Casein kinase (CK1) inhibitors and methods of use thereof

Abstract

The present application relates to compounds of Formula (I) or an enantiomer thereof, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. The application relates to compositions comprising these compounds, to processes for their preparation, and their use in therapy such as in the treatment or prevention of fungal-related diseases, disorders or conditions.

Description

CASEIN KINASE (CK1) INHIBITORS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority of co-pending U.S. Provisional Patent Application No. 63 / 664,441 , which was filed June 26, 2024, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present application relates to compounds, to processes for their preparation, to compositions comprising them, and to their use in therapy. More particularly, it relates to type 1 casein kinase inhibitors, useful in the treatment or prevention of fungal- related diseases, disorders or conditions.BACKGROUND

[0003] Fungal pathogens have an enormous impact on human health worldwide (Fisher et al., Science 360, 739-742 (2018)). Poor clinical outcome for most invasive fungal infections is attributable to the very limited number of effective antifungals available for systemic infections and the emergence of clinical resistance to each of the three main modes of action they target (Brown et al., Sci Transl Med B, 165rv13 (2012)). A rapidly escalating need exists for new, more effective and resistance-aversive antifungals (Banumathy et al., Science 425, 407-410 (2012)).

[0004] Protein kinases have emerged as a particularly promising, but to date, clinically unexploited target space for new antifungal drug development. Protein kinases are core signaling molecules central to the regulation of proliferation, survival, and stress responses. As a result, they have been widely studied as potential targets for diverse therapeutic indications, most prominently cancer (Elkins et al., Nat Biotechnol 34, 95-103 (2016); Zhang, et al., Nat Rev Cancer 9, 28-39 (2009)). Kinase inhibitors, however, also possess considerable promise as antimicrobials against diverse pathogenic organisms, including those causing tuberculosis (Carette et al., mBio 9, e02333-17 (2018)), malaria (Derbyshire et al., Chembiochem 15, 1920-30 (2014)) and the most common systemic mycoses (Mattos et al., mBio 11 , e02962-19 (2020); LaFayette et al., PLoS Pathog 6, e1001069 (2010); Lee et al., Nat Commun 11 (1):1521 (2020)). In fungi, kinases have been implicated in the regulation of diverse biological processes required for the major pathogenic species to cause lifethreatening systemic disease (Mattos et al., mBio 11 , e02962-19 (2020); LaFayette et al., PLoS Pathog 6, e1001069 (2010); Lee et al., Nat Commun 11 , 1521 (2020); Fu et al., Nat Commun 12, 6497 (2021); O'Meara et al., mBio 9, e01581-18 (2018)), but no kinase inhibitorshave been approved as antifungals for clinical use to date (Perfect JR., Nat Rev Drug Discov 16, 603-616 (2017)).

[0005] Members of the Type 1 casein kinase (CK1) family of serine / threonine kinases are expressed in most eukaryotes (Cheong et al., Int. J. Biochem. Cell Biol 43, 465-469 (2011); Knippschild et al., Cell Signal 17, 675-89 (2005)), but considerable opportunity exists for the development of isoform-specific inhibitors (Fulcher et al., Biochem J 477, 4603-4621 (2020); Monastyrskyi et al., Bioorg Med Chem 26, 590-602 (2018); Wager et al., ACS Chem Neurosci 5, 1253-65 (2014)). In the model fungus Saccharomyces cerevisiae, CK1-family members have been implicated in cell cycle progression, cell morphology, and cell wall integrity as well as endocytosis, cell morphogenesis, mRNA localization, and nutrient sensing (Robinson et al., Mol Biol Cell 10, 1077-1092 (1999); Robinson et al., Mol Cell Biol 13, 2870-2881 (1993); Snowdon et al., Mol Biol Cell 27, 3369-3375 (2016); Hoekstra et al., Science 253, 1031-4 (1991); Ho et al., Proc Natl Acad Sci U S A, 94, 581-6 (1997)).

[0006] In diverse human fungal pathogens, the CK1 -family members Yck2 and Hrr25 are known to play key roles in cell wall integrity, genome maintenance, virulence and drug resistance (Wang et al., Eukaryot Cell 10, 1455-1464 (2011); Caplan et al., Cell Chem Biol 27, 1-14 (2020)). In Candida albicans, the most common cause of invasive fungal infection in humans, the kinase domains of Yck2 and Hrr25 are very highly conserved, but the proteins themselves play very different biological roles. Yck2 is non-essential under rich laboratory growth conditions, but is required for virulence and antifungal drug-resistance (Park et al., Eukaryot Cell 8, 1498-510 (2009); Jung et al., Pios one 12, e0187721 (2017); Liboro et al., Front Cell Infect Microbiol 11 , 636834 (2021)).

[0007] In contrast, Hrr25 has been shown essential for fungal viability even under rich laboratory culture conditions (Segal et al., mBio 9, e02048-18 (2018)). The role of Yck2 in virulence has been investigated most extensively in C. albicans using both genetical techniques and small molecule inhibitors (Caplan et al., Cell Chem Biol 27, 1-14 (2020)). Genetic-depletion of YCK2 or treatment with inhibitors disrupts the C. albicans morphogenetic program, induces a cell-wall stress response and sensitizes drug-resistant isolates to conventional antifungals in culture. As proof-of-concept, suppression of YCK2 expression using genetic techniques has also been shown to dramatically reduce fungal burden and prolong survival of mice infected with C. albicans (Caplan et al., Cell Chem Biol 27, 1-14 (2020)).

[0008] There is a need for new therapeutics for abrogating fungal virulence and enhancing the efficacy of conventional antifungals.SUMMARY

[0009] The present application includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,wherein one of X and Y is N and the other is C; each — represents a single or a double bond with two non-adjacent — being double bonds positioned to provide an heteroaryl group;R1is selected from phenyl substituted with one or more R7and 5- to 10-membered heteroaryl optionally substituted with one or more R7;R2is selected from 6-, 9- and 10-membered aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R8, and 5- to 10-membered heterocycloalkyl which is optionally substituted with one or more R8';R3is selected from H, halo, Ci.6alkyl and OCi.6alkyl;R4is selected from H, halo, C^alkyl, OCi.6alkyl, CN, CONR9R10, CO2R9, Ci.6alkyleneNR11R12, NR11R12, C3-iocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 6-, 9- and 10-membered aryl and Ci.6alkyleneR13, wherein each of the cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more R14and wherein each alkyl and alkylene is optionally substituted with one or more halo, Ci-ealkyl, OH, OCi.6alkyl, NH2, NHCi.6alkyl and N(Ci-6alkyl)(Ci-6alkyl) and / or optionally interrupted by one or more heteroatoms selected from NR15and O;R5is selected from H and Ci.6alkyl;R6is selected from H and Ci.6alkyl;R7is selected from halo or Ci.6alkyl;R8is selected from halo, C^alkyl, OCi.6alkyl, NR15R16, OH, CN, C(O)NR15R16, CO2R15, and 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halo and Ci.6alkyl;R8' is selected from halo, C^alkyl, OCi.6alkyl, NR15R16, =0, OH, CN, C(O)NR15R16, CO2R15, and 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halo and Ci.6alkyl;R9is selected from H, Ci_6alkyl, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R13;R10is selected from H and Ci-salkyl; orR9and R10together with the N atom to which they are bound form a 3- to 10-membered heterocycloalkyl which is optionally substituted with one or more R14;R11is selected from H, Ci-salkyl, C(=NH)NH2, Cs-iocycloalkyl, 3- to 10-membered heterocycloalkyl, C(O)NH2, CO2H, C(O)N(Ci.6alkyl)(Ci.6alkyl), C(O)NHCi.6alkyl, C(O)Ci.6alkyl, CO2Ci.6alkyl, OH and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more halo, OH, Ci_6alkyl, =0, CO2H, C(O)NR17R18, CO2R17, C(O)NR17R18, and NR17R18;R12is selected from H and Ci.6alkyl;R13is selected from C3-iocycloalkyl, 6-, 9- and 10-membered aryl, 3- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R14; orR13is selected from C(O)NH2, CO2H, C(O)N(Ci-6alkyl)(Ci-6alkyl), C(O)NHCi-6alkyl, C(O)Ci-6alkyl , CO2Ci-6alkyl, OH and NH2, wherein each alkyl, is optionally substituted with one or more halo, =0, CO2R17, C(O)NR17R18, CO2R17, OR17and NR17R18;R14is selected from NR17R18, Ci-6alkyl, Ci.6alkyleneNR17R18, halo, OH, OCi.6alkyl, =0, CONR17R18and CO2R17;R15is selected from H and Ci.6alkyl;R16is selected from H, Ci-salkyl and C3.6cycloalkyl; andR17and R18are independently selected from H and Ci-salkyl; wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally and independently replaced with alternate isotope thereof.

[0010] The present application also includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,wherein: one of X and Y is N and the other is C; each — represents a single or a double bond with two non-adjacent — being double bonds positioned to provide an heteroaryl group;R1is selected from phenyl substituted with one or more R7and 5- to 10-membered heteroaryl optionally substituted with one or more R7;R2is selected from 6-, 9- and 10-membered aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R8;R3is selected from H, halo, Ci.6alkyl and OCi.6alkyl;R4is selected from H, halo, C^alkyl, OCi.6alkyl, CN, CONR9R10, CO2R9, Ci.6alkyleneNR11R12, NR11R12, C3.iocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 6-, 9- and 10-membered aryl and Ci-ealkyleneR13, wherein each of the cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more R14and wherein each alkyl and alkylene is optionally substituted with one or more halo, Ci_6alkyl, OH, OCi.6alkyl, NH2, NHCi.6alkyl and N(Ci-6alkyl)(Ci-6alkyl) and / or optionally interrupted by one or more heteroatoms selected from NR15and O;R5is selected from H and Ci -ealkyl;R6is selected from H and Ci.6alkyl;R7is selected from halo or Ci.6alkyl;R8is selected from halo, Ci.6alkyl, OCi.6alkyl, NR15R16, =0, OH, CN, C(O)NR15R16, CO2R15, and 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halo and Ci.6alkyl;R9is selected from H, Ci.6alkyl, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R13;R10is selected from H and Ci.6alkyl; orR9and R10together with the N atom to which they are bound form a 3- to 10-membered heterocycloalkyl which is optionally substituted with one or more R14;R11is selected from H, Ci.6alkyl, C(=NH)NH2, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl, C(O)NH2, CO2H, C(O)N(Ci-6alkyl)(Ci-6alkyl), C(O)NHCi-6alkyl, C(O)Ci-6alkyl, CO2Ci.6alkyl, OH and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more halo, =0, CO2H, C(O)NR17R18, CO2R17, C(O)NR17R18, R17, and NR17R18;R12is selected from H and Ci.6alkyl;R13is selected from C3.iocycloalkyl, 6-, 9- and 10-membered aryl, 3- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R14; orR13is selected from C(O)NH2, CO2H, C(O)N(Ci.6alkyl)(Ci.6alkyl), C(O)NHCi.6alkyl, C(O)Ci. ealkyl, CO2Ci-ealkyl, OH and NH2, wherein each alkyl, is optionally substituted with one or more halo, =0, CO2R17, C(O)NR17R18, CO2R17, OR17and NR17R18;R14is selected from NR17R18, Ci-6alkyl, Ci.6alkyleneNR17R18, halo, OH, OCi.6alkyl, =0, CONR17R18and CO2R17;R15is selected from H and Ci.6alkyl;R16is selected from H, Ci.6alkyl and C3.6cycloalkyl; andR17and R18are independently selected from H and Ci.6alkyl; wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally independently replaced with alternate isotope thereof.

[0011] Also included is a method of treating or preventing a fungal-related disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0012] In some embodiments, the present application includes a method of inhibiting or preventing fungal growth comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0013] In some embodiments, the application includes a method of inhibiting fungal CK1 activity comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0014] In some embodiments, the application includes a method of selectively inhibiting fungal CK1 activity comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0015] In some embodiments, the application includes a method of treating or preventing mycosis comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0016] In some embodiments, the application includes a method of treating or preventing a fungal-related disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the present application in combination with another known agent useful for treatment or prevention of a fungal-related disease, disorder or condition to a subject in need thereof.

