Purine covalent based CDK12 inhibitors

Abstract

Disclosed are purine derivatives of formulae (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods involving the inventive compounds or compositions for treating and / or preventing cell proliferative diseases including certain cancers of breast, brain, ovarian, lung, colorectal cancer, leukemias, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma and inflammatory and myotonic dystrophy type 1 diseases in a mammal. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of kinases, such as a cyclin-dependent kinases (CDK) (e.g., CDK12 / 13), and therefore, induce potent antiproliferative and apoptotic effects and / or inhibit transcription in the subject.

Description

[0001] PURINE COVALENT BASED CDK12 INHIBITORS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application 63 / 637,534, filed April 23, 2024, which is incorporated by reference herein in its entirety.

[0004] STATEMENT ACKNOWLEDGING GOVERNMENT SUPPORT

[0005] This invention was made with government support under grant no. CA262530 awarded by the National Institutes of Health and grant no. W81XWH-22- 1 -0026 awarded by the Department of Defense. The government has certain rights in the invention.

[0006] FIELD

[0007] This disclosure relates to a class of inhibitors of protein kinases, in particular members of the cyclin dependent kinases, useful in the treatment of proliferative cell diseases and conditions including cancers, inflammatory and myotonic dystrophy type 1 diseases.

[0008] BACKGROUND

[0009] There is a continuing need to identify and develop new chemical entities for treating proliferative diseases and conditions including cancers and myotonic dystrophy. Among the targets for potential anti-proliferative compounds under investigation are the group of enzymes known as protein kinases. Cyclin- dependent kinases (CDKs) are a family of protein serine / threonine kinases that are regulated and activated by post translational modification such as, phosphorylation and require interaction with noncatalytic regulatory subunits known as cyclins for their activities (Genome Biol 2014, 15 (6), 122). In mammalian cells, CDKs control transcription and other important cellular functions, including cell proliferation. So far, more than 20 CDKs and 30 cyclins have been reported. Although individual CDKs have multiple cellular roles, CDKs 1 - 7 have been best characterized in regulating cell cycle progression whereas, CDKs 7 - 20 have demonstrated roles in transcription and co-transcriptional processes (Development 2013, 140(15), 3079- 3093: Malumbres M (2014) cyclin dependent kinases. Genome Biol).

[0010] Dysregulation of cell cycle control and transcription are hallmarks of cancer. Genetic alterations including amplification, overexpression and mutation of CDKs or their cognate cyclins contribute to unscheduled proliferation as well as genomic and chromosomal instability; and aberrant activity of CDKs is a common feature of most cancer types. Therefore, CDKs constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer drugs (Cancers 2015, 7(1), 179-237; Nat Rev Cancer 2009, 9(3), 153-66). Indeed, three CDK inhibitors targeting the cell cycle regulatory CDKs, CDK4 and CDK6, are approved in hormone receptor-positive metastatic breast cancer, and several inhibitors targeting the transcriptional CDKs, CDK7, CDK8 / 19 and CDK9, are currently in clinical trials for the treatment of a wide variety of malignancies (Pharmacol Res 2020, 152, 104609; Transcription 2019, 10(2), 118-136).

[0011] Cyclin-dependent kinases 12 and 13 (CDK 12 / 13) belong to the group of transcriptional CDKs and in association with their cognate cyclin, cyclin K, promote transcription elongation through phosphorylation of Ser2 and Ser5 within the YSPTSPS heptad repeats of the carboxy-terminal domain (CTD) of RNA Polymerase II (Pol II) with higher activities when Ser7 is pre-phosphorylated (Cell Div 2012, 7, 12; Nat Commun 2014, 5, 3505). Moreover, unlike other transcriptional CDKs, both CDK12 and CDK13 possess N-terminal arginine-serine-rich domains characteristic of RNA binding and splicing factors and have been shown to directly interact with splicing factors and regulate splicing and 3'- end processing. In fact, loss of CDK12 / 13, or cyclin K, impedes both global Pol II processivity and pre-mRNA processing, suggesting redundancy of the two kinases as fundamental regulators of global Pol II processivity and transcription elongation (Mol Cell Biol 2015, 35(6), 928-38; Science Advances 2020, 6(18), eaaz5041).

[0012] Upon loss of CDK12 activity, defects in elongation due to premature cleavage and termination as a result of the activation of intronic polyadenylation (IP A) sites that are enriched in longer genes, including DDR genes were observed (Dubbury S.J et al (2018) Nature). Titus, the resulting DDR defect (or BRCA-like phenotype) in CDK 12 mutant tumors might present an opportunity for development of ‘synthetic-lethal’ therapeutic strategies. Indeed, ovarian and prostate cancers with functional mutations in CDK12 elicite a BRCAness phenotype with associated hypersensitivity to poly (adenosine diphosphateribose) polymerase (PARP) inhibitors and DNA cross-linking agents (J Biol Chem 2014, 289(13), 9247-9253; Nucleic Acids Res 2015, 43(5), 2575-2589; Cancer Res 2014, 74(1), 287-97; Cancer Cell 2018, 33(2), 202-216 e6).

[0013] In addition, tumors driven by the so called “undruggable” oncogenes controlled by super-enhancers such as MYC and EWS / FLI are highly dependent on transcription and DDR gene expression for their rapid replication. Thus, inhibiting the function of CDK12 as both a transcriptional coactivator and a regulator of DNA damage related proteins is synthetically lethal with MYC overexpression (in neuroblastoma) and EWS / FLI expression (in Ewing sarcoma) (Nature 2011, 474(7353), 609-615; Nat Med 2019, 25(10), 1526; Proc Natl Acad Sci USA 2012, 109(24), 9545-9550). Furthermore, in human epidermal growth factor receptor (HER) 2-positive breast, gastric and papillary thyroid cancer a strong correlation between CDK12 level and high tumor grade exists {BMC Cancer 2010, 10, 539; Theranostics 2020, 10(14), 6201-6215; J Cancer 2020, 11(15), 4308-4315). Studies also propose that CDK12-mediated cell cycle vulnerabilities in cancer exist and are amenable for CDK12 targeted therapy {Nat Commun 2018, 9(1), 1876; EMBO Rep 2019, 20(9), e47592). The role of CDK13 in transcription is less well understood, and CDK13 mutations have not been reported in cancer; except for its amplification in hepatocellular carcinoma (HCC), where CDK13 copy number was significantly associated with clinical onset of HCC {PLoS One 2012, 7 (8), e43223). Taken together, these pre-clinical studies propose that selective CDK12 and / or CDK13 inhibitors have potential use as single agents or in combination therapy in cancer. In addition, recent studies have expanded the suitability of targeting CDK12 to inflammatory {Science Signaling 2018, 11(541), eaam8216) and myotonic dystrophy type 1 diseases {Science Translational Medicine 2020,12(541), eaaz2415).

[0014] What are thus needed are new and selective CDK12 and / or 13 inhibitors and methods of making and using thereof. The compositions and methods disclosed herein address these and other needs.

[0015] SUMMARY

[0016] Disclosed herein, in one aspect, are compounds, compositions, and methods for making and using the disclosed compounds and compositions. In a more specific aspect, disclosed herein are a class of covalent compounds for use in the prevention and / or treatment of proliferative diseases and conditions including cancers and myotonic dystrophy. While not wishing to be bound by theory, it is considered that these compounds are capable of inhibiting cell proliferation by inhibiting the activity of CDK12 and / or CDK13.

[0017] In one aspect, disclosed herein are compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as disclosed herein. In other aspects, disclosed herein are compounds of Formula II

[0018] where R5, R4, R3, and R2are as disclosed herein. Methods of making these compounds as well as methods of using these compounds to treat cancers and myotonic dystrophy are also disclosed.

[0019] Additional advantages will be set forth in part in the following description and in part will be obvious from the description or may be learned by practicing the aspects described below. The advantages described below will be realized and attained by the elements and combinations pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0020] DETAILED DESCRIPTION

[0021] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known aspects. Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0022] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0023] As can be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred in any respect. This holds for any possible nonexpress basis for interpretation, including matters of logic with respect to the arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0024] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0025] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0026] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0027] Definitions

[0028] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.

[0029] As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0030] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood 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 can be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0031] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y’, and ‘about z’ as well as the ranges of Tess than x,’ less than y’, and Tess than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y’, and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’.”

[0032] 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 all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and subrange is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5% but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0033] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be 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, formulations, 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 and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless specifically stated otherwise.

[0034] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset of the disease or condition. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, singledose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons, or virtually any other reasons.

[0035] A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, changing the disclosed compound and / or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more doses daily for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0036] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance can or cannot occur and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0037] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to humans and constituents thereof.

[0038] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom, or condition thereof, such as a cancer. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a disorder in a subject, particularly a human, and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment," as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating" can include inhibiting the disease, disorder, or condition, e.g., impeding its progress, and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0039] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0040] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect or to decreasing the rate of advancement of a disease, disorder, condition, or side effect.

[0041] Chemical Definitions

[0042] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0043] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each is specifically described unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R-) or (.S'- ) configuration. The compounds provided herein may either be enantiomerically pure or diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R-) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5-) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0044] Compounds described herein may contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, all such possible isomers are contemplated, as well as mixtures of such isomers.

[0045] Compounds described herein may also present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated.

[0046] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=0)NH2 is attached through the carbon of the keto (C=O) group.

[0047] _ i

[0048] As used herein, the symbol “ ? ” (which hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For Xy _ | example, “ * ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound

[0049] ,3XY - 1 i

[0050] CH3-R , wherein R is H or “ ? ,” infers that when R is “XY,” the point of attachment bond is the same bond as the bond by which R3is depicted as being bonded to CH3.

[0051] The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or group are replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =0), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react, or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.

[0052] Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0053] The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person in the context in which said functional groups are recited.

[0054] “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain aspects, the alkyl is C1-C2, C1-C3, or Ci-Ce (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with length of each member of the range described as an independent species. For example, Ci- Cealkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and Ci- C4alkyl as used herein indicates an alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When Co- Cnalkyl is used herein in conjunction with another group, for example (CvCvcycloalkyl )Co- C4alkyl, or -Co-CTtCvCycycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms, as in -0-Co-C4alkyl(C3-C?cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. In one aspect, the alkyl group is optionally substituted as described herein.

[0055] “Cycloalkyl” is a saturated mono- or multi -cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one aspect, the cycloalkyl group is optionally substituted as described herein.

[0056] “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2-C4alkenyl and Cb-CAalkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one aspect, the alkenyl group is optionally substituted as described herein.

[0057] “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-Csalkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one aspect, the alkynyl group is optionally substituted as described herein.

[0058] “Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3 -pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3 -methylpentoxy. Similarly, an “alkylthio” or “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In one aspect, the alkoxy group is optionally substituted as described herein. “Alkanoyl” is an alkyl group as defined above covalently bound through a carbonyl (C=O) bridge. The carbonyl carbon is included in the number of carbons, for example C2alkanoyl is a CH ,(C=O)- group. In one aspect, the alkanoyl group is optionally substituted as described herein.

[0059] “Halo” or “halogen” indicates, independently, any of fluoro, chloro, bromo or iodo.

[0060] “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one aspect, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2-naphthyl. In one aspect, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one aspect, the aryl group is optionally substituted as described herein.

[0061] The term “heterocycle” refers to saturated and partially saturated heteroatomcontaining ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions. Examples of saturated heterocycle groups including saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]: and saturated 3- to 6- membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1 ,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1, 2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza- fluorenyl, 5,6,7-trihydro-l,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzofl, 4]dioxanyl, 2,3,- dihydro- lH-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include, but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0062] “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring that contains from 1 to 4, or in some aspects 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one aspect, the only heteroatom is nitrogen. In one aspect, the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms. In some aspects, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, such as groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group excess 1, these heteroatoms are not adjacent to one another. In one aspect, the total number of S and O atoms in the heteroaryl group is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl group is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0063] A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts that are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2- acetoxy benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)I-4-COOH, and the like, or using a different acid that produced the same counterion. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

[0064] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compound. Exemplary derivatives include but are not limited to, salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0065] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gaschromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Both traditional and modem methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers.

[0066] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Sigma- Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March’s Advanced Organic Chemistry, (John Wiley and Sons, 8thEdition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3rdedition, 2017).

[0067] Compositions

[0068] Disclosed herein are compounds of Formula I wherein

[0069] R1is phenyl, monocyclic heteroaryl, or bicyclic heteroaryl, each of which is substituted with an amide-containing group that optionally contains Ci-6 alkyl, C4-6 cycloalkyl, C4-6 cycloheteroalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-6 cycloheteroalkenyl, C2-6 alkynyl, phenyl, pyridinyl, benzyl, or styrenyl, any of which are optionally substituted with one or more halo, cyano, nitro, amino, alkylamino, CF3, SO2F, or aryl substituted with CF3 or SO2F; R2is morpholino or piperazinyl optionally substituted with one or more methyl; and

[0070] R3is pyrazol substituted with Ci-6 alkyl or Ci-6 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0071] Also disclosed herein are compounds of Formula II wherein

[0072] R5is H or methyl;

[0073] R4is C4-8 cycloalkyl, C4-8 cycloheteroalkyl, C4-8 cycloalkenyl, C4-8 cycloheteroalkenyl, C4-12 bicycloalkyl, C4-12 bicycloheteroalkyl, C4-12 bicycloalkenyl, C4-12 bicycloheteroalkenyl, C5-12 spiroalkyl, C5-12 spiroheteroalkyl, each of which is substituted with an amide-containing group or a carboxy containing group substituted with C1-6 alkyl, C4-6 cycloalkyl, C4-6 cycloheteroalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, or C4-6 cycloheteroalkenyl, any of which are optionally substituted with acrylamide; and each of which are optionally substituted with one or more halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, C(O)Ci-6 alkyl, C(O)C2-6 alkenyl, or CF3;

[0074] R2is morpholino or piperazinyl optionally substituted with one or more methyl; and R3is pyrazol substituted with Ci-6 alkyl or Ci-6 haloalkyl; or a pharmaceutically acceptable salt thereof.

[0075] In some examples of Formula I, R1is phenyl. In other examples of Formula I, R1is monocyclic heteroaryl. In some other examples of Formula I, R1is bicyclic heteroaryl.

[0076] In some examples of Formula I, the amide-containing group is pyrrol or pyrazol that is N-substituted with C(O)Ci-6 alkyl, C(O)C2-6 alkenyl, or C(O)C2-6 alkynyl. In some examples, R1is phenyl, thiazonyl, oxazonyl, pyridinyl, or benzoimidazolyl. In some examples, R1is benzoimadazolyl substituted with acrylamide or propionamide, acrylamide. In some examples of Formula II, R4is a C4-8 cycloalkyl. In other examples of Formula II, R4is C4-8 cycloheteroalkyl. In other examples of Formula II, R4is C4-8 cycloalkenyl. In other examples of Formula II, R4is C4-8 cycloheteroalkenyl. In other examples of Formula II, R4is C4-12 bicycloalkyl. In other examples of Formula II, R4is C4- 12 bicycloheteroalkyl. In other examples of Formula II, R4is C4-12 bicycloalkenyl. In other examples of Formula II, R4is C4-12 bicycloheteroalkenyl. In other examples of Formula II, R4is C5-12 spiroalkyl. In other examples of Formula II, R4is C5-12 spiroheteroalkyl.

[0077] In specific examples of Formula II, R5is H. In other specific examples of Formula II, R5is methyl. In some examples of Formula II, R4is substituted with acrylate or acrylamide.

[0078] In specific examples of Formula’s I and II, R2is morpholino. In other specific examples of Formula’s I and II, R2is piperazinyl. In other specific examples of Formula’s I and II, R2is piperazinyl substituted with one or more methyl groups.

[0079] In specific examples of Formula’s I and II, R3is pyrazol substituted with CHF2. Particular examples of compounds of Formula I are shown in Table 1 below.

[0080] Table 1. Chemical structure of selected compounds.

[0081]

[0082] Particular examples of compounds of Formula II are shown in Table 2 below.

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] The present disclosure also includes compounds with at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., enriched. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,nC,13C,15N,17O,18O,18F,31P32P,35S,36C1, and125I, respectively. In one aspect, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, for example,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F-labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0092] By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H), may optionally be used anywhere in described structures that achieve the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In one aspect, the isotopic substitution is replacing hydrogen with deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect).

[0093] Isotopic substitutions, for example, deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain aspects, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some aspects, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, enrichment, at any point, is above natural abundance and, in one aspect, is enough to alter a detectable property of the compounds as a drug in a human.

[0094] The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one aspect, the disclosure includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules. Nonlimiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, or de-DMSO. A solvate can be in a liquid or solid form.

[0095] A “prodrug,” as used herein, means a compound which, when administered to a host in vivo, is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described compounds herein. Prodrugs can be used to achieve any desired effect, including to enhance the properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo. Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others. In certain aspects, the prodrug renders the parent compound more lipophilic. In certain aspects, a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner. For example, nonlimiting aspects include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or another compound that has at least two functional groups that can link the parent compound with another prodrug moiety and is typically biodegradable in vivo. In some aspects, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound. Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a hydroxylated prodrug moiety to form a phosphate ester; a hydroxyl on the parent drug and a phosphonate on the prodrug to form a phosphonate ester; a hydroxyl on the parent drug and a phosphoric acid prodrug moiety to form a phosphate ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-S-(C2-24 alky l) to form a thioester; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an ether; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an thioether; and a carboxylic acid, oxime, hydrazide, hydrazine, amine or hydroxyl on the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including but not limited to polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyanhydride, polyester, polyamide, or a peptide. In some aspects, a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug. The amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid.

[0096] Pharmaceutical Compositions

[0097] The compounds as used in the methods described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administering. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. Administration of the active components of their compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art.

[0098] Compositions, as described herein, comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort, may be useful in a variety of medical and non-medical applications. For example, pharmaceutical compositions comprising an active compound and an excipient may be useful for the treatment or prevention of a cancer in a subject in need thereof.

[0099] "Pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion), and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well-known in the art for use in pharmaceutical formulations and as described further herein.

[0100] “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and / or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0101] Exemplary excipients include but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one of skill in this art, the excipients may be chosen based on what the composition is useful for. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and / or to animals, orally, rectally, parenterally, intracistemally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some aspects, the active compounds disclosed herein are administered topically.

[0102] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.

[0103] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.

[0104] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), polyvinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof.

[0105] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0106] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0107] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0108] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0109] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0110] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl. In certain aspects, the preservative is an anti-oxidant. In other aspects, the preservative is a chelating agent.

[0111] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and combinations thereof.

[0112] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.

[0113] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. Additionally, the composition may further comprise a polymer. Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), poly acrylic acid and its salts, polyacrylamide, poly aery lie acid / acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxidepropylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), poly anhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)- 1000], 1 ,2-Distearoyl-sn-glycero- 3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000], and 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000]), copolymers and salts thereof.

[0114] Additionally, the composition may further comprise an emulsifying agent. Exemplary emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), polyvinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. In certain aspects, the emulsifying agent is cholesterol.

[0115] Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition 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, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0116] Injectable compositions, such as injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain aspects, the particles are suspended in a carrier fluid comprising 1 % (w / v) sodium carboxymethyl cellulose and 0.1% (v / v) Tween 80. The injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0117] Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.

[0118] Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form 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 sugar as well as high molecular weight polyethylene glycols and the like.

[0119] Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required.

