpyrazole‐4‐carbonitrile (27e): The title compound prepared using General Method K: 2-(1-ethoxypropylidene)malononitrile I (500 mg, 3.32 mmol), cyclopentylhydrazine hydrochloride (563 mg, 3.32 mmol), NEt3(1.4 mL, 9.9 mmol). the product was isolated with 85% yield. LC-MS m / z (M + H)+= 205.3.

[0435] 5‐amino‐1‐cyclopentyl‐3‐ethylpyrazole‐4‐carboxamide (28e): The title compound prepared from 27e using General Method L. LC-MS m / z (M + H)+= 223.2.

[0436] 1‐cyclopentyl‐3‐ethyl‐5H,7H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐dione (29e). The title compound was prepared from 28e using General Method M. LC-MS m / z (M + H)+= 249.3.

[0437] 4,6‐dichloro‐1‐cyclopentyl‐3‐ethylpyrazolo[3,4‐d]pyrimidine (30e): The title compound was prepared from 29e following General Method N. LC-MS m / z (M + H)+= 286.1.

[0438] 6‐chloro‐1‐cyclopentyl‐3‐ethyl‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐ d]pyrimidin‐4‐amine (31e): The title compound was prepared from 30e following General Method I. LC-MS m / z (M + H)+= 374.8.

[0439] p-(1-cyclopenty nyl)methyl]amino}-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (32e; SLU-0011752). Using General Method J: 6-chloro-1- cyclopentyl-3-ethyl-N-(4-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 31e (190 mg, 0.51 mmol), Pd(PPh3)4(59 mg, 0.05 mmol), K2CO3(211 mg, 1.52 mmol.), 4- carboxyphenylboronic acid (101 mg, 0.61 mmol), DMF (4 mL) and H2O (2 mL), the product was isolated (49.32 mg 21% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 13.05 (s, 1H), 8.46 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.85 (t, J = 6.0 Hz, 2H), 7.51 (t, J = 8.4 Hz, 2H),7.16 (t, J = 8.4 Hz, 2H) 5.28 - 5.21 (m, 1H), 4.86 (d, J = 6.0 Hz, 2H), 3.07 - 3.01 (q, J= 7.6 Hz, 2H), 2.07 - 1.99 (m, 4H), 1.92 - 1.89 (m, 2H), 1.71 - 1.69 (m, 2H), 1.29 (t, J= 7.6 Hz, 3 H). LC-MS m / z (M + H)+= 460.

[0440] 5‐amino‐1‐cyclohexyl‐3‐ethylpyrazole‐4‐carbonitrile (27f): The title compound prepared using General Method K: 2-(1-ethoxypropylidene)malononitrile I (500 mg, 3.32 mmol), cyclohexylhydrazine hydrochloride (502 mg, 3.32 mmol), NEt3 (1.4 mL, 9.9 mmol). the product was isolated with 89% yield. LC-MS m / z (M + H)+= 219.3.

[0441] 5‐amino‐1‐cyclohexyl‐3‐ethylpyrazole‐4‐carboxamide (28f): The title compound prepared from 27f using General Method L. LC-MS m / z (M + H)+= 237.3.

[0442] 1‐cyclohexyl‐3‐ethyl‐5H,7H‐pyrazolo[3,4‐d]pyrimidine‐4,6‐dione (29f). The title compound was prepared from 28f using General Method M. LC-MS m / z (M + H)+= 263.2.

[0443] 4,6‐dichloro‐1‐cyclohexyl‐3‐ethylpyrazolo[3,4‐d]pyrimidine (30f):The title compound was prepared from 29f following General Method N. LC-MS m / z (M + H)+= 300.2.

[0444] 6‐chloro‐1‐cyclohexyl‐3‐ethyl‐N‐[(4‐fluorophenyl)methyl]pyrazolo[3,4‐ d]pyrimidin‐4‐amine (31f): The title compound was prepared from 30f following General Method I. LC-MS m / z (M + H)+= 389.9.