[0017] Also included in the present application is a pharmaceutical composition comprising one or more compounds of the present application, or a pharmaceutically acceptable salt, and / or solvate thereof, and a pharmaceutically acceptable carrier and / or diluent.

[0018] In some embodiments, the application includes is an agricultural composition comprising one or more compounds of the present application, or a salt, and / or solvate thereof, and an agriculturally acceptable carrier and / or diluent.

[0019] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.DETAILED DESCRIPTIONI. Definitions

[0020] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0021] As used in this application and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0022] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0023] The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0024] The terms "about", “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0025] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0026] In embodiments comprising an “additional” or “second” component or effect, such as an additional or second compound, the second compound as used herein is different from the other compounds or first compound. A “third” compound is different from the other, first, and second compounds, and further enumerated or “additional” compounds are similarly different.

[0027] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present. The term “and / or” with respect to enantiomers, prodrugs, salts and / or solvates thereof means that the compounds of the application exist as individual enantiomers, prodrugs, salts and hydrates, as well as a combination of, for example, a salt of a solvate of a compound of the application.

[0028] The term “compound of the application” or “compounds of the application” and the like as used herein refers to a compound of Formula (I), or pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

[0029] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds of the application.

[0030] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art.

[0031] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0032] The term “inert organic solvent” as used herein refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and dissolve compounds that are non soluble in aqueous solutions.

[0033] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. Forexample, the term Ci -1oal ky I means an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0034] The term “alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term O-ealkylene means an alkylene group having 1 , 2, 3, 4, 5 or 6 carbon atoms.

[0035] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term C2-ealkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.

[0036] The term “alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term C2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0037] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated or unsaturated carbocyclic group containing from 3 to 20 carbon atoms and one or more rings and optionally one or more double bonds. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “Cni-n2”. For example, the term Cs-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0038] The term “aryl” as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring and contains 6 to 20 carbon atoms.

[0039] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 20 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cni-n2this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom selected from O, S and N and the remaining atoms are C. Heterocycloalkyl groups are optionally benzofused. Further, when a heterocycloalkyl groupis preceded by an expression such as “n1- to n2-membered, the “n1” and “n2” numbers represent the lower limit and upper limit, respectively, of total atoms (“or members”) in the ring, including carbon and heteroatoms.

[0040] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring containing 5-20 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. When a heteroaryl group contains the prefix Cni-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Further, when a heteraryl group is preceded by an expression such as “n1- to n2-membered, the “n1” and “n2” numbers represent the lower limit and upper limit, respectively, of total atoms (“or members”) in the ring, including carbon and heteroatoms. Heteroaryl groups are optionally benzofused.

[0041] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups, contain one or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond.

[0042] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.

[0043] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0044] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0045] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.

[0046] The term “fluorosubstituted” refers to the substitution of one or more, including all, available hydrogens in a referenced group with fluoro.

[0047] The term “fluoroalkyl” as used herein refers to an alkyl group as defined above, in which one or more, including all available hydrogens are replaced with fluoro.

[0048] The term “deuteroalkyl” as used herein refers to an alkyl group as defined above, in which one or more, including all available hydrogens are replaced with deuterium.

[0049] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0050] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0051] When a referenced group is optionally substituted with more than one of a list of substituents, it is to be understood that those substituents are independently selected from the list.

[0052] The term “cross-coupling” as used herein refers to chemical reactions in which two different starting materials, each of which is usually endowed with an activating group, are reacted together with the aid of a metal catalyst. The result is the loss of the two activating groups and the formation of a new covalent bond between the remaining fragments.

[0053] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0054] The term “subject” as used herein includes all members of the animal kingdom including mammals and the plant kingdom. Thus the methods and uses of the present application are applicable to human therapy, veterinary and agricultural applications.

[0055] The term “pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.

[0056] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0057] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects. A person skilled in the art would be able to confirm whether or not a compound can form a pharmaceutically acceptable salt based on the presence or absence of suitably acidic or basic functional groups.

[0058] The term “solvate” as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0059] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0060] The term “moiety” as used herein refers to a part of a molecule that is given a name, typically to describe the larger and characteristic parts of organic molecules.

[0061] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations.

[0062] “Palliating” a disease or disorder means that the extent and / or undesirable clinical manifestations of a disorder or a disease state are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0063] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a fungal- related disease, disorder or condition, or manifesting a symptom associated with a fungal- related disease, disorder or condition.

[0064] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.

[0065] The expression “inhibiting CK1” as used herein refers to inhibiting, blocking and / or disrupting CK1 activity in a fungal cell, whether direct or indirect. The inhibiting, blocking and / or disrupting causes a therapeutic effect in the cell.

[0066] By “inhibiting, blocking and / or disrupting” it is meant any detectable inhibition, block and / or disruption in the presence of a compound compared to otherwise the same conditions, except for in the absence in the compound.

[0067] The term “fungal-related disease, disorder or condition” means that the disease, disorder or condition to be treated is affected by, modulated by and / or has some biological basis, either direct or indirect, that includes fungal activity. These diseases respond favourably when fungal activity associated with the disease, disorder or condition is inhibited by one or more of the compounds or compositions of the application.

[0068] The term “CK1” as used herein refers to type 1 casein kinase.

[0069] The term “fungal cell uptake” or “fungal cell permeability” as used herein refers to the regulation or controlling exchanges of molecules between the cell and its environment, for example an increased cell permeability would mean an increased ability for a molecule to internalize into the cell.

[0070] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell either in cell culture or in a subject.

[0071] The term “complementary functional group” as used herein refers to a group of atoms or a single atom that will react with another group of atoms or a single atom to form a covalent bond between the two groups or atoms.

[0072] The term “reacts with” as used herein generally means that there is a flow of electrons or a transfer of electrostatic charge resulting in the formation of a covalent bond.

[0073] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0074] The term “aq.” as used herein refers to aqueous.

[0075] The term “Me” as used herein refers to methyl.

[0076] The term “Et” as used herein refers to ethyl.

[0077] The term “Bu” as used herein refers to butyl.

[0078] The term “Ac” as used herein refers to acetyl.

[0079] The term “Ph” as used herein refers to phenyl.

[0080] The term “Ts” as used herein refers to tosyl.

[0081] The term “Ms” as used herein refers to mesyl.

[0082] The term “THF” as used herein refers to tetra hydrofuran.

[0083] The term “HATU” as used herein refers to hexafluorophosphate azabenzotriazole tetramethyl uranium.

[0084] The terms “DIPEA” or “DIEA” as used herein refer to N,N- diisopropylethylamine.

[0085] The term “TEA” as used herein refers to triethylamine.

[0086] The terms “TBME” or “MTBE” as used herein refer to methyl tert-butyl ether.

[0087] The term “DMF” as used herein refers to dimethylformamide.

[0088] The term “DCM” as used herein refers to dichloromethane.

[0089] The term “DEA” as used herein refers to diethanolamine.

[0090] The term “DBU” as used herein refers to 1 ,8-diazabicyclo[5.4.0]undec-7-ene

[0091] The term “TFA” as used herein refers to trifluoroacetic acid.

[0092] The term “ACN” as used herein refers to acetonitrile.

[0093] The term “BOC” as used herein refers to tert-butyloxycarbonyl.

[0094] The term “DMSO” as used herein refers to dimethylsulfoxide.

[0095] The term “NBS” as used herein refers to N-bromosuccinimide.

[0096] The term “NIS” as used herein refers to N-iodosuccinimide.

[0097] The term “HPLC” as used herein refers to high-performance liquid chromatography.

[0098] The term “NMR” as used herein refers to nuclear magnetic resonance.

[0099] The term “LC-MS” as used herein refers to liquid chromatography mass spectrometry.

[0100] The term “MS” as used herein refers to mass spectrometry.

[0101] The term “IC5o” as used herein refers to half maximal inhibitory concentration.

[0102] The term “ATP” as used herein refers to adenosine 5'-triphosphate.

[0103] The term “PCR” as used herein refers to polymerase chain reaction.

[0104] The term “MIC” as used herein refers to minimum inhibitory concentrations.

[0105] The term “TEV” as used herein refers to tobacco etch virus.II. Compounds and Compositions

[0106] The present application describes a novel class of compounds.

[0107] Accordingly, the application includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,wherein one of X and Y is N and the other is C; each — represents a single or a double bond with two non-adjacent — being double bonds positioned to provide an heteroaryl group;R1is selected from phenyl substituted with one or more R7and 5- to 10-membered heteroaryl optionally substituted with one or more R7;R2is selected from 6-, 9- and 10-membered aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R8, and 5- to 10-membered heterocycloalkyl which is optionally substituted with one or more R8';R3is selected from H, halo, Ci.6alkyl and OCi.6alkyl;R4is selected from H, halo, C^alkyl, OCi.6alkyl, CN, CONR9R10, CO2R9, Ci.6alkyleneNR11R12, NR11R12, C3.iocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 6-, 9- and 10-membered aryl and Ci.6alkyleneR13, wherein each of the cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more R14and wherein each alkyl and alkylene is optionally substituted with one or more halo, Ci-ealkyl, OH, OCi.6alkyl, NH2, NHCi.6alkyl and N(Ci-6alkyl)(Ci-6alkyl) and / or optionally interrupted by one or more heteroatoms selected from NR15and O;R5is selected from H and Ci.6alkyl;R6is selected from H and Ci.6alkyl;R7is selected from halo or Ci.6alkyl;R8is selected from halo, Ci-6alkyl, OCi-6alkyl, NR15R16, OH, CN, C(O)NR15R16, CO2R15, and 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halo and Ci-salkyl;R8' is selected from halo, C^alkyl, OCi.6alkyl, NR15R16, =0, OH, CN, C(O)NR15R16, CO2R15, and 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halo and Ci.6alkyl;R9is selected from H, Ci_6alkyl, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R13;R10is selected from H and Ci.6alkyl; orR9and R10together with the N atom to which they are bound form a 3- to 10-membered heterocycloalkyl which is optionally substituted with one or more R14;R11is selected from H, Ci.6alkyl, C(=NH)NH2, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl, C(O)NH2, CO2H, C(O)N(Ci-6alkyl)(Ci-6alkyl), C(O)NHCi-6alkyl, C(O)Ci-6alkyl, CO2Ci.6alkyl, OH and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more halo, OH, Ci.6alkyl, =0, CO2H, C(O)NR17R18, CO2R17, C(O)NR17R18, and NR17R18;R12is selected from H and Ci.6alkyl;R13is selected from C3.iocycloalkyl, 6-, 9- and 10-membered aryl, 3- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R14; orR13is selected from C(O)NH2, CO2H, C(O)N(Ci.6alkyl)(Ci.6alkyl), C(O)NHCi.6alkyl, C(O)Ci. ealkyl, CO2Ci-ealkyl, OH and NH2, wherein each alkyl, is optionally substituted with one or more halo, =0, CO2R17, C(O)NR17R18, CO2R17, OR17and NR17R18;R14is selected from NR17R18, Ci-6alkyl, Ci.6alkyleneNR17R18, halo, OH, OCi.6alkyl, =0, CONR17R18and CO2R17;R15is selected from H and Ci.6alkyl;R16is selected from H, Ci.6alkyl and C3.6cycloalkyl; andR17and R18are independently selected from H and Ci.6alkyl; wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally and independently replaced with alternate isotope thereof.

[0108] In some embodiments, the compound has the Formula IA or IB:(IA) (IB).

[0109] In some embodiments, R1is selected from phenyl substituted with one to three R7and 5- to 6-membered heteroaryl optionally substituted with one to three R7wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R1is selected from phenyl, thiophenyl, pyridinyl, and thiazolyl, substituted with one or two R7wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

[0110] In some embodiments, R7is selected from F, Cl, CD3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3and CHF2. In some embodiments, R7is F or CF3.