[0120] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0121] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0122] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the particles in a polymer matrix or gel.

[0123] The active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. The active ingredient may be administered by any route. In some aspects, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors, including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.

[0124] The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0125] Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art.

[0126] The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary and can be administered in one or more doses daily for one or several days.

[0127] Methods of Use

[0128] The present disclosure also provides methods for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. The methods can further comprise administering one or more additional therapeutic agents, such as anti-cancer agents or anti- inflammatory agents. Additionally, the method can further comprise administering a therapeutically effective amount of ionizing radiation to the subject.

[0129] Methods of killing a cancer or tumor cell are also provided comprising contacting the cancer or tumor cell with an effective amount of a compound or composition as described herein. In some aspects, the compounds induce degradation of CMG helicase. The methods can further include administering one or more additional therapeutic agents or administering an effective amount of ionizing radiation.

[0130] The disclosed methods can optionally include identifying a patient who is or can be in need of treatment of an oncological disorder. The patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animals having an oncological disorder. In some aspects, the subject can receive the therapeutic compositions prior to, during, or after surgical intervention to remove part or all of a tumor.

[0131] The term “neoplasia” or “cancer” is used throughout this disclosure to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant, hematogenous, ascitic and solid tumors. The cancers which may be treated by the compounds or compositions disclosed herein may comprise carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastomas.

[0132] Carcinomas which may be treated by the compounds or compositions of the present disclosure include, but are not limited to, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet-ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and carcinoma vilosum.

[0133] Representative sarcomas which may be treated by the compounds or compositions of the present disclosure include, but are not limited to, liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors (including Ewing's sarcoma of bone, extraskeletal or non-bone) and primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST) and osteosarcoma (also known as osteogenic sarcoma) skeletal and extra-skeletal, and chondrosarcoma.

[0134] The compounds or compositions of the present disclosure may be used in the treatment of a lymphoma. Lymphomas which may be treated include mature B cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, precursor lymphoid neoplasms, Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders. Representative mature B cell neoplasms include, but are not limited to, B-cell chronic lymphocytic leukemia / small cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenstrom macroglobulinemia), splenic marginal zone lymphoma, hairy cell leukemia, plasma cell neoplasms (such as plasma cell myeloma / multiple myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, and heavy chain diseases), extranodal marginal zone B cell lymphoma (MALT lymphoma), nodal marginal zone B cell lymphoma, follicular lymphoma, primary cutaneous follicular center lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, Epstein- Barr virus-positive DLBCL of the elderly, lyphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman’s disease, and Burkitt lymphoma / leukemia. Representative mature T cell and NK cell neoplasms include, but are not limited to, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, lycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders (such as primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma. Representative precursor lymphoid neoplasms include B-lymphoblastic leukemia / lymphoma not otherwise specified, B-lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities, or T-lymphoblastic leukemia / lymphoma. Representative Hodgkin lymphomas include classical Hodgkin lymphomas, mixed cellularity Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma.

[0135] The compounds or compositions of the present disclosure may be used in the treatment of a Leukemia. Representative examples of leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia, adult T-cell leukemia, clonal eosinophilias, and transient myeloproliferative disease.

[0136] The compounds or compositions of the present disclosure may be used in the treatment of a germ cell tumor, for example germinomatous (such as germinoma, dysgerminoma, and seminoma), non germinomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma) and mixed tumors.

[0137] The compounds compositions of the present disclosure may be used in the treatment of blastomas, for example hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme.

[0138] Representative cancers which may be treated include, but are not limited to: bone and muscle sarcomas such as chondrosarcoma, Ewing’s sarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, osteosarcoma, rhabdomyosarcoma, and heart cancer; brain and nervous system cancers such as astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, medulloblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, and visual pathway and hypothalamic glioma; breast cancers including invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, male breast cancer, Phyllodes tumor, and inflammatory breast cancer; endocrine system cancers such as adrenocortical carcinoma, islet cell carcinoma, multiple endocrine neoplasia syndrome, parathyroid cancer, phemochromocytoma, thyroid cancer, and Merkel cell carcinoma; eye cancers including uveal melanoma and retinoblastoma; gastrointestinal cancers such as anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumors, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular cancer, pancreatic cancer, and rectal cancer; genitourinary and gynecologic cancers such as bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, prostate cancer, testicular cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor; head and neck cancers such as esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, and hypopharyngeal cancer; hematopoietic cancers such as acute biphenotypic leukemia, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid dendritic cell leukemia, AIDS -related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, intravascular large B-cell lymphoma, large granular lymphocytic leukemia, lymphop] asmacy tic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, Mast cell leukemia, mediastinal large B cell lymphoma, multiple myeloma / plasma cell neoplasm, myelodysplastic syndroms, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone B cell lymphoma, non-Hodgkin lymphoma, precursor B lymphoblastic leukemia, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sezary syndrome, splenic marginal zone lymphoma, and T-cell prolymphocytic leukemia; skin cancers such as basal cell carcinoma, squamous cell carcinoma, skin adnexal tumors (such as sebaceous carcinoma), melanoma, Merkel cell carcinoma, sarcomas of primary cutaneous origin (such as dermatofibrosarcoma protuberans), and lymphomas of primary cutaneous origin (such as mycosis fungoides); thoracic and respiratory cancers such as bronchial adenomas / carcinoids, small cell lung cancer, mesothelioma, non-small cell lung cancer, pleuropulmonary blastoma, laryngeal cancer, and thymoma or thymic carcinoma;

[0139] HIV / AIDs-related cancers such as Kaposi sarcoma; epithelioid hemangioendothelioma; desmoplastic small round cell tumor; and liposarcoma.

[0140] Compounds and compositions disclosed herein can be locally administered at one or more anatomical sites, such as sites of unwanted cell growth (such as a tumor site or benign skin growth, e.g., injected or topically applied to the tumor or skin growth), optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. Compounds and compositions disclosed herein can also be systemically administered, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent, or an assimilable edible carrier for oral delivery. In addition, the active compound can be incorporated into sustained release preparations and / or devices.

[0141] For the treatment of oncological disorder, compounds, agents, and compositions disclosed herein can be administered to a patient in need of treatment prior to, subsequent to, or in combination with other antitumor or anticancer agents or substances (e.g., chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cytotoxic agents, etc.) and / or with radiation therapy and / or with surgical treatment to remove a tumor. For example, compounds, agents, and compositions disclosed herein can be used in methods of treating cancer wherein the patient is to be treated or is or has been treated with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosphamide or ifosfamide, antimetabolites such as 5 -fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, antiestrogens such as tamoxifen, and / or other anti-cancer drugs or antibodies, such as, for example, imatinid or trastuzumab. These other substances or radiation treatments can be given at the same time as or at different times from the compounds disclosed herein. Examples of other suitable chemotherapeutic agents include, but are not limited to, altretamine, bleomycin, bortezomib, busulphan, calcium folinate, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, liposomal doxorubicin, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pentostatin, procarbazine, raltitrexed, streptozocin, tegafur-uraxil, temozolomide, thiotepa, tioguanine / thioguanine, topotexan, treosulfan, vinblastine, vincristine, vindesine, and vinorelbine. Examples of suitable immunotherapeutic agents include, but are not limited to, alemtuzumab, cetuximab, gemtuzumab, iodine 131 tositumomab, rituximab, and trastuzumab. Cytotoxic agents include, for example, radioactive isotopes and toxins of bacterial, fungal, plant, or animal origin. Also disclosed are methods of treating an oncological disorder comprising administering an effective amount of a compound described herein prior to, subsequent to, and / or in combination with administration of a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, or radiotherapy.

[0142] In another aspect, methods are provided for the treatment of medical disorders associated with a helicase, for example an SF3 and / or SF6 helicase, by administering a compound of Formula I, or pharmaceutically acceptable salts thereof. In particular aspects, the compounds described herein may be used in the treatment of cancer, either alone or in combination with one or more additional therapeutic agents, for example a chemotherapeutic agent. In some aspects, the helicase comprises CMG helicase. In other aspects, the helicase comprises HPV El helicase.

[0143] Thus in one aspect, a method is provided for treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition as further described herein. In some aspects, the subject is a human. In some aspects, the cancer is associated with dysregulation of a helicase, for example an SF3 and / or SF6 helicase. In some aspects, the cancer is associated with CMG helicase. In some aspects, the cancer is associated with HPV El helicase.

[0144] In another aspect, a method is provided for treating cancers associated with elevated expression levels of Myc and / or elevated expression levels of Cyclin E. Elevated levels of Myc and Cyclin E have been associated overactivation of CMG helicases, leading to diminished reserve MCMs available to allow the cancer cell to successfully complete the S- phase of the cell cycle. Upon exposure of the cancer cell to a CMG helicase inhibitor such as those described herein, the cancer cell faces diminished survival and potentially cell death.

[0145] Thus, in one aspect, a method is provided for treating a cancer in a subject in need thereof, the method comprising:

[0146] (a) determining whether the cancer is characterized by elevated Myc expression and / or elevated Cyclin E expression; and

[0147] (b) if the cancer is determined to be characterized by elevated Myc expression and / or elevated Cyclin E expression in (a), administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more additional therapeutic agents (such as a chemotherapeutic or cytotoxic agent).

[0148] In another aspect, a method of treating a cancer associated with elevated Myc expression and / or elevated Cyclin E expression is provided comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in combination with one or more additional therapeutic agents (such as a chemotherapeutic or cytotoxic agent).

[0149] In yet another aspect, a method is provided for promoting degradation of CMG helicase in a eukaryotic cell comprising contacting the cell with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein. In some aspects, the eukaryotic cell is a human cell.

[0150] In yet another aspect, a method for treating cancer in a subject in need thereof is provided, the method comprising:

[0151] (a) determining whether the cancer is associated with one or more signs of replicative stress; and

[0152] (b) if the cancer is determined to be associated with one or more signs of replicative stress, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0153] In another aspect, a method is provided for treating cancer in a subject in need thereof, wherein the cancer has been previously determined to be associated with one or more signs of replicative stress, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0154] In some aspects, the one or more signs of replicative stress may comprise Myc overexpression, CyclinE overexpression, Rb loss, p53 loss, PolQ overexpression, or combinations thereof. In some aspects, the one or more signs or replicative stress comprises Myc overexpression. In some aspects, the one or more signs or replicative stress comprises CyclinE overexpression. In some aspects, the one or more signs or replicative stress comprises Rb loss. In some aspects, the one or more signs or replicative stress comprises p53 loss. In some aspects, the one or more signs or replicative stress comprises PolQ overexpression.

[0155] In yet another aspect, a method for treating cancer in a subject in need thereof is provided, the method comprising:

[0156] (a) determining whether the cancer harbors one or more inherited or acquired germline mutations; and

[0157] (b) if the cancer is determined to harbor one or more inherited or acquired germ-line mutations in (a), administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0158] In another aspect, a method for treating cancer in a subject in need thereof is provided, wherein the cancer has been previously determined to harbor one or more inherited or acquired germ- line mutations, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some aspects, the one or more inherited or acquired germ-line mutations may comprise loss of: p53, Rb, BRCA1, BRCA2, ATM, a xeroderma pigmentosum gene (such as XPA, XPB, XPC, XPD, XPE, XPF, or XPG), a mismatch repair gene (such as MSH2, MLH1, MSH6, PMS2), WRN, BLM, a Fanconi anemia gene (such as FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCE, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCT, FANCU, FANCV, or FANCW), NBS, Chek2, RecqE4, MYH, PALB2, BACH1, RAC51C, or combinations thereof.

[0159] In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of p53. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of Rb. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BRCA1. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BRCA2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of ATM. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPA. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPB. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPC. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPD. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPE. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPF. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of XPG. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MSH2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MEH1. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of MSH6. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of PMS2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of WRN. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BEM. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCA. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCB. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCC. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCD2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCE. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCF. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCG. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCI. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCJ. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCL. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCM. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCN. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCO. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCP. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCQ. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCT. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCU. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCV. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of FANCW. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of NBS. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of Chek2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of RecqL4. In some aspects, the one or more inherited or acquired germ- line mutations comprise loss of MYH. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of PALB2. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of BACH1. In some aspects, the one or more inherited or acquired germ-line mutations comprise loss of RAC51C.

[0160] In another aspect, a method is provided for treating an infection resulting from a papillomavirus in a subject in need thereof comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0161] In some aspects, the papillomavirus is human papillomavirus (HPV). In some aspects, the HPV is an HPV strain selected from a strain including, but not limited to, HPV1, HPV2, HPV3, HPV4, HPV6, HPV7, HPV10, HPV11, HPV13, HPV16, HPV18, HPV22, HPV26, HPV28, HPV31, HPV32, HPV33, HPV35, HPV39, HPV42, HPV44, HPV45, HPV51, HPV52, HPV53, HPV56, HPV58, HPV59, HPV60, HPV63, HPV66, HPV68, HPV73, HPV82, or any other HPV strain which is known to result in an infection associated with a medical disorder. In another aspect, a method is provided for treating a medical disorder associated with infection with human papillomavirus comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some aspects, the medical disorder associated infection with human papillomavirus is cancer. Representative examples of medical disorders resulting from infection with HPV include, but are not limited to, common warts (associated with HPV2, HPV7, and HPV22, for example), plantar warts (associated with HPV1 , HPV2, HPV4, and HPV63, for example), flat warts (associated with HPV3, HPV10, and HPV28, for example), anogenital warts (associated with HPV6, HPV11, HPV42, and HPV42, for example), genital cancers (associated with HPV16, HPV18, HPV26 HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV53, HPV56, HPV58, HPV59, HPV66, HPV72, and HPV82, for example), epidermodysplasia verruciformis, focal epithelial hyperplasia (associated with HPV13 and HPV32, for example), mouth papillomas (associated with HPV6, HPV7, HPV11, HPV16, and HPV32, for example), oropharyngeal cancer (associated with HPV16, for example), verrucous cyst (associated with HPV60, for example), and laryngeal papillomatosis (associated with HPV6 and HPV11, for example).

[0162] In some aspects, the one or more additional therapeutic agents may comprise a Chkl inhibitor, an ATR inhibitor, a Cdc7 inhibitor, or a Parp inhibitor.

[0163] In another aspect, a method for treating cancer in a subject in need thereof is provided, the method comprising:

[0164] (a) administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and

[0165] (b) administering one or more additional therapeutic agents selected from a Chkl inhibitor, an ATR inhibitor, a Cdc7 inhibitor, and a Parp inhibitor.

[0166] Representative Chkl inhibitors which may be used in the above methods include, but are not limited to, AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, prexasertib (LY2606368), GDC-0575, SAR-020106, CCT245737, and PD 166285.

[0167] Representative ATR inhibitors which may be used in the above methods include, but are not limited to, VE-821, Berzosertib (VE-822), elimusertib (BAY-1895344), ETP-46464, CGK 733, AZ20, AZ31, ceralasertib (AZD6738), and VX-803 (M4344).

[0168] Representative examples of Cdc7 inhibitors which may be used in the above methods include, but are not limited to, XL-413, PHA-767491 (CAY10572), and LY3143921. Representative examples of Parp inhibitors which may be used in the above methods include, but are not limited to, Olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib (BGB-290), CEP 9722, E7016, 3-aminobenzamide,fluzoparib, AG-14361, A- 966492, PJ34, UPF 1069, AZD2461, ME0328, BYK204165, BGP-15, RBN-2397, NU1025, E7449, 4-hydroxyquinazoline, NMS-P118, RBN012759, and picolinamide.

[0169] EXAMPLES

[0170] The following examples are set forth below to illustrate the compounds, compositions, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art.

[0171] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0172] The present invention further provides a method of synthesizing compounds according to the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0173] With regard to the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare starting materials, it will be understood by those skilled in the art that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be readily selected. Moreover, it will be understood by those skilled in the art. that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. An example of a particularly suitable method for synthesizing a compound of the present invention is shown as schemes below. Scheme 1

[0174] General. All reagents were purchased from commercial suppliers and were used without further purification. Dichloromethane, ethanol, 1,4-dioxane, diethyl ether, N,N- dimethylformamide, acetic acid, 2-propanol, methanol and ethyl acetate were dried by being passed through a column of desiccant (activated A-l alumina). NajCOs, Triflic anhydride, mesitylene, m-CPBA, tin (II) chloride, NBS, HATU, (BocUO, Pd(PPhs)4, and all the acids were purchased from Sigma- Aldrich and used as such. Reactions were either monitored by thin-layer chromatography or analytical LC- MS. Thin-layer chromatography was performed on Kieselgel 60 F254 glass plates pre-coated with a 0.25 mm thickness of silica gel. TLC plates were visualized with UV light and / or by staining with ninhydrin solution. Normal phase column chromatography was performed on a Biotage Selekt automated flash system. Compounds were loaded onto pre-filled cartridges filled with KP-Sil 50 pm irregular silica. For microwave reactions, a Biotage Initiator Microwave system was used. Final products were isolated by reverse-phase HPLC using Waters HPLC system with UV detector, with Atlantis T3 OBD Prep Column, 100 A, 5 pm, 19 mm X 150 mm. Compounds were eluted using a gradient elution of 90 / 10 to 0 / 100 A / B over 20 min at a flow rate of 20.0 mL / min, where solvent A was water (+0.1 % formic acid), and solvent B was acetonitrile.

[0175] The structures of all compounds were verified via]H NMR,19F NMR and LCMS. The purity of isolated products was determined using an LC-MS instrument (Agilent 1290 Infinity series LC with single quadrupole MSD system, AP-ESI Ion Source) equipped with Kinetex™ 1.7 pm C18 100 A, LC Column 50 x 2.1 mm, Ea (Phenomenex) column. Elution was performed using the following conditions: 2% (v / v) acetonitrile (+0.1% FA) in 98% (v / v) H2O (+0.1% FA), ramped to 98% acetonitrile over 4.0 min, and holding at 98% acetonitrile for 0.5 min with a flow rate of 0.6 mL / min; UV absorption was detected from 200 to 950 nm using a diode array detector. The purity of each compound was >95% based on this analysis.

[0176] NMR spectra were recorded at ambient temperature on a 500 MHz Bruker NMR spectrometer in DMSO-de. All1H NMR data are reported in parts per million (ppm) downfield of TMS and were measured relative to the signals for dimethyl sulfoxide (2.50 ppm).19F NMR experiments were performed with1H decoupling. Data for1H NMR are reported as follows: chemical shift (5, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling constant (Hz). NMR data was analyzed and processed by using MestReNova software.

[0177] Synthesis of mesityl(l-methyl-lH-pyrazol-4-yl)-k^-iodaneyl trifluoromethanesulfonate (2).

[0178] To a solution of 4-iodo-l -methyl- 1 H-pyrazole (10.0 g, 48.1 mmol) in DCM (192 ml) was added triflic acid (17.08 ml, 192 mmol) and the resulting mixture was stirred at room temperature for 5 min. m-CPBA (12.44 g, 72.1 mmol) followed by mesitylene (6.36 g, 52.9 mmol) was then added (in this order). The reaction vessel was sealed and submitted to a 60 °C in oil bath with stirring for 1 h. The reaction mixture was then allowed to reach to room temperature after which it was concentrated in vacuo followed by precipitation by addition of Et2O (100 mL). The mixture was stirred at 0 °C for additional 30 min. The solid was collected by filtration and washed with Et2O.