[0445] p-(1-cyclohexyl yl)methyl]amino}-1H-1,2,5,7- tetraazainden-6-yl)benzoic acid (32f; SLU-0011761). Us...

Claims

CLAIMS:

1. A compound having the following structure: ,R1is H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl, or a substituted or unsubstituted -CH2-aryl group; R2is H, a halogen, a cyano, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted -CH2-aryl group; R5is H, a cyano, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, 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; and R3is H or a substituted or unsubstituted alkyl group and R4is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted -CH2-aryl group, or a substituted or unsubstituted -CH2-heteroaryl group; or R3and R4are connected such that a ring is formed, with the proviso the compound does not have the following structure:H .

2. The compound according claim 1, wherein R5is chosen from: ,R6N , , oneor more R6group chosen from H, halogens, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, and an aldehyde, wherein R8is H, a substituted or substituted alkyl group, a substituted or unsubstituted CO-alkyl, a substituted or unsubstituted CONH-alkyl, a substituted or unsubstituted CON-dialkyl, a substituted or unsubstituted aryl group, or a substituted or unsubstituted -CH2-aryl, and there is one or more R8groups, wherein each R9, which is the same or different, is independently H, substituted or unsubstituted aliphatic groups, or substituted or unsubstituted aryl groups, and n is 0 to 4.

3. The compound according to claim 1, wherein R5is chosen from ,, , ,, achR9, which is the same or different, is independently H, substituted or unsubstituted aliphatic groups, or substituted or unsubstituted aryl groups.

4. The compound according to claim 3, wherein R5is chosen from ,h R9, which is the same or different, is independently be H, substituted or unsubstituted aliphatic groups, or substituted or unsubstituted aryl groups.

5. The compound according to claim 1, wherein R1is a substituted or unsubstituted alkyl group.

6. The compound according to claim 1, wherein R1is chosen from H, methyl, ethyl, isopropyl, propyl, cyclopropyl, t-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and trifluoromethyl.

7. The compound according to claim 1, wherein R1is methyl.

8. The compound according to claim 1, wherein R2is a substituted or unsubstituted alkyl group.

9. The compound according to claim 8, wherein R2is chosen from ethyl, isopropyl, propyl, cyclopropyl, phenyl, benzyl, cyano, bromo, and trifluoromethyl.

10. The compound according to claim 9, wherein R2is ethyl or propyl.

11. The compound according to claim 1, wherein R4is ,,12. The compound according to claim 1, wherein when R is H, then R is ,.

13. The compound according to claim 1, wherein the compound has the following structure: ,, is chosen from methyl, -Cl, -F, alkoxy group,-CF3, and -NMe2 and there is one or more R7groups.

14. The compound according to claim 13, wherein the compound has the following structure: Cl R2 HNR2 HN,15. The compound according to claim 13, wherein the compound has the following structure: HN HN N R7R7or16. The compound according to claim 15, wherein the compound has the following structure: Cl HN HN N O N or17. The compound according to claim 16, wherein R5is chosen from O F ,18. The compound according to claim 1, wherein the compound has the following structure: , ,, , , ,,,, ,,N F F F O H , O H ,Cl Cl O , O , O ,Cl Cl Cl O H ,F F HN HN HN N N O N H , ,Cl Cl HN HN HN N O ,,F H , , , ,, H , , ,, ,F , , ,, , ,F F H ,19. The compound according to claim 18, wherein the compound has the following structure: , ,,20. A compound according to claim 19, wherein the compound has the following structure: .

21. The compound according to claim 1, wherein the compound has the following structure: , substituted andunsubstituted 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 -CH2-aryl groups and there is one or more R8groups.

22. The compound according to claim 21, wherein the compound has the following structure: .

23. The compound according to claim 22, wherein R5is chosen from .

24. A compound according to claim 23, wherein the compound has the following structure: O N ,25. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.

26. The composition according to claim 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.

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 claim 1 or a composition comprising the compound according to claim 1.

28. A kit comprising one or more compounds according to claim 1 or a composition comprising the compound according to claim 1 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.

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