[0111] In some embodiments, R1is selected from:wherein > represents the point of attachment to remainder of the compound.

[0112] In some embodiments, R2is selected from phenyl and 5- to 6-membered heteroaryl, each of which is optionally substituted with one to three R8wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R2is selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl pyrazolyl, phenyl, thiadiazolyl, oxadiazolyl. imidazolyl, tetrazolyl, triazolyl, each of which is optionally substituted with one to three, one or two, or one, R8wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

[0113] In some embodiments, R2is selected from 5- to 10-membered heterocycloalkyl which is optionally substituted with one or more R8'. In some embodiments, R2is selected from1 ,2-dihydropyridinyl, 1 ,2,3,4-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl and 2H-pyranyl which is optionally substituted with one R8'

[0114] In some embodiments, R8is selected from F, Cl, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, NHR16, OH, CN, C(O)NH2, C(O)NHCi.4alkyl, C(O)N(Ci.4alkyl)(Ci.4alkyl), C(0)NHCi-4fluoroalkyl, C(O)N(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci.4fluoroalkyl, C02Ci.4deuteroalkyl and 3- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one to three halo, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl. In some embodiments, R8is selected from F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, NH2, NHCi-4alkyl, NHCs-ecycloalkyl, OH, CN, C(O)NH2, CO2H, piperazinyl optionally substituted with Ci _4alkyl and / or Ci.4fluoroalkyl, pyrrolidinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl, and azetidinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl.

[0115] In some embodiments, R8' is selected from F, Cl, Ci_4alkyl, Ci.4fluoroalkyl, C1-4deuteroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, NHR16, =0, OH, CN, C(O)NH2, C(O)NHCi.4alkyl, C(O)N (Chalky I) (Chalky I), C(0)NHCi-4fluoroalkyl, C(O)N(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci.4fluoroalkyl, C02Ci.4deuteroalkyl and 3- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one to three halo, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl. In some embodiments, R8' is selected from F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, NH2, NHCi.4alkyl, =0, NHC3. ecycloalkyl, OH, CN, C(O)NH2, CO2H, piperazinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl, pyrrolidinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl, and azetidinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl. In some embodiments, R8' is =0.

[0116] In some embodiments, R2is selected from:wherein > represents the point of attachment to the remainder of the compound.

[0117] In some embodiments, R2is selected from:wherein > represents the point of attachment to the remainder of the compound.

[0118] In some embodiments, R3is selected from H, F, Cl, Ci_4alkyl, Ci.4fluoroalkyl, OCi.4fluoroalkyl, Ci.4deuteroalkyl, OCi.4deuteroalkyl and OCi.4alkyl. In some embodiments, R3is selected from H, F, Cl, methyl, trifluoromethyl, ethyl, propyl, methoxy, trifluoromethoxy, ethoxy and propoxy.

[0119] In some embodiments, R4is selected from H, F, Cl, Ci_4alkyl, Ci.4fluoroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, CN, CONR9R10, CO2R9, Ci.5alkyleneNR11R12, NR11R12, C3.6cycloalkyl, 5- or 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, 6- membered aryl and Ci.4alkyleneR13, wherein each of the cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with one to three, one or two, or one, R14and wherein each alkyl and alkylene is optionally substituted with one to three, one or two, or one, F, Cl, Ci.4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl, OH, OCi.4alkyl, OCi._4fluoroalkyl, OCi.4deuteroalkyl, NH2, NHCi.4alkyl, N(Ci.4alkyl)(Ci.4alkyl), NHCi.4fluoroalkyl, NH(Ci.4fluoroalkyl)(Ci.4fluoroalkyl), NHCi.4deuteroalkyl and N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), and / or optionally interrupted by one to three, one or two, or one, heteroatoms selected from NR15and O. In some embodiments, in R4, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, the heteroaryl is selected from pyridinyl, imidazolyl, pyrazolyl and pyrimidinyl, and the heterocycloalkyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, diazepanyl, oxetanyl, tetrahydropyranyl, tetrahydropyridinyl thiomorpholinyl and tetrahydrothiopyranyl, and in each, all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R9is selected from H, methyl, CF3, ethyl, propyl, 3- to 6-membered heterocycloalkyl and NH2, wherein the heterocycloalkyl is optionally substituted with one to three, one or two, or one, R13.

[0120] In some embodiments, R10is selected from H, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl.

[0121] In some embodiments, R9and R10together with the N atom to which they are bound to form a 5- or 6-membered heterocycloalkyl which is optionally substituted with one or more R14wherein all available hydrogen atoms are optionally and independently replaced with deuterium In some embodiments, R9and R10together with the N atom to which they are bound to form a 5- or 6-membered heterocycloalkyl which is optionally substituted with one to three, one or two, or one, R14

[0122] In some embodiments, R11is selected from H, Ci.5alkyl, Ci.5fluoroalkyl, Ci. sdeuteroalkyl, C(=NH)NH2, C3.6cycloalkyl, 3- to 6-membered heterocycloalkyl, C(O)NH2,CO2H, C(O)N(Ci.4alkyl)(Ci.4alkyl), C(O)NHCMalkyl, C(0)NHCi.4fluoroalkyl, C(O)N(Ci.4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), C(O)Ci.4alkyl, C(0)Ci_4fluoroalkyl, C(0)Ci.4deuteroalkyl, CO2Ci.4alkyl, CO2Ci.4fluoroalkyl, C02Ci-4deuteroalkyl, OH and NH2, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one to three, one or two, or one, F, Cl, =0, CO2H, C(O)NH2, C(O)NHCi.4alkyl, C(O)N(CMalkyl)(Ci.4alkyl), C(0)NHCi.4fluoroalkyl, C(O)N(Ci.4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci.4fluoroalkyl, C02Ci.4deuteroalkyl, Ci.4alkyl, Ci-4fluoroalkyl, Ci.5deuteroalkyl, NH2, NHCi.4alkyl and N(Ci.4alkyl)2and wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

[0123] In some embodiments, R11is selected from H, Ci.5alkyl, Ci.5fluoroalkyl, Ci.5deuteroalkyl, C(=NH)NH2, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, C(O)NH2, CO2H, C(O)N(Ci-4alkyl)(Ci-4alkyl), C(O)NHCi.4alkyl, C(0)NHCi-4fluoroalkyl, C(O)N(Ci-4fluoroalkyl)(Ci.4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), C(O)Ci.4alkyl, C(0)Ci_4fluoroalkyl, C(0)Ci.4deuteroalkyl, CO2Ci.4alkyl, CO2Ci.4fluoroalkyl, C02Ci_4deuteroalkyl, OH and NH2, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one to three, one or two, or one, F, Cl, =0, OH, CO2H, C(O)NH2, C(O)NHCi.4alkyl, C(O)N(Ci.4alkyl)(Ci.4alkyl), C(0)NHCi-4fluoroalkyl, C(O)N(Ci-4fluoroalkyl)(Ci.4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci.4fluoroalkyl, C02Ci.4deuteroalkyl, Ci.4alkyl, Ci-4fluoroalkyl, Ci-sdeuteroalkyl, NH2, NHCi.4alkyl and N(Ci.4alkyl)2and wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

[0124] In some embodiments, R12is selected from H, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci.4alkyl.

[0125] In some embodiments, R13is selected from C3-6cycloalkyl, 6-membered aryl, 5- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl, each of which is optionally substituted with one to three, one or two, or one, R14and wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R13is selected from C(O)NH2, CO2H, C(O)N(Ci.4alkyl)(Ci.4alkyl), C(O)NHCi.4alkyl, C(0)NHCi_4fluoroalkyl, C(0)N(Ci.4fluoroalkyl)(Ci.4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), C(O)Ci.4alkyl, C(0)Ci.4fluoroalkyl, C(O)Ci.4deuteroalkyl, CO2Ci.4alkyl, C02Ci_4fluoroalkyl, C02Ci_4deuteroalkyl, OH and NH2, wherein each alkyl is optionally substituted with one to three, one or two, or one, F, Cl, =0, C(O)NH2, C(O)NHCi.4alkyl, C(O)N(CMalkyl)(Ci.4alkyl), C(0)NHCi.4fluoroalkyl, C(O)N(Ci.4fluoroalkyl)(Ci.4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci-4fluoroalkyl, C02Ci.4deuteroalkyl, OCi-4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, OH, NH2, NHCi.4alkyl, N(Ci.4alkyl)2, NHCi.4fluoroalkyl, NH(Ci.4fluoroalkyl)(Ci-4fluoroalkyl), NHCi.4deuteroalkyl and N(Ci-4deuteroalkyl)(Ci-4deuteroalkyl)

[0126] In some embodiments, R4is selected from methyl, F, OEt, CN, CO2H, CONH2, CH2-NH2, NH-NH2, NH2,wherein * represents the point of attachment to the remainder of the compound.

[0127] In some embodiments, R4is selected from methyl, F, OEt, CN, CO2H, CONH2,CH2-NH2, NH-NH2, NH2,wherein5represents the point of attachment to the remainder of the compound.

[0128] In some embodiments, R4is selected from Ci.4alkyleneNR11R12, R11is selected from H, Ci-4alkyl, Ci.4fluoroalkyl and Ci.4deuteroalkyl; and R12is selected from H, Ci- alkyl Ci-4fluoroalkyl and Ci-4deuteroalkyl.

[0129] In some embodiments, R14is selected from NR17R18, Ci-4alkyl, Ci-4fluoroalkyl, Ci.4deuteroalkyl, Ci.4alkyleneNR17R18, F, Cl, OH, OCMalkyl, =0, CONR17R18and CO2R17.

[0130] In some embodiments, wherein R15is selected from H, Ci-4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl.

[0131] In some embodiments, R16is selected from H, Ci-4alkyl, Ci.4fluoroalkyl, Ci-4deuteroalkyl and C3.5cycloalkyl.

[0132] In some embodiments, R17and R18are independently selected from H, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl.

[0133] In some embodiments, the available atoms optionally and independently replaced with alternate isotope thereof are available H being replaced with D and the compound of Formula I comprises at least one D.

[0134] In some embodiments the compound of Formula I is a compound wherein:R1is selected from phenyl substituted with one or two groups independently selected from F and Cl;R2is selected from phenyl and 6-membered heteroaryl, each of which is optionally substituted with one R8,R4is selected from Ci.4alkyleneNR11R12;R8is selected from OCi-4deuteroalkyl,R11is selected from H, Ci-4alkyl, Ci- fluoroalkyl and Ci- deuteroalkyl; andR12is selected from H, Ci- alkyl Ci- fluoroalkyl and Ci- deuteroalkyl, or a pharmaceutically acceptable salt and / or solvate thereof.

[0135] In some embodiments, the compound of Formula (I) is selected from the compounds listed in Table 1 :Table 1or, an enantiomer thereof (where relevant), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0136] The present application further includes a pharmaceutical composition comprising one or more compounds of the present application, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier and / or diluent. In some embodiments, the pharmaceutical composition further comprising an additional therapeutic agent.

[0137] In some embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0138] The compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0139] The compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0140] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0141] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p- toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0142] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0143] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like.

[0144] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0145] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0146] A compound of the application including salts and / or solvates thereof is suitably used on their own but will generally be administered in the form of a composition in which the one or more compounds of the application (the active ingredient) is in association with an acceptable carrier. Depending on the mode of administration, the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition.

[0147] The compounds of the application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. A compound of the application may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Administration can be by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, forexample, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0148] Parenteral administration includes intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0149] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.

[0150] A compound of the application may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions can be formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0151] Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Such liquid preparations for oral administration may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0152] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0153] A compound of the application may also be administered parenterally. Solutions of a compound of the application can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0154] The compounds of the application may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0155] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.

[0156] For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0157] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administrationare conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0158] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0159] Compounds of the application may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, compounds of the application may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0160] In some embodiments, compounds of the application may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers.