[0179] ]H NMR (500 MHz, DMSO-d6) 5 9.78 (s, 1H), 8.55 (s, 1H), 8.06 (S, 1 H), 7.16 (S, 2H), 3.89 (s, 3H), 2.64 (s, 6H), 2.26 (s, 3H).13C NMR (101 MHz, DMSO-d6) 5 143.02, 142.90, 140.86, 137.02, 129.59, 124.58, 120.80 (q, J= 322.3 Hz), 79.06, 39.43, 26.43, 20.56. LCMS (m / z): 327.3 (M+H)+, 7?t: 2.577 min.

[0180] Synthesis of 2,6-dichloro-9-(l-methyl-lH-pyrazol-4-yl)-9H-purine (3).

[0181] 2,6-dichloro-9H-purine (9.16 g, 48.5 mmol), copper(l)bromide (1.390 g, 9.69 mmol) and mesityl) I -methyl- 1 H-pyrazol-4-yl)- / Aiodaney I trifluoromethanesulfonate (30 g, 63.0 mmol) in dichloromethane (194 ml) were mixed in 500 ml round bottom flask (previously backfilled with argon). Then TEA (10.13 ml, 72.7 mmol) was added dropwise. The resulting mixture was heated 60 °C for 4 h and monitored by LCMS. Upon consumption of all salt, the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc).

[0182] ’H NMR (500 MHz, DMSO-d6) 5 9.00 (S, 1 H), 8.36 (d, J= 0.8 Hz, 1H), 7.97 (d, J = 0.8 Hz, 1H), 3.96 (s, 3H).13C NMR (101 MHz, DMSO-Cf6) 5 152.54, 151.60, 150.02, 147.17, 132.54, 130.58, 125.27, 116.15, 39.31. LCMS (m / z): 269.3 (M+H)+, Rt: 2.531 min.

[0183] Synthesis of 2-chloro-9-(l-methyl-lH-pyrazol-4-yl)-2V-((5-nitro-lH- benzo[r / ]imidazol-2-yl)methyl)-9 / / -purin-6-amine (4).

[0184] 2,6-dichloro-9-(l-methyl-lH-pyrazol-4-yl)-9H-purine (6 g, 22.30 mmol), (5-nitro- lH-benzo[<7]imidazol-2-yl)methanamine, 2HC1 (6.77 g, 23.41 mmol) were charged into 250 round bottom flasks followed by addition of 2-propanol (89 ml) at room temperature. Then DIPEA (19.47 ml, 111 mmol) was added to the suspension and vial was heated in conventional oil bath at 90 °C for 1 h. The reaction mixture was allowed to reach room temperature, then precipitate was filtered and washed with EtzO to afford the pure product as a pale-yellow solid.]H NMR (500 MHz, DMSO-d6) 5 8.31 (s, 1H), 8.21 (s, 2H), 7.99 (S, 1 H), 7.71 (s, 2H), 4.82 (s, 2H), 3.91 (s, 3H). LCMS (m / z): 425.0 (M+H)+, Rt: 2.263 min.

[0185] Synthesis of 9-(l-methyl-l / / -pyrazol-4-yl)-2-morphoIino-iV-((5-nitro-l / / - benzo[<Z]imidazol-2-yl)methyl)-9H-purin-6-amine (5).

[0186] 2-chloro-9-(l-methyl-177-pyrazol-4-yl)7V-((5-nitro-lH-benzo[<f|imidazol-2- yl)methyl)-9 / 7-purin-6-amine (8 g, 17.83 mmol) was added to 250 ml round bottom flask followed by addition of morpholine (40 ml, 178 mmol). Mixture was stirred at 130 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (DCM:MeOH, 10: 1, gradient). Pure fractions containing product were combined, and organic phase was washed 2 times with NH4CI (to remove residual morpholine), and finally once with brine. The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure to yield compound 5 as a pale-yellow solid (74%).

[0187] ]H NMR (500 MHz, DMSO-d6) 6 8.31 (s, 1H), 8.21 (s, 2H), 7.99 (S, 2 H), 7.71 (s, 2H), 4.82 (s, 2H), 3.91 (s, 3H), 3.58 - 3.45 (m, 8H). LCMS (w / z): 476.1 (M+H)+, Rt: 2.231 min.

[0188] Synthesis of 2V-((5-amino-lH-benzo[d]imidazol-2-yl)methyl)-9-(l-methyl-lH- pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (6).

[0189]

[0190] To a solution of 9-(l-meihy1-iH-pyTdzol-4-yl)-2-morpho1ino-.¥-((5-niLro-lH- beozo[« / ]imidazoL2-yl)methyl)-97 / -purin-6-amine (4.0 g, 8.41 mmol) in ethyl acetate and methanol (80 mL, 1: 1) were added tin(Il) chloride dihydrate (5.69 g. 25.24 mmol) and cone HC1 (3 drops). After stirring for 1 h al 80 °C, the reaction mixture was diluted with dichloromethane and methanol (4:1), neutralized with saturated NaHCOj, and filtered. 'The filtrate was extracted with dichloromethane and methanol (4: 1), concentrated under reduced pressure and crude was triturated with diethyl ether and concentrated in vacuo to obtain the product as a pale brown solid. (80%). ]H NMR (500 MHz, DMSO-d6) 8 8.31 (s, 1H), 8.21 (s, 2H), 7.99 (S, 2 H), 7.71 (s,

[0191] 2H), 4.82 (s, 2H), 3.91 (s, 3H), 3.58 - 3.45 (m, 8H). LCMS (m / z): 446.2 (M+H)+, Rt: 1.645 min.

[0192] General procedure for step 6 (7a-7b). To a solution of A'-((5-amino- l / / --benzo(<f]imidazol--2--yl)methyi)-9--(l -methyl- ILL pyrazol-4-yl)-2-morpholino-97 / -purin-6-amine (50 mg. 1 eq) in ACN (5 mL) was added DIPEA (1.3 eq). The reaction mixture was cooled to 0 °C, then acryloyl chloride (1.2 eq) in DMF(1 mL.) and THE (1 mL) was added in dropwise, then sti rred at same temp for 30 min. After completion, the reaction mixture was diluted with 20% MeOH in DCM, washed with 10% NaHCO? and concentrated in vacuo. The crude was purified by PREP HPLC purification to afford the pure product as a white solid.

[0193] General procedure for step 6 (7c-7i).

[0194] To a solution of Af-((5-amino-lf / -benzo[d]imidazol-2-yl)methyl)-9-(l -methyl- IH- pyTazol-4-yl)-2-niorpholino-9? / -purin-6-amine (50 mg, 1 eq) in DMF (2 ml.) was carboxylic acids ( 1.3 eq) followed by the addition of DIPEA (1 .5 eq) and HATH (1.5 eq). The reaction mixture was, then stirred at room temperature for 3 h. After completion, the reaction mixture was diluted with 20% MeOH in DCM, washed with waiter, and concentrated in vacuo. The crude was purified by PREP HPLC purification to afford die pure product as a white solid.

[0195] Synthesis of M-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-lH-benzo[d]imidazol-5-yl)propionamide (7a)

[0196] Synthesized accordingly procedure, described in (7a-7b).

[0197] Yield (20.0 mg, 29.61%), Off-white solid.]H NMR (500 MHz, DMSO) 5 12.00 (s, 1H), 9.76 (d, J = 35.2 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.51 (s, 4H), 2.30 (q, J = 7.5 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H). LCMS (m / z): 502.2 (M+H)+, Rt: 1.742 min.

[0198] Synthesis of A-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-lW-benzo[d]imidazol-5-yl (acrylamide (7b)

[0199]

[0200] Synthesized accordingly procedure, described in (7a-7b).

[0201] Yield (19.0 mg, 28.54%), Off-white solid.]H NMR (500 MHz, DMSO) 5 12.07 (s, 1H), 10.07 ( d, 7 = 31.1 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.44 (d, 7 = 8.7 Hz, 1H), 7.34 (s, 1H), 6.45 (dd, 7 = 17.0, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.1

[0202] Hz, 1H), 5.72 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.80 (s, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.51 (s, 4H). LCMS (w / z): 500.2 (M+H)+, Rt: 1.789 min.

[0203] Synthesis of (£)-4-(dimethylamino)-Ar-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyI)-lH-benzo[d]imidazol-5-yl)but-2-enamide (7c)

[0204] Synthesized accordingly procedure, described in (7c-7i).

[0205] Yield (8.0 mg, 12.81%), Off-white solid.!H NMR (500 MHz, DMSO) 5 12.05 (s, 1H), 10.01 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.40 (s, 1H), 6.72 - 6.67 (m, 1H), 6.29 (dt, 7 = 15.4, 1.7 Hz, 1H), 4.80 (s, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.51 (s, 4H), 3.12 (d, 7 = 6.0 Hz, 2H), 2.22 (s, 6H). LCMS (m / z): 555.3 (M+H)’, Rt: 1.648 min.

[0206] Synthesis of 2-fluoro-Ar-(2-(((9-(l -methyl-l / / -pyrazol-4-yl)-2-morphoIino-9H- purin-6-yl)amino)methyI)-lH-benzo[d]imidazol-5-yl)acrylamide (7d)

[0207] Synthesized accordingly procedure, described in (7c-7i).

[0208] Yield (8.0 mg, 13.77%), Off-white solid. ’H NMR (500 MHz, DMSO) 6 12.13 (s, 1H), 10.23 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.15 - 8.08 (m, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 5.69 (dd, 7 = 47.8, 3.6 Hz, 1H), 5.39 (dd, 7 = 15.7, 3.5 Hz, 1H), 4.85 - 4.75 (m, 2H), 3.91 (s, 3H), 3.56 (s, 4H), 3.53 - 3.47 (m, 4H). LCMS (m / z): 518.2 (M+H)+, 7?t: 1.920 min.

[0209] Synthesis of N-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-lH-benzo[d]imidazol-5-yl)but-2-ynamide (7e)

[0210] Synthesized accordingly procedure, described in (7c-7i). Yield (10.0 mg, 17.42%), Pale-yellow solid.:H NMR (500 MHz, DMSO) 5 12.05 (d, J = 18.1 Hz, 1H), 10.51 (d, 7 = 40.1 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.43 - 7.30 (m, 2H), 4.84 - 4.74 (m, 2H), 3.91 (s, 3H), 3.56 (s, 4H), 3.53 - 3.46 (m, 4H), 2.03 (s, 3H). LCMS (m / z): 512.2 (M+l), Rt: 1.900 min.

[0211] Synthesis of N-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-LH-benzo[d]imidazol-5-yl)but-2-ynamide (7f)

[0212] Synthesized accordingly procedure, described in (7c-7i).

[0213] Yield (10.0 mg, 16.51%), Pale-yellow solid.:H NMR (500 MHz, DMSO) 5 12.21 (s, 1H), 9.56 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.67 (p, J = 2.3 Hz, 1H), 4.81 (s, 2H), 3.91 (s, 3H), 3.56 (s, 4H), 3.51 (s, 4H), 2.58 (ddt, J= 10.0, 4.5, 2.3 Hz, 2H), 1.93 - 1.88 (m, 2H). LCMS (m / z): 540.2 (M+H)+, Rt: 3.678 min.

[0214] Synthesis of (E)-N-(2-(((9-(l-methyl-lH-pyrazol-4-yI)-2-morpholino-9H-purin- 6-yl)amino)methyl)-lH-benzo[zZ]imidazol-5-yl)-3-(4- (trifluoromethyl)phenyl)acrylamide (7g)

[0215]

[0216] Synthesized accordingly procedure, described in (7c-7i).

[0217] Yield (8.0 mg, 13.92%), Pale-yellow solid. H NMR (500 MHz, DMSO) 5 12.12 - 12.05 (m, 1H), 10.29 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.13 - 8.10 (m, 1H), 7.99 (s, 1H), 7.82 (q, J = 8.4 Hz, 4H), 7.64 (d, J = 15.7 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.24 (s, 1H),

[0218] 6.98 (d, 7 = 15.7 Hz, 1H), 4.85 - 4.77 (m, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.51 (s, 4H). LCMS (m / z): 644.2 (M+H)+, Rt: 4.470 min.

[0219] Synthesis of 4-((2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-lH-benzo[d]imidazol-5-yl)carbamoyl)benzenesulfonyl fluoride (7h)

[0220] Synthesized accordingly procedure, described in (7c-7i).

[0221] Yield (10.0 mg, 14.11%), Pale-yellow solid.:H NMR (500 MHz, DMSO) 5 12.25 (s, 1H), 10.58 (s, 1H), 8.32 (s, 1H), 8.30 (d, 7 = 2.2 Hz, 3H), 8.21 (s, 1H), 8.17 - 8.11 (m, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.49 - 7.42 (m, 2H), 4.83 (s, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.51 (s, 4H). LCMS (m / z): 632.2 (M+H)+, Rt: 4.070 min.

[0222] Synthesis of 3-((2-(((9-(l -methyl-lH-pyrazol-4-yl)-2-morpholino-9 / / -purin-6- yl)amino)methyl)-lH-benzo[d]imidazol-5-yl)carbamoyl)benzenesulfonyl fluoride (7i)

[0223] Synthesized accordingly procedure, described in (7c-7i).

[0224] Yield (9.0 mg, 12.0%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 12.27 (s, 1H), 10.59 (s, 1H), 8.66 (t, 7 = 1.9 Hz, 1H), 8.53 - 8.50 (m, 1H), 8.35 (dt, 7 = 8.0, 1.5 Hz, 1H), 8.31 (s, 1H), 8.21 (d, 7 = 2.4 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.96 (t, 7 = 7.9 Hz, 1H), 7.48 - 7.42 (m, 2H), 4.83 (s, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.54 - 3.49 (m, 4H).

[0225] LCMS (m / z): 632.2 (M+H)+, Rt: 4.032 min.

[0226] Scheme 2

[0227] Synthesis of ( l-(difluoromethyl)-lH-pyrazol-4-yl)(mesityl)-X^-iodaneyl trifluoromethanesulfonate (9).

[0228] To a solution of 4-iodo-(l -difluoro methyl)-l H-pyrazole (10.0 g, 40.99 mmol) in DCM (150 ml) was added triflic acid (14.47 ml, 163.95 mmol) and the resulting mixture was stirred at room temperature for 5 min. m-CPBA (7.43 g, 43.04 mmol) followed by mesitylene (6.27 mL, 45.09 mmol) was then added (in this order). The reaction vessel was sealed and submitted to a 60 °C in oil bath with stirring for 1 h. The reaction mixture was then allowed to reach to room temperature after which it was concentrated in vacuo followed by precipitation by addition of Et2O (100 mL). The mixture was stirred at 0 °C for additional 30 min. The solid was collected by filtration and washed with EtzO.

[0229] Yield (15.0 g, 55.26%), Off-white solid.]H NMR (500 MHz, DMSO) 5 9.16 (s, 1H), 8.40 (s, 1H), 7.82 (d, J = 58.5 Hz, 1H), 7.19 (d, J = 18.1 Hz, 2H), 2.65 (d, J = 3.9 Hz,

[0230] 6H), 2.28 (d, J = 8.0 Hz, 3H). LCMS (m / z): 363.0 (M+H)+, Rt: 1.824 min.

[0231] Synthesis of 2,6-dichloro-9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-9H-purine (10).

[0232]

[0233] 2,6-dichloro-9H-purine (4.0 g, 21.16 mmol), copper(l) bromide (911 mg, 6.35 mmol) and (l-(difluoromethyl)-lH-pyrazol-4-yl)(mesityl)-X^ -iodaneyl trifluoromethanesulfonate (14.72 g, 22.22 mmol) in dichloromethane (150 ml) were mixed in 500 ml round bottom flask (previously backfilled with argon). Then TEA (14.75 ml, 84.66 mmol) was added dropwise. The resulting mixture was heated 60 °C for 4 h and monitored by LCMS. Upon consumption of all salt, the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc).

[0234] LCMS (m / z): 304.9 (M+H)+, Rt: 2.393 min.

[0235] Synthesis of 2-chloro-9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2V-((5-nitro-lH- benzo[d]imidazol-2-yl)methyl)-9 / / -purin-6-amine (11).

[0236] 2,6-dichloro-9-(l -(difluoromethyl)- l / 7-pyrazol-4-yl)-9H-purine (450 mg, 1.48 mmol), (5-nitro-lH-benzo[^]imidazol-2-yl)methanamine, 2HC1 (31 1.82 mg, 1.62 mmol) were charged into 100 round bottom flasks followed by addition of 2-propanol (9 ml) at room temperature. Then DIPEA (0.52 ml, 2.95 mmol) was added to the suspension and vial was heated in conventional oil bath at 90 °C for 1 h. The reaction mixture was allowed to reach room temperature, then precipitate was filtered and washed with Et20 to afford the pure product as a pale-yellow solid (0.45 g, 66.21%).

[0237] LCMS (m / z): 461.0 (M+H)+, Rt: 2.513 min. Synthesis of 9-(l-(difluoromethyl)-l / / -pyrazol-4-yl)-2-morpholino-A-((5-nitro- lH-benzo[d]imidazol-2-yl)methyl)-9H-purin-6-amine (12).

[0238] 2-chloro-9-( 1 -(difluoromethyl )- 177-pyrazol-4-yl)-A-((5-nitro- 1 H-benzo[d]imidazol- 2-yl (methyl )-97 / -purin-6 (1.20 g, 2.60 mmol) was added to 100 ml round bottom flask followed by addition of morpholine (15 ml) and the reaction mixture was stirred at 130 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (DCM:MeOH, 10: 1, gradient). Pure fractions containing product were combined, and organic phase was washed 2 times with NH4CI (to remove residual morpholine), and finally once with brine. The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure to yield compound 5 as a pale-yellow solid (1.0 g, 75.08%).

[0239] !H NMR (500 MHz, DMSO-d6) 5 8.31 (s, 1H), 8.21 (s, 2H), 7.99 (S, 2 H), 7.71 (s, 2H), 4.82 (s, 2H), 3.58 - 3.45 (m, 8H). LCMS (m / z): 512.1 (M+H)+, Rt: 2.501 min.

[0240] Synthesis of N-((5-amino- LH-benzo[d]imidazol-2-yl)methyl)-9-( 1-

[0241] (ditluoromethyI)-lH-pyrazoI-4-yl)-2-morpholino-9H-purin-6-amine (13). To a solution of 9-(l-(difluoromethyl)-17 / -pyrazol-4-yl)-2-morpholino-iV-((5-nitro- 177-benzo[<i]imidazol-2-yl)methyl)-9H-purin-6-amine (1.0 g, 1.96 mmol) in ethyl acetate and methanol (20 mL, 1 : 1) were added tin(II) chloride dihydrate (2.21 g, 9.78 mmol) and cone HC1 (3 drops). After stirring for 1 h at 80 °C, the reaction mixture was diluted with dichloromethane and methanol (4:1), neutralized with saturated NaHCCL, and filtered. The filtrate was extracted with dichloromethane and methanol (4:1), concentrated under reduced pressure and crude was triturated with diethyl ether and concentrated in vacuo to obtain the product as a pale brown solid. (0.7 g, 74.36%).

[0242] !H NMR (500 MHz, DMSO-d6) 5 8.31 (s, 1H), 8.21 (s, 2H), 7.99 (S, 2 H), 7.71 (s, 2H), 4.82 (s, 2H), 3.58 - 3.45 (m, 8H). LCMS (m / z): 482.2 (M+H)+, Rt: 1.934 min.

[0243] General procedure for step 6 (14a- 14b).

[0244] To a solution of N-((5-amino-l H-benzo[d]imidazol-2-yl)methyl)-9-(l - (difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (50 mg, 1 eq) in ACN (5 mL) was added DIPEA (1.3 eq). The reaction mixture was cooled to 0 °C, then acryloyl chloride (1.2 eq) in DMF(1 mL) and THF (1 mL) was added in dropwise, then stirred at same temp for 30 min. After completion, the reaction mixture was diluted with 20% MeOH in DCM, washed with 10% NaHCCL and concentrated in vacuo. The crude was purified by PREP HPLC purification to afford the pure product as a white solid.

[0245] General procedure for step 6 (14c-14i).

[0246] To a solution of N-((5-amino-lH-benzo|d|imidazol-2-yl)methyl)-9-(l- (difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (50 mg, 1 eq) in DMF (2 mL) was carboxylic acids (1.3 eq) followed by the addition of DIPEA (1.5 eq) and HATU (1.5 eq). The reaction mixture was, then stirred at room temperature for 3 h. After completion, the reaction mixture was diluted with 20% MeOH in DCM, washed with water, and concentrated in vacuo. The crude was purified by PREP HPLC purification to afford the pure product as a white solid. Synthesis of A^-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)-lH-benzo[d]imidazol-5-yI)propionamide (14a)

[0247] Synthesized accordingly procedure, described in (14a- 14b).

[0248] Yield (20.0 mg, 35.83%), Off-white solid.]H NMR (500 MHz, DMSO) 5 12.02 (s, 1H), 9.76 (d, J= 35.2 Hz, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.94 (d,

[0249] J = 16.0 Hz, 1H), 7.83 (d, J = 23.6 Hz, 1H), 7.49 - 7.04 (m, 3H), 4.80 (s, 2H), 3.58 (d, J = 5.1 Hz, 4H), 3.51 (s, 4H), 2.31 (q, 7 = 7.5 Hz, 2H), 1.08 (t, 7 = 7.6 Hz, 3H).19F NMR (471 MHz, DMSO) 8 -94.43, -94.55. LCMS (m / z): 538.2 (M+H)+, Rv. 1.977 min.

[0250] Synthesis of N-(2-(((9-(l-(difhioromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)-lH-benzo[d]imidazol-5-yl)acrylamide (14b)

[0251]

[0252] Synthesized accordingly procedure, described in (14a- 14b).

[0253] Yield (20.0 mg, 35.96%), White solid. H NMR (500 MHz, DMSO) 5 12.09 (s, 1H), 10.10 (s, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 6.5 Hz, 1H), 7.92 (s, 1H), 7.39 (d, J = 47.3 Hz, 2H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.23

[0254] (dd, J = 17.0, 2.1 Hz, 1H), 5.72 (dd, J = 10.1, 2.1 Hz, 1H), 5.46 (d, J = 6.6 Hz, 1H), 4.81 (s, 2H), 3.58 (s, 4H).19F NMR (471 MHz, DMSO) 5 -94.43, -94.55. LCMS (m / z): 536.2 (M+H)+, Rt: 1.979 min.

[0255] Synthesis of (E)-N-(2-(((9-( l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yI)amino)methyI)-lH-benzo[d]imidazol-5-yI)-4-(dimethylamino)but-2- enamide (14c)

[0256] Synthesized accordingly procedure, described in (14c- 14i). Yield (10.0 mg, 16.25%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 12.08 (s,

[0257] 1H), 10.00 (s, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.15 (s, 2H), 8.03 (d, J = 13.9 Hz, 1H), 7.86 (d, J = 58.8 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 6.73 - 6.67 (m, 1H), 6.28 (dt, J = 15.4, 1.7 Hz, 1H), 4.80 (s, 2H), 3.10 (dd, 7 = 6.0, 1.6 Hz, 2H), 2.21 (s, 6H).19F NMR (471 MHz, DMSO) 5 -94.49. LCMS (m / z): 593.3 (M+H)+, Rt: 2.994 min.

[0258] Synthesis of N-(2-(((9-(l-(difhioromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yl)amino)methyl)-lH-benzo[d]imidazol-5-yl)-2-fluoroacrylamide (14d)

[0259] Synthesized accordingly procedure, described in (14c- 14i). Yield (12.0 mg, 20.88%), Off-white solid.]H NMR (500 MHz, DMSO) 5 12. 16 (s,

[0260] 1H), 10.23 (s, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.40 (s, 2H), 5.69 (dd, 7 = 47.7, 3.5 Hz, 1H), 5.39 (dd, 7 = 15.7, 3.5 Hz, 1H), 4.81 (s, 2H), 3.58 (s, 4H), 3.51 (s, 4H).19F NMR (471 MHz, DMSO) 5 -94.49, -116.33. LCMS (m / z): 554.2 (M+H)+, Rt: 3.760 min. Synthesis of Ar-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yl)amino)inethyl)-lH-benzo[d]imidazol-5-yl)but-2-ynamide (14e)

[0261]

[0262] Synthesized accordingly procedure, described in (14c- 14i).

[0263] Yield (8.0 mg, 14.07%), Pale-yellow solid. ’H NMR (500 MHz, DMSO) 5 12.07 (d, J = 19.8 Hz, 1H), 10.51 (d, 7 = 39.6 Hz, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.44 - 7.16 (m, 2H), 4.86 - 4.74 (m, 2H), 3.57 (s, 4H),

[0264] 3.53 - 3.42 (m, 4H), 2.03 (s, 3H).19F NMR (471 MHz, DMSO) 8 -94.49. LCMS (m / z): 548.2 (M+H)+, Rt: 3.720 min.

[0265] Synthesis of N-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyI)-lH-benzo[d]imidazol-5-yI)cyclopent-l-ene-l-carboxamide (14f)

[0266] Synthesized accordingly procedure, described in (14c- 14i). Yield (10.0 mg, 16.73%), Pale-yellow solid.:H NMR (500 MHz, DMSO) 5 12.06

[0267] (s, 1H), 9.54 (d, 7 = 27.2 Hz, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.06

[0268] - 7.86 (m, 2H), 7.40 (dd, J = 20.7, 8.7 Hz, 1H), 7.29 (td, J = 10.2, 8.8, 5.0 Hz, 1H), 6.67 (p, 7 = 2.3 Hz, 1H), 4.81 (s, 2H), 3.59 (s, 4H), 3.52 (s, 4H), 2.58 (td, J = 7.6, 2.5 Hz, 2H), 2.48 (d, J = 2.7 Hz, 2H), 1.90 (p, J = 7.6 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -94.43, -94.55.

[0269] LCMS (m / z): 576.2 (M+H)+, Rt: 4.058 min.

[0270] Synthesis of (E)-N-(2-(((9-(l-(difhioromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)amino)methyl)-lH-benzo[d]imidazol-5-yI)-3-(4- (trifluoromethyl)phenyl)acrylamide (14g)

[0271] Synthesized accordingly procedure, described in (14c- 14i).

[0272] Yield (12.0 mg, 17.73%), Pale-yellow solid.JH NMR (500 MHz, DMSO) 5 12.27 (s, 1H), 10.28 (s, 1H), 8.86 (s, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.82 (q, J = 8.5 Hz, 4H), 7.65 (d, 7 = 15.7 Hz, 1H), 7.44 (d, 7 = 8.7 Hz, 1H), 7.30 (d, 7 = 8.5 Hz, 1H), 6.98 (d, 7 = 15.7 Hz, 1H), 4.83 (s, 2H), 3.58 (s, 4H), 3.51 (s, 4H).19F NMR (471 MHz, DMSO) 6 -61.14, -94.43, -94.55. LCMS (m / z): 680.2 (M+H)+, Rt: 4.783 min.

[0273] Synthesis of 4-((2-(((9-(l-(difhioromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)-lH-benzo[d]imidazol-5-yI)carbamoyl)benzenesulfonyl fluoride (14h)

[0274]

[0275] Synthesized accordingly procedure, described in (14c- 14i).

[0276] Yield (5.0 mg, 7.73%), Pale-yellow solid. ’H NMR (500 MHz, DMSO) 5 10.64 (s, 1H), 8.86 (s, 1H), 8.47 (s, 1H), 8.35 - 8.28 (m, 4H), 8.11 (s, 1H), 7.92 id, 7 = 3.4 Hz, 1H), 7.52 (s, 1H), 4.87 (s, 2H), 3.55 (s, 4H), 3.50 (s, 4H).19F NMR (471 MHz, DMSO) 5 -70.15

[0277] (d, 7 = 711.7 Hz), -94.44 (d, 7 = 6.6 Hz), -94.56 (d, 7 = 6.4 Hz). LCMS (m / z): 668.2 (M+H)+, Rt: 4.417 min.

[0278] Synthesis of 3-((2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)-lH-benzo[rf]imidazol-5-yI)carbamoyl)benzenesulfonyl fluoride (14i)

[0279] Synthesized accordingly procedure, described in (14c- 14i). Yield (2.30 mg, 3.32%), Pale-yellow solid. LCMS (m / z): 668.2 (M+H)+, Rt: 4.407 min.

[0280] Synthesis of N-(2-(((2-(2,2-dimethylmorpholino)-9-(l-methyI-lH-pyrazol-4-yl)- 9H-purin-6-yI)amino)methyI)-lH-benzo[d]imidazol-5-yI)acrylamide (15) Yield (12.0 mg, 21.60%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 12.08 (s,

[0281] 1H), 10.06 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.23 (dd, J = 17.0, 2.1 Hz, 1H), 5.71 (dd, J = 10.1, 2.1 Hz, 1H), 4.75 (s, 2H), 3.91 (s, 3H), 3.65 (s, 2H), 3.38 (q, J = 7.0 Hz, 2H), 2.37 (s, 2H), 2.07 (s, 3H), 0.72 (s, 6H). LCMS (m / z): 541.3 (M+H)+, Rt: 1.517 min.

[0282] Synthesis of N-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-(4-methyIpiperazin-l-yl)- 9H-purin-6-yl)amino)methyl)-lH-benzo[d]imidazol-5-yl)acrylamide (17)

[0283] Synthesized accordingly procedure, described in 5. Yield (10.0 mg, 18.99%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 12.07 (s,

[0284] 1H), 10.08 (s, 1H), 8.30 (s, 1H), 8.17 (d, J = 4.7 Hz, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.98 (d, 7 = 3.1 Hz, 1H), 6.45 (dd, 7 = 16.9, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.1 Hz, 1H), 5.71 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.80 (s, 2H), 3.92 (s, 3H), 3.61 (s, 4H), 2.29 - 2.22 (m, 4H), 2.16 (s, 3H). LCMS (m / z): 513.2 (M+H)+, Rt: 1.506 min. Synthesis of N-(2-(((9-(l-methyl-lH-pyrazoI-4-yl)-2-(piperazin-l-yl)-9H-purin-

[0285] 6-yl)amino) methyl) - IH-benzo [d] imidazol-5 -yl)acrylamide (18) Synthesized accordingly procedure, described in 5.

[0286] Yield (1.80 mg, 3.41%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 12.07 (s, 1H), 10.07 (d, 7 = 31.1 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.1 Hz, 1H), 5.72 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.80 (s, 2H), 3.91 (s, 3H), 3.57 (s, 4H), 3.51 (s, 4H). LCMS (m / z): 499.2 (M+H)+, Rt: 1.508 min.

[0287] Scheme 3

[0288] Synthesis of tert-butyl (thiazol-2-ylmethyl)carbamate (16).

[0289] To a stirred solution of thiazol-2-ylmethanamine, (15) (2.0 g, 17.52 mmol) in Dichloromethane (60 mL) and Methanol (10 mL) was added and stirred for 5 min, and then Triethylamine (0.366 mL, 2.63 mmol) with stirring at room temperature for 5 minutes, before adding (Boc)2O (4.01 g, 18.39 mmol), with continued stirring for 16 hours. The progress of the reaction was monitored by TLC and LCMS. LCMS showed the desired product mass; the RM was quenched in ice-cold water and extracted with DCM (50 mL x 3), and the combined organic layer was washed with sat. NaCl solution (1 x 80 mL). The organic layer dried over Anhydrous NaiSCU, and the solvent was evaporated under a vacuum to afford crude compound, which was washed hexane and dried to give pure tertbutyl (thiazol-2-ylmethyl)carbamate (16) that appeared as a white solid (3.65 g, 97.23%).

[0290] ’H NMR (500 MHz, CDCI3) 6 7.74 (d, J = 3.3 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 5.40 (s, 1H), 4.68 (d, J = 5.9 Hz, 2H), 1.46 (s, 10H). LCMS (m / z): 215.0 (M+H)+, / ?,: 2.101 min.

[0291] Synthesis of tert-butyl ((5-bromothiazol-2-yl)methyl)carbamate (17).

[0292] To a stirred solution of tert-butyl (thiazol-2-ylmethyl)carbamate (16) (2.4 g, 11.20 mmol) in anhydrous DMF (25.0 mL) was added stirred for 5 min, NBS (2.19 g, 12.32 mmol) was added in one portion to a solution with stirring at room temperature under nitrogen. The reaction mixture was then warmed to 45 °C with continued stirring overnight. The progress of the reaction is monitored by TLC and LCMS. The crude LCMS showed the desired product, RM quenched in ice cold water and stirred for 15 min, then extracted with ethyl acetate (70 mL x 3) and washed with Sat.NaCl solution (1 x 70 mL) and drying over anhydrous Sodium sulfate. The organic phase was then filtered and concentrated to give the crude product, which was purified by using Combi-flash column chromatography over silica, eluting with 40-50% ethyl acetate in hexane, to afford tert-butyl ((5-bromothiazol-2- yl)methyl)carbamate (17) appeared as a pale yellow oil (1.85 g, 56.34%).

[0293] ]H NMR (500 MHz, CDCI3) 6 7.57 (s, 1H), 5.34 (s, 1H), 4.60 - 4.41 (m, 2H), 1.46 (s, 9H).13C NMR (126 MHz, CDCh) 5 142.72, 42.39, 28.32. LCMS (m / z): 292.9 (M+H)+, Rt: 2.637 min.

[0294] Synthesis of (5-bromothiazoI-2-yl)methanamine hydrochloride (18).

[0295] To a stirred solution of tert-butyl ((5-bromothiazol-2-yl)methyl)carbamate (17) (1.0 g, 3.41 mmol) in DCM (10.0 mL) was added 4M HC1 in 1,4-dioxane (1.28 mL) at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction monitored by TLC and LCMS, it’s indicating the completion of SM, the reaction mixture was concentrated in vacuo and triturated with diethyl ether and dried in vacuo to give the pure compound (5-bromothiazol-2-yl)methanamine hydrochloride (18) appeared as an off white solid in (750 mg, 95.80%).

[0296] !H NMR (500 MHz, DMSO) 5 8.71 (br, 3H), 7.97 (s, 1H), 4.39 (s, 2H). LCMS

[0297] To a stirred solution of 2,6-dichloro-9-( 1-methyl- 1 H-pyrazol-4-yl)-9H-purine (3) (300 mg; 1.11 mmol), (5-bromothiazol-2-yl)methanamine hydrochloride (18) (269 mg; 1.17 mmol), and DIPEA (0.777 mL; 4.46 mmol) were added in IPA (1.0 mL) at room temperature in sealed tube under argon gas. The reaction mixture was stirred at 90 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS, and both data showed completion of SM. To the reaction mixture, diethyl ether was added to RM, it formed the solid, which was filtered by Buchner funnel and solid dried to give the desired compound A-((5-bromothiazol-2-yl)methyl)-2-chloro-9-( 1-methyl-l A / -pyrazol-4-yl j-9H- purin-6-amine (19) appeared as an off white solid (340 mg, 71.64%).

[0298] ]H NMR (500 MHz, DMSO) 5 9.24 (d, J = 6.3 Hz, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 4.87 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H). LCMS (m / z): 426.9 (M+H)+, Rt: 2.572 min.

[0299] Synthesis of A-((5-bromothiazol-2-yl)methyl)-9-(l-methyl-lH-pyrazol-4-yl)-2- morpho!ino-9H -purin -6-amine (20) .

[0300] To a stirred solution of M((5-bromothiazol-2-yl)methyl)-2-chloro-9-(l -methyl- \ H- pyrazol-4-yl)-977-purin-6-amine (19) (330 mg; 0.775 mmol) in Morpholine (1.0 mL mg) was added, and heated at 130 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS, and both data showed completion of SM. The reaction mixture was concentrated to dryness and purified by flash chromatography to give a pure compound, and the desired compound1H NMR shows the Morpholine. 30 mg of the compound was washed with water 3 times purified by Prep.HPLC give pure compound M-((5-bromothiazol-2- yl)methyl)-9-(l-methyl-177-pyrazol-4-yl)-2-morpholino-97 / -purin-6-amine (20) appeared as an off white solid, and the remaining compound is used for the next step (300 mg, 81.24%).

[0301] ]H NMR (500 MHz, DMSO) 5 8.49 (d, J = 8.9 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 4.83 (s, 2H), 3.92 (s, 3H), 3.68 - 3.60 (m, 8H). LCMS (m / z): 476.0 (M+H)+, Rt: 2.556 min.

[0302] General procedure for Step 6 (22a- 22c).

[0303] Boc

[0304] To a stirred solution of N-((5-bromothiazol-2-yl)methyl)-9-(l-methyl-177-pyrazol-4- yl )-2-morpholino-9H-purin-6-amine (60.0 mg, 1.0 eq) and NtoCCh (2.5 eq) in 1,4-dioxane - water mixture was added (4:1 ; 1 mL of 1,4-dioxane and 0.25 mL ofwater) in the Biotage vial and degassed with Ar for 5 min, and PdiPPhiL (0.06 eq) Boronic ester (21) (1.20 eq) were added in the RM and degassed for another 5 min. The Biotage vial was sealed, and the reaction mixture was stirred at 100 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. The TLC showed a new spot, and crude LCMS showed the desired product mass. RM was diluted with Ethyl acetate and filtered through a celite pad; the MLs were concentrated under reduced pressure to give the crude compound, which was purified via combi-flash eluted 40-60% hexane in Ethyl acetate to give pure 22a-22c compounds in 65-88% yield.

[0305] Synthesis of tert-butyl 3-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9 / / - purin-6-yl)amino)methyl)thiazol-5-yl)-2,5-dihydro-lH-pyrrole-l -carboxylate (22a).

[0306] Synthesized accordingly procedure described in step 6 (22a- 22c)

[0307] Yield (50.0 mg, 70.30%), Off-white solid. 1H NMR (500 MHz, DMSO) 5 8.48 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.66 (d, J = 3.5 Hz, 1H), 6.07 (dt, J = 22.9, 2.1 Hz, 1H), 4.84 (s, 2H), 4.33 (dt, J = 4.5, 2.3 Hz, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.72 - 3.55 (m, 8H), 1.43 (d, J = 8.4 Hz, 9H). LCMS (m / z): 565.2 (M+H)+, Rt: 2.881 min.

[0308] Synthesis of tert-butyl 5-(2-(((9-(l-methyl-LH-pyrazol-4-yI)-2-morpholino-9H- purin-6-yl)amino)methyl)thiazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (22b).