[0161] In some embodiments, depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient (one or more compounds of the application), and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of one or more pharmaceutically acceptable carriers, all percentages by weight being based on the total composition.

[0162] In some embodiments, a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage formsor together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of the application (e.g. a compound of Formula (I)), an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0163] To be clear, in the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced.III. Methods and Uses of the Application

[0164] The compounds of the application have been shown to be capable of inhibiting fungal activity.

[0165] Accordingly, the present application further includes a method of treating or preventing a fungal-related disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0166] The present application also includes a method of inhibiting or preventing fungal growth comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0167] Also provided is a method of inhibiting fungal CK1 activity comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof. In some embodiments, the method comprises selectively inhibiting fungal CK1 activity.

[0168] The present application further provides a method of treating a fungal-related disease, disorder or condition that is treatable by inhibiting fungal CK1 comprising administering a therapeutically effective amount of one or more compounds of the present application in combination with another known agent useful for treatment of a fungal-related disease, disorder or condition that is treatable by inhibiting fungal CK1 to a subject in need thereof.

[0169] The application also includes a use of one or more compounds of the application for treating or preventing a fungal-related disease, disorder or condition as well as a use of one or more compounds of the application for the preparation of a medicament for treating or preventing a fungal-related disease, disorder or condition. The application further includes one or more compounds of the application for use in treating or preventing a fungal-related disease, disorder or condition.

[0170] As the compounds of the application have been shown to be capable of inhibiting fungal activity, the compounds of the application are useful for treating orpreventing a fungal-related disease, disorder or condition by inhibiting fungal activity. Therefore the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.

[0171] In some embodiments, the fungal-related disease, disorder or condition comprises mycosis including superficial, subcutaneous and systemic mycosis. In some embodiments, the fungal-related disease, disorder or condition includes dermatomycosis, candidiasis, pneumocytosis, pityriasis versicolor, aspergillosis, mucormycosis, talaromycosis, basidiobolomycosis, blastomycosis, chromoblastomycosis cryptococcosis, coccidioidomycosis, conidiobolomycosis, eumycetoma, histoplasmosis, lobomycosis, paracoccidioidomycosis, phaeohyphomycosis, scedosporisis, sporotrichosis and emmonsiosis.

[0172] Accordingly, the present application thus provides a method of treating or preventing a fungal infection or mycosis comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof. In some embodiments, the mycosis is candidiasis,

[0173] In some embodiments, fungi that cause infections include the yeasts, molds, and / or dimorphic fungi responsible for the infections specified herein.

[0174] When used in combination with other agents or therapies useful in treating fungal-related diseases, disorders or conditions, it is an embodiment that the compounds of the application are administered contemporaneously with those agents or therapies. As used herein, “contemporaneous administration” of two substances ortherapies to a subject means providing each of the two substances or therapies so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances or therapies in the presence of each other, and can include administering the two substances or therapies within a few hours of each other, or even administering one substance or therapy within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, the substances or therapies will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition in the case of administration of two substances. It is a further embodiment of the present application that a combination of agents or therapies is administered to a subject in a noncontemporaneous fashion.

[0175] In some embodiments, the subject is a mammal. In some embodiments, the subject is a livestock, such as cattle, sheep, goat, poultry, etc. In some embodiments, the subject is human. In some embodiments, mycoses in human affect skin, mucosa such asmouth and vagina, nails, organs such as lungs and brain, eyes, nose, sinuses, bones, joints, etc.

[0176] In some embodiments, the subject is a crop, such as rice, wheat, barley, oat, rye, sugarcane and other sugar crops, maize (corn), potatoes, palm, canola, flax, safflower cassava, legume pulses such as beans, soybeans, peas, chickpeas, peanuts, lentils, lupins, mesquite, carob, tamarind, alfalfa, and clover, sunflower, rape, mustard, sorghum, millet, hemp, sugar beet, groundnuts, sweet potatoes, bananas, cotton, yams, various nuts or other vegetables or fruits.

[0177] In the context of treating a fungal-related disease, disorder or condition, an effective amount is an amount that, for example, inhibits fungal activity, compared to the inhibition without administration of the one or more compounds. Effective amounts may vary according to factors such as the disease state, age, sex and / or weight of the subject, type of fungi. The amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. The effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.

[0178] The dosage of compounds of the application can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds of the application from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg. For administration in suppository form, a representative amount isfrom about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg. In an embodiment of the application, compositions are formulated for oral administration and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet. Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three or four daily doses.

[0179] In some embodiments, the compounds of the application are administered at least once a week. However, in another embodiment, the compounds are administered to the subject from about one time per two weeks, three weeks or one month. In another embodiment, the compounds are administered about one time per week to about once daily. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the compounds of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject.IV. Methods of Preparing the Compounds of the Application

[0180] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula (I) is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0181] In some embodiments, as shown in Scheme 1 , compounds of Formula (I) are synthesized by reacting intermediate 1 a bearing a suitable protecting group (PG) with a pyridine compound 1 b, wherein R3, R4, R5and R6are as defined in Formula (I), under conditions to provide intermediate salt 1c. Intermediate 1 c may then be reacted with compound 1d, wherein R1is as defined in Formula (I) and Raxis any suitable hydrolysable group, such as methyl or ethyl, to provide intermediate 1 e, which may be subjected to known hydrolysis conditions, followed by halogenation with, for example an N-halosuccinamide (NXS, whereinX is halo) to provide intermediate 1f. Intermediate 1f may then be coupled with borate compound 1g, wherein R2is as defined in Formula (I), under known Suzuki cross-coupling conditions to obtain compounds of Formula (I).Scheme 1

[0182] Throughout the processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide toFunctional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry", March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994).

[0183] Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0184] Salts of the compounds of the application are generally formed by dissolving the neutral compound in an inert organic solvent and adding either the desired acid or base and isolating the resulting salt by either filtration or other known means.

[0185] The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”.

[0186] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0187] The following non-limiting examples are illustrative of the present application.EXAMPLESGeneral methods

[0188] All starting materials used herein were commercially available or earlier described in the literature. The1H and13C NMR spectra were recorded either on Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for1H NMR respectively, using TMS or the residual solvent signal as an internal reference, in deuterated chloroform as solvent unless otherwise indicated. All reported chemical shifts are in ppm on the delta-scale, and the fine splitting of the signals as appearing in the recordings is generally indicated, for example as s: singlet, br s: broad singlet, d: doublet, t: triplet, q:quartet, m: multiplet. Unless otherwise indicated, in the tables below,1H NMR data was obtained at 400 MHz, using CDCI3as the solvent.

[0189] Purification of products was carried out using Chem Elut Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat # 12256018; 12256026; 12256034) or by flash chromatography in silica-filled glass columns.Preparation of intermediates and specific examplesExample 1 - Synthesis of 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5- a]pyridine (1-1) and 2-(4-fluorophenyl)-4-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (I-9)1-1 I-9

[0190] Procedure of the synthesis of compounds 1-1 and I-9 is shown in Scheme 2:Scheme 2Mix of methyl 2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridine-3-carboxylate and methyl 2- (4-fluorophenyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate

[0191] To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (10 g, 56.1 mmol) and 1-amino-3-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (20 g, 67.4 mmol) in dry acetonitrile (60 mL) was added, dropwise over 10 minutes, a solution of DBU (10.2 g, 67.4 mmol) in 10 mL acetonitrile. The mixture was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum and the residue was dissolved in EtOAc (200 mL), washed with water (200 mL), dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column with PE:EA 10:1 to afford a mix of methyl 2-(4-fluorophenyl)- 6-methylpyrazolo[1 ,5-a]pyridine-3-carboxylate and methyl 2-(4-fluorophenyl)-4- methylpyrazolo[1 ,5-a]pyridine-3-carboxylate (5.4 g 33% yield, ratio: 2 / 5) as a white solid.

[0192] 1H NMR (400 MHz, CDCI3) 5 8.36 (d, J = 6.8 Hz, 1H), 8.30 (s, 0.4H), 8.06 (d, J = 8 Hz, 0.4H), 7.81 - 7.77 (m, 0.8H), 7.67 - 7.64 (m, 2H), 7.18 - 7.16 (m, 0.5H), 7.16 - 7.07 (m, 3.7H), 3.84 (s, 1.2H), 3.76 (s, 3H), 2.62 (s, 3H), 2.38 (s, 1.2H).Mix of 2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid and 2-(4- fluorophenyl)-4-methylpyrazolo[ 1, 5-a]pyridine-3-carboxylic acid

[0193] A solution of a mix of methyl 2-(4-fluorophenyl)-6-methylpyrazolo[1 ,5- a]pyridine-3-carboxylate and methyl 2-(4-fluorophenyl)-4-methylpyrazolo[1 ,5-a]pyridine-3- carboxylate (5.4 g, 19.1 mmol) in 2N aqueous NaOH solution (60 mL) and MeOH (60 mL) was heated at reflux for 3 hours. The mixture was concentrated under vacuum to about half of volume. The pH of the residue was adjusted to pH 2 with 2N HCI solution and the precipitate was collected by filtration and washed with water (60 mL), dried under vacuum to afford a mix of 2-(4-fluorophenyl)-6-methylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid and 2-(4- fluorophenyl)-4-methylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid (2.7 g, 53% yield, ratio: 2 / 5) as a yellow solid.Mix of 3-bromo-2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridine and 3-bromo-2-(4- fluorophenyl)-4-methylpyrazolo[ 1, 5-a]pyridine

[0194] To a solution of a mix of 2-(4-fluorophenyl)-6-methylpyrazolo[1 ,5-a]pyridine-3- carboxylic acid and 2-(4-fluorophenyl)-4-methylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid (2.7 g, 10 mmol) and sodium bicarbonate (1.6 g, 20 mmol) in dry DMF (40 mL) was added NBS(1.78 g, 10 mmol) and the reaction was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction mixture. The solid was collected and washed with water (100 mL) and dried under vacuum to afford a mix of 3-bromo-2-(4-fluorophenyl)-6- methylpyrazolo[1 ,5-a]pyridine and 3-bromo-2-(4-fluorophenyl)-4-methylpyrazolo[1 ,5- a]pyridine (2.3, 76% yield) as a yellow solid.2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (1-1) and 2-(4- fluorophenyl)-4-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (I-9)

[0195] A solution of a mix of 3-bromo-2-(4-fluorophenyl)-6-methylpyrazolo[1 ,5- a]pyridine and 3-bromo-2-(4-fluorophenyl)-4-methylpyrazolo[1 ,5-a]pyridine (200 mg, 0.65 mmol), pyridin-4-ylboronic acid (103 mg, 0.84 mmol), sodium carbonate ( 137 mg, 1.3 mmol) and dichlorobis(triphenylphosphine)palladium (295 mg, 0.42 mmol) in DMF (4 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite™ and rinsed with EtOAc (50 mL). The filtrate was washed with water (20 mL*2), brine (20 mL), dried and concentrated. The residue was purified by Prep- HPLC (ACN / H2O with 0.05%NH3) to afford 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4- yl)pyrazolo[1 ,5-a]pyridine (10 mg, 10% yield) as a white solid and 2-(4-fluorophenyl)-4-methyl- 3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine (20 mg, 20% yield) as a white solid.2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (1-1)

[0196] 1H NMR (400 MHz, DMSO) 5 8.66 (d, J = 1.1 Hz, 1 H), 8.56 (dd, J = 4.5, 1.6 Hz, 2H), 7.69 (d, J = 9.1 Hz, 1 H), 7.56 - 7.51 (m, 2H), 7.31 (dd, J = 4.5, 1.6 Hz, 2H), 7.29 - 7.23 (m, 3H), 2.36 (s, 3H).2-(4-fluorophenyl)-4-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (I-9)

[0197] 1H NMR (400 MHz, DMSO) 5 8.65 (d, J = 6.9 Hz, 1 H), 8.60 (dd, J = 4.4, 1.6 Hz, 2H), 7.45 - 7.38 (m, 4H), 7.21 - 7.14 (m, 2H), 7.08 - 7.04 (m, 1H), 6.91 (t, J= 6.9 Hz, 1 H), 2.04 (s, 3H).Example 2 - Synthesis of 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5- a]pyridine-7-d (I-2)

[0198] Procedure of the synthesis of compound i-2 is shown in Scheme 3:Scheme 3

[0199] To a solution of 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1 ,5- a]pyridine (20 mg, 0.07 mmol) in dry THF (3 mL) was added 4A molecular sieve (5 mg) and added dropwise a solution of n-BuLi (2.5 M, 0.28 mL) in hexanes at -78°C. The mixture was stirred at this temperature for 0.5 hours. To the mixture was added D2O (0.5 mL) at -78°C and the mixture was gradually brought back to room temperature. The mixture was concentrated under vacuum and the residue was purified by Prep-HPLC (ACN / H2O as mobile phase) to afford 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-7-d (3.9 mg 19% yield) as a white solid.