[0309] Synthesized accordingly procedure described in step 6 (22a- 22c) Yield (45.0 mg, 58.12%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 8.45 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.62 (s, 1H), 6.13 (s, 1H), 4.82 (s, 2H), 4.14 (q, 7= 2.4 Hz, 2H), 3.92 (s, 3H), 3.70 - 3.56 (m, 8H), 3.42 (t, J= 5.7 Hz, 2H), 2.19 (dp, 7 = 8.2, 2.8 Hz, 2H), 1.41 (s, 9H). LCMS (m / z): 579.3 (M+H)+, Rt: 2.978 min. Synthesis of tert-butyl 4-(2-(((9-(l-methyI-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)thiazol-5-yl)-3,6-dihydropyridine- 1 ( 27 / ) -carboxyl ate (22c).

[0310] Synthesized accordingly procedure described in step 6 (22a-22c)

[0311] Yield (50.0 mg, 68.60%), Off-white solid.]H NMR (500 MHz, DMSO) 5 8.44 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.63 (s, 1H), 5.98 (s, 1H), 4.91 - 4.72 (m, 2H),

[0312] 3.92 (s, 5H), 3.73 - 3.55 (m, 8H), 3.49 (t, J = 5.8 Hz, 2H), 2.44 - 2.37 (m, 2H), 1.40 (s, 9H). LCMS (m / z): 579.2 (M+H)+, Rt: 2.962 min.

[0313] General procedure for Step 7 (23a- 23c). To a stirred solution of tert-butyl 3-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyl)thiazol-5-yl)-2,5-dihydro-lH-pyrrole-l- carboxylate (50.0 mg, 1.0 eq) in DCM (1.0 mL) was added 4M HC1 in 1,4-dioxane (1.5 eq) at 0°C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction monitored by TLC and LCMS, it's indicating the completion of SM; the reaction mixture was concentrated in vacuo triturated with diethyl ether and dried in vacuo to give the pure compounds 23a-23c appeared as a pale brown solid in 78-95% yield. Synthesis of M-((5-(2,5-dihydro-lH-pyrrol-3-yl)thiazol-2-yl)methyl)-9-(l- methyl-l / f-pyrazol-4-yl)-2-morphoIino-9H-purin-6-amine hydrochloride (23a).

[0314] Synthesized accordingly procedure described in step 7 (23a- 23c)

[0315] Yield (35.0 mg, 78.89%), Pale brown solid.]H NMR (500 MHz, DMSO) 5 9.89 - 9.60 (m, 2H), 8.56 (s, 1H), 8.30 (d, J = 18.9 Hz, 2H), 7.99 (s, lH), 7.78 (s, 1H), 6.13 (p, J =

[0316] 2.2 Hz, 1H), 4.87 (s, 2H), 4.27 (dt, J = 5.8, 2.9 Hz, 2H), 4. 15 - 3.83 (m, 5H), 3.75 - 3.45

[0317] (m, 8H). LCMS (m / z): 465.2 (M+H)+, Rt: 1.840 min.

[0318] Synthesis of 9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-lV-((5-(l, 2,5,6- tetrahydropyridin-3-yl)thiazol-2-yl)methyl)-9 / f-purin-6-amine hydrochloride (23b).

[0319] Synthesized accordingly procedure described in step 7 (23a- 23c)

[0320] Yield (28.0 mg, 78.65%), Pale brown solid.]H NMR (500 MHz, DMSO) 5 9.32 (s, 2H), 8.52 (s, 1H), 8.30 (d, J = 19.2 Hz, 2H), 7.99 (s, 1H), 7.71 (s, 1H), 6.18 (d, J = 4.2, 2.0 Hz, 1H), 4.90 - 4.79 (m, 4H), 3.99 - 3.84 (m, 5H), 3.75 - 3.50 (m, 8H), 2.40 (d, J = 8.8, 2.5

[0321] Hz, 2H). LCMS (m / z): 479.2 (M+H)+, Rt: 1.889 min.

[0322] Synthesis of 9-(l-methyl-l / / -pyrazol-4-yl)-2-morphoIino- / V-((5-(l, 2,3,6- tetrahydropyridin-4-yl)thiazol-2-yl)methyl)-9H-purin-6-amine hydrochloride (23c).

[0323] Synthesized accordingly procedure described in step 7 (23a- 23c)

[0324] Yield (25.0 mg, 93.64%), Pale brown solid.JH NMR (500 MHz, DMSO) 59.10 (s, 2H), 8.52 (s, 1H), 8.30 (d, J = 18.4 Hz, 2H), 7.99 (s, 1H), 7.73 (s, 1H), 6.03 - 5.95 (m, 1H), 4.84 (s, 3H), 4.65 (s, 4H), 3.92 (s, 3H), 3.68 - 3.60 (m, 8H), 3.26 (dt, J = 8.2, 4.0 Hz, 2H), 2.65 (dt, 7 = 4.9, 2.6 Hz, 2H). LCMS (m / z): 479.2 (M+H)+, Rt: 1.905 min.

[0325] General procedure for step 8 (24a- 24c).

[0326] To a stirred so] ution of N-t ( 5 -(2 ,5-dihy dro- 1 B -pyrrol-3 -y l)thi azol -2-yDme-thyl )-9-( 1 - methyl- 17 / -pyrazol-4-yl)-2-morpholino-9 / / -purin-6-amine hydrochloride (20 mg, 1 eq) in THF (0.5 ml..) was added DIPEA (2.0 eq). The reaction mixture was cooled to 0 °C, then acryloyl chloride (1.1 eq) in THF (0.5 mL) was added in dropwise, then stirred at the same temp for 45 min. After completion, the reaction mixture was diluted with 20% MeOH in DCM, washed with 10% NaHCOs and concentrated in vacuo. The crude was purified by Prep.HFLC purification to afford the pure product as an off-white solid.

[0327] Synthesis of l-(3-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)thiazol-5-yl)-2,5-dihydro-lH-pyrrol-l-yl)prop-2-en-l-one (24a).

[0328] Synthesized accordingly procedure described in step 8 (24a- 24c).

[0329] Yield (10.0 mg, 48.30%), Off white solid.]H NMR (500 MHz, DMSO) 5 8.49 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.71 (d, J = 17.3 Hz, 1H), 6.68 - 6.54 (m, 1H), 6.24 - 6.11 (m, 2H), 5.73 (td, 7 = 9.6, 2.3 Hz, 1H), 4.91 - 4.78 (m, 2H), 4.71 (td, 7 = 3.6, 1.9 Hz, 1H), 4.48 (s, 2H), 4.25 (q, 7 = 3.2 Hz, 1H), 3.92 (s, 3H), 3.71 - 3.51 (m, 8H). LCMS

[0330] (m / z): 519.2 (M+H)+, Rt: 2.328 min.

[0331] Synthesis of l-(3-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)thiazol-5-yI)-2,5-dihydro-lH-pyrrol-l-yl)prop-2-en-l-one (24b). Synthesized accordingly procedure described in step 8 (24a- 24c).

[0332] Yield (8.0 mg, 51.57%), Off white solid. *H NMR (500 MHz, DMSO) 5 8.46 (s, 1H), 8.31 (d, 7 = 0.7 Hz, 1H), 8.19 (s, 1H), 7.99 (d, 7 = 0.8 Hz, 1H), 7.66 (s, 1H), 6.91 (ddd, 7 = 53.9, 16.6, 10.4 Hz, 2H), 6.22 - 6.07 (m, 2H), 5.70 (dd, 7 = 10.5, 2.4 Hz, 1H), 4.83 (s, 2H), 4.47 - 4.30 (m, 2H), 3.92 (s, 3H), 3.72 - 3.44 (m, 8H), 2.23 (d, 7 = 29.2 Hz, 2H). LCMS (m / z): 533.2 (M+H)+, Rt: 2.393 min.

[0333] Synthesis of l-(3-(2-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)thiazol-5-yl)-2,5-dihydro-lH-pyrrol-l-yl)prop-2-en-l-one (24c).

[0334] Synthesized accordingly procedure described in step 8 (24a- 24c).

[0335] Yield (7.0 mg, 45.13%), Off white solid. H NMR (500 MHz, DMSO) 5 8.48 (s, 1H), 8.30 (d, 7 = 0.7 Hz, 1H), 8.19 (s, 1H), 7.99 (d, J = 0.8 Hz, 1H), 7.72 (d, J = 50.5 Hz, 1H), 6.96 (dd, 7 = 16.6, 10.4 Hz, 1H), 6.85 (dd, 7 = 16.7, 10.4 Hz, 1H), 6.22 - 6.07 (m, 2H), 5.70 (dd, 7 = 10.5, 2.4 Hz, 1H), 4.86 (s, 2H), 4.47 - 4.33 (m, 2H), 3.90 (s, 3H), 3.72 - 3.44

[0336] (m, 8H), 2.23 (d, 7 = 29.2 Hz, 2H). LCMS (m / z): 533.2 (M+H)+, Rt: 2.328 min.

[0337] Scheme 4

[0338] Synthesis of . / V-((5-bromothiazol-2-yI)methyl)-2-chIoro-9-(l-(difhioromethyl)- lH-pyrazol-4-yl)-9H-purin-6-amine (25).

[0339] To a stirred solution of 2,6-dichloro-9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-9H- purine (10) (500 mg; 1.64 mmol), (5-bromothiazol-2-yl)methanamine hydrochloride (18) (395 mg; 1.72 mmol), and DIPEA (1.14 mL; 6.56 mmol) were added in IPA (2.0 mL) at room temperature in sealed tube under argon gas. The reaction mixture was stirred at 90 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS, and both data showed completion of SM. To the reaction mixture, diethyl ether was added to RM, it formed the solid, which was filtered by Buchner funnel and solid dried to give the desired compound 2 / -((5-bromothiazol-2-yl)methyl)-2-chloro-9-(l -(difluoromethyl)- I / / -pyrazol-4- yl)-9#-purin-6-amine (25) appeared as a pale yellow solid (550 mg, 72.69%).

[0340] ’H NMR (500 MHz, DMSO) 5 9.36 - 9.24 (m, 1H), 8.87 (s, 1H), 8.65 (s, 1H), 8.39 (s, 1H), 8.10 - 7.78 (m, 2H), 4.88 (d, 7 = 6.0 Hz, 2H). LCMS (m / z): 460.9 (M+H)+, Rt: 2.864 min.

[0341] Synthesis of A^-((5-bromothiazol-2-yl)methyl)-9-(l-(difluoromethyl)-lH- pyrazol-4-yI)-2-morpholino-9H-purin-6-amine (26).

[0342] To a stirred solution of N-((5-bromothiazol-2-yl)methyl)-2-chloro-9-(l- (difluoromethyl)-177-pyrazol-4-yl)-977-purin-6-amine (25) (500 mg; 1.08 mmol) in Morpholine (1.0 mL mg) was added, and heated at 130 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS, and both data showed completion of SM. The reaction mixture was concentrated to dryness and purified by flash chromatography to give a pure compound, and the desired compound1H NMR shows the Morpholine. 30 mg of the compound was washed with water 3 times purified by Prep.HPLC gives pure compound N- ((5-bromothiazol-2-yl)methyl)-9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-amine (26) appeared as an off white solid, and the remaining compound is used for the next step (510 mg, 91.91%).

[0343] ]H NMR (500 MHz, DMSO) 5 8.85 (s, 1H), 8.46 (s, 2H), 8.33 (s, 1H), 8.05 - 7.75 (m, 2H), 4.84 (s, 2H), 3.71 - 3.57 (m, 8H). LCMS (m / z): 512.0 (M+H)+, Rt: 2.816 min.

[0344] General procedure for Scheme 4, Step 3 (27a- 27d).

[0345]

[0346] To a stirred solution of N-((5-bromothiazol-2-yl)methyl)-9-(l-(difluoromethyl)-lH- pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (26) (70.0 mg, 1.0 eq) and Na2COi (2.5 eq) in 1,4-dioxane - water mixture was added (4:1; 1 mL of 1,4-dioxane and 0.25 mL of water) in the Biotage vial and degassed with Ar for 5 min, and Pd(PPhs)4 (0.06 eq) Boronic ester (21) (1.20 eq) were added in the RM and degassed for another 5 min. The Biotage vial was sealed, and the reaction mixture was stirred at 100 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. The TLC showed a new spot, and crude LCMS showed the desired product mass. RM was diluted with Ethyl acetate and filtered through a celite pad; the MLs were concentrated under reduced pressure to give the crude compound, which was purified via combi-flash eluted 40-60% hexane in Ethyl acetate to give pure 27a- 27d compounds in 53-68% yield.

[0347] Synthesis of tert-butyl 3-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morpholino-9 / 7-purin-6-yl)amino)methyl)thiazol-5-yl)-2,5-dihydro-l / 7-pyrrole-l- carboxylate (27a). Synthesized accordingly procedure described in Scheme 4, step 3 (27a-27d).

[0348] Yield (54.0 mg, 65.80%), Off-white solid.]H NMR (500 MHz, DMSO) 5 8.85 (s, 1H), 8.47 (s, 2H), 8.32 (s, 1H), 7.93 (s, 1H), 7.67 (d, J = 3.5 Hz, 1H), 6.07 (dt, J = 23.0, 2.1 Hz, 1H), 4.91 - 4.76 (m, 2H), 4.34 (dq, J = 5.5, 2.9, 1.9 Hz, 2H), 4.12 (dq, 7 = 7.7, 3.7 Hz, 2H), 3.75 - 3.53 (m, 8H), 1.43 (d, J = 8.4 Hz, 9H). LCMS (m / z): 601.2 (M+H)+, Rt: 3.076 min.

[0349] Synthesis of tert-butyl 4-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyl)thiazol-5-yl)-2,3-dihydro-lH-pyrrole-l- carboxylate (27b).

[0350] Synthesized accordingly procedure described in Scheme 4, step 3 (27a-27d).

[0351] Yield (50.0 mg, 60.93%), Off-white solid. LCMS (m / z): 601.2 (M+H)+, Rt: 3.125 min.

[0352] Synthesis of tert-butyl 5-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyl)thiazol-5-yl)-3,6-dihydropyridine-l(2H)- carboxylate (27c).

[0353]

[0354] Synthesized accordingly procedure described in Scheme 4, step 3 (27a-27d).

[0355] Yield (45.0 mg, 53.58%), Off-white solid. ’H NMR (500 MHz, DMSO) 5 8.85 (s, 1H), 8.47 (s, 2H), 8.32 (s, 1H), 7.93 (t, 7 = 58.8 Hz, 2H), 7.66 - 7.60 (m, 1H), 7.58 - 7.41 (m, 1H), 6.13 (s, 1H), 4.83 (s, 2H), 4.14 (q, 7 = 2.4 Hz, 2H), 3.79 - 3.56 (m, 8H), 3.42 (t, 7

[0356] = 5.8 Hz, 2H), 2.18 (td, 7 = 6.0, 2.8 Hz, 2H), 1.41 (s, 8H). LCMS (m / z): 615.2 (M+H)+, Rt:

[0357] 3.157 min.

[0358] Synthesis of tert-butyl 4-(2-(((9-( l-(difluoromethyl)-l / / -pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyl)thiazol-5-yl)-3,6-dihydropyridine-l(2H)- carboxylate (27d).

[0359] Synthesized accordingly procedure described in Scheme 4, step 3 (27a-27d)

[0360] Yield (57.0 mg, 67.87%), Off-white solid.]H NMR (500 MHz, DMSO) 8 8.85 (s,

[0361] 1H), 8.47 (s, 2H), 7.93 (s, 2H), 7.66 - 7.60 (m, 2H), 5.98 (s, 1H), 4.82 (s, 2H), 3.92 (s, 2H), 3.73 - 3.57 (m, 7H), 3.49 (t, 7 = 5.8 Hz, 2H), 2.45 - 2.34 (m, 2H). LCMS (m / z): 615.2 (M+H)+, Rt: 3.125 min.

[0362] General procedure for Scheme 4, step 4 (28a-28d). To a stirred solution of rer / -butyl 3-(2-(((9-(l-(difhioromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyl)thiazol-5-yl)-2,5-dihydro-lH-pyrrole-l- carboxylate (50.0 mg, 1.0 eq) in DCM (1.0 mL) was added 4M HC1 in 1,4-dioxane (1.5 eq) at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction monitored by TLC and LCMS, it's indicating the completion of SM; the reaction mixture was concentrated in vacuo triturated with diethyl ether and dried in vacuo to give the pure compounds 28a-28d appeared as a pale brown solid in 78-92% yield.

[0363] Synthesis of 9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-M-((5-(2,5-dihydro-lH- pyrrol-3-yl)thiazol-2-yl)methyl)-2-morpholino-9H-purin-6-amine hydrochloride (28a). Synthesized accordingly procedure described in Scheme 4, step 4 (28a-28d).

[0364] Yield (38.0 mg, 85.01%), Pale brown solid.]H NMR (500 MHz, DMSO) 5 10.01 -

[0365] 9.81 (m, 2H), 8.87 (s, 1H), 8.69 - 8.37 (m, 3H), 8.01 - 7.71 (m, 2H), 6.12 (s, 1H), 4.88 (s, 2H), 4.38 - 4.20 (m, 2H), 4.05 (s, 2H), 3.80 - 3.39 (m, 8H). LCMS (m / z): 501.1 (M+H)+, Rt: 2.019 min.

[0366] Synthesis of 9-(l-(difluoromethyI)-lH-pyrazol-4-yl)-2V-((5-(4,5-dihydro-lH- pyrrol-3-yl)thiazol-2-yl)methyl)-2-morpholino-9H-purin-6-amine hydrochloride (28b).

[0367] Synthesized accordingly procedure described in Scheme 4, step 4 (28a-28d).

[0368] Yield (38.0 mg, 85.01 %), Pale yellow solid. LCMS (m / z): 501.1 (M+H)+, Rt: 1.908 min.

[0369] Synthesis of 9-(l-(difluoromethyl)-lH-pyrazol-4-yI)-2-morpholino-7V-((5- (l,2,5,6-tetrahydropyridin-3-yl)thiazol-2-yI)methyl)-9H-purin-6-amine hydrochloride (28c).

[0370] Synthesized accordingly procedure described in Scheme 4, step 4 (28a-28d).

[0371] Yield (30.0 mg, 92.96%), Pale brown solid. 'H NMR (500 MHz, DMSO) 5 9.39 (s, 2H), 8.87 (s, 1H), 8.58 (s, 1H), 8.43 (d, 7 = 43.3 Hz, 2H), 7.88 (d, 7 = 58.8 Hz, 1H), 7.71 (s,

[0372] 1H), 7.65 - 7.54 (m, 1H), 6.18 (t, 7= 3.1 Hz, 1H), 4.84 (s, 2H), 3.93 (td, 7 = 4.8, 2.4 Hz, 2H), 3.77 - 3.45 (m, 8H), 3.17 (q, 7 = 6.4, 4.6 Hz, 2H), 2.45 - 2.32 (m, 2H). LCMS (m / z): 515.2 (M+H)+, Rt: 2.068 min.

[0373] Synthesis of 9-(l-(difluoromethyI)-lH-pyrazol-4-yl)-2-morpholino-2V-((5-

[0374] (l,2,3,6-tetrahydropyridin-4-yl)thiazol-2-yl)methyl)-9H-purin-6-amine hydrochloride (28d).

[0375] Synthesized accordingly procedure described in Scheme 4, step 4 (28a-28d).