[0200] 1H NMR (400 MHz, CD3CN) 58.59 (d, J = 6.2 Hz, 2H), 7.79 (d, J= 9.1 Hz, 1H), 7.69 (d, J = 6.5 Hz, 2H), 7.63 - 7.55 (m, 2H), 7.38 (d, J = 9.2 Hz, 1 H), 7.21 (t, J = 8.9 Hz, 2H), 2.42 (s, 3H).Example 3 - Synthesis of 6-fluoro-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5- a]pyridine (i-3)

[0201] Procedure of the synthesis of compound I-3 is shown in Scheme 4:Scheme 41 -amino-3-fluoropyridin- 1 -ium 2, 4, 6-trimethylbenzenesulfonate

[0202] TFA (50 mL) was added to N-tert-butoxycarbonyl-O- (mesitylsulfonyl)hydroxylamine (25 g, 79.3 mmol) in portions at 0°C over 15 mins. The solution was stirred for 15 minutes at room temperature. The solution was poured into the ice water mixture and the resulting precipitate was collected by filtration. The solid was re-dissolved in 100 mL DCM and dried over Na2SO4. The Na2SO4was removed by filtration and the filtrate was added to a solution of 3-bromopyridine (7.7 g, 79.3 mmol) in DCM (100 mL). The mixture was stirred for 1 hour. To the mixture was added MTBE (200 mL) and the product was allowed to precipitate. The solid was collected by filtration, washed with METB (100 mL) to afford a crude 1-amino-3-fluoropyridin-1-ium 2, 4, 6-trimethylbenzenesulfonate (14 g) and directly used for the next step.Methyl 6-fluoro-2-(4-fluorophenyl) pyrazolo[ 1, 5-a]pyridine-3-carboxylate

[0203] To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (5 g, 28 mmol) and 1-amino-3-fluoropyridin-1-ium 2, 4, 6-trimethylbenzenesulfonate (21.8 g, 70 mmol) in dry acetonitrile (40 mL) was added, dropwise over 10 minutes, a solution of DBU (10.6 g, 70 mmol)in 15 mL acetonitrile. The mixture was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum and the residue was dissolved in EtOAc (100 mL), washed with water (100 mL), dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column with PE:EA 10:1 to afford methyl 6-fluoro-2-(4- fluorophenyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (1.5 g 18% yield) as a pale yellow solid.

[0204] 1H NMR (400 MHz, CDCI3) 58.38 (d, J= 6.2 Hz, 1 H), 7.77 - 7.70 (m, 2H), 7.19 - 7.13 (m, 3H), 7.13 - 7.05 (m, 1 H), 6.93 - 6.85 (m, 1 H), 3.83 (s, 3H).6-fluoro-2-(4-fluorophenyl)pyrazolo[ 1, 5-a]pyridine-3-carboxylic acid

[0205] To a solution of methyl 6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3- carboxylate (1.5 g, 5.2 mmol) in MeOH (10 mL) and THF (10 mL) was added 2N aqueous NaOH solution (20 mL) and heated at reflux for 3 hours. The mixture was concentrated under vacuum to about half of volume. The pH of the residue was adjusted to pH 2 with 2N HCI solution and the precipitate was collected by filtration and washed with water (10 mL), dried under vacuum to afford 6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (1.2 g, 85% yield) as a white solid.3-bromo-6-fluoro-2-(4-fluorophenyl)pyrazolo[ 1, 5-a]pyridine

[0206] To a solution of 6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (1.2 g, 4.3 mmol) and sodium bicarbonate (1.3 g, 12.9 mmol) in dry DMF (20 mL) was added NBS (765 mg, 4.3 mmol) and the reaction was stirred at room temperature for 3 hours. To the reaction mixture was added water (40 mL). The solid was collected and washed with water (20 mL) and dried under vacuum to afford 3-bromo-6-fluoro-2-(4- fluorophenyl)pyrazolo[1 ,5-a]pyridine (1 g, 76% yield) as a yellow solid.

[0207] 1H NMR (400 MHz, DMSO) 5 8.68 (d, J = 8 Hz, 1 H), 8.01 - 7.96 (m, 2H), 7.42 - 7.38 (m, 2H), 7.03 - 7.01 (m, 1 H), 6.99 - 6.96 (m, 1 H).6-fluoro-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[ 1, 5-a]pyridine ( I -3)

[0208] A solution of 3-bromo-6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine (50 mg, 0.16 mmol) pyridin-4-ylboronic acid (39 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmol) and dichlorobis(triphenylphosphine)palladium (56 mg, 0.08 mmol) in DMF (3 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite and rinsed with EtOAc (50 mL). The filtrate was washed with water (20 mL*2), brine (20 mL), dried and concentrated. The residue was purified by Prep- HPLC (ACN / H2O with 0.05% NH3) to afford 6-fluoro-2-(4-fluorophenyl)-3-(pyridin-4- yl)pyrazolo[1 ,5-a]pyridine (12.7 mg, 25% yield) as a white solid.

[0209] 1H NMR (400 MHz, DMSO) 5 8.72 (d, J = 6.5 Hz, 1 H), 8.57 (d, J = 6.0 Hz, 2H), 7.51 - 7.43 (m, 2H), 7.36 - 7.31 (m, 2H), 7.29 - 7.20 (m, 3H), 7.06 - 6.99 (m, 1 H).Example 4 - Synthesis of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6- carbonitrile (I-4) and 6-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (1-251)

[0210] Procedure of the synthesis of compound I-4 is shown in Scheme 5:Scheme 51 -amino-3-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate

[0211] TFA (20 mL) was added to N-tert-butoxycarbonyl-O-(mesitylsulfonyl)hydroxylamine (15 g, 47.6 mmol) in portions at 0°C over 15 mins. The solution was stirred for 15 minutes at room temperature. The solution was poured into the ice water mixture and the resulting precipitate was collected by filtration. The solid was re-dissolved in 20 mL DCM and dried over Na2SO4. The Na2SO4was removed by filtration and the filtrate was added to a solution of 3-bromopyridine (6.7 g, 47.6 mmol) in DCM (20 mL). The mixture was stirred for 45 minutes and then filtered. To the filtrate was added MTBE (60 mL) and the product was allowed to precipitate. The solid was collected by filtration, washed with METB (60 mL) and directly used for the next step.Methyl 6-bromo-2-(4-fluorophenyl)pyrazolo[ 1, 5-a]pyridine-3-carboxylate

[0212] To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (6.8 g, 38.2 mmol) and 1-amino-3-bromopyridin-1-ium 2, 4, 6-trimethylbenzenesulfonate (47.6 mmol from the previous step) in dry acetonitrile (30 mL) was added, dropwise over 10 minutes, a solution of DBU (7.1 mL, 47.6 mmol) in 10 mL acetonitrile. The mixture was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum and the residue was dissolved in EtOAc (100 mL), washed with water (100 mL), dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column with PE:EA 10:1 to afford methyl 6-bromo-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (2.1 g, 22% yield) as a white solid.

[0213] 1H NMR (400 MHz, DMSO) 5 9.29 (d, J = 1 .3 Hz, 1 H), 8.06 (d, J = 8 Hz, 1 H), 7.82 - 7.80 (m, 2H), 7.77 (d, J = 10 Hz, 1 H), 7.33 - 7.28 (m, 2H), 3.78 (s, 3H).6-bromo-2-(4-fluorophenyl) pyrazolo[ 1, 5-a]pyridine-3-carboxylic acid

[0214] A solution of methyl 6-bromo-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3- carboxylate (350 mg, 1 mmol) in 2N aqueous NaOH solution (3 mL) and MeOH (3 mL) was heated at reflux for 3 hours. The mixture was concentrated under vacuum to about half of volume. The pH of the residue was adjusted to pH 2 with 2N HCI solution and the precipitate was collected by filtration and washed with water (5 mL), dried under vacuum to afford 6- bromo-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (320 mg, 96% yield) as a white solid.3-bromo-2-(4-fluorophenyl)-6-(trifluoromethyl) pyrazolo[ 1, 5-a]pyridine

[0215] To a solution of 6-bromo-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-3- carboxylic acid (320 mg, 0.95 mmol) and sodium bicarbonate (240 mg, 2.85 mmol) in dry DMF (5 mL) was added NIS (214 mg, 0.95 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was added water (10 mL). The solid was collected and washed with water (10 mL) and dried under vacuum to afford 3-bromo-2-(4-fluorophenyl)-6- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine (210 mg, 53% yield) as a white solid.6-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine (1-251)

[0216] A solution of 3-bromo-2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine (350 mg, 0.84 mmol), pyridin-4-ylboronic acid (103 mg, 0.84 mmol), sodium carbonate ( 178 mg, 1.68 mmol) and dichlorobis(triphenylphosphine)palladium (295 mg, 0.42 mmol) in DMF (4 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite and rinse with EtOAc (50 mL). The filtrate was washed with water (20 mL*2), brine (20 mL), dried and concentrated. The residue was purified by reverse phase column with H2O / MeOH 5%-95% to afford 6-bromo-2- (4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine (30 mg, 9% yield) as a white solid.2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6-carbonitrile (I-4)

[0217] To a solution of 6-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5- a]pyridine (30 mg, 0.082 mmol) and cuprous cyanide (CuCN) (146 mg, 1.63 mmol) in DMF (3 mL) was added dichlorobis(triphenylphosphine)palladium (29 mg, 0.041 mmol) and the reaction solution was stirred at 110° C for 20 hours under nitrogen atmosphere. The reaction solution was cooled down to room temperature and added water (10 mL). The resulting solution was extracted EtOAc (10 mL*2). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC (ACN / H2O with 0.05% NH3) to afford 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (6.4 mg, 25%) as a white solid.

[0218] 1H NMR (400 MHz, DMSO) 5 9.73 - 9.70 (m, 1 H), 8.61 (dd, J = 4.4, 1.6 Hz, 2H), 7.84 (dd, J = 9.3, 0.9 Hz, 1 H), 7.60 (dd, J = 9.3, 1.5 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.34 (dd, J = 4.4, 1 .6 Hz, 2H), 7.33 - 7.27 (m, 2H).Example 5 - Synthesis of 6-fluoro-2-(4-fluorophenyl)-3-(2-fluoropyridin-4- yl)pyrazolo[1 ,5-a] pyridine (I-6)Scheme 66-fluoro-2-(4-fluorophenyl)-3-(2-fluoropyridin-4-yl)pyrazolo[ 1, 5-a]pyridine ( I -6)

[0220] A solution of 3-bromo-6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine (50 mg, 0.16 mmol), (2-fluoropyridin-4-yl)boronic acid (45 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmol) and dichlorobis(triphenylphosphine)palladium (56 mg, 0.08 mmol) in DMF (3 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite and rinsed with EtOAc (50 mL). The filtrate was washed with water (20 mL*2), brine (20 mL), dried and concentrated. The residue was purified by Prep-HPLC (ACN / H2O with 0.05% NH3) to afford 6-fluoro-2-(4-fluorophenyl)-3-(2- fluoropyridin-4-yl)pyrazolo[1 ,5-a]pyridine (5.5 mg, 10% yield) as a white solid.

[0221] 1H NMR (400 MHz, DMSO) 5 8.74 (d, J = 6.9 Hz, 1 H), 8.22 (d, J = 5.2 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.32 - 7.24 (m, 4H), 7.18 (s, 1H), 7.05 (td, J = 7.4, 5.3 Hz, 1H).Example 6 - Synthesis of 6-fluoro-2-(4-fluorophenyl)-3-(2-methoxypyridin-4- yl)pyrazolo[1 ,5-a] pyridine (I-7)

[0222] Procedure of the synthesis of compound I-7 is shown in Scheme 7:Scheme 76-fluoro-2-(4-fluorophenyl)-3-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyridine (I-7)

[0223] A solution of 3-bromo-6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine (100 mg, 0.32 mmol), (2-methoxypyridin-4-yl)boronic acid (98 mg, 0.64 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichlorobis(triphenylphosphine)palladium (56 mg, 0.08 mmol) in DMF (6 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite and rinsed with EtOAc (50 mL). The filtrate was washed with water (20 mL*2), brine (20 mL), dried and concentrated. The residue waspurified by Prep-HPLC (ACN / H20 with 0.05% NH3) to afford 6-fluoro-2-(4-fluorophenyl)-3-(2- fluoropyridin-4-yl)pyrazolo[1 ,5-a]pyridine (37 mg, 34% yield) as a white solid.

[0224] 1H NMR (400 MHz, DMSO) 0 8.70 (d, J = 6.9 Hz, 1 H), 8.15 (d, J = 5.2 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.27 - 7.20 (m, 3H), 7.03 - 7.01 (m, 1 H), 6.89 (d, J = 5.4 Hz, 1 H), 6.79 (s, 1 H).Example 7 - Synthesis of 4-(6-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3- yl)pyridin-2-amine (I-8)4-(6-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine (I-8)

[0226] A solution of 3-bromo-6-fluoro-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine (100 mg, 0.32 mmol), (2-methoxypyridin-4-yl)boronic acid (88 mg, 0.64 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichlorobis(triphenylphosphine)palladium (56 mg, 0.08 mmol) in DMF (6 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite and rinsed with EtOAc (50 mL). The filtrate was washed with water (20 mL *2), brine (20 mL), dried and concentrated. The residue was purified by Prep-HPLC (ACN / H2O with 0.05% NH3) to afford 4-(6-fluoro-2-(4- fluorophenyl)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-amine (30 mg, 29% yield) as a white solid.

[0227] 1H NMR (400 MHz, DMSO) 5 8.67 (d, J = 6.9 Hz, 1 H), 7.90 (d, J = 5.2 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.27 - 7.18 (m, 3H), 7.01 - 6.96 (m, 1 H), 6.43 - 6.40 (m, 2H), 5.92 (s, 2H).Example 8 - Synthesis of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6- carboxylic acid (1-10), 2-(4-fluorophenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)pyrazolo[1,5- a]pyridine (I-252) and Ethyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6- carboxylate (I-253)

[0228] Procedure of the synthesis of compound 1-10 is shown in Scheme 9:Scheme 91-amino-3-(trifluoromethyl)pyridin-1-ium 2,4,6-trimethyl-benzylsulfonate

[0229] TFA (20 mL) was added to N-tert-butoxycarbonyl-O- (mesitylsulfonyl)hydroxylamine (10 g, 31 ,7 mmol) in portions at 0 °C over 15 mins. The solution was stirred for 15 minutes at room temperature. The solution was poured into the ice water (50 mL) and the resulting precipitate was collected by filtration. The solid was re-dissolved in DCM and dried with Na2SO4. The Na2SO4was removed by filtration and the filtrate was added to a solution of 3-(trifluoromethyl)pyridine (4.6 g ,31.7 mmol) in DCM (50 mL). The mixture was stirred for 45 minutes and then filtered. To the filtrate was added MTBE (100 mL) and the product was allowed to precipitate. The solid was collected by filtration, washed with METB (50 mL) and directly used for the next step.Methyl 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0230] To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (1.78 g, 10 mmol) and 1-amino-3-(trifluoromethyl)pyridin-1-ium 2,4,6-trimethyl-benzylsulfonate (31.7 mmol from the previous step) in dry acetonitrile (20 mL) was added dropwise over 10 minutes a solution of DBU (4.7 mL, 31.7 mmol) in acetonitrile (5 mL). The mixture was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum and the residue was dissolved in EtOAc (100 mL), washed with water (100 mL), dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column with PE:EA 10:1 to afford methyl 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (700 mg, 20% yield) as a white solid.2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0231] A solution of methyl 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-3-carboxylate (700 mg, 2 mmol) in 2N aqueous NaOH solution (10 mL) and MeOH (5 mL) was heated at reflux for 3 hours. The mixture was concentrated under vacuum to about half of volume. The pH of the residue was adjusted to pH 2 with 2N HCI solution and the precipitate was collected by filtration and washed with water, dried under vacuum to afford 2- (4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (470 mg, 70% yield) as a white solid.3-bromo-2-(4-fluorophenyl)-6-(trifluoromethyl) pyrazolo[ 1, 5-a]pyridine

[0232] To a solution of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3- carboxylic acid (470 mg, 1.45 mmol) in dry DMF (10 mL) was added sodium bicarbonate (365 mg, 4.35 mmol) followed by NBS (258 mg, 1.45 mmol) and the mixture was stirred at room temperature under nitrogen protection for 2 hours. The mixture was diluted with EtOAc (20 mL), washed with water (10 mL*2), dried with anhydrous Na2SO4and concentrated. Theresidue was purified by silica gel column with DCM:MeOH 20: 1 to afford 3-bromo-2-(4- fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (470 mg, 90% yield) as a brown solid.2-(4-fluorophenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (1-252)

[0233] A solution of 3-bromo-2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine (479 mg, 1.31 mmol) 2-fluoro-4-pyridinylboronic acid (177 mg, 1.44 mmol), sodium carbonate ( 208 mg, 1.97 mmol) and dichlorobis(triphenylphosphine)palladium (455 mg, 0.66 mmol) in DMF (5 mL) was stirred at 110°C in a microwave for 2 hours. Then the reaction was cooled to room temperature and filtered through a pad of Celite and rinsed with EtOAc (50 mL). The filtrate was washed with water (20 mL*2), brine (20 mL), dried with anhydrous ISfeSCU and concentrated. The residue was purified by Prep-HPLC (H2O / MeOH 5%-95%) to afford 2- (4-fluorophenyl)-3-(pyridin-4-yl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (300 mg, 64% yield) as a white solid .

[0234] 1H NMR (400 MHz, DMSO) 5 9.50 (s, 1 H), 8.62 (d, J = 6.0 Hz, 2H), 7.91 (d, J = 9.4 Hz, 1 H), 7.63 - 7.51 (m, 3H), 7.39 - 7.27 (m, 4H).2-(4-fluorophenyl)-3-(pyridin-4-yl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridine

[0235] To a solution of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-6- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine (300 mg, 0.84 mmol) in ethanol (1 mL) was added a solution of sodium ethoxide in ethanol (20%, 3 mL), and the reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic layer was washed with brine (20 mL), and then dried over anhydrous ISfeSCM, filtered and concentrated to afford 2-(4-fluorophenyl)-3-(pyridin-4-yl)-6-(triethoxymethyl)pyrazolo[1 ,5-a]pyridine (300 mg, 82% yield) as an off-white solid.Ethyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[ 1, 5-a]pyridine-6-carboxylate (1-253)

[0236] solution2-(4-fluorophenyl)-3-(pyridin-4-yl)-6-(triethoxymethyl)pyrazolo[1 ,5-a]pyridine (300 mg, 0.69 mmol) in acetone (4 mL) and water (1 mL) was added p-toluenesulfonic acid monohydrate (328 mg, 1.73 mmol). The reaction mixture was stirred at 40 °C for 6 hours. The reaction mixture was cooled and saturated aqueous sodium bicarbonate solution (5 mL) was added. The reaction mixture was concentrated and purified by reverse phase column with H2O / MeOH 5%-95% to afford ethyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6-carboxylate (200 mg, 80% yield) as a white solid.2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1, 5-a]pyridine-6-carboxylic acid (1-10)

[0237] To a solution of ethyl 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6-carboxylate (200 mg, 0.55 mmol) in dioxane (4 mL) and water (1 mL) was added lithium hydroxide monohydrate (120 mg, 5 mmol). The reaction mixture was heated at 95 °C for 5 hours. The reaction mixture was concentrated and purified by reverse phase column with H2O / MeOH 5%-95% to afford 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6- carboxylic acid (38.4 mg, 21% yield) as a white solid.

[0238] 1H NMR (400 MHz, DMSO) 5 13.46 (s, 1 H), 9.25 (s, 1 H), 8.61 (d, J = 3.4 Hz, 2H), 7.84 - 7.78 (m, 1 H), 7.74 dd, J = 9.3, 1.4 Hz, 1 H), 7.61 - 7.53 (m, 2H), 7.36 (d, J = 5.8 Hz, 2H), 7.33 - 7.24 (m, 2H)Example 9 - Synthesis of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6- carboxamide (1-11)

[0239] Procedure of the synthesis of compound 1-11 is shown in Scheme 10:Scheme 102-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1, 5-a]pyridine-6-carboxamide (1-11 )

[0240] To a solution of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6- carboxylic acid (333 mg, 1 mmol) in DCM (20 mL) was added NH4CI (216 mg, 4 mmol), DIPEA (260 mg, 2 mmol) and HATU (570 mg, 1.5 mmol). The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with H2O (20 mL). The reaction mixture was separated and the organic phase was concentrated and purified by reverse phase column with H2O / MeOH 5%-95% to afford 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6- carboxamide (250 mg, 69% yield) as a white solid.

[0241] 1H NMR (400 MHz, DMSO) 5 9.35 (s, 1H), 8.61 (d, J = 3.4 Hz, 2H), 8.18, (S, 1H), 7.80 (d, J = 2.1 Hz, 2H), 7.64, (S, 1H), 7.59-7.54 (m, 2H), 7.35 (d, J = 5.8 Hz, 2H), 7.33- 7.24 (m, 1 H).Example 10 - Synthesis of (2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-6- yl)methanamine (1-12)

[0242] Procedure of the synthesis of compound 1-12 is shown in Scheme 11 :Scheme 11O-(mesitylsulfonyl)hydroxylamine

[0243] TFA (100 mL) was cooled to ice temperature, then tert-butyl ((mesitylsulfonyl)oxy)carbamate (50.0 g, 158.7 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours, then poured onto crushed ice (100 mL). The resulting white-coloured precipitate was filtered and then washed with water (500 mL) and dried under vacuum to obtain 0-(mesitylsulfonyl)hydroxylamine (25 g, 73% yield) as a white solid. This material was taken crude to the next step without any purification.2-(4-fluorophenyl)pyrazolo[ 1, 5-a]pyridine-6-carbonitrile

[0244] A solution of 0-(mesitylsulfonyl)hydroxylamine (50 g, 232.5 mmol) and 6-(2-(4- fluorophenyl)-2-oxoethyl)nicotinonitrile (18.4 g, 76.7 mmol) in DCM (500 ml) was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column with DCM to afford 2-(4- fluorophenyl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (7g, 38.5% yield) as a brown solid.