[0376] Yield (27.0 mg, 83.66%), Pale brown solid.]H NMR (*H NMR (500 MHz, DMSO) 59.11 (s, 2H), 8.86 (s, 1H), 8.66 - 8.24 (m, 3H), 8.00 (d, 7= 58.8 Hz, 1H), 7.76 - 7.55 (m, 2H), 6.00 (s, 1H), 4.94 - 4.67 (m, 2H), 3.81 - 3.52 (m, 10H), 3.27 (t, J = 4.3 Hz, 2H), 2.65

[0377] (d, J = 6.6 Hz, 2H). LCMS (m / z): 515.2 (M+H)+, Rt: 2.068 min.

[0378] General procedure for Scheme 4, step 5 (29a-29d).

[0379] To a stirred solution of 9-(l -(difluororaethy1)-1H-pyrazol-4-yl)-A,’-((5-(2,5-dihydro- l / f-pyrrol-3-y1)thiazo1-2-yi)methyl)-2-morpholino-9£?-purin-6-amine hydrochloride (20 Rig, 1 eq) in THF (0.5 raL) was added DIPEA (2.0 eq). The reaction mixture was cooled to 0 °C, then acryloyl chloride (Id eq) in THF (0.5 ml..) was added in drop wise, then stirred at the same temp for 45 min. After completion, the reaction mixture was diluted with 20% MeOH in DCM, washed with 10% NaHCCh and concentrated in vacuo. The crude was purified by Prep.HPLC purification to afford the pure product as an off-white solid.

[0380] Synthesis of l-(3-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9ff-purin-6-yI)amino)methyI)thiazol-5-yl)-2,5-dihydro-lff-pyrroI-l-yl)prop-2-en-l-one (29a).

[0381] Synthesized accordingly procedure described in Scheme 4, step 5 (29a-29d).

[0382] Synthesis of l-(4-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)amino)methyl)thiazol-5-yl)-2,3-dihydro-lH-pyrrol-l-yl)prop-2-en-l-one (29b).

[0383] Synthesized accordingly procedure described in Scheme 4, step 5 (29a-29d). Synthesis of l-(5-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yI)amino)methyl)thiazol-5-yl)-3,6-dihydropyridin-l(2 / f)-yl)prop-2-en-l- one (29c). Synthesized accordingly procedure described in Scheme 4, step 5 (29a-29d).

[0384] Synthesis of l-(4-(2-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yI)-2-morpholino- 9H-purin-6-yI)amino)methyI)thiazol-5-yl)-3,6-dihydropyridin-l(2H)-yl)prop-2-en-l- one (29d). Synthesized accordingly procedure described in Scheme 4, step 5 (29a-29d) Scheme 5

[0385] General procedure for Scheme 5, Step 1.

[0386] Synthesis of tert-butyl ((5-aminopyridin-2-yl)methyl)carbamate (31a).

[0387] To a 2mL MW vial was added tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate 30a (72.7 mg, 0.253 mmol), L-proline (23.3 mg, 0.203 mmol), K2CO3 (105 mg, 0.760 mmol), and Cui (19.2 mg, 0.101 mmol), followed by DMSO (0.5 ml). NH4OH (70.4 pL, 0.506 mmol) was then added and the vial was microwaved at 90 °C for 12 hr. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, dried over sodium sulfate, then concentrated in vacuo. The residue was purified via flash chromatography (hexanes / EtOAc), yielding the pure product as a clear oil (26 mg, 46%).

[0388] LCMS (m / z): 224.1 (M+H)+, Rt: 1.344 min.

[0389] General procedure for Scheme 5, Step 2 and Scheme 6, step 2.

[0390] Synthesis of 6-(aminomethyl)pyridin-3-amine dihydrochloride (32a).

[0391] To a solution of 31a (39 mg, 0. 175 mmol) in EtOAc (4 ml) was added cone. HC1 (0.75mL). The solution was stirred overnight, then the precipitate was filtered off and washed with EtOAc to yield the product as an off-white solid (28 mg, 81 .8%).

[0392] LCMS (m / z): 124.0 (M+H)+, Rt: 0.207 min. Synthesis of tert-butyl ((6-aminopyridin-3-yl)methyl)carbamate (31b).

[0393] Synthesized from tert-butyl ((6-bromopyridin-3-yl)methyl)carbamate 30b according to the general procedure for Scheme 5, Step 1. (30.9mg, 27.4%).

[0394] LCMS (m / z): 224.1 (M+H)+, Rt: 1.448 min.

[0395] Synthesis of 5-(aminomethyl)pyridin-2-amine dihydrochloride (32b).

[0396] Synthesized from 31b according to the general procedure for Scheme 5, Step 2

[0397] (24mg, 88.4%).

[0398] LCMS (m / z): 124.1 (M+H)+, Rt: 0.201 min.

[0399] Scheme 6

[0400] General procedure for Scheme 6, Step 1.

[0401] Synthesis of tert-butyl ((4'-amino-[l,l'-biphenyl]-4-yl)methyl)carbamate (34ca). To a 5mL MW vial was added tert-butyl (4-bromobenzyl)carbamate 30c (300 mg, 1.05 mmol), (4-aminophenyl)boronic acid pinacol ester 33a (344.5 mg, 1.57 mmol), K2CO3 (434.7 mg, 3.14 mmol), and PdiPPhL (121.1 mg, 0.105 mmol), followed by 1,4-dioxane (1.8 ml) and water (0.47 mb). The solution was degassed with argon, then the vial was microwaved at 80 °C for 4 hr. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with water, dried over sodium sulfate, then concentrated in vacuo. The residue was purified via flash chromatography (hexanes / EtOAc), yielding the product as a clear oil (317 mg, 101 %).

[0402] LCMS (m / z): 299.1 (M+H)+, 7?t: 2.405 min.

[0403] Synthesis of 4'-(aminomethyl)-[l,l'-biphenyl]-4-amine dihydrochloride (35ca).

[0404] Synthesized from 34ca according to the general procedure for Scheme 6, Step 2

[0405] (280.5mg, 90.8%).

[0406] LCMS (m / z): 199.1 (M+H)+, 7?t: 0.215 min.

[0407] Synthesis of tert-butyl ((3'-amino-[l,l'-biphenyl]-4-yl)methyl)carbamate (34cb).

[0408] Synthesized from 30c and (3-aminophenyl)boronic acid pinacol ester 33b according to the general procedure for Scheme 6, Step 1 (213.5mg, 102.4%).

[0409] LCMS (zn / z): 299.1 (M+H)+, Rt: 2.447 min.

[0410] Synthesis of 4'-(aminomethyl)-[l,l'-biphenyl]-3-amine dihydrochloride (35cb).

[0411]

[0412] Synthesized from 34cb according to the general procedure for Scheme 6, Step 2 (14L3mg, 77.7%).

[0413] LCMS (m / z): 199.1 (M+H)+, Rt: 0.215 min.

[0414] Synthesis of tot- butyl ((5-(4-aminophenyl)pyridin-2-yl)methyl)carbamate (34aa).

[0415] Synthesized from 30a and 33a according to the general procedure for Scheme 6, Step 1 (311 mg, 99.4%).

[0416] LCMS (m / z): 300.1 (M+H)+, Rt: 1.809 min.

[0417] Synthesis of 4-(6-(aminomethyl)pyridin-3-yl)aniline trihydrochloride (35aa).

[0418] Synthesized from 34aa according to the general procedure for Scheme 6, Step 2 (282.4mg, 88.1%).

[0419] LCMS (m / z): 200.0 (M+H)+, Rt: 0.214 min.

[0420] Synthesis of tot-butyl ((6-(4-aminophenyl)pyridin-3-yl)methyl)carbamate (34ba).

[0421]

[0422] Synthesized from 30b and 33a according to the general procedure for Scheme 6, Step 1 (171mg, 54.7%).

[0423] LCMS (m / z): 300.1 (M+H)+, Rt: 1.732 min. Synthesis of 4-(5-(aminomethyI)pyridin-2-yI)aniline trihydrochloride (35ba).

[0424] Synthesized from 34ba according to the general procedure for Scheme 6, Step 2 (166mg, 94.2%).

[0425] LCMS (m / z): 200.1 (M+H)+, Rt: 0.214 min. Synthesis of tert-butyl ((5-(3-aminophenyl)pyridin-2-yl)methyl)carbamate

[0426] (34ab).

[0427] Synthesized from 30a and 33b according to the general procedure for Scheme 6, Step 1 (92.8mg, 44.5%). LCMS (m / z): 300.1 (M+H)+, Rt: 1.886 min.

[0428] Synthesis of 3-(6-(aminomethyl)pyridin-3-yl)aniline trihydrochloride (35ab).

[0429] Synthesized from 34ab according to the general procedure for Scheme 6, Step 2

[0430] (76.4mg, 79.9%).

[0431] LCMS (m / z): 200.0 (M+H)+, Rt: 0.215 min.

[0432] Synthesis of to t- butyl ((6-(3-aminophenyl)pyridin-3-yl)methyl)carbamate

[0433] (34bb).

[0434] Synthesized from 30b and 33b according to the general procedure for Scheme 6, Step 1 (proceeded without determining yield).

[0435] LCMS (m / zy. 300.1 (M+H)+, Rt: 1.885 min.

[0436] Synthesis of 3-(5-(aminomethyl)pyridin-2-yl)aniline trihydrochloride (35bb).

[0437] Synthesized from 34bb according to the general procedure for Scheme 6, Step 2

[0438] (135.3mg, 40.9% from 30b).

[0439] LCMS (m / z): 200.1 (M+H)+, Rt: 0.214 min. Scheme 7

[0440] 36 32e

[0441] Synthesis of 4-(aminomethyl)-3-fluoroaniline dihydrochloride (32e). To a 5mL RBF under argon was added 4-amino-2-fluorobenzonitrile 36 (100 mg,

[0442] 0.735 mmol) and Raney Ni (47.9 mg), followed by anhydrous MeOH (1.8 mL). While stirring, KBH4 (158.5mg, 2.94 mmol) was added and the reaction heated at 50°C for 1 hr. Once complete, the catalyst was filtered off and the filtrate concentrated in vacuo. The residue was taken up in water and extracted with EtOAc. The organic layer was separated, dried over sodium sulfate, and filtered. Concentrated HC1 was added and the mixture was sonicated. The precipitate was filtered off yielding the product as an orange-brown solid, which was used without further purification (70mg, 44.7%).

[0443] LCMS (m / z)'. 124.1* (M+H)+, Rf. 0.218 min. *fragment corresponding to elimination of NH3

[0444] Scheme 8

[0445] General procedure for Scheme 8, Step 1.

[0446] Synthesis of A,-(4-aniinobenzyl)-9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-amine (37c).

[0447]

[0448] 3 (150 mg, 0.56 mmol) and 4-(aminomethyl)aniline 32c (71.5 mg, 0.585 mmol) were charged into a 5mL MW vial followed by iPrOH (3 ml). DIPEA (291 pL, 1 .67 mmol*) was added and the vial was microwaved at 90 °C for 30 min. The reaction mixture was allowed to reach room temperature, then the precipitate was filtered and added back to the vial. Morpholine (1.5 mL) and dioxane (1.5 mL) were added and the vial was microwaved at 130°C for 20 min. Upon cooling, the mixture was transferred to a flask and concentrated to dryness. The residue was triturated in water and the product filtered off. (120.5mg, 53.7%) * +leq. DIPEA for each HC1 salt equivalent of amines 32a-b, 32e, 35

[0449] LCMS (m / z): 406.2 (M+H)+, Rt: 1.816 min.

[0450] General procedure for Scheme 8, Step 2a.

[0451] Synthesis of 2V-(4-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)phenyl)acrylamide (38c).

[0452] To a stirred solution of 50 mg (0.123 mmol) of 37c in MeCN (2.5mL) was added DIPEA (43 pL, 0.247 mmol). The solution was cooled to 0°C then 13pL (0.16 mmol) of acryloyl chloride in 0.5mL of DCM was added dropwise. After stirring for 1 hour, the reaction was quenched with methanol and concentrated to dryness. The residue was purified by flash chromatography (DCM / MeOH), yielding the product as a white solid (7mg, 12.4%, not all fractions collected).

[0453] LCMS (m / z): 460.2 (M+H)+, Rt: 2.130 min.

[0454] 1H NMR (500 MHz, DMSO) 5 10.08 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.57 (d, 2H), 7.31 (d, 2H), 6.41 (dd, 7 = 17.0, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.72 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.57 (s, 2H), 3.91 (s, 3H), 3.68 - 3.59 (m, 8H).

[0455] Synthesis of Ar-(3-aminobenzyl)-9-(l-methyI-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-amine (37d).

[0456] Synthesized from 3 and 3-(aminomethyl)aniline 32d according to the general procedure for Scheme 8, Step 1 (lOlmg, 44.7%).

[0457] LCMS (m / z): 406.2 (M+H)+, Rt: 1.888 min.

[0458] Synthesis of A'-(3-(((9-(l -methyl- l / / -pyrazol-4-yl)-2-morpholino-9 / / -purin-6- yl)amino)methyl)phenyl)acrylamide (38d).

[0459] Synthesized from 37d according to the general procedure for Scheme 8, Step 2a (5mg, 14.7%, not all fractions collected).

[0460] LCMS (m / z): 460.2 (M+H)+, Rt: 2.330 min.

[0461] ’H NMR (500 MHz, DMSO) 5 10.08 (s, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.53 (d, 7 = 8.0 Hz, 1H), 7.24 (t, 7 = 7.8 Hz, 1H), 7.07 (d, 7 = 7.6 Hz, 1H), 6.41 (dd, 7 = 16.9, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.72 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.59 (s, 2H), 3.91 (s, 3H), 3.66 - 3.57 (m, 8H).

[0462] Synthesis of 7V-(4-aminobenzyl)-9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-amine

[0463] Synthesized from 10 and 32c according to the general procedure for Scheme 8, Step 1 (65mg, 60.2%).

[0464] LCMS (m / z): 442.2 (M+H)+, Rt: 2.043 min.

[0465] Synthesis of A^-(4-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)phenyl)acrylamide (40c).

[0466] Synthesized from 39c according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 496.2 (M+H)+, Rt: 2.594 min.

[0467] ]H NMR (500 MHz, DMSO) 5 10.08 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.92 (t, 7 = 58.8 Hz, 1H), 7.57 (d, 2H), 7.32 (d, 2H), 6.41 (dd, 7 = 17.0,

[0468] 10.2 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.73 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.58 (s, 2H), 3.72 - 3.60 (m, 8H).

[0469] Synthesis of M-(3-aminobenzyl)-9-(l-(difluoromethyl)-l / / -pyrazol-4-yl)-2- morphoIino-9H-purin-6-amine (39d).

[0470]

[0471] Synthesized from 10 and 32d according to the general procedure for Scheme 8, Step 1 (40mg, 34.6%).

[0472] LCMS (m / z): 442.1 (M+H)+, Rt: 2.148 min. Synthesis of Ar-(3-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yl)amino)methyl)phenyI)acrylamide (40d).

[0473] Synthesized from 39d according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 496.2 (M+H)+, Rt: 2.623 min. ]H NMR (500 MHz, DMSO) 5 10.08 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 8.29 (s,

[0474] 1H), 8.27 (s, 1H), 7.92 (t, J = 58.8 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.41 (dd, J = 17.0, 10.1 Hz, 1H), 6.23 (dd, J = 17.0, 2.1 Hz, 1H), 5.72 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.60 (s, 2H), 3.68 - 3.58 (m, 8H).

[0475] Synthesis of A^-((4'-amino-[l,l'-biphenyl]-4-yl)methyl)-9-(l-methyl-lH-pyrazol- 4-yl)-2-morpholino-9H-purin-6-amine (37ca).

[0476]

[0477] Synthesized from 3 and 35ca according to the general procedure for Scheme 8, Step 1 (42.5mg, 47.7%).

[0478] LCMS (m / z): 482.2 (M+H)+, Rt: 2.320 min. Synthesis of A^-(4'-(((9-(l-methyI-l / 7-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-[l,l'-biphenyl]-4-yl)acrylamide (38ca).

[0479] Synthesized from 37ca according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 536.2 (M+H)+, Rt: 2.717 min. ]H NMR (500 MHz, DMSO) 5 10.21 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.16 (s,

[0480] 1H), 7.98 (s, 1H), 7.74 (d, 2H), 7.61 (d, 2H), 7.58 (d, 2H), 7.43 (d, 2H), 6.45 (dd, J = 17.0, 10.2 Hz, 1 H), 6.27 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.76 (dd, 7 = 10.1 , 2.0 Hz, 1 H), 4.65 (s, 2H), 3.91 (s, 3H), 3.69 - 3.60 (m, 8H).

[0481] Synthesis of 2V-((5-(4-aminophenyl)pyridin-2-yl)niethyl)-9-(l-methyl-lH- pyrazol-4-yI)-2-morpholino-9H-purin-6-amine (37aa).

[0482]

[0483] Synthesized from 3 and 35aa according to the general procedure for Scheme 8, Step

[0484] 1 (70mg, 78.3%).

[0485] LCMS (m / z): 483.2 (M+H)+, Rt: 1.891 min. Synthesis of A^-(4-(6-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morphoIino-9H-purin-6- yl)amino)methyl)pyridin-3-yl)phenyl)acrylamide (38aa).

[0486] Synthesized from 37aa according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 537.2 (M+H)+, Rt: 2.155 min. 1H NMR (500 MHz, DMSO) 5 10.28 (s, 1H), 8.80 (d, 1H), 8.31 (s, 1H), 8.22 (s,

[0487] 1H), 8.19 (s, 1H), 8.01 (dd, 7 = 8.2, 2.4 Hz, 1H), 7.99 (s, 1H), 7.79 (d, 2H), 7.69 (d, 2H), 7.39 (d, 7 = 8.2 Hz, 1H), 6.46 (dd, 7 = 16.9, 10.1 Hz, 1H), 6.28 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.78 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.75 (s, 2H), 3.91 (s, 3H), 3.63 - 3.54 (m, 8H).

[0488] Synthesis of A,-((6-(4-aminophenyl)pyridin-3-yl)methyl)-9-(l-methyl-l / / - pyrazol-4-yI)-2-morpholino-9H-purin-6-amine (37ba).

[0489]

[0490] Synthesized from 3 and 35ba according to the general procedure for Scheme 8, Step

[0491] 1 (61.5mg, 57.2%).

[0492] LCMS (m / z): 483.2 (M+H)+, Rt: 1.897 min. Synthesis of Ar-(4-(5-(((9-(l-methyI-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)pyridin-2-yl)phenyl)acrylamide (38ba).

[0493] Synthesized from 37ba according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 537.2 (M+H)+, Rt: 2.182 min. ]H NMR (500 MHz, DMSO) 5 10.30 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H),

[0494] 8.25 (s, 1H), 8.17 (s, 1H), 8.03 (d, 2H), 7.97 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 8.2, 2.2 Hz, 1H), 7.77 (d, 2H), 6.46 (dd, 7 = 16.9, 10.2 Hz, 1H), 6.28 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.77 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.66 (s, 2H), 3.91 (s, 3H), 3.69 - 3.56 (m, 8H).

[0495] Synthesis of Ar-((3'-amino-[l,l'-biphenyI]-4-yI)methyl)-9-(l-methyl-lH-pyrazoI- 4-yl)-2-morpholino-9H-purin-6-amine (37cb).

[0496]

[0497] Synthesized from 3 and 35cb according to the general procedure for Scheme 8, Step 1 (26.1mg, 29.2%).

[0498] LCMS (m / z): 482.2 (M+H)+, Rt: 2.364 min. Synthesis of Ar-(4'-(((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)-[l,l'-biphenyl]-3-yl)acrylamide (38cb).