[0245] 1H NMR (400 MHz, CDCI3) 5 6.90 (s, 1 H), 7.15, (m, 3H), 7.57 (d, 1 H, J = 8.0 Hz), 7.93 (dd, 2H, J = 5.2, 8.4 Hz), 8.82 (s, 1 H).3-bromo-2-(4-fluorophenyl) pyrazolo[ 1, 5-a]pyridine-6-carbonitrile

[0246] To a solution of 2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (7 g, 29.5 mmol) in DMF (70 mL) was added NBS (6.3 g,35.4 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction was poured into water (200 mL) and extracted with ethyl acetate (3*150 mL). The combined organic phases were washed with brine (300 mL), dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column with DCM to afford 3-bromo-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (7.8 g, 83% yield) as a yellow solid.

[0247] 1H NMR (400 MHz, CDCI3) 5 7.21 (2H, t) 7.30 (1 H, dd) 7.62 (1 H, dd) 8.06 (2H, m) 8.80 (1H, s).2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6-carbonitrile

[0248] A solution of 3-bromo-2-(4-fluorophenyl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (8 g, 25.3 mmol), 2-fluoro-4-pyridinylboronic acid (15.5 g, 126.5 mmol), sodium carbonate ( 5.4 g, 50.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.9 g, 2.5 mmol) in dioxane (200 mL) and H2O (40 mL) was stirred at 100°C for 16 hours under N2atmosphere. Then the reaction was cooled to room temperature and filtered and the filtrate was diluted with EtOAc (300 mL) and washed with water (300 mL), brine (300 mL), dried with anhydrous Na2SO4and concentrated. The residue was purified by silica gel column with PE / EA 10-50% to afford 2-(4- fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (6.0 g, 75% yield) as a pale yellow solid.

[0249] 1H NMR (400 MHz, DMSO) 5 9.72 (s, 1H), 8.61 (d, J = 5.5 Hz, 2H), 7.84 (d, J = 9.3 Hz, 1 H), 7.62 - 7.58 (m, 1 H), 7.58 - 7.54 (m, 2H), 7.35 - 7.28 (m, 4H).(2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1, 5-a]pyridin-6-yl)methanamine (1-11 )

[0250] To 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridine-6-carbonitrile (6 g, 19.1 mmol) in a 500 mL round-bottomed flask was added 7M NH3in MeOH (200 mL) and Raney™ nickel (1.2g, 20%wt). The mixture was stirred at room temperature under hydrogen atmosphere for 5 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column with DCM / MeOH 0-20% to afford (2-(4- fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridin-6-yl)methanamine (3.1 g, 51% yield) as a pale yellow solid.

[0251] 1H NMR (400 MHz, DMSO) 5 8.67 (s, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 2H), 7.71 (d, J= 9.1 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.40 (d, J= 9.2 Hz, 1 H), 7.31 (d, J = 5.9 Hz, 2H), 7.27 (t, J = 8.9 Hz, 2H), 3.78 (s, 2H).Example 11 - Synthesis of 1-(2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-6- yl)-N,N-dimethylmethanamine (1-13)

[0252] Procedure of the synthesis of compound 1-13 is shown in Scheme 12:Scheme 121-(2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)-N,N-dimethylmethanamine (I- 13)

[0253] To a solution of (2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5-a]pyridin-6- yl)methanamine (100 mg, 0.31 mmol) and formaldehyde aqueous solution (50 mg, 37% wt.) in MeOH (5 ml) was added NaBH3CN (40 mg, 0.62 mmol) stirred at room temperature for 4hours. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (ACN / H2O with 0.05%NH3) to afford 1-(2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1 ,5- a]pyridin-6-yl)-N,N-dimethylmethanamine (28 mg, 26% yield) as a white solid.

[0254] 1H NMR (400 MHz, DMSO) 0 8.71 (s, 1 H), 8.57 (dd, J = 4.6, 1 .5 Hz, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.37 (dd, J = 9.2, 1.3 Hz, 1H), 7.32 (dd, J = 4.5, 1.6 Hz, 2H), 7.32-7.25 (m, 2H), 3.49 (s, 2H), 2.22 (s, 6H).B: Biological Assays(a) AssayHotSpot kinase assay

[0255] IC50s were determined using the in vitro HotSpot kinase assay (purified enzymes,33P-ATP, an appropriate substrate and 1 pM ATP). For enzyme inhibition assays, compounds were tested in range often concentrations from 10 pM to 0.0005 pM using purified recombinant Yck2. Reaction conditions were 1 pM ATP, one hour incubation with inhibitor, and kinase activity detected using 33-ATP phosphorylation of an appropriately selected peptide substrate.Recombinant Yck2 protein

[0256] Yck2 residues 37-345 were PCR amplified from C. albicans genomic DNA and subcloned into the vector pMCSG53, which codes for a N-terminal His6 tag, TEV protease site, followed by the Yck2 protein. E. coli BL21 (DE3)-Gold competent cells were transformed with this plasmid and the Yck2 protein was purified using methodology previously described (Stogios et al., ACS Chem. Biol.13, 1322-1332 (2018)).Table 2: Hotspot kinase assay results(b) Assay Antifungal Sensitivity Testing

[0257] Minimum inhibitory concentrations (MICs) were determined in flat bottom, 96- well plate format using a modified broth microdilution protocol as previously described (Singh et al., PLoS Pathog. 5, e1000532 (2009); LaFayette et al., PLoS Pathog. 6, 79-80 (2010)).Compounds were formulated in dimethyl sulfoxide (DMSO, Sigma-Aldrich Co.). Each compound was tested in duplicate in at least two independent experiments.Table 3: Antifungal Sensitivity Testing Results(c) Assay Mammalian Cell Toxicity.

[0258] HepG2 cells were seeded overnight at 500 cells / well in 384-well plate, then incubated with compounds (10-point concentration titration) for 48 h. Cell Titer-Gio® reagent (ThermoFisher Scientific) was added to each well and after 10-minute incubation at room temperature the luminescent signal was measured using an Envision plate reader (Perkin Elmer).Table 5: Mammalian Cell Toxicity Results(d) Assay Human and Mouse Liver Microsome Stability Studies

[0259] The objective of this study was to estimate in vitro metabolic stability of compounds in pooled human and male mouse liver microsomes. The concentrations of exemplary compounds in reaction systems were evaluated by LC-MS / MS for estimating the stability in pooled human and male mouse liver microsomes. The in vitro intrinsic clearances of test compounds were determined as well. The master solution was prepared according to Table 6.Table 6. Preparation of master solution

[0260] Two separated experiments were performed as follows, a) With cofactors (NADPH): 25 pL of 10 mM NADPH was added to the incubations. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively, b) Without cofactors (NADPH): 25 pL of 100 mM phosphate buffer was added to the incubations. The final concentration of microsomes was 0.5 mg / mL. The mixture was pre-warmed at 37°C for 10 minutes.

[0261] The reaction was started with the addition of 2.5 pL of 1000 pM test compound solutions or 2.5 pL of 100 pM control compound. Verapamil was used as positive control in this study. The final concentration of test compound was 10 pM, and control compound was 1 pM. The incubation solution was incubated in water batch at 37°C.

[0262] Aliquots of 30 pL were taken from the reaction solution at 0.5 and 60 minutes. The reaction was stopped by the addition of 5 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide). Samples were centrifuged at 3.220 g for 40 minutes. Aliquot of 100 pL of the supernatant was mixed with 100 pL of ultra-pure H2O and then used for LC-MS / MS analysis.

[0263] All calculations are carried out using Microsoft Excel™. Peak areas are determined from extracted ion chromatograms. Percent parent remaining was calculated from peak area of test compound or PC. The slope value, k, is determined by linear regression of the natural logarithm of percent parent remaining vs. incubation time curve.

[0264] The in vitro half-life (in vitro tv2) was determined from the slope value: in vitro 1 1 / 2= - (0.693 / k)Conversion of the in vitro t2(in min) into the in vitro intrinsic clearance (in vitro CL int, in pL / min / mg proteins) is done using the following equation: in vitro CLmt= (0.693 / 1 > / 2) * (volume of incubation (pL) / amount of protein (mg))

[0265] For the exemplary compound of the application or control compound that showed an initial fast disappearance followed by a slow disappearance, only the time points that were within the initial rate were included in the calculation.

[0266] Human and mouse liver microsomes contain a wide variety of drug metabolizing enzymes and are commonly used to support in vitro ADME (absorption, distribution, metabolism and excretion) studies. These microsomes are used to examine the potential first - pass metabolism by - products of orally administered drugs. Exemplary compounds of the application were evaluated for their stability in human and mouse livermicrosomes. The majority of the compound 1-12, in human and mouse liver microsomes, was recovered within a 60 minute time period indicating that the compound was not rapidly cleared. This is in contrast to compound 1-1 , which was cleared quickly (see Table 7).Table 7: Human and Mouse Liver Microsome Results

[0267] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the present application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0268] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Claims

CLAIMS1. A compound of Formula (I) or an enantiomer thereof, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof,wherein: one of X and Y is N and the other is C; each — represents a single or a double bond with two non-adjacent — being double bonds positioned to provide a heteroaryl group;R1is selected from phenyl substituted with one or more R7and 5- to 10-membered heteroaryl optionally substituted with one or more R7;R2is selected from 6-, 9- and 10-membered aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R8, and 5- to 10-membered heterocycloalkyl which is optionally substituted with one or more R8';R3is selected from H, halo, Ci.6alkyl and OCi.6alkyl;R4is selected from H, halo, Ci.6alkyl, OCi.6alkyl, CN, CONR9R10, CO2R9, Ci.6alkyleneNR11R12, NR11R12, C3-iocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, 6-, 9- and 10-membered aryl and Ci.6alkyleneR13, wherein each of the cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more R14and wherein each alkyl and alkylene is optionally substituted with one or more halo, Ci-ealkyl, OH, OCi.6alkyl, NH2, NHCi.6alkyl and N(Ci-6alkyl)(Ci-6alkyl) and / or optionally interrupted by one or more heteroatoms selected from NR15and O;R5is selected from H and Ci.6alkyl;R6is selected from H and Ci.6alkyl;R7is selected from halo or Ci.6alkyl;R8is selected from halo, Ci.6alkyl, OCi.6alkyl, NR15R16, =0, OH, CN, C(O)NR15R16, CO2R15, and 3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halo and Ci.6alkyl;R9is selected from H, Ci_6alkyl, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R13;R10is selected from H and Ci.6alkyl; orR9and R10together with the N atom to which they are bound form a 3- to 10-membered heterocycloalkyl which is optionally substituted with one or more R14;R11is selected from H, Ci.6alkyl, C(=NH)NH2, C3-iocycloalkyl, 3- to 10-membered heterocycloalkyl, C(O)NH2, CO2H, C(O)N(Ci-6alkyl)(Ci-6alkyl), C(O)NHCi-6alkyl, C(O)Ci-6alkyl, CO2Ci.6alkyl, OH and NH2, wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more halo, OH, Ci.6alkyl, =0, CO2H, C(O)NR17R18, CO2R17, C(O)NR17R18, and NR17R18;R12is selected from H and Ci.6alkyl;R13is selected from C3.iocycloalkyl, 6-, 9- and 10-membered aryl, 3- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R14; orR13is selected from C(O)NH2, CO2H, C(O)N(Ci.6alkyl)(Ci.6alkyl), C(O)NHCi.6alkyl, C(O)Ci. ealkyl, CO2Ci-ealkyl, OH and NH2, wherein each alkyl, is optionally substituted with one or more halo, =0, CO2R17, C(O)NR17R18, CO2R17, OR17and NR17R18;R14is selected from NR17R18, Ci-6alkyl, Ci.6alkyleneNR17R18, halo, OH, OCi.6alkyl, =0, CONR17R18and CO2R17;R15is selected from H and Ci.6alkyl;R16is selected from H, Ci.6alkyl and C3.6cycloalkyl; andR17and R18are independently selected from H and Ci.6alkyl; wherein all available hydrogen atoms are optionally and independently replaced with a fluorine atom or chlorine atom and all available atoms are optionally independently replaced with alternate isotope thereof.

2. The compound of claim 1 , having the Formula IA or IB:(IA) (IB) .

3. The compound of claim 1 or 2, wherein R1is selected from phenyl substituted with one to three R7and 5- to 6-membered heteroaryl optionally substituted with one to three R7wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

4. The compound of any one of claims 1 to 3, wherein R1is selected from phenyl, thiophenyl, pyridinyl, thiazolyl, substituted with one or two R7wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

5. The compound of any one of claims 1 to 4, wherein R7is selected from F, Cl, CD3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3and CHF2.

6. The compound of any one of claims 1 to 5, wherein R7is F or CF3.

7. The compound of any one of claims 1 to 6, wherein R1is selected from:wherein * represents the point of attachment to remainder of the compound.

8. The compound of any one of claims 1 to 7, wherein R2is selected from phenyl and 5- to 6-membered heteroaryl, each of which is optionally substituted with one to three R8wherein all available hydrogen atoms are optionally and independently replaced with deuterium, or R2is selected from 5- to 10-membered heterocycloalkyl which is optionally substituted with one or more R8'.

9. The compound of any one of claims 1 to 8, wherein R2is selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl pyrazolyl, phenyl, thiadiazolyl, oxadiazolyl.1imidazolyl, tetrazolyl, triazolyl, each of which is optionally substituted with one to three R8wherein all available hydrogen atoms are optionally and independently replaced with deuterium, or R2is 1 ,2-dihydropyridinyl, 1 ,2,3,4-tetrahydropyridinyl, 3,4-dihydro-2H-pyranyl and 2H-pyranyl which is optionally substituted with one R8'.

10. The compound of any one of claims 1 to 9, wherein R8is selected from F, Cl, Chalky I , Ci.4deuteroalkyl, Ci.4fluoroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, NHR16, OH, CN, C(O)NH2, C(O)NHCi-4alkyl, C(O)N(Ci-4alkyl)(Ci-4alkyl), C(0)NHCi-4fluoroalkyl, C(O)N(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi.4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci.4fluoroalkyl, C02Ci.4deuteroalkyl and 3- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one to three halo, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl, or R8' is selected from F, Cl, Ci.4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, NHR16, =0, OH, CN, C(O)NH2, C(O)NHCi-4alkyl, C(O)N (Chalky I) (Chalky I), C(0)NHCi-4fluoroalkyl, C(0)N(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi_4deuteroalkyl, C(0)N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci.4fluoroalkyl, C02Ci.4deuteroalkyl and 3- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one to three halo, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl.1 1. The compound of any one of claims 1 to 10, wherein R8is selected from F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, NH2, NHCi.4alkyl, NHCs-ecycloalkyl, OH, CN, C(O)NH2, CO2H, piperazinyl optionally substituted with Ci.4alkyl and / or Ci.4fluoroalkyl, pyrrolidinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl, and azetidinyl optionally substituted with Ci.4alkyl and / or Ci.4fluoroalkyl, or R8' is selected from F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, NH2, NHCi-4alkyl, =0, NHC3-6cycloalkyl, OH, CN, C(O)NH2, CO2H, piperazinyl optionally substituted with Ci.4alkyl and / or Ci.4fluoroalkyl, pyrrolidinyl optionally substituted with Ci-4alkyl and / or Ci.4fluoroalkyl, and azetidinyl optionally substituted with Ci.4alkyl and / or Ci.4fluoroalkyl, or R8' is =0.

12. The compound of any one of claims 1 to 1 1 , wherein R2is selected from:wherein?represents the point of attachment to the remainder of the compound.

13. The compound of any one of claims 1 to 12, wherein R3is selected from H, F, Cl, Ci-4alkyl, Ci.4fluoroalkyl, OCi.4fluoroalkyl, Ci.4deuteroalkyl, OCi.4deuteroalkyl and OCi.4alkyl.

14. The compound of any one of claims 1 to 13, wherein R3is selected from H, F, Cl, methyl, trifluoromethyl, ethyl, propyl, methoxy, trifluoromethoxy, ethoxy and propoxy.

15. The compound of any one of claims 1 to 14, wherein R4is selected from H, F, Cl, Ci.4alkyl, Ci.4fluoroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, CN, CONR9R10, CO2R9, Ci-5alkyleneNR11R12, NR11R12, C3-6cycloalkyl, 5- or6-membered heteroaryl, 6-membered aryl, 4- to 6-membered heterocycloalkyl and Ci.4alkyleneR13, wherein each of the cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with one to three R14and wherein each alkyl and alkylene is optionally substituted with one to three F, Cl, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl, OH, OCi.4alkyl, OCi._4fluoroalkyl, OCi.4deuteroalkyl, NH2, NHCi.4alkyl, N(Ci-4alkyl)(Ci_4alkyl), NHCi.4fluoroalkyl, NH(Ci.4fluoroalkyl)(Ci.4fluoroalkyl), NHCi.4deuteroalkyl and N(Ci.4deuteroalkyl)(Ci.4deuteroalkyl), and / or optionally interrupted by one to three heteroatoms selected from NR15and O.

16. The compound of any one of claims 1 to 15, wherein in R4, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, the heteroaryl is selected from pyridinyl, imidazolyl, pyrazolyl and pyrimidinyl, and the heterocycloalkyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, azetidinyl, diazepanyl, tetrahydropyranyl, tetrahydropyridinyl, thiomorpholinyl and tetrahydrothiopyranyl, and in each, all available hydrogen atoms are optionally and independently replaced with deuterium.

117. The compound of any one of claims 1 to 16, wherein R9is selected from H, methyl, CF3, ethyl, propyl, 3- to 6-membered heterocycloalkyl and NH2, wherein the heterocycloalkyl is optionally substituted with one to three R13.

18. The compound of any one of claims 1 to 17, wherein R10is selected from H, Ci. 4fluoroalkyl, Ci.4deuteroalkyl and Ci-4alkyl.

19. The compound of any one of claims 1 to 16, wherein R9and R10together with the N atom to which they are bound to form a 5- or 6-membered heterocycloalkyl which is optionally substituted with one or more R14wherein all available hydrogen atoms are optionally and independently replaced with deuterium20. The compound of any one of claims 1 to 19, wherein R11is selected from H, Ci-salkyl, Ci.5fluoroalkyl, Ci.5deuteroalkyl, C(=NH)NH2, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, C(O)NH2, CO2H, C(O)N(Ci.4alkyl)(Ci.4alkyl), C(O)NHCi.4alkyl, C(O)NHCi. 4fluoroalkyl, C(0)N(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi-4deuteroalkyl, C(O)N(Ci. 4deuteroalkyl)(Ci-4deuteroalkyl), C(O)Ci-4alkyl, C(0)Ci-4fluoroalkyl, C(0)Ci-4deuteroalkyl, C(O)Ci-4alkyl, C(0)Ci-4fluoroalkyl, C(0)Ci-4deuteroalkyl, CO2Ci-4alkyl, C02Ci-4fluoroalkyl, C02Ci-4deuteroalkyl, OH and NH2, wherein each cycloalkyl and heterocycloalkyl is optionallyand N(Ci-4alkyl)(Ci-4alkyl), and wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

21. The compound of any one of claims 1 to 20, wherein R12is selected from H, Ci. 4fluoroalkyl, Ci.4deuteroalkyl and Ci-4alkyl.

22. The compound of any one of claims 1 to 21 , wherein R13is selected from C3.6cycloalkyl, 6-membered aryl, 5- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl, each of which is optionally substituted with one to three R14wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

23. The compound of any one of claims 1 to 22, wherein R13is selected from C(O)NH2, CO2H, C(O)N(Ci-4alkyl)(Ci-4alkyl), C(O)NHCi-4alkyl, C(0)NHCi-4fluoroalkyl, C(O)N(Ci- 4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi-4deuteroalkyl, C(0)N(Ci-4deuteroalkyl)(Ci.4deuteroalkyl), C(O)Ci-4alkyl, C(0)Ci-4fluoroalkyl, C(0)Ci-4deuteroalkyl, CO2Ci-4alkyl, CO2Ci.4fluoroalkyl, C02Ci-4deuteroalkyl, OH and NH2, wherein each alkyl is optionally substituted with one or more F, Cl, =0, C(O)NH2, C(O)NHCi.4alkyl, C(O)N(CMalkyl)(Ci.4alkyl), (O)NHCi.4fluoroalkyl, C(0)N(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), C(0)NHCi-4deuteroalkyl, C(O)N(Ci.14deuteroalkyl)(Ci-4deuteroalkyl), CO2H, CO2Ci.4alkyl, C02Ci_4fluoroalkyl, C02Ci.4deuteroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuterooalkyl, OH, NH2, NHCi-4alkyl, N(Ci_4alkyl)(Ci_4alkyl), NHCi.4fluoroalkyl, NH(Ci-4fluoroalkyl)(Ci-4fluoroalkyl), NHCi.4deuteroalkyl and N(Ci.4d eute rooa I ky I) (C 1.4de ute roa I ky I)24. The compound of any one of claims 1 to 23, wherein R4is selected from methyl, OEt, F, CN, CO2H, CONH2, CH2-NH2, NH-NH2, NH2,wherein?represents the point of attachment to the remainder of the compound.

25. The compound of any one of claims 1 to 23, wherein R4is selected from Ci.4alkyleneNR11R12, R11is selected from H, Ci_4alkyl, Ci.4fluoroalkyl and Ci.4deuteroalkyl; and R12is selected from H, Ci.4alkyl Ci.4fluoroalkyl and Ci.4deuteroalkyl.

26. The compound of claim 1 , wherein:R1is selected from phenyl substituted with one or two groups independently selected from F and Cl;R2is selected from phenyl and 6-membered heteroaryl, each of which is optionally substituted with one R8,R4is selected from Ci.4alkyleneNR11R12;R8is selected from F, Cl, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4deuteroalkyl, NH2, OH and CN;R11is selected from H, Ci-4alkyl, Ci.4fluoroalkyl and Ci.4deuteroalkyl; andR12is selected from H, Ci.4alkyl Ci.4fluoroalkyl and Ci.4deuteroalkyl.

27. The compound of any one of claims 1 to 25, wherein R14is selected from NR17R18, Ci-4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl, Ci.4alkyleneNR17R18, F, Cl, OH, OCi-4alkyl, =0, CONR17R18and CO2R17.

28. The compound of any one of claims 1 to 25 and 27, wherein R15is selected from H, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl.

29. The compound of any one of claims 1 to 25 and 27 to 28, wherein R16is selected from H, Ci.4alkyl, Ci.4fluoroalkyl, Ci.4deuteroalkyl and C3.5cycloalkyl.

30. The compound of any one of claims 1 to 25 and 27 to 29, wherein R17and R18are independently selected from H, Ci.4fluoroalkyl, Ci.4deuteroalkyl and Ci_4alkyl.

31. The compound of any one of claims 1 to 30, wherein the available atoms optionally and independently replaced with an alternate isotope thereof are available H atoms being replaced with D and the compound of Formula I comprises at least one D.

32. The compound of claim 1 , wherein the compound of Formula (I) is selected from the compounds listed in Table 1 , or a salt and / or solvate thereof.

33. A method of treating or preventing a fungal-related disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds ofany one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, to a subject in need thereof.

34. A method of inhibiting or preventing fungal growth comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, to a subject in need thereof.

35. A method of inhibiting fungal CK1 activity comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, to a subject in need thereof.

36. A method of selectively inhibiting fungal CK1 activity comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, to a subject in need thereof.

37. A method of treating or preventing mycosis comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, to a subject in need thereof.

38. A method of treating or preventing a fungal-related disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, in combination with another known agent useful for treatment or prevention of a fungal-related disease, disorder or condition to a subject in need thereof.

39. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 32, or a pharmaceutically acceptable salt, and / or solvate thereof, and a pharmaceutically acceptable carrier and / or diluent.

40. The pharmaceutical composition of claim 39 further comprising an additional therapeutic agent.41 . An agricultural composition comprising one or more compounds of any one of claims 1 to 32, or a salt, and / or solvate thereof, and an agriculturally acceptable carrier and / or diluent.

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