[0499] Synthesized from 37cb according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 536.2 (M+H)+, Rt: 2.744 min. ]H NMR (500 MHz, DMSO) 5 10.22 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.16 (s,

[0500] 1H), 7.98 (s, 1H), 7.95 (t, 7 = 1.9 Hz, 1H), 7.64 (d, 7 = 8.0, 2.1, 1.1 Hz, 1H), 7.56 (d, 2H), 7.47 (d, 2H), 7.39 (t, 7 = 7.9 Hz, 1H), 7.33 (dt, 7 = 7.8, 1.4 Hz, 1H), 6.45 (dd, 7 = 17.0, 10.2 Hz, 1H), 6.27 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.77 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.67 (s, 2H), 3.91 (s, 3H), 3.69 - 3.59 (m, 8H). Synthesis of 7V-((5-(3-aminophenyl)pyridin-2-yl)methyl)-9-(l-methyl-lH- pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (37ab).

[0501]

[0502] Synthesized from 3 and 35ab according to the general procedure for Scheme 8, Step 1 (35.9mg, 66.7%).

[0503] LCMS (m / z): 483.2 (M+H)+, Rt: 1.947 min. Synthesis of Ar-(3-(6-(((9-(l-methyI-lH-pyrazol-4-yI)-2-morpholino-9H-purin-6- yl)amino)methyl)pyridin-3-yl)phenyl)acrylamide (38ab).

[0504] Synthesized from 37ab according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 537.2 (M+H)+, Rt: 2.213 min. ]H NMR (500 MHz, DMSO) 5 10.30 (s, 1H), 8.75 (d, J= 2.4 Hz, 1H), 8.31 (s, 1H),

[0505] 8.22 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.98 (s, 1H), 7.96 (dd, J = 8.2, 2.4 Hz, 1H), 7.70 (d, J = 8.0, 1.5 Hz, 1H), 7.45 (d, J = 16.2 Hz, 1H), 7.43 (d, J = 17.0 Hz, 1H), 7.39 (dt, 7 = 7.7, 1.5 Hz, 1H), 6.46 (dd, J = 17.0, 10.2 Hz, 1H), 6.28 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.78 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.77 (s, 2H), 3.91 (s, 3H), 3.64 - 3.52 (m, 8H). Synthesis of A,-((6-(3-aminophenyl)pyridin-3-yl)methyl)-9-(l-methyl-l / / - pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (37bb).

[0506]

[0507] Synthesized from 3 and 35bb according to the general procedure for Scheme 8, Step 1.

[0508] LCMS (m / z): 483.2 (M+H)+, Rt: 1.957 min. Synthesis of 2V-(3-(5-(((9-( 1-methyl- lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)methyl)pyridin-2-yl)phenyl)acrylamide (38bb).

[0509] Synthesized from 37bb according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 537.2 (M+H)+, Rt: 2.279 min. ]H NMR (500 MHz, DMSO) 5 10.28 (s, 1H), 8.68 (s, 1H), 8.36 (t, J = 2.0 Hz, 1H),

[0510] 8.31 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.89 - 7.83 (m, 2H), 7.79 (dd, 1H), 7.71 (dt, 7 = 8.0, 1.3 Hz, 1H), 7.42 (t, 7 = 7.9 Hz, 1H), 6.46 (dd, 7 = 17.0, 10.1 Hz, 1H), 6.28 (dd, 7= 17.0, 1.9 Hz, 1H), 5.77 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.68 (s, 2H), 3.91 (s, 3H), 3.69 - 3.57 (m, 8H). Synthesis of A^-((4'-amino-[l,l'-biphenyl]-4-yl)methyl)-9-(l-(difluoromethyl)-

[0511] LH-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (39ca).

[0512]

[0513] Synthesized from 10 and 35ca according to the general procedure for Scheme 8, Step 1 (25mg, 29.5%).

[0514] LCMS (m / z): 518.1 (M+H)+, Rt: 2.662 min.

[0515] Synthesis of A^-(4'-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)-[l,l'-biphenyl]-4-yl)acrylamide (40ca).

[0516] Synthesized from 39ca according to the general procedure for Scheme 8, Step 2a.

[0517] LCMS (m / z): 572.2 (M+H)+, Rt: 2.960 min.

[0518] ‘H NMR (500 MHz, DMSO) 8 10.21 (s, 1H), 8.84 (s, 1 H), 8.46 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 7.92 (t, 7 = 58.8 Hz, 1H), 7.74 (d, 2H), 7.61 (d, 2H), 7.58 (d, 2H), 7.43 (d, 7 = 8.2 Hz, 2H), 6.45 (dd, 7= 17.0, 10.1 Hz, 1H), 6.27 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.76 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.66 (s, 2H), 3.72 - 3.60 (m, 8H).

[0519] Synthesis of Ar-((5-(4-aminophenyl)pyridin-2-yl)methyl)-9-(l-(difluoromethyl)- LH-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (39aa).

[0520]

[0521] Synthesized from 10 and 35aa according to the general procedure for Scheme 8, Step 1 (46.3mg, 54.5%).

[0522] LCMS (m / z): 519.1 (M+H)+, Rt: 2.156 min. Synthesis of jV-(4-(6-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morphoIino-

[0523] 9H-purin-6-yI)amino)methyl)pyridin-3-yl)phenyl)acrylamide (40aa).

[0524] Synthesized from 39aa according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 573.1 (M+H)+, Rt: 2.413 min. ]H NMR (500 MHz, DMSO) 5 10.27 (s, 1H), 8.85 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H),

[0525] 8.47 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.99 (dd, 7 = 8.1, 2.4 Hz, 1H), 7.92 (t, 7 = 58.8 Hz, 1H), 7.78 (d, 2H), 7.69 (d, 2H), 7.38 (d, 7 = 8.2 Hz, 1H), 6.45 (dd, 7 = 17.0, 10.1 Hz, 1H), 6.28 (dd, 7 = 16.9, 2.0 Hz, 1H), 5.78 (dd, 7= 10.1, 2.0 Hz, 1H), 4.76 (s, 2H), 3.70 - 3.52 (m, 8H).

[0526] Synthesis of 7V-((6-(4-aminophenyl)pyridin-3-yl)methyl)-9-(l-(difluoromethyl)- LH-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (39ba).

[0527] Synthesized from 10 and 35ba according to the general procedure for Scheme 8, Step 1 (16mg, 15.7%).

[0528] LCMS (m / z): 519.2 (M+H)+, Rt: 2.194 min.

[0529] Synthesis of Ar-(4-(5-(((9-(l-(difluoromethyl)-l / / -pyrazol-4-yl)-2-morphoIino- 9H-purin-6-yI)amino)methyI)pyridin-2-yl)phenyl)acrylamide (40ba).

[0530] Synthesized from 39ba according to the general procedure for Scheme 8, Step 2a.

[0531] LCMS (m / z): 573.2 (M+H)+, Rt: 2.443 min.]H NMR (500 MHz, DMSO) 5 10.28 (s, 1H), 8.83 (s, 1H), 8.64 (d, 7 = 2.2 Hz, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.92 (t, J = 59.0 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.3, 2.3 Hz, 1H), 7.77 (d, 2H), 6.46 (dd, J = 16.9, 10.1 Hz, 1H), 6.28 (dd, 7 = 16.9, 2.0 Hz, 1H), 5.77 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.67 (s, 2H), 3.71 - 3.59 (m, 8H).

[0532] Synthesis of A^-((3'-amino-[l,l'-biphenyl]-4-yl)methyl)-9-(l-(difluoromethyl)- LH-pyrazol-4-yI)-2-morpholino-9H-purin-6-amine (39cb).

[0533] Synthesized from 10 and 35cb according to the general procedure for Scheme 8, Step 1 (36mg, 42.4%).

[0534] LCMS (m / z): 518.2 (M+H)+, Rv. 2.667 min.

[0535] Synthesis of A,-(4'-(((9-(l-(difluoromethyl)-l / / -pyrazol-4-yl)-2-morpholino-9 / / - purin-6-yl)amino)methyI)-[l,l'-biphenyl]-3-yl)acrylamide (40cb). Synthesized from 39cb according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 572.2 (M+H)+, Rt: 2.983 min.

[0536] ]H NMR (500 MHz, DMSO) 5 10.22 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 7.95 (t, 7 = 2.0 Hz, 1 H), 7.92 (t, J = 58.8 Hz, 1 H), 7.64 (d, lH), 7.56 (d, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.33 (dt, J = 7.9, 1.4 Hz, 1H), 6.45 (dd, 7 = 17.0, 10.2 Hz, 1H), 6.27 (dd, 7= 17.0, 2.0 Hz, 1H), 5.77 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.68 (s, 2H), 3.71 - 3.60 (m, 8H).

[0537] Synthesis of Ar-((5-(3-aminophenyl)pyridin-2-yl)methyl)-9-(l-(difluoromethyl)- LH-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (39ab). Synthesized from 10 and 35ab according to the general procedure for Scheme 8,

[0538] Step 1 (47.8mg, 76%).

[0539] LCMS (m / z): 519.1 (M+H)+, Rt: 2.224 min.

[0540] Synthesis of A^-(3-(6-(((9-(l-(difluoromethyI)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)amino)inethyl)pyridin-3-yl)phenyl)acrylamide (40ab).

[0541] Synthesized from 39ab according to the general procedure for Scheme 8, Step 2a.

[0542] LCMS (m / z): 573.2 (M+H)+, Rt: 2.481 min.]H NMR (500 MHz, DMSO) 5 10.28 (s, 1H), 8.85 (s, 1H), 8.76 (d, 7 = 2.4 Hz, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.96 (dd, J = 8.1, 2.4 Hz, 1H), 7.92 (t, J = 58.8 Hz, 1H), 7.70 (d, 1H), 7.45 (d, J = 16.2 Hz, 1H), 7.43 (d, J = 16.9 Hz, 1H), 7.39 (dt, 7 = 7.7, 1.4 Hz, 1H), 6.46 (dd, 7 = 17.0, 10.2 Hz, 1H), 6.28 (dd, 7 = 17.0, 1.9 Hz, 1H), 5.78 (dd, 7= 10.1, 2.0 Hz, 1H), 4.77 (s, 2H), 3.63 - 3.55 (m, 8H).

[0543] Synthesis of A^-((6-(3-aminophenyl)pyridin-3-yl)methyl)-9-(l-(difluoromethyl)- lH-pyrazol-4-yI)-2-morpholino-9H-purin-6-amine (39bb).

[0544] Synthesized from 10 and 35bb according to the general procedure for Scheme 8, Step l .

[0545] LCMS (m / z): 519.2 (M+H)+, Rt: 2.194 min.

[0546] Synthesis of A^-(3-(5-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yI)amino)methyI)pyridin-2-yI)phenyl)acrylamide (40bb). Synthesized from 39bb according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 573.2 (M+H)+, Rt: 2.555 min.

[0547] ]H NMR (500 MHz, DMSO) 5 10.28 (s, 1H), 8.84 (s, 1H), 8.69 (s, 1H), 8.52 - 8.22 (m, 4H), 8.1 1 - 7.82 (m, 3H), 7.79 (d, J = 10.3 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.42 (t, 1H), 6.46 (dd, J = 17.2, 9.7 Hz, 1H), 6.27 (dd, 7 = 17.2 Hz, 1H), 5.77 (dd, 7 = 10.2 Hz, 1H), 4.69 (s, 2H), 3.90 - 3.50 (m, 8H).

[0548] Synthesis of A'-((5-aminopyridin-2-yl)methyl)-9-(l-(difluoromethyl)-l / / - pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (39a).

[0549] Synthesized from 10 and 32a according to the general procedure for Scheme 8, Step 1 (40mg, 78.8%).

[0550] LCMS (m / z): 443.1 (M+H)+, Rt: 1.843 min.

[0551] Synthesis of . / V-(6-(((9-(l -(difluorometh yl)-l / / -pyrazol-4-yl)-2-morpholino-9 / / - purin-6-yl)amino)methyI)pyridin-3-yl)acrylamide (40a). Synthesized from 39a according to the general procedure for Scheme 8, Step 2a.

[0552] LCMS (m / z): 497.1 (M+H)+, Rt: 2.165 min.]H NMR (500 MHz, DMSO) 5 10.33 (s, 1H), 8.84 (s, 1H), 8.74 (d, 7 = 2.5 Hz, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.01 (dd, J = 8.5, 2.6 Hz, 1H), 7.92 (t, 7 = 58.8 Hz, 1H), 7.31 (d, 7 = 8.5 Hz, 1H), 6.43 (dd, 7 = 17.0, 10.1 Hz, 1H), 6.27 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.79 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.74 - 4.64 (m, 2H), 3.65 - 3.53 (m, 8H).

[0553] Synthesis of A,-((6-aininopyridin-3-yl)methyl)-9-(l-(difluoromethyl)-l / / - pyrazol-4-yl)-2-morpholino-9H-purin-6-amine (39b).

[0554] Synthesized from 10 and 32b according to the general procedure for Scheme 8, Step 1 (34mg, 45.1%).

[0555] LCMS (m / z): 443.1 (M+H)+, Rt: 1.864 min.

[0556] Synthesis of Ar-(5-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yI)-2-morpholino-9H- purin-6-yl)amino)methyl)pyridin-2-yl)acryIamide (40b).

[0557] Synthesized from 39b according to the general procedure for Scheme 8, Step 2a (3.6mg, 9.44%).

[0558] LCMS (m / Zy 497.1 (M+H)+, Rt: 2.378 min.

[0559] !H NMR (500 MHz, DMSO) 5 10.68 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.29 (d, 2H), 8.12 (d, 7 = 8.5 Hz, 1H), 8.05 - 7.77 (m, 2H), 6.58 (dd, 7 = 17.0, 10.2 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.76 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.59 (s, 2H), 3.71 - 3.61 (m, 8H).

[0560] Synthesis of 7V-(4-amino-2-fluorobenzyl)-9-(l-(difluoromethyl)-lH-pyrazol-4- yl)-2-morpholino-9H-purin-6-amine (39e).

[0561] Synthesized from 10 and 32e according to the general procedure for Scheme 8, Step 1 (73mg, 88.1%).

[0562] LCMS (m / z): 460.1 (M+H)+, Rt: 2.521 min.

[0563] Synthesis of A^-(4-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)methyl)-3-fluorophenyl)acrylamide (40e).

[0564] Synthesized from 39e according to the general procedure for Scheme 8, Step 2a. LCMS (m / z): 514.2 (M+H)+, Rt: 2.693 min.

[0565] ’H NMR (500 MHz, DMSO) 5 10.28 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.92 (t, J = 58.8 Hz, 1H), 7.67 (dd, J = 12.6, 2.0 Hz, 1H), 7.34 (t, J = 8.5

[0566] Hz, 1H), 7.24 (dd, J = 8.4, 2.0 Hz, 1H), 6.40 (dd, 7 = 16.9, 10.1 Hz, 1H), 6.26 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.77 (dd, 7 = 10.0, 1.9 Hz, 1H), 4.62 (s, 2H), 3.69 - 3.59 (m, 8H). Synthesis of tert-butyl 4-(((9-(l-(difhioromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyI)piperidine-l -carboxylate (42a).

[0567] Boo

[0568] Synthesized from 10 and tert-butyl 4-(aminomethyl)piperidine- 1 -carboxylate 41a according to the general procedure for Scheme 8, Step 1 (84.2mg, 96.2%).

[0569] LCMS (m / z): 534.2 (M+H)+, Rt: 3.108 min.

[0570] General procedure for Scheme 8, Step 2b

[0571] Synthesis of l-(4-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yl)amino)methyl)piperidin-l-yl)prop-2-en- 1-one (43a).

[0572] To a stirred solution of 84 mg (0.157 mmol) of 42a in EtOAc (3mL) was added cone. HC1 (0.5mL). The solution was stirred overnight then concentrated to dryness. MeCN (2.5mL) was added followed by DIPEA (59 pL, 0.339 mmol). The solution was cooled to 0°C then l lpL (0.136 mmol) of acryloyl chloride in 0.5mL of DCM was added dropwise. After stirring for 1 hour, the reaction was quenched with methanol and concentrated to dryness. The residue was purified by flash chromatography (DCM / MeOH), yielding the product as a white solid (not all fractions collected). LCMS (m / z): 488.2 (M+H)+, Rt: 2A97 min.

[0573] ]H NMR (500 MHz, DMSO) 5 8.84 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.92 (t, J = 58.8 Hz, 1 H), 7.74 (s, 1 H), 6.79 (dd, J = 16.7, 10.5 Hz, 1H), 6.06 (dd, J = 16.7, 2.5 Hz, 1H),

[0574] 5.63 (dd, J = 10.5, 2.4 Hz, 1H), 4.39 (d, J = 12.9 Hz, 1H), 4.03 (d, J= 13.6 Hz, 1H), 3.71 -

[0575] 3.64 (m, 8H), 3.40 - 3.33 (m, 2H), 3.00 (t, 7 = 12.7 Hz, 1H), 2.61 (t, 7 = 13.5 Hz, 1H), 1.93 (s, 1H), 1.72 (s, 2H), 1.15 - 1.01 (m, 2H).

[0576] Synthesis of tert-butyl 3-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H -purin -6-yl)amino)methyl)pyrrolidine- 1 -carboxylate (42b) .

[0577] Synthesized from 10 and tert-butyl 3-(aminomethyl)pyrrolidine-l -carboxylate 41b according to the general procedure for Scheme 8, Step 1 (81mg, 95.1%).

[0578] LCMS (m / z): 520.2 (M+H)+, Rt: 2.981 min.

[0579] Synthesis of l-(3-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yl)amino)methyl)pyrrolidin- l-yl)prop-2-en- 1-one (43b).

[0580] Synthesized from 42b according to the general procedure for Scheme 8, Step 2b.

[0581] LCMS (m / z): 474.2 (M+H)+, Rt: 2.395 min.

[0582] ’H NMR (500 MHz, DMSO) 5 8.85 (s, 1H), 8.47 (s, 1H), 8.29 (d, J = 1.0 Hz, 1H), 7.93 (t, J = 58.8 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 6.57 (dd, 0.5H), 6.52 (dd, 0.5H), 6.13 (dd, 7 = 5.2, 2.4 Hz, 0.5H), 6.10 (dd, 7 = 5.3, 2.5 Hz, 0.5H), 5.64 (td, 7 = 10.7, 2.5 Hz, 1H), 3.67 (m, 9H), 3.58 - 3.34 (m, 4.5H), 3.22 (dd, 7 = 12.3, 6.6 Hz, 0.5H), 2.69 - 2.60 (m, 1H), 2.05 - 1.88 (m, 1H), 1.80 - 1.63 (m, 1H).

[0583] Synthesis of tert-butyl (l / ?,3r,5S’)-3-(((9-(l-(difluoroinethyl)-l / / -pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyI)-8-azabicycIo[3.2.1]octane-8-carboxyIate (42c).

[0584] Synthesized from 10 and tert-butyl (12?,3r,5S)-3-(aminomethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate 41c according to the general procedure for Scheme 8, Step 1.

[0585] LCMS (m / z): 560.3 (M+H)+, Rt: 3.208 min.

[0586] Synthesis of l-((l / ?,3r,5S)-3-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)methyI)-8-azabicycIo[3.2.1 ]octan-8-yl)prop-2-en-l- one (43c).

[0587] Synthesized from 42c according to the general procedure for Scheme 8, Step 2b.

[0588] LCMS (m / z): 514.2 (M+H)+, Rt: 2.583 min.]H NMR (500 MHz, DMSO) 5 8.83 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.92 (t, 7 = 58.8 Hz, 1H), 7.86 - 7.81 (m, 1H), 6.67 (dd, J = 16.7, 10.4 Hz, 1H), 6.14 (dd, J= 16.7, 2.5 Hz, 1H), 5.64 (dd, J = 10.3, 2.4 Hz, 1H), 4.49 - 4.39 (m, 2H), 3.71 - 3.63 (m, 8H), 3.64 - 3.53 (m, 2H), 2.14 - 2.04 (m, 1H), 2.03 - 1.94 (m, 3H), 1.90 - 1.81 (m, 3H), 1.57 (d, J =

[0589] Synthesized from 10 and tert-butyl (lR,3.y,5S)-3-(aminomethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate 41d according to the general procedure for Scheme 8, Step 1.

[0590] LCMS (m / z): 560.3 (M+H)+, Rt: 3.211 min.

[0591] Synthesis of l-((lZf,3s,5S)-3-(((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2- morphoIino-9H-purin-6-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-l- one (43d).

[0592] Synthesized from 42d according to the general procedure for Scheme 8, Step 2b. LCMS (m / z): 514.2 (M+H)+, Rt: 2.583 min.

[0593] ]H NMR (500 MHz, DMSO) 5 8.83 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.92 (t, J = 58.8 Hz, 1 H), 7.66 (s, 1 H), 6.68 (dd, J = 16.7, 10.3 Hz, 1 H), 6.14 (dd, 7 = 16.6, 2.4 Hz, 1H), 5.65 (dd, 7 = 10.3, 2.5 Hz, 1H), 4.53 - 4.44 (m, 2H), 3.69 - 3.65 (m, 8H), 3.26 - 3.18 (m, 2H), 2.44 - 2.31 (m, 1H), 1.98 - 1.88 (m, 1H), 1.84 - 1.75 (m, 1H), 1.74 - 1.65 (m, 2H),

[0594] 1.66 - 1.57 (m, 2H), 1.39 - 1.31 (m, 1H), 1.29 - 1.17 (m, 1H).

[0595] Scheme 9

[0596] General procedure for Scheme 9, Step 1. Synthesis of tert-butyl (9-( 1 -methyl- lH-pyrazoI-4-yl)-2-morpholino-9H-purin-6- yl)glycinate (45).

[0597]

[0598] 3 (350 mg, 1.3 mmol) and tert-butyl glycinate hydrochloride 44 (218 mg, 1.3 mmol) were charged into a 20mL MW vial followed by nBuOH (7 ml). DIPEA (567 pL, 3.25 mmol) was added and the vial was microwaved at 90 °C for 30 min. Once cooled, morpholine (7 mL) was added and the vial was microwaved at 130°C for 20 min. Upon cooling, the mixture was transferred to a flask and concentrated to dryness. The residue was triturated in water and the product filtered off as white solid (466mg, 86%).

[0599] LCMS (m / z): 415.2 (M+H)+, Rt: 2.515 min.

[0600] General procedure for Scheme 9, Step 2.

[0601] Synthesis of (9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6-yl)glycine trifluoroacetate (46).

[0602] To 466 mg (1.12 mmol) of 45 in a 50mL flask was added 16mL of DCM. While stirring, 4mL of trifluoroacetic acid was added. After stirring overnight, the reaction was concentrated to dryness and Et20 was added. The flask was sonicated, causing the product to precipitate. The solid was filtered off, yielding the product as a white solid (521mg, 98%)

[0603] LCMS (m / z): 359.1 (M+H)+, Rt: 1.836 min.

[0604] Synthesis of tert-butyl (9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)glycinate (50).

[0605]

[0606] Synthesized from 10 according to the general procedure for Scheme 9, Step 1 (244mg, 94.4%).

[0607] LCMS (m / z): 451.2 (M+H)+, Rt: 2.805 min. Synthesis of (9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)glycine (51).

[0608] Synthesized from 50 according to the general procedure for Scheme 9, Step 2 (214.3mg, 100.32%). LCMS (m / z): 395.1 (M+H)+, Rt: 2.099 min.

[0609] Synthesis of tert-butyl 4-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morphoIino-9H- purin-6-yl)amino)acetamido)piperidine-l-carboxylate (54a).

[0610] General procedure for Scheme 9, Step 3.

[0611] Boc

[0612] A 5mL flask was charged with 46 (25 mg, 0.053 mmol), / <? / 7-bulyl 4- aminopiperidine- 1 -carboxylate 53a (10.6 mg, 0.053 mmol), and HATU (20.1 mg, 0.053 mmol). DCM (ImL) was added, followed by triethylamine (29.5 pL, 0.212 mmol), and the reaction was left to stir overnight. The reaction was poured into a separatory funnel with additional DCM and washed with water. The organic layer was separated and dried over sodium sulfate, then filtered and concentrated to yield the crude product (28.8mg, 100.7%, impure).

[0613] LCMS (m / z): 541.3 (M+H)+, Rt: 2.367 min. General procedure for Scheme 9, Step 4.

[0614] Synthesis of A^-(l-acryloylpiperidin-4-yI)-2-((9-(l-methyl-l / f-pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)acetamide (55a).

[0615] To a lOmL flask containing 54a (28mg, 0.052 mmol) was added DCM (1.5mL) and TFA (0.25mL). The reaction was stirred for 1 hour (or overnight) then concentrated to dryness. MeCN (2mL) and DMF (0.5mL) were added, followed by TEA (72 pL, 0.518 mmol), then the mixture was cooled to 0°C. Acryloyl chloride (4.72 pL, 0.058 mmol) was added and left to stir for 1 hour. The reaction was quenched with methanol then concentrated to dryness. The residue was purified by flash chromatography (DCM / MeOH), yielding the product as a white solid (11.6mg, 45.3%).

[0616] LCMS (m / z): 495.2 (M+H)+, Rt: 1.894 min.

[0617] Synthesis of tert-butyl (S)-3-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)amino)acetamido)piperidine-l -carboxylate (54b).

[0618] Synthesized from 46 and tert -butyl CS j-3-ami nopiperidine- 1 -carboxylate 53b according to the general procedure for Scheme 9, Step 3 (36.5mg, 127.6%, crude).

[0619] LCMS (m / z): 541.3 (M+H)+, Rt: 2.383 min. Synthesis of (S)-Ar-(l-acryloylpiperidin-3-yl)-2-((9-(l-methyl-lH-pyrazol-4-yl)-

[0620] 2-morpholino-9H-purin-6-yl)amino)acetamide (55b).

[0621] Synthesized from 54b according to the general procedure for Scheme 9, Step 4 (13.6mg, 53.1%). LCMS (m / z): 495.2 (M+H)+, Rt: 1.929 min.

[0622] Synthesis of tert-butyl (7?)-3-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)amino)acetamido)piperidine-l -carboxylate (54c).

[0623] Synthesized from 46 and tert-butyl (R)-3 -aminopiperidine- 1 -carboxylate 53c according to the general procedure for Scheme 9, Step 3 (30.6mg, 111.4%, crude).

[0624] LCMS (m / z): 541.3 (M+H)+, Rt: 2.383 min.

[0625] Synthesis of (Z?)-M-(l-acryloylpiperidin-3-yl)-2-((9-(l-methyl-lH-pyrazol-4-yl)- 2-morpholino-9H-purin-6-yl)amino)acetamide (55c).

[0626] Synthesized from 54c according to the general procedure for Scheme 9, Step 4.

[0627] LCMS (m / z): 495.2 (M+H)+, Rt: 1.929 min.

[0628] Synthesis of tert-butyl (S)-3-(2-((9-(l-methyl-lH-pyrazoI-4-yl)-2-morpholino- 9H-purin-6-yl)amino)acetamido)pyrrolidine- 1 -carboxylate (54d). Synthesized from 46 and tert-butyl (.S')-3-ami nopyrrolidine- 1 -carboxylate 53d according to the general procedure for Scheme 9, Step 3 (28mg, 100.5%, crude).

[0629] LCMS (m / z): 527.3 (M+H)+, Rt: 2.273 min.

[0630] Synthesis of (S)-Ar-(l-acryloylpyrrolidin-3-yl)-2-((9-(l-methyl-lH-pyrazol-4-yl)- 2-morpholino-9H-purin-6-yI)amino)acetamide (55d).

[0631] Synthesized from 54d according to the general procedure for Scheme 9, Step 4 (14.4mg, 56.8%).

[0632] LCMS (m / z): 481.1 (M+H)+, Rt: 1.827 min. Synthesis of tert-butyl ( / ?)-3-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-

[0633] 9H-purin-6-yI)amino)acetamido)pyrrolidine- 1 -carboxylate (54e).

[0634] Synthesized from 46 and fert-butyl (7? )-3 -ami nopyrrolidine- 1 -carboxy late 53e according to the general procedure for Scheme 9, Step 3 (32mg, 114.8%, crude). LCMS (m / z): 527.3 (M+H)+, Rt: 2.274 min.

[0635] Synthesis of (Z?)-M-(l-acryloylpyrrolidin-3-yl)-2-((9-(l-methyl-lH-pyrazol-4-yl)- 2-morpholino-9H-purin-6-yI)amino)acetamide (55e).

[0636]

[0637] Synthesized from 54e according to the general procedure for Scheme 9, Step 4 (12.3mg, 48.5%).

[0638] LCMS (m / z): 481.1 (M+H)+, Rt: 1.828 min. Synthesis of tert-butyl 6-(2-((9-(l-methyl-lH-pyrazoI-4-yl)-2-morpholino-9H- purin-6-yI)amino)acetamido)-2-azaspiro[3.3]heptane-2-carboxylate (54f).

[0639] Synthesized from 46 and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate 53f according to the general procedure for Scheme 9, Step 3 (23.5mg, 80.4%). LCMS (m / z): 553.3 (M+H)+, Rt: 2.398 min.

[0640] Synthesis of M-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-2-((9-(l-methyl-lH- pyrazol-4-yl)-2-morpholino-9H-purin-6-yl)amino)acetamide (55f).

[0641]

[0642] Synthesized from 54f according to the general procedure for Scheme 9, Step 4.

[0643] LCMS (m / z): 507.1 (M+H)+, Rt: 1.918 min.

[0644] Synthesis of / ( / / -butyl (S)-3-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino- 9H-purin-6-yl)amino)acetamido)piperidine-l -carboxylate (56b).

[0645] Synthesized from 51 and 53b according to the general procedure for Scheme 9, Step 3 (37.3mg, 127.6%, crude).

[0646] LCMS (m / z): 577.3 (M+H)+, Rt: 2.625 min. Synthesis of (S)- / V-(l-acryloylpiperidin-3-yI)-2-((9-( 1 -methyl- lH-pyrazol-4-yl )-

[0647] 2-morpholino-9H-purin-6-yl)amino)acetamide (57b).

[0648]

[0649] Synthesized from 56b according to the general procedure for Scheme 9, Step 4.

[0650] LCMS (m / z): 531.2 (M+H)+, Rt: 2.167 min.

[0651] Synthesis of tert-butyl (3-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)acetamido)phenyl)carbamate (48b).

[0652] Synthesized from 46 and tert-butyl (3-aminophenyl)carbamate 47b according to the general procedure for Scheme 9, Step 3 (40mg, 140.4%, crude).

[0653] LCMS (m / z): 549.3 (M+H)+, Rt: 2.547 min. Synthesis of 7V-(3-(2-((9-(l -methyl-lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)acetamido)phenyl)acrylamide (49b).

[0654] Synthesized from 48b according to the general procedure for Scheme 9, Step 4. LCMS (m / z): 503.2 (M+H)+, Rt: 2.131 min.

[0655] 'H NMR (500 MHz, DMSO) 5 10.13 (s, 1H), 10.10 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.36 (d, J = 8.2, 1.6 Hz, 1H), 7.30 (d, J = 8.3,

[0656] 1.4 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.44 (dd, J = 16.9, 10.2 Hz, 1H), 6.24 (dd, J= 17.0, 2.0 Hz, 1H), 5.74 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.12 (s, 2H), 3.91 (s, 3H), 3.66 - 3.59 (m, 4H), 3.55 - 3.51 (m, 4H).

[0657] Synthesis of tert- butyl (4-(2-((9-(l-methyl-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yl)amino)acetamido)phenyl)carbamate (48a).

[0658] Synthesized from 46 and tert-butyl (4-aminophenyl)carbamate 47a according to the general procedure for Scheme 9, Step 3 (41.3mg, 118.5%, crude).

[0659] LCMS (m / z): 549.3 (M+H)+, Rt: 2.504 min. Synthesis of / V-(4-(2-({9-( 1 -methyl- lH-pyrazol-4-yl)-2-morpholino-9H-purin-6- yl)amino)acetamido)phenyl)acrylamide (49a).

[0660]

[0661] Synthesized from 48a according to the general procedure for Scheme 9, Step 4 (7mg, 24%).

[0662] LCMS (m / z): 503.2 (M+H)+, Rt: 2.064 min.

[0663] ’H NMR (500 MHz, DMSO) 5 10.09 (s, 1H), 10.05 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.59 (d, J = 9.1 Hz, 2H), 7.53 (d, 2H), 6.41 (dd, J = 16.9, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.72 (dd, 7 = 10.1, 2.0 Hz, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 3.65 - 3.60 (m, 4H), 3.56 - 3.52 (m, 4H).

[0664] Synthesis of tert-butyl (3-(2-((9-(l-(difluoromethyl)-l / / -pyrazol-4-yl)-2- morpholino-9H-purin-6-yl)amino)acetamido)phenyl)carbamate (52b).

[0665] Synthesized from 51 and tert-butyl (3-aminophenyl)carbamate 47b according to the general procedure for Scheme 9, Step 3 (36mg, 97.1 %, crude).

[0666] LCMS (m / z): 585.2 (M+H)+, Rt: 2.786 min.

[0667] Synthesis of lV-(3-(2-((9-(l-(difhioromethyl)-l.H-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)acetamido)phenyI)acrylamide (53b).

[0668] Synthesized from 52b according to the general procedure for Scheme 9, Step 4 (32.6mg, 97.8%).

[0669] LCMS (m / z): 539.2 (M+H)+, Rt: 2.373 min. ]H NMR (500 MHz, DMSO) 5 10.14 (s, 1H), 10.12 (s, 1H), 8.85 (s, 1H), 8.46 (s,

[0670] 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.92 (t, 7 = 58.8 Hz, 1H), 7.89 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.23 (t, 7 = 8.1 Hz, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.24 (dd, 7 = 17.0, 2.0 Hz, 1H), 5.73 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.13 (s, 2H), 3.67 - 3.61 (m, 4H), 3.56 - 3.48 (m, 4H).

[0671] Synthesis of tert-butyl (4-(2-((9-(l-(difluoromethyl)-LH-pyrazol-4-yl)-2- morphoIino-9H-purin-6-yl)amino)acetamido)phenyI)carbamate (52a).

[0672] Synthesized from 51 and te / 't-butyl (4-aminophenyl)carbamate 47a according to the general procedure for Scheme 9, Step 3 (57mg, 153.8%, crude).

[0673] LCMS (m / z): 585.2 (M+H)+, Rt: 2.734 min. Synthesis of A-(4-(2-((9-(l-(difluoromethyl)-lH-pyrazol-4-yl)-2-morpholino-9H- purin-6-yI)amino)acetamido)phenyl)acrylamide (53a).

[0674] Synthesized from 52a according to the general procedure for Scheme 9, Step 4 (33mg, 99%).

[0675] LCMS (m / z): 539.2 (M+H)+, Rt: 2.315 min.

[0676] ]H NMR (500 MHz, DMSO) 5 10.07 (s, 1H), 10.05 (s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.92 (t, J = 58.8 Hz, 1H), 7.88 (s, 1H), 7.59 (d, 2H), 7.53 (d, 2H), 6.41 (dd, 7 = 16.9, 10.1 Hz, 1H), 6.23 (dd, 7 = 17.0, 2.1 Hz, 1H), 5.72 (dd, 7 = 10.1, 2.1 Hz, 1H), 4.12 (s, 2H), 3.67 - 3.61 (m, 4H), 3.56 - 3.52 (m, 4H).

[0677] Table 2. Biological activity of CDK12 / 13 covalent inhibitors

[0678] Different human cancers involve deregulation of transcription-CDKs processes. CDK9 was considered the only transcription-CDK with a causative role in cancer until recently. New evidence supports the importance of CDK12 in transcription and RNA processing, maintaining genomic stability / integrity and tumorigenesis. This chemical series offers new opportunities for treatment of cancers with CDK12 mutations and defective DNA repair.

[0679] In view of the described compounds, compositions, and methods, hereinbelow are described certain more particular aspects of the disclosure. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein, or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulae literally used therein.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula IwhereinR1is phenyl, monocyclic heteroaryl, or bicyclic heteroaryl, each of which is substituted with an amide-containing group that optionally contains Ci-6 alkyl, C4-6 cycloalkyl, C4-6 cycloheteroalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-6 cycloheteroalkenyl, C2-6 alkynyl, phenyl, pyridinyl, benzyl, or styrenyl, any of which are optionally substituted with one or more halo, cyano, nitro, amino, alkylamino, CF3, SO2F, or aryl substituted with CF3 or SO2F;R2is morpholino or piperazinyl optionally substituted with one or more methyl; and R3is pyrazol substituted with C1-6 alkyl or C 1-6 haloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the amide-containing group is pyrrol or pyrazol that is N-substituted with C(O)Ci-6 alkyl, C(O)C2-6 alkenyl, or C(O)C2-6 alkynyl.

3. The compound of any one of the previous claims, wherein R1is phenyl, thiazonyl, oxazonyl, pyridinyl, or benzoimidazolyl.

4. The compound of any one of the previous claims, wherein R1is benzoimadazolyl substituted with acrylamide or propionamide, acrylamide.

5. The compound of any one of the previous claims, wherein the compound is in Table 1.

6. A compound of Formula IIwhereinR5is H or methyl;R4is C4-8 cycloalkyl, C4-8 cycloheteroalkyl, C4-8 cycloalkenyl, C4-8 cycloheteroalkenyl, C4-12 bicycloalkyl, C4-12 bicycloheteroalkyl, C4-12 bicycloalkenyl, C4-12 bicycloheteroalkenyl, C5-12 spiroalkyl, C5-12 spiroheteroalkyl, each of which is substituted with an amide-containing group or a carboxy containing group substituted with C1-6 alkyl, C4-6 cycloalkyl, C4-6 cycloheteroalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, or C4-6 cycloheteroalkenyl, any of which are optionally substituted with acrylamide; and each of which are optionally substituted with one or more halo, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, C(0)Ci-6 alkyl, C(O)C2-6 alkenyl, or CF3;R2is morpholino or piperazinyl optionally substituted with one or more methyl; and R3is pyrazol substituted with C1-6 alkyl or C1-6 haloalkyl; or a pharmaceutically acceptable salt thereof.

7. The compound of any one of the previous claims, wherein R2is morpholino.

8. The compound of any one of the previous claims, wherein R2is piperazinyl.

9. The compound of any one of the previous claims, wherein R3is pyrazol substituted with CHF2.

10. A method of treating cancer, comprising: administering a therapeutically effective amount of the compound of any one of the previous claims to a patient in need thereof.

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